Biomonitoring for Children

Baseline Report on

”Biomonitoring of Children” in the framework of the European Environment and Health Strategy (COM(2003)338 final)

Produced by the Technical Working Group on Integrated Monitoring

subgroup Biomonitoring of children

09 January 2004

This report reflects the opinions of the members of the Working Group and it highlights the different opinions contained within the group where appropriate. It should not be considered as an official statement of the position of the European Commission.

Further information relating to this work is available on the project website: www.brussels-conference.org or from the Technical Secretariat:

Dr. Reinhard Joas

BiPRO GmbH Grauertstr. 12 81545 Munich Germany Telephone +49 89 18979050 Facsimile +49 89 18979052 Email: [email protected]

This Baseline Report is prepared by the subgroup “Biomonitoring of Children” that has been set up by the European Commission in the framework of the “Environment & Health Strategy” (COM(2003)338final).

The subgroup is chaired by Ludwine Casteleyn and co-chaired by Lisbeth E. Knudsen and Carlo Sala.

The members of the subgroup are:

Bedossa Adrien Bloemen Louis Boogaard Peter Casteleyn Ludwine Coppo Rosanna Fernandez Torija D. Carlos Fréry Nadine Fucic Aleksandra Harrison Paul Jakubowski Marek Knudsen Lisbeth E. Lehners Maryse Pullen Ron Ramet José Reis Maria de Fatima Calado Varela Sala Carlo Sampaio Carla Susanna Roque Bento Seifert Bernd Schoeters Greet Steenhout Anne Swanson John Tcheshmedjiev Svetoslav Tusscher Gavin W Ten Wattiez Catherine Wijnen Joop van

The subgroup is assisted by Reinhard Joas from BIPRO as a technical consultant and by Birgit Van Tongelen from the European Commission, DG Environment.

Table of Content

Executive Summary ...... 4

1 Preface ...... 9

2 Overview...... 11

2.1 Methodology of Data Collection...... 11 2.2 Overview on feed back and basic data...... 11 2.3 Objectives of biomonitoring in children...... 12

3 Problems and deficits...... 14

4 Advantages of integrated biomonitoring of children...... 18

5 Requirements for an integrated EU Biomonitoring effort ...... 21

6 Annex I – Definitions ...... 22

7 Annex II – Mandate...... 23

8 Annex III – Questionnaire and Manual ...... 27

9 Annex IV – Draft working document for the discussion on requirements for an integrated biomonitoring ...... 31

10 Annex V – Returned questionnaires...... 38

11 Annex VI: Written Comments on the baseline report...... 387

Executive Summary

Preface

Biomonitoring in children1 may increase knowledge on the link between children’s health and the environment and contribute to the development of national and international environmental health programmes and policies for preventing diseases.

This report provides a preliminary overview of existing Environment & Health biomonitoring activities2 related to children being undertaken in Europe. One basis for this is a questionnaire that has been sent to institutions and researchers all over Europe. It also presents reported problems and deficits of existing biomonitoring systems and sets out advantages of an integrated approach. It starts to explore the requirements for integrated EU biomonitoring of children.

At the finalisation of this report (5th December 2003) 97 completed answers to the questionnaire were available. Countries and researchers have provided different levels of detail in their response to the questions. Gaps in information clearly exist and no straightforward assessment or assumption can be made on the level of representativeness of the data at hand. Information was received for all except 2 of the Member States, for 4 Acceding Countries and also for Norway and Croatia. Evaluation of the material is not yet finalised as relevant information is still coming in or is promised to be provided soon, e.g. related to some international studies.

Objective of biomonitoring in children

In general, the objective of biomonitoring is to increase knowledge on the relation between human health and the environment and to use this knowledge to improve environmental health.

Distinction is made between (1) activities that aim at periodical measurements in order to produce information on the prevalence of exposure to environmental agents and the related public health impact with a view to developing and evaluating policies that protect health (survey projects) and (2) activities that aim at improvement of knowledge on causal links between environmental factors and health by hypothesis generation and testing (research projects). In general, the number of study persons are small in research programs due to the exploratory character of the studies and the limitations of available resources. This very

1 Biomonitoring in children was defined by the working group as ‘monitoring activities in children, using biomarkers, that focus on environmental exposures, diseases and/or disorders and genetic susceptibility, and their potential relationships. Biomonitoring of children includes the prenatal period up to an age of 18 years and follow-up activities for monitored children into adulthood’ (see Annex I).

2 ongoing activities and activities that have been completed within the last 10 years.

often limits the power of the research studies, whereas surveillance programs more commonly are designed with a high number of participants.

More precise objectives reported are :

(1) To provide data on the distribution of exposure to a variety of environmental factors and on health effects across the entire population (applies to representative population studies) (2) To monitor trends in exposure levels over time and space (3) To obtain data which are representative for specific areas with expected different types of environmental loads (urban areas, dense traffic, intensive agriculture, industry). Biomarker data and public health data therefore to be analysed geographically and presented per geographical unit. (4) To establish reference ranges/values that can be used to identify people with unusually high exposure or the percentage of the population that has exposure above levels considered to be elevated (e.g., lead). (5) To determine which specific population groups, such as minorities, people with low incomes, children (different ages), are at high risk for exposure and adverse health effects. (6) To provide a bridge to understanding the relationships between environmental factors, exposure to these factors (including factors in food) and health problems. (7) To design and evaluate precautionary3, preventive, interventive and control strategies within the framework of policy measures related to health and environment. (8) To establish an “early warning system” based on biomarker measurements in a representative fraction of the population living in different areas that may help alert physicians, scientists, and health & environment officials to diseases that result from exposure to environmental factors.

Problems and deficits

Problems and deficits (non exhaustive) in conducting biomonitoring in children, as highlighted in the questionnaires and by the group members, relate to :

(1) recruitment of study population (2) biomarkers addressed (3) the logistics of conducting biomonitoring (4) biosafety (5) collaboration between disciplines (6) comparability of questionnaire data (7) communication of results (8) authorisation of study

3 Issues related to the Precautionary Principle have been raised at several occasions during the discussions in the working group. An in-depth discussion on this has been postponed to Step 2 addressing options for actions and recommendations.

Advantages of integrated biomonitoring of children

The overview demonstrates that within Europe, both nationally as internationally, a substantial amount of biomarker data on children are collected and that huge resources are devoted to these efforts. Many of the biomonitoring activities reported integrate data on environmental factors with health data. Several studies address both children and their parents (particularly their mothers, therefore integrating prenatal and postnatal exposure) and simultaneously address markers of exposure, effect and susceptibility. Overall, it is highlighted that similar aspects are addressed in biomonitoring programmes in nearly all countries. Exposures to heavy metals, PCBs and dioxins are the subject of many studies. Endpoints such as asthma, allergy and neurodevelopmental disorders, as well as exposures to genotoxic agents are covered, and multidisciplinarity is typical of many activities. In many cases establishment of biobanks (archives of biological materials/samples) is part of the activity allowing for later follow-up.

Integration of local initiatives in a wider national and also European perspective should allow for a better insight in the environmental impact on children’s health and therefore constitute a better basis for environmental health policy decisions by:

− elucidating children’s exposure in Europe to a wide range of environmental factors; − comparing environmental levels of, and exposure to, these factors in different areas, within and between countries (spatial trends) − investigating temporal trends in exposure levels of those factors; − gaining a comprehensive picture of the situation regarding human exposure to those factors in different geographical areas, identifying disproportionately exposed populations; − investigating effects on all aspects of human health, including the reproductive/developmental, endocrine and immune systems; − enabling the establishment of relations between low exposures to environmental factors and health effects and also health effects that occur at a low incidence, by increasing the power of studies − avoid limited predictivity and power of the studies performed, possibly associated with relative small sample sizes involved

Integrated efforts should allow for better use of resources (human, financial) in addressing the environmental impacts on children’s health.

Relevance for policymakers

The establishment of periodically updated biomonitoring and reporting systems to evaluate the impact of environmental measures on children’s health may be particularly relevant for policymakers. It may provide authorities with a more comprehensive view on actual exposure at the population level and guide them in the development of regulatory strategies for disease prevention through:

- identification of priorities in ambient levels and exposure reduction strategies - providing a warning signal as to the urgency of environmental measures to be taken - allowing follow up of the efficiency of reduction strategies, including comparing results over time, e.g. before and after preventive actions, in order to see whether the actions have helped improve or protect health and to what extent.

- allowing the development of a geographically differentiated environmental policy taking into account public health information together with economic, industrial and technological specificities.

Research projects may be grafted on such a surveillance framework, allowing reduction in costs by using already existing infrastructure.

Environmental issues are global, interdependent and transboundary, and environmental health policies are to a large extent defined at European level. Member states are requested to provide relevant data to European organisations. A European environmental policy will be supported by better data comparability and accessibility within and between countries. Coordination of biomonitoring activities through Europe may contribute to this and allow for a better integration of information by bringing together available knowledge and actively promoting exchange of experiences between teams and countries and enable a more effective use of resources by shared development of tools and strategies.

Efforts in biomonitoring are not equally distributed amongst European countries due to differences in resources available, political and public interest, etc. Coordination at the European level may allow for better respecting the rights of each citizen of the European Union on healthy environments.

Requirements for an integrated EU biomonitoring effort

A cost-efficient monitoring system should cover major health endpoints that might be related to environmental factors. The program needs flexibility and should remain adaptable to new information which may become available during the activities (e.g. new non- invasive techniques, new markers with increased specificity and sensitivity, new threats to health). Practical feasibility of the fieldwork and cost-efficiency are major issues. Existing operational structures should be used if possible. The objective, duration and period of the biomonitoring activities should be well defined.

Integration of local, regional and national initiatives in a wider European perspective needs, above all, sound and harmonised study design, adequate biomarkers, reliable tools for sampling and analysis with consistent/comparable protocols, common to each participating country and/or geographical area within a country, harmonised data treatment, and adequate quality control. Also reporting and dissemination of results together with data storage, protection and release should be taken into account.

The extent to which existing efforts within Europe might be coordinated and how a permanent harmonised European biomonitoring system could be built around ongoing monitoring in the Member States and the Acceding Countries will be the subject of further discussions within the working group.

The following requirements (non exhaustive) will form a basis for these discussions:

(1) Choice and recruitment of the study population (2) Selection and validation of biomarkers (3) Analysis (4) Harmonised data treatment (5) Quality control (6) Field work (7) Communication (8) Ethical aspect (9) Cost-efficiency (10) Research needs (11) Legal requirements

Further work on those requirements together with an in-depth analysis of the individual questionnaires received will enable the working group to develop proposals for options for actions as foreseen in step 2 of the working group’s mandate.

Readers of this report are invited to send their comments to be included in the discussions to [email protected] and or to [email protected].

1 Preface

Prenatal and postnatal exposure to environmental pollutants may have large implications for children’s health and also determine morbidity occurring later in life, including asthma and allergy, cancer, mental illnesses, delayed neurodevelopment and cardiovascular diseases. Recent studies (WHO/EEA 2002) indicate that gene-environment interactions are important in many diseases. Exposures during early life are important because children are often more susceptible than adults and because critical periods of exposure in early life can condition later health effects.

Gaps in knowledge exist between environment and health linkages relative to children and appropriate policy responses. Biomonitoring in children4 may increase knowledge on the relation between children’s’ health and the environment and allow the development of national and international environmental health programmes and policies for preventing disease.

Recent observational birth cohorts that incorporate both questionnaire data and collection of biological samples have enrolled a total of more than 200.000 newborns in Belgium, Denmark, the Faroe islands, Finland, France, Germany, Italy, Norway, Spain, Sweden, the Netherlands and the UK. It is expected that in the next 2-3 years several hundred thousand newborns will be enrolled in ongoing studies. The question is raised if and how coordination of these efforts could provide important added value and if the development of a permanent harmonised European biomonitoring system built around ongoing monitoring in the Member States and the Acceding Countries could allow better understanding of environment and health linkages and long-term health effects and could be used as an additional tool for the development of integrated environment and health policy.

On 9-10 October 2003 the first meeting of the working group on biomonitoring in children was held in Brussels. The aim of this working group was to establish an overview of the existing biomonitoring activities in the EU, to assess the possibilities to integrate the existing activities and to develop options for harmonised EU biomonitoring of children based on current knowledge (see mandate in annex II). The first step therefore consisted of a “definition of a baseline”, which includes – under the given time restrictions - an as complete as possible picture of the existing activities regarding biomonitoring of children in Europe. On the 26th November the working group met again to discuss results obtained and a draft for this document.

This report provides a preliminary overview of existing E & H biomonitoring activities related to children being undertaken in Europe. It also presents reported problems and deficiencies of existing biomonitoring systems and sets out advantages of an integrated approach. It starts to explore the requirements for integrated EU biomonitoring of children.

4 Biomonitoring in children was defined by the working group as ‘monitoring activities in children, using biomarkers, that focus on environmental exposures, diseases and/or disorders and genetic susceptibility, and their potential relationships. Biomonitoring of children includes the prenatal period up to an age of 18 years and follow-up activities for monitored children into adulthood’ (see Annex I).

Collecting as much information as possible on existing biomonitoring activities required a substantial part of the time allowed for the first stage of the work, and discussion of the responses within the group is not yet finalised. Nor was it possible to request additional information from some responders. The report at hand was mainly prepared and agreed by electronic mailing procedures. Given the short time available, members of the group were not able to receive feed back from all the contacts in their respective countries or companies. Further discussion on the results and feedback will be part of the work at the beginning of the next stage. Readers of this report are invited to send their comments to be included in these discussions to [email protected] and or to [email protected].

2 Overview

2.1 Methodology of Data Collection

At the first meeting on 9-10 October 2003 the technical working group for “Biomonitoring of Children” agreed on the procedure and format for the collection of information on biomonitoring activities in Europe. Following the mandate it was decided that the survey would cover ongoing activities and activities that have been completed within the last 10 years.

Information collection followed a strategy A and a strategy B. By strategy A all ministries of health/environment in 25 EU countries were contacted. By strategy B all institutions known by group members to be active in the field of “biomonitoring” were contacted directly and the group members themselves gave their input.

A questionnaire and accompanying guidance note were developed and agreed by the group (see annex III). Information was sought on population under study, biomarker and additional data collected, analysis and quality control procedures, strategies for data protection, data availability, and communication at the individual level and at the group level. In addition, information was requested on problems and shortcomings identified, as these might be a source of intended improvements within the European Environment and Health Strategy. Also positive aspects and suggestions that might be helpful for similar activities were requested.

Given the very short time available, responders were asked to return even incomplete forms if completion of the questionnaire was not feasible, and to indicate if information was available but could not be provided for any reason. Respondents were also asked to indicate whether confidentiality of certain data could be an obstacle for adding the response into the annex of this report.

2.2 Overview on feed back and basic data

At the finalisation of this report (5th December 2003) 97 completed forms were available. Countries and researchers have provided different levels of detail in their response to the questions. Some of the information was not provided but was said to be available on request. Some research groups replied they were not able to provide the information requested for various reasons, mainly time and effort constraints and duplication with other questionnaires.

Although the response to our call was encouraging, gaps in information clearly exist and no straightforward assessment or assumption can be made on the level of representativeness of the data at hand. Information was received for all except 2 of the Member States, for 4 Acceding Countries and also for Norway and Croatia.

The overview of existing monitoring activities being undertaken in the Member States and Acceding Countries demonstrates that within these countries, both nationally as internationally, a substantial amount of biomarker data on children are collected and that huge resources are devoted to these efforts. Many of the biomonitoring activities reported integrate data on environmental factors with health data. Several studies address both children and their parents (particularly their mothers, therefore integrating prenatal and

postnatal exposure) and simultaneously address markers of exposure, effect and susceptibility. Useful information, relevant for policymakers, is already being collected.

A very preliminary analysis of basic data of questionnaires obtained so far (30-11-2003) is summarized below:

(1) total number of questionnaires received: 97 (2) reported budget with 47 questionnaires: about 57 million euro (3) average budget per project 1,2 million euro (4) about 480 000 children are covered (basis 90 questionnaires) (5) average about 5200 children per project (6) average duration of a project 4,5 years (7) average budget per monitored child is about 220 euro with a wide range from 30 euro to 8.210 euro (8) average yearly budget for a project is about 250.000 euro with a wide range from 3.000 euro to 3.000.000 euro (9) 19 projects covered dioxin/PCB exposure, 42 heavy metals, 4 endocrine disrupters (10) 25 projects examined asthma or allergies

Evaluation of the material is not yet finalised as relevant information is still coming in or is promised to be provided soon, e.g. related to some international studies.

Hopefully, with the assistance of Kira Bang Bove (DK), at the end of the year we will be able to compile an overview of the material submitted. This overview will present the types of studies submitted, number of children included and age groups, as well exposures under study.

All individual responses received before 1-12-2003 are provided in annex V to this report.

2.3 Objectives of biomonitoring in children

In general, the objective of biomonitoring is to increase knowledge about the relation between human health and the environment and to use this knowledge to improve environmental health.

More precise objectives reported are :

(1) To provide data on the distribution of exposure to a variety of environmental factors and on health effects across the entire population (applies to representative population studies)

(2) To monitor trends in exposure levels over time and space

(3) To obtain data which are representative for specific areas with expected different types of environmental loads (urban areas, dense traffic, intensive agriculture, industry). Biomarker data and public health data therefore to be analysed geographically and presented per geographical unit.

(4) To establish reference ranges/values that can be used to identify people with unusually high exposure or the percentage of the population that has elevated exposure levels (e.g., lead).

(5) To determine which specific population groups, such as minorities, people with low incomes, children (different ages), are at high risk for exposure and adverse health effects.

(6) To provide a bridge to understanding the relationships between environmental factors, exposure to these factors (including factors in food) and health problems.

(7) To design and evaluate precautionary5, preventive, interventive and control strategies within the framework of policy measures related to health and environment.

(8) To establish an “early warning system” based on biomarker measurements in a representative fraction of the population living in different areas that may help alert physicians, scientists, and health officials to diseases that result from exposure to environmental factors.

Overall, it is highlighted that similar aspects are addressed in biomonitoring programmes in nearly all countries. Exposures to heavy metals, PCBs and dioxins are the subject of many studies. Endpoints such as asthma, allergy and neurodevelopmental disordes, as well as exposures to genotoxic agents are covered, and multidisciplinarity is typical of many activities. In many cases establishment of biobanks (archives of biological materials/samples) is part of the activity allowing for later follow-up.

5 Issues related to the Precautionary Principle have been raised at several occasions during the discussions in the working group. An in-depth discussion on this has been postponed to Step 2, addressing options for actions and recommendations. 13

3 Problems and deficits

Problems and deficits (non exhaustive) in conducting biomonitoring in children, as highlighted in the questionnaires and by the group members, relate to :

(1) recruitment of study population

(2) biomarkers addressed

(3) the logistics of conducting biomonitoring

(4) biosafety

(5) collaboration between disciplines

(6) comparability of questionnaire data

(7) communication of results

(8) authorisation of study

(1) Recruitment of study population A major problem in biomonitoring studies or programmes reported is to achieve good participation of the population, i.e. a sufficiently high response rate, in order to guarantee the representativeness of the study. Measuring biomarkers often means that biological samples such as blood and urine need to be obtained. Collection of blood samples is perceived in some Member States as a significant disincentive to participation (e.g. participation less then 30 %), leading to a loss of data and therefore to lower representativeness and consistency of results. Development of less- or non-invasive sampling techniques is suggested to be crucial for the success of future large-scale biomonitoring studies. Other Member States, however, report response rates over 60% and report financial incentives or gifts to be appropriate tools to increase the response rate.

This problem is even be more marked in studies or programmes involving children. Neonates and infants are a more difficult study population for biomonitoring because recruitment can be particularly problematic. Liquid samples are reported to be more difficult to obtain: both newborns and infants are too young to easily collect urine in bottles or other vessels. Also parents are reluctant for a blood sample at that age. Blood sampling needs to be performed by personnel experienced in infant blood-withdrawals and obtaining urine samples.

On the other hand, these two groups are of high interest because of various reasons6. Also in teenagers the collection of blood samples may be a significant disincentive to participation. Other material such as hair or buccal scrape is easier to collect.

Particular problems are also mentioned on the recruitment of children belonging to lower social classes, of single working mothers and of immigrants. When response rate was reported to decline with time, in some studies the reduced response was linked with the level of education and the social class of the mother.

Participation level was reported to increase when siblings of selected children were accepted for the study or if a gift and/or reimbursement of travel cost were offered. In some countries such practices are, however, not ethically accepted or commonly used, resulting in a lower participation level.

Parents are mostly interested in the results (e.g. blood level) of an agent in their children. Some reports remark that in the case of low (normal) levels being found, parents may refuse further health examination. Others report participation to increase with good experiences from previous participation

(2) Biomarkers addressed Validation of markers is incomplete. Gaps in knowledge exist on the differences between children and adults and within different age groups of children within areas of mechanistic actions, uptake, distribution, metabolism, storage and excretion of environmental agents.

Questions arise on the best available techniques and the interpretation of results, particularly in children. Whereas, for example, in adults urine results are generally expressed by creatinine level to take into account the diuresis, in children the variability of urinary creatinine may be more important due to growth of the muscular mass, to an important physical activity, and to puberty. Also Specific Physiologically Based Pharmokinetic (PBPK) models for children need to be developed to allow a better health risk assessment. Children’s health parameters seem not to have the same sensitivity at different ages, and shows great inter-subject variability. In genetic toxicology, reference data are missing for children.

For some markers (e.g. related to dioxins), the volume of blood needed is too large for children. Alternatives using smaller volumes or blood or other material should be studied.

6 (i) the body composition of the foetus, neonate and infant are very different to that of the adult, especially with regard to the adipose tissue to body ratio. This is very important to consider in lipophilic and hydrophobic toxicants such as dioxins, PCBs, solvents, etc. The storage of these substances in adipose tissues means that the substances are difficult to metabolise, resulting in long periods of exposure (for instance, dioxins have a half-life of 7 to 12 years in humans); (ii) the foetus, neonate and infant (and young child) are growing and developing (this includes the brain). Exposure in this period, during the various developmental windows, may lead to various (long-term) effects; (iii) the neoanate and infant consume relatively huge amounts of feed, approximately 150 mL/kg/day while older children and adults consume approximately 30-40 mL/kg/day. Contaminated food stuffs (especially dairy products) then result in far larger exposures to the neonate and infant than to older children and adults.

(3) Logistics of conducting biomonitoring Recruitment may be difficult and slow and sufficient staff are not always available. Also, personnel (other than the scientific staff) to implement the logistic aspects of the study or programme is sometimes lacking.

High time-investment of medical staff is often required. In one member state, medical services or centres were reported to refuse to participate in studies for this reason. Also in other studies it was reported that individuals satisfying the inclusion criteria were sometimes “lost” from the study due to lack of involvement of health professionals.

Transport and storage of samples requires particular attention. Recruitment of laboratories that perform chemical analyses may be time consuming.

Continued funding of long-term studies was a recurrent problem. Reasons reported for this were e.g. that studies do not produce quick results which the funding agencies would want to see. Also funding for studies with “sensitive data” was not easy to find.

(4) Biosafety Biological media can serve as vectors of infectious disease, such as HIV and hepatitis. Because of this hazard, rigorous procedures must be used when collecting, transporting, storing, analysing and disposing of any human biological samples. All personnel must be trained for the proper handling of biological samples and protocols must include instructions for this.

(5) Collaboration between disciplines Collaboration between disciplines (e.g. epidemiologists, toxicologists, molecular biologists, paediatricians, oncologists, exposure assessors, environmentalists and regulators) in order to develop and implement systematic biomonitoring systems to produce additional useful results for regulatory and/or policy decision-making is lacking in many of the activities reported. Reporting results to the relevant authorities is often not foreseen in the research projects at hand.

(6) Comparability of questionnaire data In international studies especially, an important methodological problem is the collection of comparable data through questioning of children or parents, despite the cultural differences between ethnicities, regions, countries. International standardisation of obtained data in questionnaires is lacking.

(7) Communication of results For many biomarkers the link to health risk, especially at the individual level, is not well defined. Reporting of these results to the individual may therefore be problematic. Ethical questions on communication and on access to own data (right to know, right not to know) are therefore raised: e.g. is it acceptable not to report on the individual results?

Also communication with the public was reported to raise difficulties and to need careful consideration and preparation. An active involvement of professionals in the field of communication and sociology may contribute to resolving these constraints.

(8) Authorisation of study Obtaining the necessary legal agreements by the bodies concerned (national authorities, ethics committees, privacy commissions) may cause substantial delay in implementing a study or programme. The question was raised if legislation needs to be adapted in view of the public interest of the activities at hand.

4 Advantages of integrated biomonitoring of children

(1) Biomonitoring entails integration

The preliminary overview of existing monitoring activities being undertaken in Europe shows that within these countries, both nationally and internationally, a substantial amount of biomarker data is collected and that huge resources are devoted to these efforts. Many of the biomonitoring activities reported integrate data on environmental factors with health data. Several studies address both children and their parents (particularly their mothers, therefore integrating prenatal and postnatal exposure) and simultaneously address markers of exposure, effect and susceptibility. Biological markers may present a unique tool for multimedia exposure assessment. Some are highly sensitive indicators of an individual’s exposure to chemicals and radiation, since they provide a measure of the internal dose, account for all routes of exposure and integrate over a variety of sources of exposure. Therefore, they can represent past exposure, recent exposure to an external source and even future internal exposure sources (e.g. radioisotopes). Biomarkers which integrate over long periods of time (e.g. PCB concentration in breast milk) can be used to evaluate past exposure in a more accurate manner than historical record review and exposure reconstruction.

(2) Integration in a wider national and European perspective should allow for a better insight in the environmental impact on children’s health

Information gaps still exist in occurrence and severity of the most relevant adverse effects potentially induced in children’s health by a variety of environmental factors acting alone or in combination.

Integration of local initiatives in a wider national and also European perspective7 should allow for a better insight in the environmental impact on children’s health and therefore constitute a better basis for environmental health policy decisions by:

7 through adequate biomarkers of exposure, effect and susceptibility, and following consistent/comparable protocols for both sampling and analytical strategies, common to each participating country and/or geographical area within a country, and expected (i) to keep the inherent variability of human samples to a minimum, (ii) to improve comparability of results from different studies/programmes and countries and (iii) to allow more consistent data on trends over time, 18

− enabling the establishment of relations between low exposures to environmental factors and health effects and also health effects that occur at a low incidence, by increasing the power of studies − avoid limited predictivity and power of the studies performed, possibly associated with relative small sample sizes involved Integrated efforts should allow for better use of resources in addressing the environmental impacts on children’s health.

(3) Relevance

− identification of priorities in ambient levels and exposure reduction strategies − providing a warning signal8 as to the urgency of environmental measures to be taken − allowing follow up of the efficiency of reduction strategies, including comparing results over time, e.g. before and after preventive actions, in order to see whether the actions have helped improve or protect health and to what extent. − allowing the development of a geographically differentiated environmental policy taking into account public health information together with economic, industrial and technological specificities. Research projects may be grafted on such a surveillance framework, allowing reduction in costs by using already existing infrastructure.

8 A biomarker network can provide early warning signals in population groups. These signals are assumed more prevalent than disease outcome and may therefore be more sensitive. They may indicate increased health risks on the population level but are not unequivocally linked to adverse health effects. They may allow preventive action before an actual disease or disorder develops. Complementary information may be obtained from registers with health indicators. They contain data on the prevalence of mortality and morbidity. As such they cannot be used in a preventive way. But linking data between both networks may provide information on the specificity, sensitivity and relevance of the early warning signals for adverse health effects at the population level. However, such information might only become available over a long monitoring period.

5 Requirements for an integrated EU Biomonitoring effort

A cost-efficient monitoring system should cover major health endpoints that might be related to environmental factors. The program needs flexibility and should be adaptable to new information which may become available during the activities (e.g. new non-invasive techniques, new markers with increased specificity and sensitivity, new threats to health). Practical feasibility of the fieldwork and cost-efficiency are major issues. Existing operational structures should be used if possible. The objective, duration and period of the biomonitoring activities should be well defined.

The following requirements (non exhaustive) will form a basis for these discussions (see Annex IV for draft working document) :

(12) Choice and recruitment of the study population (13) Selection and validation of biomarkers (14) Analysis (15) Harmonised data treatment (16) Quality control (17) Field work (18) Communication (19) Ethical aspect (20) Cost-efficiency (21) Research needs (22) Legal requirements

6 Annex I – Definitions

Biomarkers are seen as indicators of the continuum of biological events that can occur between exposure to an external agent and disease. Within this continuum four classes of biomarkers have been identified: markers of internal dose, markers of biologically effective dose, markers of early response and markers of altered structure and function9. In addition susceptibility markers are measurable indicators of genetic and acquired factors that influence the probability that a disease will result from external exposure10.

Biomonitoring in children was defined by the working group at the first meeting as ‘monitoring activities in children, using biomarkers, that focus on environmental exposures, diseases and/or disorders and genetic susceptibility, and their potential relationships. Biomonitoring of children includes the prenatal period up to an age of 18 years and follow- up activities for monitored children into adulthood’.

Biomarkers are defined by IARC as ‘any substance, structure or process that can be measured in the body or its products and may influence or predict the incidence or outcome of disease’. WHO defines biomarker for exposure as ‘an exogenous substance or first metabolite or the product of an interaction between a xenobiotic agent and some target molecule or cell that is measured in a compartment within an organism’, biomarker for effect as ‘a measurable biochemical, physiological, behavioural or other alteration within an organism, that depending upon the magnitude, can be recognized as associated with an established or possible health impairment or disease’ and biomarker for susceptibility as ‘an indicator of an inherent or acquired ability of an organism to respond to the challenge of exposure to a specific xenobiotic substance’.

9 Markers of internal dose indicate the level of exogenous chemicals, either unchanged or its metabolites, found in the biological medium (e.g. 1-hydroxypyrene in urine or lead in blood). Markers of the biological effective dose represent the level of absorbed chemicals that has interacted with critical sub-cellular, cellular, and tissue targets (e.g. adducts in DNA, haemoglobin or other proteins). Markers of early biological response comprise biological and biochemical changes in target cells or tissues that result from the action of the chemical and are thought to be a step in the pathological process toward disease. The markers of early biological response consist of more stable alterations in cells and tissues compared to the biological effective dose markers, with persistence over time. (e.g. sister chromatid exchanges, micronuclei, chromosomal aberrations, induced DNA repair, mutations in marker loci and proto-oncogene activation). The markers of altered structure and function, also known as markers of (sub clinical) disease, indicate a biochemical or biological event that represents a sub clinical stage of disease or is a manifestation of the disease itself (e.g. preneoplastic lesions - tumor associated antigens such as CEA and tumor markers such as CA-125- , altered pulmonary diffusion capacity and haematological changes). 10 Lack of metabolic activity to promote detoxification and excretion e.g. with genotype gluthathion transferases M1 null or increased sensibility to allergens are examples of markers of susceptibility. 22

7 Annex II – Mandate

Mandate : “Biomonitoring of children” Introduction

Prenatal and postnatal exposure to environmental pollutants may have large implications for children’s health and also determine morbidity occurring later in life including asthma and allergy, cancer, mental illnesses, delayed neurodevelopment, cardiovascular diseases. Recent studies (WHO/EEA 2002) indicate that gene-environment interactions are important in many diseases. Exposures at early life are important because children are often more susceptible than adults and because critical periods of exposure in early life condition later health effects. Recent observational birth cohorts that incorporate both questionnaire data and collection of biological samples have enrolled a total of more than 200.000 newborns in Belgium, Denmark, the Faroe islands, Finland, France, Germany, Italy, Norway, Spain, Sweden, the Netherlands, the UK. It is expected that in the next 2-3 years several hundred thousands newborns will be enrolled in ongoing studies. This information has originated from an initial coordination process among several research groups in EU countries but it is possible that additional cohorts exist.

Problems identified

Many studies to explore environmental factors that influence children’s health are conducted in EU countries but research is unco-ordinated. Individual areas of expertise do exist but the problem is in integrating them. Progress in this line of research can only come from a close collaboration at a European level having enough power to evaluate hypotheses and sufficient know-how in a wide spectrum of exposures and diseases.

Objectives

An EU biomonitoring framework would provide harmonised data on a much larger sample population, thereby improving the validity of results and allowing a wider variety of environmental factors to be studied in a more cost-efficient way. An EU biomonitoring system will therefore allow a better understanding of environment & health linkages and long-term health effects and could be used as a tool for the development of environment and health policy.

Tasks of the Working Group

Step 1 : definition of the baseline The WG will first provide a Baseline Report by the end of December 2003, including : • an overview of the existing E & H biomonitoring activities related to childern in the Member States and Acceding Countries. In particular biomonitoring activities evaluating a wide spectrum of exposures and effects, within cycle I including: 1. environmental exposures (e.g. pesticides, water contaminants, organochlorinated compounds, indoor & outdoor air pollution, heavy metals, endocrine disruptors, environmental tobacco smoke, radiation…). 2. gene-environment interactions 3. outcomes such as reproductive disorders (birth weight, birth defects, spontaneous abortion, …), respiratory disorders, allergies & asthma, neurodevelopmental disorders, cancer. • problems and deficits of ongoing children biomonitoring activities e.g. related to the coordination of the monitoring activities and the existing expertise that are due to specific problems such as differing data collection (e.g. different parameters) only local monitoring, etc. Such problems and deficits make it difficult to provide a clear overview on the situation based on reliable and European-wide data. • advantages of an integrated biomonitoring of children including the advantages at local, regional, national and Community level such as use of synergies, consistent and reliable data base, comparable data, time trends, consistent follow up results, saving of resources, etc. • requirements for an integrated EU biomonitoring of children e.g. the establishment of an appropriate data base, exchange of expertise and experiences between different cohorts, harmonised sampling, parameters, nomenclature, registries and reporting, geographical coordination of activities, duty to notify relevant diseases with harmonised reporting forms. [note: The determination of requirements is essential for the next task]. • an assessment of the possibility to integrate the existing activities & programmes and identify the missing links in order to develop an integrated EU biomonitoring of children

Step 2 : establishment of options for action & recommendations On the basis of the outcome of the previous tasks, the Working Group will then : • Establish options for action and recommendations for the Commission’s “AP 2004- 2010”. In particular : – Proposals for an EU biomonitoring system to be used as a tool for the development of further environmental policy. The possibilities for an EU biomonitoring legislative framework should be explored, including revision of current relevant EU legislation – Proposals for actions to rectify any information deficits and gaps identified. These may include research where greater understanding of environmental and health interactions may be required. – Proposals for preventive actions such as further legislation, regulation, enforcement of monitoring/emissions compliance, education and information programmes. • Each recommendation or option presented will be accompanied by a justification of the choices, practicability the estimated impacts and costs involved, the time lines and the interlinkages with other measures or policies. • The recommendations must respect the following principles: They should promote integration, as explained in the Communication (COM (2003) 338 final, p. 8/9) – They should single out specific actions of relevance for children – They should address the specific needs of Accession Countries where relevant – They should contribute to the construction of an integrated environment and health monitoring and response system

– They should address the priorities of the first cycle (respiratory diseases, asthma and allergies; neurodevelopmental disorders, childhood cancer; and human health effects of endocrine disruptionResearch recommendations • Extended impact assessment Links with other TWGs should be ensured in step 1 as well as in step 2. Chairs

The Working Group will be chaired by Ludwine Casteleyn and co-chaired by Lisbeth Ehlert Knudsen and Carlo Sala

Members

Final list of members has been established after the Preliminary Meeting of the Consultative Group on 10/9.

Co-ordination, work methods, planning and deliverables

Guidelines and requirements common to all groups are specified in the Framework Mandate and in the Co-ordination Mandate (which will be provided to the participants before the conference).

Detailed planning is to be established by the chair and co-chair, in consultation with the Commission services.

8 Annex III – Questionnaire and Manual

Questionnaire

Information for the European Environment and Health Strategy with respect to biomonitoring of children

Number General data 1 Type 2 Country 3 Title 4 Aim 5 beginning date 6 ending date 7 contact person 8 Initiator 9 involved/responsible organisations 10 budget available 11 who is financing

Description of the population 12 total number of children 13 age groups and number of persons in each group 14 inclusion criteria, exclusion criteria 15 sampling strategy 16 time schedule of biomonitoring 17 consent procedures 18 how is participation encouraged?

Data collection 19 biomarkers of exposure 20 biomarkers of effect 21 biomarkers of susceptibility

Other data 22 environmental data 23 lifestyle data 24 health data 25 parental exposure 26 Medication 27 socio-economic factors

Data protection and availability

33 privacy legislation 34 intellectual property rights 35 banking of biological samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to general public, to participant 37 professionals involved, contacts between professionals and participants 38 role of media 39 public debate 40 consequences of external communication

41 Problems

42 Experiences

Accompanying letter

Dear Colleague,

This guide as well as the enclosed example of a completed questionnaire may help you in completing the questionnaire.

In addition the technical working group on biomonitoring of children within the EU environment & health strategy kindly asks you to

• Specify if confidentiality of certain data is needed (in this case data will be used in an anonymous and aggregated way only) • Return even incomplete forms if completion of the questionnaire is not feasible If information is available but can not be provided immediately, please indicate this

In order to receive as complete information as possible in a short period of time we have send out letters to the governments as well as to individual researchers. Therefore it might happen that you receive the questionnaire more than once. Please accept our apologies for this.

If you have any further questions, please do not hesitate to contact) the chair of the technical working group, Ludwine Casteleyn at [email protected] or at +32 496 70 77 34.

Thank you for your support!

Guide to completing the questionnaire

1 Please indicate if the activity is „international“, „national“ or „regional“ and indicate whether it is a research study or a survey.

2 Indicate country of population 3 Indicate characterising title or acronym 4 Write a short description of the aim of the activity 5 This survey covers ongoing activities and activities that have been completed within the last 10 years 6 Please insert end date if the activity is finished. 7 Please insert contact details (e-mail, tel, fax, name, institution) of lead investigator 8 Please insert initiating organisation 9 Please give names of all the other organisations involved in the study/survey 10 Please indicate total budget, to the nearest thousand Euros 16 Please provide information on time, season and frequency of sampling, follow up, etc. 17 Specify whether there is written informed consent and by whom 18 Please indicate what methods were used to promote participation in the study 19-21 In addition to indicating the type of biomarker measured (see below) please also specify, where appropriate, the method used to obtain data (questionnaire, interview, functional test, biological sample, etc.). 19 Indicate the chemical, physical or biological agents that are being monitored; examples might be concentrations of dioxins, heavy metals, endocrine disrupters, etc. in urine, blood etc. 20 Please indicate the effect biomarkers being studied; e.g. chromosomal aberrations, interleukin concentration, functional tests 21 Please indicate the susceptibility biomarker being investigated, e.g. genotype 22-27 For these aspects, please indicate data being collected in addition to the biomarkers. Please also specify, where appropriate, the method used to obtain data (questionnaire, interview, functional test, biological sample, environmental sample, etc.). 22 Please mention items such as indoor pollution, outdoor pollution, etc. 23 Please mention items such as food, nutrition, smoking habit, etc. 24 Please mention items such as asthma, cancer, neurodevelopmental disorder 25 Please mention items such as occupational exposure 26 Please indicate if use of medicines is recorded 27 Please mention any socio-economic factors measured or recorded 28-32 Describe briefly the relevant procedures adopted. 32 To include information on recruitment efficiency, for example 33 Indicate nature of personal data (anonymous or identifiable) and access to data; how is confidentiality ensured? 34 Indicate if there are there any patents, copyright issues, etc. 35 Please indicate yes or no; if yes, please give details of location, etc. 36-40 Add information on communication procedures at various points of the activity, including notifications to participants

41 Please give a short summary of the problems and shortcomings you have identified within your activity. These problems might be a source of intended improvements within the European Environment and Health Strategy. Please refer to the structure above (line n°) when mentioning the problems and shortcomings. 42 Please give a short summary including also positive aspects and suggestions that might be a help for similar activities. Please refer to the structure above (line n°) as far as possible.

9 Annex IV – Draft working document for the discussion on requirements for an integrated biomonitoring

A cost-efficient monitoring system should cover major health endpoints that might be related to environmental pressure. The program needs flexibility and should be adaptable to new information, that may become available during the activities (new non-invasive techniques, new markers with increased specificity and sensitivity, new threats to health). Practical feasibility of the fieldwork and cost-efficiency are major issues. Existing operational structures should be used if possible. The duration and period of the biomonitoring activities should be well defined.

Integration of local, regional and, national initiatives in a wider European perspective needs above all sound and harmonised study design, adequate biomarkers, reliable tools for sampling and analysis with consistent/comparable protocols, common to each participating country and/or geographical area within a country, and likely (i) to keep the inherent variability of human samples to a minimum, (ii) to improve comparability of results from different studies/programmes and countries and (iii) to allow more consistent data on trends over time, harmonised data treatment, and adequate quality control. Also reporting and dissemination of results together with data storage, protection and release should be taken into account.

The following requirements are a basis for further discussions:

(1) Choice and recruitment of the study population The sampling strategy used is fundamental to allow comparisons between studies. Study populations should be strictly defined (age group, gender, geographical area, several inclusion/exclusion criteria), the geographical area defined and the pros and cons of the different choices for sampling discussed. Multistage sampling, stratification, clustering, systematic sampling should be weighed against each other. A sampling strategy based on census data may require particular accompanying measures to allow for sufficient participation. Participants may be approached most easily through existing (health) structures. The number of participants required in a study (sample size) depends on the

statistical power of calculations for the selected biomarkers. (Smaller) pilot studies need to be supported, in order to test hypothesis and methodology . Non-responder analysis should be performed.

(2) Selection and validation of biomarkers Before applying a biomarker, clear information should be available on the accuracy of the biomarker which depends on its validity and reliability11. The relevance of a marker to its objective, the degree to which it gives useful information about the problem under consideration, should be clarified. Defining the monitoring objective is therefore crucial. Relevance may be considered separately at the individual level and at the level of the population. Also the extent to which the presumed objective of monitoring the biomarker cannot be met in a different way, has to be defined. This aspect might also be termed ‘subsidiarity’. It includes an evaluation of whether the marker is necessary to obtain the information, or whether the information could be obtained by another test (for instance without needing a blood sample) by interview or by clinical examination. It also includes an assessment of whether the information is needed in order to reach the objective, i.e. whether the information is an essential element that is irreplaceable by other means for the objective to be met.

Arguments in favour of a biomarker may be found in their linkage to broadly identified common problems and global priorities, in their appropriateness for inter-country comparisons, in their relevance for international initiatives and guidelines/regulations, in their usefulness to a range of stakeholders, partners and institutions, in their usefulness for decision making at different levels of government, and in their collection being relatively easily and inexpensively.

Collection of blood samples is often perceived as a significant disincentive to participation. International development of less- or non-invasive sampling techniques would be crucial for the succeeding of future large-scale biomonitoring studies. Besides blood and urine, exhaled breath and saliva can be used to document recent exposures; past exposure can be evaluated using keratinized tissues (hair and nails), breast milk and less often ossified tissue (teeth and bone) and adipose tissue. Other media available for biomarker studies include faeces, nasal lavage, tears, sputum, ear wax, cord blood and buccal cells. E.g. breast milk monitoring for evaluation of exposure mainly to dioxin and related compounds (using mixed analytical strategies, including bioassay for screening and instrumental methodologies for confirmation), as well as cord blood monitoring for prenatal heavy metals exposure evaluation, which use less- or non-invasive sampling techniques, would allow for more consistent data on trends over time and would provide useful information for guiding exposure reduction efforts.

11 Validity is the extent to which the biomarker assesses what it is intended to assess. The most useful parameter for describing the performance (validity) of a test in a population is its predictive value, which is related not only to the sensitivity and specificity of the practice but also to the prevalence of the factor being studied. Availability of reference values in the population under study is therefore needed for assessing the predictivity of a marker. Reliability is the reproducibility of a result or the degree of similarity among results when the practice is repeated under similar circumstances. Reliability depends on the variability of the manifestation on which the test is based and on the variability of the method of measurement and the skill with which it is done.

Biomarkers have to be evaluated on criteria such as variation in the population (interindividual and intra-individual variation) and specificity within the population of interest,, confirmation of hypotheses on exposure effect relationships, observed differences among study areas and on technical criteria such as availability of reference values, of international standard protocols, sampling volume, storage conditions, duration of the analyses and cost. Validation of a biomarker also includes determination of exposure-related toxicokinetics and toxicodynamics and of behavioural factors that influence exposure.

Ideally, a biological marker of exposure should be specific, detectable in trace quantities (to get a low limit of detection and quantification to measure exposure in general population), available by non-invasive techniques and inexpensive to assay. It must relate consistently and quantitatively to the extent of exposure and ideally integrate exposure over time. Currently, there are few biomarkers that possess all these characteristics, but their number is increasing.

Biomarkers of recent, past and cumulated exposures should be identified and biomarkers of complex chemical families (cf. pesticides) / multiple residues and chemical/radiation complex exposure analysis methods should be developed.

Some advantages and limitations of biological markers for environmental exposure assessment are summarized below (source: IPCS 200012,).

Advantages Limitations Demonstration that exposure has occurred Source and route identification need of an integrated biomonitoring with environmental data Integration over all exposure routes Kinetics and timing of exposure Characterization of individual exposure- Biological variations and confounders doses Inclusion of internal sources Altered response as a result of multiple exposure Improved health effects investigations Invasive sampling (mainly for blood) Improved population risk assessment/ risk Availability of human samples management Validation of exposure models Specificity/sensitivity Lack of normative values for comparisons

Information in addition to the biomarkers is needed. E.g. to evaluate the contribution of host factors (e.g. individual susceptibility) or environmental factors to internal dose, information of relevant co-variables is needed. By questionnaire information the following items can be obtained: age, demography and socio-economical status, occupation and potential occupational exposure, general health, medication use, active and passive smoking, nutritional, asthma and allergy of the parents

12 Environmental Health Criteria 214 :Human exposure assessment. International on chemical safety (IPCS), WHO, Geneva, 2000, pg 375. 33

(3) Analyses To increase comparability of results, different strategies may be envisaged including centralisation of work related to specific agents or tests. Laboratories for analyses should be selected a.o. on the basis of experience and quality control (accreditation).

(4) Harmonised data treatment Standardised protocols are needed for the selection of study persons, sample collection and processing, sample analysis, reporting and dissemination, data storage, protection and release.

Standardised and harmonised questionnaires on different exposure, effect and susceptibility variables, so that the information collected would be very precise and mutually comparable for the different European countries involved may increase substantially the sensitivity of the studies.

Integration of information from different databases (e.g. environmental databases, biomarkers and health indicators) may be used for geographical analyses and linking data.

(5) Quality control Quality control should be implemented in every stage of the work including fieldwork, laboratory and toxicology tests and data analyses. Data from different locations and times need to be comparable. Internal and external quality control of the work is essential.

(6) Field work Field work should be well coordinated and guided by a work plan/manual a.o. specifying the sampling procedure, the inclusion/exclusion criteria, the informed consent letters, instructions for procedures for contact of maternity’s, schools, hospitals, the training of field workers, the organisation of a contact point for participants in the study and the communication programme. Experience and continuity are the main requirements for the coordination task.

(7) Communication Communication of activities and results requires particular attention. Critical phases for communication should be identified and a communication program should be developed by professionals in the field. Such a communication program should involve the authorities, the scientific community, the general public, schoolteachers, hospitals, or other intermediaries and the participants to the study. This is needed for reporting results, but also for recruitment of participants, and to feed the public debate on environmental health issues with scientifically valid information. Communication should also be incorporated in the fieldwork.

The participants should be informed on the duration of the program, the place of examination, duration of the examination, compensation for participating, types of examination, confidentiality of data, type of questionnaire. Individual participants could receive their own data as far as they are clinically interpretable. Particular care is needed for data which are difficult to interpret at the individual level and specific strategies have to be established.

Cooperation from Health and Environment authorities may improve the participation of the population. A net of focal information points among local health, environment and education professionals may increase involvement and individual participation from each

local community. Local sessions, in different communities, conducted by the respective ‘focal point’ proved to be a good strategy to organize participation of different stakeholders. Media should be involved. A website devoted to the subject was proven to be useful together with support from the local radios, TV and newspapers.

Feedback information has been shown to be an incentive for the involvement of professionals in the fields of health, environment and education in biomonitoring programs.

In contact with migrants emphasis should be put on specific cultural aspects.

(8) Ethical aspect A children biomonitoring project addresses sensitive ethical issues on several counts: involvement of children as age groups of the population and collection13 and use of human tissues (blood/placental tissue/urine/breast milk), use of personal data. Ensuring confidentiality both for subjects and for the obtained individual results is imperative. Ethical concerns may limit the extent of investigations of exposed individuals and populations

Participants in biomonitoring projects should be well informed on a.o. the objectives and the procedures of the study before enrolment. Written informed consent is a requirement for participation. This is also in accordance with general ethics principles. Informed consent means that the study subject is first informed of the need for the study, of what the study implies for the subject, and of the possible complications of the study (for example, testing lung function can instigate an asthma attack, blood withdrawal may lead to bacteraemia or coagulation problems in sensitive subjects). Subjects should be able to decline or withdraw without detriment or antagonism. Also for long term storage of any clinical material, consent should be obtained.

Specific information documents should be provided for different target populations and age groups. Parents should give consent on behalf of their offspring for children. Parents and children may both give consent where the child has reached a certain age. The autonomy given back to the child in this matter encourages participation and follow-up14.

The question was raised whether informed consent should only be obtained via medical doctors. While this may make recruitment more difficult, it was argued that this protects study subjects in various ways. The training of a nurse and of non-medical staff is different

13 Samples like blood, being collected by invasive techniques and in relatively high volumes (needed for certain type of measurements, e.g. dioxines by instrumental methodology), invole ethical imperatives of using available alternatives in terms of sampling and analytical strategies. 14 Assent: informed assent means a child's agreement (acquiescence) to medical procedures in circumstances where he or she is not legally authorized or lacks sufficient understanding for giving consent competently. When the medical procedure involves a child aged 7 years or older, permission must be obtained from the parent or legal representative and assent must be obtained from the child. Each institution (hospital, university etc) has its own responsibility to determine the necessity of obtaining assent from these children. The regulations also state that age, maturity, and psychologic state should be considered in the determination of whether children are capable of assenting to the medical procedure (see also: Cuttini M. Proxy informed consent in pediatric research: a review. Early Human Development 2000; 60:89-100).

from that of a physician. A physician is trained (and practised) in these aspects of health and therefore is the best person for obtaining informed consent and inclusion of the subjects in the study or programme. According to others however both the medical and non-medical staff, well motivated and influent in the respective communities, may be equally successful and acceptable in recruitment of participants.

Institutional or regional ethics committees, depending on national structures need to approve all studies performed.

(9) Cost-efficiency In the design of a monitoring program, cost-efficiency has to be taken into account (pooling of samples, making use of existing organisations, structures, and databases).

The integration and translation of results of biomonitoring (be it within survey programmes or research activities) into intervention strategies that can be used to reduce the incidence of environmentally related childhood diseases should be promoted.

(10) Research needs Integration of monitoring activities into a European biomonitoring program raises the need for validation and standardisation of biomarkers at several levels. Development of less- or non-invasive sampling techniques is suggested to be crucial for the succeeding of future large-scale biomonitoring studies.

Since children are developing organisms biomonitoring projects should also include considerations regarding which age groups to monitor. Gaps in knowledge of differences between children and adults and within different age groups of children are also significant within areas of mechanistic actions, uptake, distribution, metabolism, storage and excretion of environmental pollutants:

- the exposure and the susceptibility of the fetus to transplacentally transported agents

- mechanisms of actions of DNA damage and repair at different ages to be studied by toxicogenomics/proteomics

- molecular epidemiology studies of children and mothers enrolled in European mother/child cohorts studying eg the impact of genetic polymorphisms on birth outcomes (e.g. birth weight, intrauterine growth rate, spontaneous abortions) and child morbidity

Also efforts studying the interpretation of biomonitoring studies, including molecular epidemiology studies for the risk assessment are important.

In several European countries biobanks have been established from so called mother/child cohorts where prenatal exposure, development and growth are recorded. These cohorts are most useful tools for the study of adverse effects of environmental exposures and more harmonised protocols for such studies should be developed together with concerted analysis of common exposures within EU.

Limited data exist on specific susceptibility of children. Improvement in knowledge of xenobiotic metabolisms should be encouraged to understand variations according to age,

metabolic and enzymatic maturity and radiosensitivity, which can be very different from adults.

Ongoing research projects15 have valuable experiences with the availability of data regarding environment & health and children in EU countries and concerted and/or combined analysis Experiences from these projects and large national studies should be exploited. For the initiation of collaborative European networks close collaboration with the EU DG Research, Quality of Life program, Key action 4, Environment and Health is recommended

(11) Legal requirements Establishment of European mandatory biomonitoring activities may require the development of EU legislative frames in the format of recommendations, guidelines or directives. A directive on biomonitoring in workplaces is already in force and implemented in member states.

Adherence to existing directives of Good Laboratory Practice, Good Clinical Practice Directive of and Data Protection is also a prerequisite.

15 Prevention of allergy - risk factors for sensitisation in children related to farming and anthroposophic lifestyle.(QLK4-1999-01391); Effects of outdoor and indoor air pollution on the development of allergic disease in children.(QLK4-2000-00073) Environmental influences and infection as aetiological agencies in atopy and asthma in young children (QLK4-2000-00263) Road traffic and aircraft noise exposure and children's cognition and health: exposure-effect relationships and combined effects. (QLK4-2000-00197) CHILDREN ALONG A NORTH-SOUTH GRADIENT (HELIOS) PREVENTION OF ALLERGY - RISK FACTORS FOR SENSITISATION IN CHILDREN RELATED TO FARMING AND ANTHROPOSOPHIC LIFE STYLE (PARSIFAL) Effects of outdoor and indoor air pollution on the development of allergic disease in children (AIRALLERG) ENVIRONMENTAL INFLUENCES AND INFECTION AS AETIOLOGICAL AGENCIES IN ATOPY AND ASTHMA IN YOUNG CHILDREN (E2I-4AYC) Placental Uptake and Transfer of Environmental Chemicals Relating to Allergy in Childhood Years (PLUTOCRACY) Protection against Allergy: Study in Rural Environments (PASTURE) EUROPEAN NETWORK ON CHILDREN'S SUSCEPTIBILITY AND EXPOSURE TO ENVIRONMENTAL GENOTOXICANTS (CHILDRENGENONETWORK) Policy Interpretation Network on Children's Health and Environment (PINCHE) Studies of respiratory health of children and air pollution (PATY) QLK4-2000-00073 Effects of outdoor and indoor air pollution on the development of allergic disease in children.(AIR ALLERG) 37

10 Annex V – Returned questionnaires

This annex is subject to changes as additional information is arriving and the questionnaires are further analysed.

Austria ...... 39

Belgium ...... 40

Croatia ...... 70

Czech Republic...... 83

Denmark ...... 88

Finland...... 95

France ...... 102

Germany ...... 135

Greece...... 241

Italy...... 257

Lithuania...... 276

Luxembourg ...... 282

The Netherlands...... 286

Norway ...... 297

Poland...... 300

Portugal...... 365

Slovakia ...... 378

Sweden ...... 382

United Kingdom ...... 384

Austria

Short summary

A study on the relation between lead and psychological effects in children in Vienna is under consideration.

A small study on passive smoking of children by measuring cotinine as a marker has been conducted.

A study on lead exposure, measuring blood levels, was conducted in Carinthia, before and after remediation measures at a lead smelter facility.

Belgium

Short summary to the questionnaires: For Belgium, 7 questionnaires on biomonitoring studies were completed. 3 projects are rather research oriented. The FONIA study (€174000 over 3 years) involves 127 newborns aiming the evaluation of immunological development and relation to allergy by in vitro cytokine secretion measurements in relation to allergen exposure in cord blood. In a follow- up study the children are monitored at the age of 1, 2 and 6 years: cytokines are measured in peripheral blood and a skin prick/RAST test is performed, also assessment of exhaled NO lung function tests are included. The goal of the Plutocracy project is to link the kinetics of the placental transfer of xenobiotics with the epidemiologic associations of allergic diseases among 1000 newborn-mother pairs and follow-up of 500 18 months old toddlers. As biomarkers of exposure lead and cadmium concentrations, organochlorine insecticides and polychlorinated biphenyls are measured in placental tissue and serum from mothers. As biomarkers of effect, oxidative enzyme status and Th1/Th2 cytokine response in maternal peripheral blood and cord blood are measured. A third research biomonitoring study (€50000 over 3 years) compares the repair genotype and phenotype of 40 newborn-mother pairs exposed to in vitro mutagens (PAHs and H2O2), the comet assay and micronucleus test are performed.

In Hoboken, a surveillance program (€12000/year) for monitoring lead in a capillary blood sample of 450 1-12 year old children has been set up since 1978 with 2 yearly sampling periods scheduled in spring and autumn. In 2001 a cross sectional study (€16000 for one year) evaluated the prevalence of respiratory symptoms and risk factors in an industrial and urban region of Mechelen. A lung function and RAST tested is performed on 600 children aged 6-12 years.

In 3 regions in Flanders a feasibility biomonitoring study (€25000 over 1 year) has been conducted, including a large set of biomarkers of exposure (heavy metals, PAHs, PCBs, Dioxin activity, VOCs) and effect (renal function, cytogenetic tests, sexual maturation, immunology, bone function, cardiovascular funcion, lung function and neurology) in 16-20 year old adolescents (average age 17.4y).

Following the feasibility study, a Flemish biomonitoring program (€ 3 400 000 for 5 years) for surveillance of environmental health has been set up. Two age groups are involved: 1600 newborn-mother pairs( with two follow-up studies on neurological development on 300 children and an asthma and allergy on 200 children) and 1600 13-14 year olds. A wide range of biomarkers is measured based upon the feasibility study.

Belgium 01 Number General Data 1 type Regional biomonitoring study + survey The biomonitoring study involves 3 age groups 1. newborns and their mothers 2. Children 14-15 years 3. Adults: not covered in this survey

2 country Belgium

3 title Centre for environmental health: Flemish biomonitoring program for surveillance of environmental health

4 aim To start a monitoring network, focused on specific indicators of public health 1) an “early warning system” based on biomarker measurements in a representative fraction of the population living in different areas of Flanders 2) a monitoring programme based on epidemiological data of public health indicators. Indicators are directed towards priority public health problems to which environmental factors are estimated to contribute: development and reproduction, increased incidence of asthma and allergy and cancer. To organise a multidisciplinary operational unit which should be available for monitoring, ready to operate if specific environmental health questions arise or if signals of environmental health problems are captured which need verification according to a stepwise risk assessment plan. To obtain data on health indicators and biomarkers which are representative for the Flemish population including sensitive subgroups (children and elderly people). To obtain data which are representative for areas in Flanders with different types of environmental loads (urban areas, dense traffic, intensive agriculture, industry). Biomarker data and public health data will therefore be analysed geographically and presented per geographical unit. To identify relevant covariables. To develop a monitoring tool for exposure and confounding by ingestion. To have this network accepted by the public and the authorities. 5 beginning date 2002

6 ending date 2006

7 contact person Prof. Dr. Greet Schoeters Vito - Environmental Toxicology Boeretang 200

Belgium 01 2400 Mol Belgium [email protected] +32 14 335200

8 initiator Flemish Ministry of Health and Flemish Ministry of Environment 9 involved/responsible VITO, PIH, UA, KUL, LUC, UG and VUB organisations

10 budget available € 3 400 000 (approximately) 11 who is financing Flemish government

Description of the population

12 total number of children 3200 children (and parents)

13 age groups and number Age groups: of persons in each 1. Newborns: 1600 group In the neurological follow-up study 300 mother-newborns will be monitored. In the asthma and allergy follow-up study, 200 newborns will be monitored. 2. 14-15 years old: 1600 The numbers 1. and 2. in the answers below refer to these biomonitoring groups. 14 inclusion criteria, Inclusion criteria are: exclusion criteria Written informed consent Age Mothers and children should be living in the area for 5 years minimum. 15 sampling strategy A random stratified sampling scheme is followed. 1. Mothers-newborns are recruited via the maternity department 2. Children are recruited via schools 16 time schedule of 1. Mothers-newborns are sampled in the period September biomonitoring 2002 – December 2003 2. Children will be sampled once in the period September 2003 - June 2004 17 consent procedures 1. Mothers: written informed consent 2. Child and 1 parent: written informed consent 18 how is participation 1. Results of individual measurements and of the entire study encouraged? are offered to the participants and also a small present 2. Schools are offered an educational package on environment and health. Children are offered 2 cinema tickets or one recreation park ticket. Results of individual measurements and of the entire study are offered to the participants

Belgium 01 Data collection

19 biomarkers of exposure 1. Cadmium and Lead in cord blood. Marker PCBs, dioxin- activity (Calux) and chlorinated pesticides in serum (from cord blood). In the neurological development follow-up study: PCBs and lead in serum of the mother and cadmium in the urine of the mother. In the 6th week after birth, PCBs are measured in breastmilk or powdered milk. At age 42 months PCBs and lead are measured in the serum of the toddler, cadmium in the urine. 2. Cadmium and Lead in blood. Marker PCB’s and chlorinated pesticides in serum. Cadmium, 1-OH-pyrene and tt-muconic acid in urine 20 biomarkers of effect 1. Biometry, TSH (heel-prick), Apgar-score, ‘time to pregnancy’. Follow-up studies with children: a) neurological and neuropsychological development (tests+ survey) b) asthma & allergy: analysis of interferon gamma in the cord blood, analysis of faeces of the infant at 3 weeks, 6 months and 1 year, lung function and allergy skin test at 3 years(+ survey). 2. Comet assay on whole blood,hormone levels in serum, biometry, sexual development, hearing test, questionnaire on asthma and allergy 21 biomarkers of 1. Genotypes, Cholesterol, Iron-status in cord blood susceptibility 2. Genotypes, Cholesterol, Iron-status in blood (urinary creatinine)

Other data

22 environmental sampling Questionnaires on contaminant intake via food. (mothers- newborns and children) Air quality data will be analysed and modelled to calculate individual exposure (mother-newborns and children) In a small subset of the adolescent population: passive samplers for BTEX will be carried by 200 children. In addition, ambient air quality in the living/school area of these 200 children will be monitored 23 lifestyle data 1. Nutrition of the mother: type/frequency/amount of bread, cereals, fats, fish (+ own caught fish), meat, wild meats, poultry, sauces, pastries, coffee, tea, milk products, vegetables, fruit, soup, drinks, barbecue in the past few days, vegetarian, eating outdoors, alcohol use (frequency/amount before and during pregnancy). Active/passive smoking of the mother(starting age, amount, frequency, exposure), contact with chemicals, drug-use (frequency, type), hobbies, pets (questionnaire), contact with chemicals and time spent outdoors/indoors over the past 2 days and exposure to traffic in this short period. Nutrition of the baby: breastfeeding or powdered milk 2. Nutrition : type/frequency/amount of bread, cereals, fats, fish (+ own caught fish), meat, wild meats, poultry, sauces, pastries, coffee, tea, milk products, vegetables, fruit, soup,

Belgium 01 drinks, barbecue in the past few days, vegetarian, eating outdoors, alcohol use (starting age/frequency, amount) Active/passive smoking (starting age, amount, frequency, exposure), contact with chemicals, drug-use (frequency, type), hobbies, pets (questionnaire), contact with chemicals and spent-time outdoor/indoor over the past 2 days and exposure to traffic in this short period 24 health data 1. Duration of the pregnancy, biometry, apgar score, medical history, breastfeading 2. Biometry, allergies, eczema, respiratoy problems, illnesses in the past 14 days and past year 25 parental exposure 1. Alcohol use and smoking during pregnancy, medication during pregnancy, medication during delivery. Asthma or allergy in the family. Home environment: traffic ‘pressure’, construction works, decoration works, heating, use of pesticides in house/garden. 2. idem 26 medication 1. Use of medication during pregnancy or during delivery. For the follow-up study asthma and allergy: use of antibiotics by the infant 2. Contraceptives, antibiotics and other medication 27 socio-economic factors 1. Structure of the family, educational level of parents, home- owning, educational level of child 2. idem

Analysis and quality control procedures

28 intra/interlaboratory An inventory of quality assurance programs used in the testing contracting laboratories is made. Identification of critical phases will be identified (collection, identification, transport, storage and preparation of the samples, sample preparation, analytical technique, reference materials, process control, calibrations, storage of samples and reporting of analytical data) Inspection of non-accredited laboratories according to ISO 17025 for the specific analyses used for monitoring 29 external laboratory ‘Round robin test’ for PCBs and tt-MA control Interlaboratory assessment for dioxin-activity (Calux)

30 accuracy, limit of Data for all parameters are available on request detection/quantification, reproducibility 31 data analysis (statistics, Power calculations were based on a feasibilty biomonitoring power calculations) study involving 200 participants in 2 areas (1999). Statistical analysis wll be performed according to a stratified plan 32 representativity Recruitment efficiency is monitored. Non-responder analysis is ongoing.

Data protection and availability

33 privacy legislation Samples and questionnaires are maintained by the ibl dildt d b tl idi 44

Belgium 01 responsible medical doctor and subsequently anonymised in order to maintain confidentiality under secure conditions in accordance with the 1995 EC Data Protection Directive and data protection legislation. Measures are taken to ensure confidentiality and security of the data. Ethical advice has been taken to determine the maximum volume of blood samples that may be taken in order to minimise distress to the participant. 34 intellectual property No patents. rights Data will be published upon approval of the steering group. 35 banking of biological No long term storage is foreseen samples

Communication (individual level, group level, level (sub)population )

36 reporting results to Each month the Flemish authorities are informed on the public authority, to progress/problems of the study. 1.5 years after the final general public, to recruitment the results will be reported and communicated to participant the public. Local authorities, GP’s, local action groups on environmental health were informed when the study started, results will be communicated. The participant will be given individual results as far as they are interpretable, as well as group results either directly or through the GP (participant’s choice). The results of the monitoring campaigns are available to the general public by the web site www.milieu-en- gezondheid.be They can be integrated in the annual publications of public health indicators. A three-monthly journal “The Biomonitor” will be supplied to several groups. Results of the studies will be communicated to the scientific community preferentially by publication in peer reviewed journals after approval by the management committee and according to specifications mentioned in the call. 37 professionals involved , A steering group including scientists for the entire programme. contacts between GP’s and teachers are the in-between professionals. professionals and participants

38 role of media The start of the study was given attention in all media (TV, Newspapers, radio,…). Because of the scale of the study and the public opinion on pollution problems in some of the included areas, media attention is significant. 39 public debate Occasional symposia are organised which may include debates between different stake-holders.

Belgium 01 40 consequences of Pollution in surroundings of industries and incinerators are external communication hot-topics, therefore communication needs to be prepared carefully. A communication program is developed by professionals in the field of communication and sociology.

41 Problems

42 Experiences

A lot of energy has to be spent in communication for organising participation of different stakeholders. Collaboration with existing initiatives such as the blood bank and educational centres is highly recommended. The educational package was very helpful to involve schools in the encouragement of their students. An introduction letter from the Flemish Minister of Environment helped persuade schools to collaborate. Participation level is higher when offering a gift (free tickets).

Belgium 02 Number General Data

1 type Regional biomonitoring study The biomonitoring study involves 1 age group : newborn girls and their mothers 2 country Belgium 3 title Vrije Universiteit Brussel - Faculteit Wetenschappen - Cellulaire Genetica 4 aim To compare the repair genotype and phenotype of mother and daughters exposed in vitro to mutagens (PAHs and

H2O2) 5 beginning date 2003 6 ending date 2006 7 contact person Prof. Dr. Micheline KIRSCH-VOLDERS Vrije Universiteit Brussel Faculteit Wetenschappen Vakgroep Biologie Laboratorium voor Cellulaire Genetica Pleinlaan 2 1050 Brussel [email protected] +32 2 629 34 23 8 initiator EU - Childrengenotox network 9 involved/responsible Vrije Universiteit Brussel (Prof. M. Kirsch-Volders), organisators Universiteit Maastricht (Prof. J. Kleinjans), St. Peter Hospital Brussels (Prof. D. Haumont), Universiteit Copenhagen (Prof. E. Knudsen) 10 budget available € 50.000 (approximately) 11 who is financing European Union

Description of the population

12 total number of children 40 children + 40 mothers (and parents) 13 age groups and number Newborns : 40 of persons in each group Mothers : 40 14 inclusion criteria, Inclusion criteria are : written consent, non-smokers, non- exclusion criteria exposed to mutagens, healthy 15 sampling strategy A random stratified sampling scheme is followed : mothers- newborns are recruited via maternity hospitals (?) 16 time schedule of Mothers-newborns are sampled in the period December biomonitoring 2003-December 2004 17 consent procedures Mothers : written informed consent 18 how is participation Results of individual measurements offered to the participants encouraged ?

Data collection

Belgium 02

19 biomarkers of exposure Cotinine 20 biomarkers of effect 1. In vitro challenge repair phenotype (Comet and MN) 2. Comet assay on whole blood 3. MN test 21 biomarkers of Genotypes of metabolism and DNA repair susceptibility

Other data

22 environmental sampling 23 lifestyle data Nutrition of the mother : coffee, tea, fruit, vegetarian, alcohol use (frequency/amount before and during pregnancy). Active/passive smoking of the mother (starting age, amount, frequency, exposure), contact with chemicals, drug-use (frequency, type), hobbies, contact with chemicals. Nutrition of the baby : breastfeeding or powdered milk. 24 health data Duration of the pregnancy, biometry, medical history, breastfeeding, follow-up after delivery 25 parental exposure Alcohol use and smoking during pregnancy, medication during pregnancy, medication during delivery. Asthma or allergy in the family. Home environment. 26 medication Use of medication during pregnancy or during delivery. 27 socio-economic factors

Analysis and quality control procedures

28 intra/interlaboratory Use of methods internationally validated by the laboratories testing 29 external laboratory control 30 accuracy, limit of Data for all parameters are available on request detection/quantification, reproducibility 31 data analysis (statistics, Small sample power calculations) 32 representativity

Data protection and availability

33 privacy legislation Samples and questionnaires are maintained by the responsible medical doctor and subsequently anonymised in order to maintain confidentiality under secure conditions in accordance with the 1995 EC Data Protection Directive and data protection legislation. Measures are taken to ensure confidentiality and security of the data. Ethical advice has been taken to determine the maximum volume of blood samples that may be taken in order to minimise distress to

Belgium 02 the participant. 34 intellectual property No patents. Data will be published upon approval of the rights steering group 35 banking of biological Long-term storage is foreseen samples

Communication (individual level, group level, level (sub)population)

36 reporting results to public Results of the studies will be communicated to the scientific authority, to general community by publication in peer reviewed journals. public, to participants 37 professionals involved, contacts between professionals and participants 38 role of media 39 public debate Symposia are organised by the EU network which may include debates between different stake-holders. Relationships with INCHE 40 consequences of external communication

41 Problems

42 Experience

Importance to have good communication with the paediatricians of the hospital and to integrate this in the research project.

Belgium 03 N° General data 1 type birth cohort from 0 to 6y of age 2 country belgium 3 title FONIA-study: Follow-up study of Newborns regarding the Immunological Development and its relation with Atopy 4 aim immunological development and relation to allergy: cytokine measurements in vitro at birth and at different ages in relation to atopic sensitization; role of regulatory T cells?: could we predict atopic outcome? 5 beginning date 01.05.2001 6 ending date 2007 7 contact person Dominique Bullens: laboratory of exp immunology, 8th floor O&N, Herestraat 49, 3000 Leuven, [email protected] 8 initiator Laboratory of experimental Immunology; prof dr JL Ceuppens 9 involved/responsible KUL lab of immunol; UZ Gasthuisberg pediatric and organisations obstetric department 10 budget available until 2004:€ 174 000 11 who is financing Fund for Scientific Research Vlaanderen (FWO) and LEVENSLIJN Vlaanderen

Description of the population 12 total number of children 127 13 age groups and number of from day 0 persons in each group 14 inclusion criteria, exclusion normal pregnancy criteria 15 sampling strategy cord blood; blood; DMSO stocked PBMC 16 time schedule of biomonitoring cord blood; blood at age of 1; 2 and 6 years 17 consent procedures informed consent 18 how is participation orally and written reports encouraged?

Data collection 19 biomarkers of exposure in vitro cytokine secretion in relation to allergen exposure both in cord blood and peripheral blood 20 biomarkers of effect skin prick test/RASTtest specific IgE: at 1 and 2 years old/exhaled NO monitoring off-line at 2 years or 4 years old/lung function + SPT+ specific IgE at 6y 21 biomarkers of susceptibility IgE and specific IgE; SPT

Other data 22 environmental data yes: questionnaire food intake first 2 years and time of intake

Belgium 03 23 lifestyle data minimal: smoke/pets/antibiotics/doctor visits 24 health data yes: doctor diagnosed disease by diary 25 parental exposure yes: smoke/atopic risk/profession 26 medication yes: use of antibiotics and type of antibiotics/use of anti- asthma medication 27 socio-economic factors minimal:parent profession/day care attendance/family structure

Analysis and quality control procedures 28 intra/interlaboratory testing yes: in pilotstudies tested in our own laboratory 29 external laboratory control no 30 accuracy, limit of ELISA data less sensitive but more specific; RT-PCR data detection/quantification, highly sensitive; specific IgE: <0,35 IU/ml reproducibility 31 data analysis (statistics, power power study done in epidemiologic and biomedical statistic calculations) department of KUL based on pilotstudies in adults and litterature data 32 representativity epidemiologically based: inclusion of all atopic risk and 1/2 inclusion if no atopic risk in first line; recalculation towards population risk will be done by epidemiology department following accepted rules

Data protection and availability 33 privacy legislation confidential data/informed consent 34 intellectual property rights no patents 35 banking of biological samples banking of PBMC on DMSO for each child; in between storage at -70°C of all supernatants and of total RNA before analysis

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to general public, to participant 37 professionals involved, contacts between professionals and participants 38 role of media later? 39 public debate later? 40 consequences of external prediction of allergy might be possible communication

41 Problems financial implications

42 Experiences it is difficult and time consuming for clinicians in the field to persuade parents to participate

Belgium 04 N° General Data 1 type Biomonitoring in adolescents in 3 regions in Flanders (Peer, rural control area; Wilrijk, urban polluted area; Hoboken, urban polluted area) 2 country Belgium

3 title Environment and Health (Milieu en Gezondheid)

4 aim Feasibility study to set up a biomonitoringsystem in adolescents. 5 beginning date May 1999

6 ending date October 1999

7 contact person Dr. J.A. Staessen, Dr. E. Den Hond Hypertension and Cardiovascular Rehabilitation University Hospital Gasthuisberg Herestraat 49 B-3000 Leuven Belgium Tel. + 32 16 34 7104 Fax. + 32 16 34 7106 E-mail: [email protected] [email protected] 8 initiator Flemish Ministry of Health (Department of science, innovation and media) 9 involved/responsible KUL, VITO, PIH, UA, UG organisations

10 budget available € 25.000 (approximately) 11 who is financing Flemish government

Description of the population 12 total number of children (and 200 adolescents parents)

13 age groups and number of mean (SD) age = 17.4 (0.8) years persons in each group age range = 15.8 – 19.6 years

14 inclusion criteria, exclusion inclusion criteria: criteria - life-long resident in one of the 3 study areas - stratification for sex within each study area 15 sampling strategy random selection starting from class lists of local schools and examination centres 16 time schedule of May 1999 to October 1999 biomonitoring

Belgium 04

17 consent procedures written informed consent of adolesents and parents

18 how is participation with the help of the school and the school doctors: encouraged? examinations were performed by the school doctor (confidential relation), in the school (acquainted environment), and during school hours (minimal time loss for the participant)

Data collection 19 biomarkers of exposure - Heavy metals - blood lead - blood cadmium - urinary cadmium - Polychlorinated aromatic hydrocarbons (PCAHs) - serum marker PCBs - Calux assay - Volatile organic compounds (VOCs) - urinary t,t’-muconic acid (benzene) - urinary o-cresol (toluene) - Polycyclic aromatic hydrocarbons (PAHs) - urinary 1-OH-pyrene 20 biomarkers of effect - renal function - serum cystatin-c - urinary β2-microglobulin - cytogentic tests - comet assay - chromatid breaks - chromosome breaks - chromosome aberrations - urinary 8-OH-deoxyguanosine - sexual maturation - testicular volume in boys - age at menarche in girls - puberty stage (Marshall-Tanner) - serum sex and thyroid hormones (only in boys) - immunology - phenotypes (CD markers) - RAST tests - serum immunoglobulines - bone function - serum osteocalcin - urinary calcium - cardiovascular function - blood pressure - lung function - spirometry - neurology - NES tests 21 biomarkers of susceptibility - serum Se, Fe, Cu, ferritin - plasma vitamin E, vitamin A - serum cholesterol, triglycerides - haemoglobin, haematocrit - urinary cotinine - questionnaire data (sex, age, BMI, smoking, alcohol consumption, food intake)

Belgium 04

Other data 22 environmental sampling - passive samplers for BTEX - environmental monitoring data from official instances (VMM, Vlaamse Milieumaatschappij; OVAM, Openbare afvalstoffenmaatschappij)

- other data: houses of participants and potential sources of pollution were located by a global positioning system (GPS). The calculated distances between the house of the participant and the source of pollution were used in regression models and to produce maps. In order to protect privacy, no individuals were mapped but the data were summarized per statistical sector. 23 lifestyle data - smoking and passive smoking - alcohol consumption - physical activity index - short food frequency questionnaire - detailed information on consumption of local food products - detailed information on contact with toxic substances in daily life 24 health data - adolescent (examination by school doctor): - detailed medical history (ICD codes) - routine health examination (blood pressure, heart rate, etc.) - anthropometry (BMI, waist-hip, skin fold) - mother of the adolescent (home visit by study nurse): - detailed medical history of the pregnancy of the mother (questionnaire) 25 parental exposure - medical history, smoking and alcohol intake during pregancy and breastfeeding - professional exposure of mother, father and other family members 26 medication detailed questionnaire on drug use of the adolescent (international codes) 27 socio-economic factors social class according to KUL classification

Analysis and quality control procedures

28 intra/interlaboratory testing all tests were done in specialised laboratories that met national and international quality-control standards 29 external laboratory control all tests were done in specialised laboratories that met national and international quality-control standards 30 accuracy, limit of Limits of detection: detection/quantification, - hemoglobin: 0.3 g/dL reproducibility - hematocrit: 3% - red blood cells: 0.06*106/mm3 - white blood cells: 50/mm3 - platelets: 3 x103/mm3 - glucose: 5 mg/dL - IgA: 6 mg/dL - IgG: 90 mg/dL - IgM: 10 mg/dL

Belgium 04 - cholesterol: 30 mg/dL - triglycerides: 10 mg/dL - SGOT (AST): 4 E/L - SGPT (ALT): 4 E/L - GGT: 4 E/L - alkaline phosfatase: 10 E/L - LDH: 50 E/L - IgE: 2 kE/L - rast mixed grass pollens: 0.35 kE/L - rast house dust mite: 0.35 kE/L - rast common silver birch: 0.35 kE/L - rast cat dander: 0.35 kE/L - osteocalcin: 5 ng/L - blood cadmium: 0.5 µg/L - blood lead: 10 µg/L - serum copper: 50 µg/L - serum selenium: 5 µg/L - cadmium in urine: 0.05 µg/L - cotinine in urine: 0.05 mg/dL - 1-hydroxypyrene in urine: 0.2 µg/L - t, t’-muconic acid in urine: 0.02 mg/L - ortho-cresol in urine: 0.05 mg/L - vitamin A in plasma: 15 µg/dL - vitamin E in plasma: 250 µg/dL - serum iron: 5 µg/dL - serum ferritin: 10.5 µg/L - serum soluble transferrin receptor: 0.14 mg/L - cystatin-C in serum: 0.26 mg/L - antibody CD3: 0.1 % positief - antibody CD4: 0.1 % positief - antibody CD8: 0.1 % positief - antibody CD45: 0.1 % positief - antibody CD19: 0.1 % positief - antibody CD56/CD16: 0.1 % positief - antibody CD4/CD8: 0.1 % positief - total lipids in blood: 3 mg/dL - total dioxine toxic capacity: 10 pgTEQ/g vet - PCB marker 28: 0.04 µg/L - PCB marker 52: 0.06 µg/L - PCB marker 101: 0.06 µg/L - PCB marker 138: 0.07 µg/L - PCB marker 153: 0.05 µg/L - PCB marker 180: 0.03 µg/L - thyroid-stimulating hormone: 0.014 µIU/mL - thyroxine: 0.023 ng/dL - triiodothronine: 0.26 pg/mL - follicle stimulating hormone: 0.1 mIU/mL - testosterone: 2.88 ng/dL - oestradiol: 0.5 ng/dL - inhibine B: 15 pg/mL 31 data analysis (statistics, Data-management and statistical analysis were performed power calculations) with the SAS program (SAS Institute, Cary, NC, USA) according to the statistical analysis plan stipulated in the protocol. Power calculations were based on biomarkers that had already been studied previously (i.e. heavy metals, renal function). 32 representativity - Non-responders had a similar age, sex distribution and social class as responders and lived at similar distance from the main sources of pollution. - Biomarkers of exposure were usually lower in the control area compared to the polluted areas.

Belgium 04

Data protection and availability

33 privacy legislation Anonymous data with unique coding number for each participant. 34 intellectual property rights The database is managed by the coördinator (Dr. J. Staessen) and is available to other partners of the consortium. Publication of results needs approval of the coördinator (as determined by the ethical committee of the University of Leuven) 35 banking of biological samples Yes, serum and urine samples are being stored at –20°C.

Communication 36 reporting results to public - ‘Environment and Health in adolescents’ was part of a authority, to general public, to larger ‘Environment and Health’ project. A summary participant report was presented to the Flemish minister of health. - The summary report is available on the website: http://www.wvc.vlaanderen.be/gezondmilieu/onderzoek/ koepel/koepeltekst - Local press conferences in the 3 study areas were held to inform the participants on the general conclusions. - Individual medical results were sent to the general practitioner of the participant if the parents and adolescent had given consent to do so. GPs received a letter with general information about the main aims of the study. - Scientific publications: • Staessen JA, Nawrot T, Den Hond E, Thijs L, Fagard R, Hoppenbrouwers K, Koppen G, Nelen V, Schoeters G, Vanderschueren D, Van Hecke E, Verschaeve L, Vlietinck R, Roels HA and the Environment and Health Study Group. Renal function, cytogenetic measurements and sexual development in adolescents in relation to common environmental pollutants. Lancet 2001; 357;1660-69. • Den Hond E, Staessen JA, Hoppenbrouwers K, Vanderschueren D, Roels H. Delayed sexual development in adolescents. (Letter-to-the-Editor) Lancet 2001; 358:1815-1816. • Nawrot T, Staessen JA, Den Hond E, Koppen G, Schoeters G, Fagard R, Thijs L, Winneke G, Roels HA. Host and Environmental Determinants of Polychlorinated Aromatic Hydrocarbons in Serum of Adolescents. Environ Health Perspect, 2002; 110:583-9. • Van Den Heuvel RL, Koppen G, Staessen JA, Den Hond E, Verheyen G, Nawrot TS, Roels HA, Vlietinck R, Schoeters GER. Immunologic effects at current exposure levels of PCBs and dioxins in adolescents of Flanders (Belgium). Environ Health Perspect, 2002; 110:595-600. • Den Hond E, Roels HA, Hoppenbrouwers K, Nawrot T, Thijs L, Vandermeulen C, Winneke G, Vanderschueren

Belgium 04 D, Staessen JA. Sexual maturation in relation to polychlorinated aromatic hydrocarbons: Sharpe and Skakkebaek’s hypothesis revisited. Environ Health Perspect 2002; 110:771-6. • Den Hond E, Roels HA, Staessen JA. Sexual maturation in relation to polychlorinated aromatic hydrocarbons. (Letter-to-the-Editor) Environ Health Perspect 2003; 111:A203-4. 37 professionals involved , - A steering committee communicated with the Flemish contacts between Government. professionals and participants - A Data Monitoring Committee (DMC) decided on data analysis and reports. - Daily contacts between data managers, study nurses, schools, school doctors and participants throughout the project helped to realize the study within the given time limits. 38 role of media - local press conferences - results were reported in national media 39 public debate The public debate was rather confusing because the results of the environment project in adolescents was presented together with an environment project in adults with a totally different protocol, different recruitment strategies and other biomarkers. 40 consequences of external There was a general consensus on the feasibility and communication importance of biomonitoring. The ‘Environment and Health’ study has lead to the start of a permanent biomonitoringsystem in Flanders.

Problems 41 Problems Confusing communication because two different studies (one in adolescents and one in adults) - with an enormous amount of biomarkers in each study - were reported together. Few people were able to see the wood for the trees. It would have been better to report the data of one study protocol with a well-defined research question and a clearcut conclusion.

Experiences 42 Experiences Factors that have contributed to a successful ending of the ‘Environment and Health’ study in adolescents: - detailed protocol and a strict application of the protocol - experienced study nurses (15 years experience in epidemiological research) - incorporation of the study in an existing structure, i.e. school health examinations - high-quality laboratories - a statistical analysis plan

Belgium 05 N° General Data 1 type Screening of children aged 1-12years on lead in blood 2 times a year 2 country Belgium 3 title Follow-up of lead exposure in children in Antwerp, Hoboken

4 aim -Follow-up of the lead exposure in children in Hoboken, a village near an industrial non-ferro plant -detection of elevated blood lead levels 5 beginning date 1978 6 ending date continuing 7 contact person Dr. Vera Nelen PIH, health department Kronenburgstraat 45 2000 Antwerpen

8 initiator Flemish Ministry of Health, province of Antwerp 9 involved/responsible PIH, UA, city of Antwerp, health inspectorate, GP’s, organisations schooldoctors, VMM

10 budget available € 12000 a year 11 who is financing Flemish government, province of Antwerp Description of the population 12 total number of children 450 children 13 age groups and number Age groups: of persons in each group 1-12 years

14 inclusion criteria, Inclusion criteria are: exclusion criteria -Living in the area -Age -parents consent 15 sampling strategy All children are invited - by mail - via the school in the village 16 time schedule of 2 times a year in april-may and October-november biomonitoring

17 consent procedures - written informed consent for children going to the local school - mother present for children not going to the local school, oral consent 18 how is participation Results of individual measurements are mailed to the encouraged? participants and their GP’s, collective results appear in a news letter Data collection

Belgium 05 19 biomarkers of exposure Lead in blood on a capillary sample

20 biomarkers of effect not collected

21 biomarkers of Not collected susceptibility Other data 22 environmental sampling air quality in the environment is monitored by VMM 23 lifestyle data - 24 health data - 25 parental exposure - 26 medication - 27 socio-economic factors age, sex, address, going to the local school or not Analysis and quality control procedures 28 intra/interlaboratory Accrediation of the laboratory according to ISO 17025. testing 29 external laboratory ring tests control 30 accuracy, limit of Data are available on request detection/quantification, reproducibility 31 data analysis (statistics, Mean, median, percentile values are compared between power calculations) exposure groups and over time 32 representativity Participation :

In school: 65-80% Outside the school: 25-30% Data protection and availability 33 privacy legislation Data have to be processed to retrieve personal results, they are not anonymous. Databases are protected 34 intellectual property rights - 35 banking of biological - No long term storage samples Communication (individual level, group level, level (sub)population ) -individual results by mail -collective results by news letters -over time there have been several info meetings in the village 36 reporting results to public -The medical working group Hoboken is a steering group authority, to general reviewing the results and reporting to the Flemish public, to participant government

-the general public in the region is informed by newsletters -participants get their personal results, the GP and school doctors receive personal results for their patients

Belgium 05 37 professionals involved , -GP’s contacts between -school doctors professionals and -scientist are involved trough the medical working group participants Hoboken 38 role of media -The media have given some attention to this situation at several points in time. -press conferences have been given over time by the medical working group 39 public debate -the UA has implemented a program of population participation(local inhabitants) through focus group discussions recently 40 consequences of external communication 41 Problems

Participation stays high especially in the school. Means have decreased over time but so have the treshold values for effect. Decision making in order to improve the situation, taking into account all interests stays difficult.

Belgium 06 Number General Data 1 type Cross sectional Study on respiratory symptoms in Mechelen 2 country Belgium 3 title Study on the prevalence of respiratory problems in two regions in Mechelen 4 aim -cross sectional study looking at the prevalence of respiratory symptoms and risk factors -objective conformation of elevated respiratory health problems 5 beginning date 2001 6 ending date 2001 7 contact person Dr. Vera Nelen PIH, Kronenburgstraat 45, 2000 Antwerp 8 initiator City of Mechelen, Province of Antwerp 9 involved/responsible PIH, city of Mechelen, UA, KUL, IDEWE, GP’s, local organisations inhabitants, industry

10 budget available € 16.000 11 who is financing City of Mechelen, Province of Antwerp

Description of the population 12 total number of children 600 children 13 age groups and number of persons in Age groups: each group 6-12 years 14 inclusion criteria, exclusion criteria Inclusion criteria are: -Living in the areas -going to school in the two areas -parents consent 15 sampling strategy All children are invited 3. via the schools 16 time schedule of biomonitoring Februari-june 2001

17 consent procedures 3. written informed consent for allergy testing and for spyrometry

18 how is participation encouraged? Results of individual measurements are mailed to the participants and their GP’s, collective results are presented locally

Data collection

19 biomarkers of exposure - 20 biomarkers of effect Lung function, RAST on house dust mite, questionnaire

Belgium 06 21 biomarkers of susceptibility questionnaire

Other data 22 environmental sampling air quality in the environment is monitored by VMM 23 lifestyle data questionnaire 24 health data questionnaire 25 parental exposure - 26 medication questionnaire 27 socio-economic factors age, sex, address, ethnic origin

Analysis and quality control procedures 28 intra/interlaboratory testing - 29 external laboratory control - 30 accuracy, limit of - detection/quantification, reproducibility 31 data analysis (statistics, power Mean, median, percentile values are compared calculations) between exposure groups and over time

32 representativity Participation : 93%

Data protection and availability

33 privacy legislation Data have to be processed to retrieve personal results, they are not anonymous. Databases are protected 34 intellectual property rights - 35 banking of biological samples -

Communication (individual level, group level, level (sub)population ) -individual results by mail -collective results by local presentation

36 reporting results to public authority, to − A steering committee housed in the city of general public, to participant Mechelen guided the program

− the general public in the region is informed by local presentation of collective results

− participants get their personal results, and the GP 37 professionals involved , contacts − GP’s between professionals and participants − school doctors

Belgium 06 − farmacists

− scientists 38 role of media A press conference has been given to present the collective results 39 public debate - 40 consequences of external - communication

41 Problems

42 Experiences

Belgium 07 Number General Data 1 type International biomonitoring study The biomonitoring study involves 1. newborns and their mothers 2. Children 18 months 2 country Belgium, Slovakia, Romania 3 title PLUTOCRACY (Placental Uptake and Transfer of Environmental Chemicals Relating to Allergy in Childhood Years.) 4 aim Our goal is to link the kinetics of the placental transfer of xenobiotics with the epidemiologic associations of allergic diseases (AD) among children. The specific objectives of the proposed study are two-fold: 1) to determine whether placental contamination with selected inorganic and organic xenobiotics changes the immune response as determined by the Th1/Th2 cytokine balance in the placenta, and the cord blood and neonatal peripheral blood immune cells of the birthed cohort of children, and

2) to determine whether enhanced exposure affects health outcome by investigation of the epidemiologic relationship between the exposures (risk factors) which occur in utero and during early childhood with the health outcome of AD among Central European children.

A series of work packages (WP) have been constructed to detail the work required. The WPs will involve the collection of biological samples from regions with varying pollution characteristics, across Europe. A minimum of 200 mothers per region will be enrolled from a total of 5 regions to provide a total of 1000 sets of preliminary biological samples in order to generate adequate statistical power.

5 beginning date 2001 6 ending date 2005 7 contact person Coordinator: Dr Margaret Saunders University of Bristol, Medical Physics Research Centre, Bristol Oncology Centre, Horfield Road, Bristol BS2 8ED, UK +44 117 928 2984 [email protected]

Dr. Rosette Van Den Heuvel Vito - Environmental Toxicology

Belgium 07 Boeretang 200 2400 Mol Belgium [email protected] +32 14 335214

8 initiator EU (FP5) 9 involved/responsible P1. Coordinator University of Bristol, Bristol, United organisations Kingdom P2. Contractor Institute of Preventive and Clinical Medicine, Bratislava, Slovakia P3. Contractor University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania P4. Contractor VITO, Vlaamse Instelling voor Technologisch Onderzoek NV, Mol, Belgium P5. Contractor Emory University, Atlanta, United States of America P6. Contractor University of Antwerp, Wilrijk, Belgium 10 budget available € 11 who is financing EU (FP5) Description of the population

12 total number of children (and parents) 1000 children

13 age groups and number of persons in Age groups: each group 1. Newborns: 5 x 200 2. Mothers: 5 x 200 3. 18 months old: 5 x 100

14 inclusion criteria, exclusion criteria Inclusion criteria are: Written informed consent Exclusion criteria: The PLUTOCRACY project requests the recruitment of healthy babies that have had normal gestations and normal births. The mother should not plan to move outside the study region after the birth. The child should be between 37-42 weeks at the time of birth and have no prenatal and perinatal pathology that would result in the transportation of the child to another hospital during 48 hours after delivery. The following categories provide more specific guidelines for exclusion from the project. Mother: Excluded if she has any chronic autoimmune diseases (such as multiple sclerosis, diabetes, rheumatoid arthritis)

Excluded if she has taken medications during last 3 weeks of pregnancy and/or during delivery including:

Belgium 07 1. Tocolytics 2. Corticosteroids (orally, intravenously, and intramuscular) 3. General anesthesia (acceptable if small dose used during routine C-section) 4. Insulin (during any time of pregnancy) Child: <37 weeks <2500 grams Severe postnatal complications (infections, pulmonary problems, asphyxia, neurological, jaundice requiring exchange transfusion, etc) Congenital malformations (heart, bowel, etc.) Mother and child: Excluded if either/both of them show any signs of infections in perinatal and postnatal period, including: 1. Pyelonephritis (kidney infection) 2. Gonorrhea 3. Chlamydia 4. Syphilis/HIV 5. Trichomonas 6. Herpes 7. Sepsis 8. Pneumonia 9. Meningitis Other exclusion in prenatal and postnatal period: 1. Gestational diabetes 2. Chronic hypertension (high blood pressure before 20 weeks’ gestation) 3. Pregnancy-induced hypertension/preeclampsia (high blood pressure after 20 wks’ gestation) 4. Oligohydramnios (too little amniotic fluid) 5. Polyhydramnios (too much amniotic fluid)

15 sampling strategy Mothers-newborns are recruited via the maternity department 16 time schedule of biomonitoring Recruitment of mothers in Belgium: 1/1/-31/12/2003 Recruitment of mothers in Slovakia 1/12/2001 – 31/12/2003 Recruitment of mothers in Romania 1/12/2001 – 31/12/2003 Follow-up of children at the age of 18 months 17 consent procedures Mothers: written informed consent 18 how is participation encouraged? Results of individual measurements and of the entire study are offered to the mothers and also a small present.

Belgium 07 Data collection 19 biomarkers of exposure maternal environmental exposure to selected xenobiotics (chemical pollutants) and heavy metals by analysis of placental tissue and serum from mothers -lead and cadmium concentrations -organochlorine insecticides -polychlorinated biphenyls 20 biomarkers of effect - oxidative enzyme status of the placenta and erythrocyte lysate from cord and maternal peripheral blood - Th1/Th2 cytokine response of mononuclear cells (MNC) from maternal peripheral blood and cord blood to food and inhalant allergens - Th1 and Th2 cytokine responses of placental trophoblast cells 21 biomarkers of susceptibility evaluation of atopic status

Other data

22 environmental sampling Questionnaires on contaminant intake via food. (mothers-newborns and children) Outdoor pollution: air quality data will be analysed

23 lifestyle data Preparation of the questionnaire form No.1 (prenatal exposure, placental and newborn parameters). Questions will be designed to elicit biographical data, pregnancy health markers for the mother and child, external placental parameters, newborn weight and length, some socio-economic markers, household characteristics, environmental exposures (e.g. smoking status of the family, housing conditions, heating, pets), and allergy status of immediate family members. Preparation of the questionnaire form No.2 (postnatal risk factors) at 18 months. 24 health data Mother: Questionnaire 1 Child: Questionnaire 2 + Clinical examination will be performed 25 parental exposure Questionnaire 1

26 medication Questionnaire 1

27 socio-economic factors Questionnaire 1

Belgium 07

Analysis and quality control procedures 28 intra/interlaboratory testing Standardization of methods between the 3 partners: collection, identification, transport, storage and preparation of the samples 29 external laboratory control All procedures are reported. 30 accuracy, limit of detection/quantification, reproducibility 31 data analysis (statistics, power The final data set will be used for analyses calculations) which will involve descriptive epidemiologic and analytic epidemiologic studies. With childhood AD as the bivariate outcome, univariate analyses will be performed using Epi-Info to establish crude odds ratios for the evaluated risk factors (including in utero exposures and early childhood exposures). Multivariate logistic regression will be performed using SAS to model the outcome against several important risk factors and determine adjusted odds ratios.

32 representativity

Data protection and availability 33 privacy legislation Ethical approval of the project in the different countries. FWA approval. 34 intellectual property rights No patents. Data will be published in peer review journals. 35 banking of biological samples Samples will be stored for analyses in the future if new funding becomes available.

Communication (individual level, group level, level (sub)population )

36 reporting results to public authority, to Each year the EU authorities are informed on general public, to participant the progress/problems of the study. The participant will be given individual results as far as they are interpretable, as well as group results. Results of the studies will be communicated to the scientific community preferentially by publication in peer reviewed. 37 professionals involved , contacts between professionals and participants 38 role of media No media attention.

39 public debate Occasional symposia are organised which may include debates between different stakeholders.

Belgium 07 40 consequences of external No communication program. communication

41 Problems

Collection of blood samples (especially children) is a significant disincentive to participation. The logistic preparation before recruitment can start is time consuming. Transport of biological samples between countries is very expensive and difficult.

42 Experiences

Maternity: Collaboration of gynecologists is required. Enthusiastic gynecologists and nurses are indispensable.

Croatia

Croatia 01 N° General data 1 type Regional biomonitoring study + survey (children and adolescents) 2 country Croatia 3 title Project “Calcium Metabolism and Osteoporosis” (1996-2002) 4 aim 1. To determine a bone mass with ultrasound technique in healthy Croatian children and adolescents and to show their anthropometric characteristics and nutritional habits. 2. To analyse the relationships of puberty phase, anthropometric parameters, nutrition and, physical activity with ultrasound bone parameters.

5 beginning date 1997 6 ending date 2000 7 contact person Selma Cvijeti ć M. D., Ph. D., Research Associate Unit for Osteoporosis Institute for Medical Research & Occupational Health P. O. Box 291, HR-10001 Zagreb Croatia [email protected] Phone +385 1 2347 884 8 initiator Croatian Ministry of Science and Technology 9 involved/responsible organisations Institute for Medical Research & Occupational Health, Zagreb, Croatia; Faculty of Food Technology and Biotechnology, Zagreb, Croatia 10 budget available ca 10,000 per year (without personnel costs) 11 who is financing Croatian government: Ministry of Science and Technology

Description of the population 12 total number of children In total 503

13 age groups and number of - 244 children 7-10 yrs old (pre puberty) persons in each group - 259 children 15-18 yrs old (post puberty) 14 inclusion criteria, exclusion criteria Exclusion criteria: children or adolescents suffering from chronic diseases or taking medication on a regular basis 15 sampling strategy Participants were recruited from the local primary and high schools. 16 time schedule of biomonitoring Recruitment, data collection and measurements were performed between 1997 and 2000. 17 consent procedures Parents were informed about the projects from the school physician and their consents were obtained 18 how is participation encouraged? Results of individual measurements are available to participants. Data collection 19 biomarkers of exposure /

Croatia 01 20 biomarkers of effect bone mass, anthropometric characteristics 21 biomarkers of susceptibility / Other data 22 environmental data 23 lifestyle data Dietary data were assessed with specially designed semiquantitative food frequency questionnaire (FFQ). Physical activity during the last year was assessed by questionnaire. 24 health data Medical history was obtained from the school physician. 25 parental exposure 26 medication 27 socio-economic factors Analysis and quality control procedures 28 intra/interlaboratory testing 29 external laboratory control 30 accuracy, limit of The instrumental quality control was performed daily by detection/quantification, scanning the manufacturer-provided, temperature- reproducibility sensitive phantom. To examine short-term precision in vivo, 10 pre-pubertal and 10 post-pubertal had two repositioned measurements. The coefficient of variation percent (CV%) was calculated. 31 data analysis (statistics, The significance of differences was evaluated by two- power calculations) sided t-test. The association between variables was analysed by multiple regression. 32 representativity Data protection and availability 33 privacy legislation 34 intellectual property rights 35 banking of biological samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to public Journal of Clinical Epidemiology 2003;56:591-7. authority, to general public, to participant 37 professionals involved, contacts experienced researchers in human bone metabolism between professionals and school physician participants 38 role of media TV, radio, popular paper articles 39 public debate 40 consequences of external communication

41 Problems (Data could be provided later on upon request)

42 Experiences (Data could be provided later on upon request)

Croatia 02 N° General data 1 type Research studies - Regional biomonitoring study + survey Included cohort of mothers (parturients)-newborn using placentas as an indicator tissue of environmental exposure to selected toxicants - Joined animal studies in vivo using experimental model of suckling rats

2 country Croatia 3 title Projects “Metals: Exposure, Effects, and Antidotes” (1996-1999) “Exposure, Intake and Effects of Toxic and Essential Elements” (in progress)

Workpackage directly related to maternal-foetal-newborn environmental biomonitoring: Metal concentrations and steroid hormone disruption in human placentas in capital city Zagreb (PLACENTAL STUDY) 4 aim Main objective: assessment of factors influencing toxic metal concentrations in the body at an early age. A) Regional biomonitoring studies 1) Assessment of steroid hormone disruption in placenta as a ‘dual’ indicator tissue for monitoring both foetal and maternal environment: - in relation to concentrations of toxic metals (lead, cadmium, mercury) in placental tissue; - in relation to concentrations of essential trace elements (iron, zinc, copper) in placental tissue 2) Biomonitoring of metals in the environment with special emphasis on food metal intake evaluation.

B) Accompanying experimental studies on young animal model (suckling and weaned rats) to assess: - Impact of dietary components (calcium, selenium, and vitamin C) on body retention of toxic metals (lead, cadmium, mercury); - Efficiency of chelation therapy by usage of single or combined compounds (*), during ongoing exposure to the toxic metal (eg. lead), and in combination with dietary supplements, as a contribution to the treatment of metal poisoning in children (*meso-2,3-dimercaptosuccinic acid, DMSA; sodium-(RS)-2,3- dimercapto-1-propanesulfonate, DMPS; calcium-threesodium- diethylenetriaminepentaacetate, DTPA);

- Potential side effects on growth, general health, and tissue essential element concentrations during treatments with chelating agent(s); - Effects of calcium supplementation and other dietary components (eg. sodium, potassium) during suckling period on bone mineral contents; assessment of calcium

Croatia 02 supplementation as a preventive measure of osteoporosis development. _____ NOTE: Further data (No. 5-42) refers to the PLACENTAL STUDY only. 5 beginning date June 2002 - in progress 6 ending date 1996-1999 7 contact person For investigation of metals in human placentas: Martina Piasek, M. D., Ph. D., Scientific Adviser Mineral Metabolism Unit, Deputy Head Institute for Medical Research & Occupational Health P. O. Box 291, HR-10001 Zagreb Republic of Croatia [email protected] Phone +385 1 4673 188

Project Principal Investigator: Maja Blanuša, Ph. D., Chemist, Scientific Adviser Mineral Metabolism Unit, Head Institute for Medical Research & Occupational Health P. O. Box 291, HR-10001 Zagreb Republic of Croatia [email protected] Phone +385 1 4673 188

8 initiator Croatian Ministry of Science and Technology 9 involved/responsible Institute for Medical Research & Occupational Health, Zagreb, organisations Croatia (Mineral Metabolism Unit); Maternity Clinic of Medical School in Zagreb 10 budget available ca. 25,000 annually (without personnel costs - paid separately; more details could be obtained by request) 11 who is financing Croatian government: Ministry of Science and Technology

Description of the population 12 total number of children Children are not recruited in the studies.

13 age groups and number of Cohort recruited so far: in total 264 mothers-newborn. persons in each group Parturients, 28 (19-40) yrs old (average parity of mothers = 2) Preliminary study: 30 nonsmokers + 26 smokers Study in progress: 109 nonsmokers + 99 smokers

14 inclusion criteria, exclusion Inclusion criteria: criteria - Informed consent obtained from each participant. - Data from healthy parturients (without any major health disorder) and with normal pregnancies and deliveries at term whose placentas were collected at the maternity hospital and included in the study. - Criteria for inclusion in sub-groups based upon smoking habit: “Nonsmokers”: women who never smoked, did not smoke during

Croatia 02 pregnancy and former smokers who stopped smoking more than twelve months before the onset of the last pregnancy. “Smokers”: women who smoked during pregnancy and former smokers who stopped smoking less than twelve months before the onset of the last pregnancy.

15 sampling strategy Mothers-newborn recruitment: after giving birth in Zagreb Maternity Clinic, following inclusion criteria, the parturients were interviewed after delivery by a physican, and data were recorded in a pre-designed questionnaire format. Data from the medical history files were also looked.

Sampling of the placentas: provided following strictly required standard procedures of biological sampling for metal analysis avoiding external metal contamination. Immediately after delivery the entire placenta was weighed and placed in a plastic bag, marked with the subject's identification code, and placed on ice in a portable refrigerator for transport to the freezer in the analytical laboratory. Placentas were kept at -20°C until analysed. For metal and steroid hormone analyses, three representative samples are taken from each partially thawed placenta, excluding the chorionic plate and decidua basalis; from the centre, avoiding the umbilical cord insertion and from the place between the central region and the periphery within 3 cm of the outer placental margin (see also in Reprod Toxicol 2001;15:673-81).

16 time schedule of Mothers-newborn were recruited during 1996, data were collected biomonitoring by questionnaire at site and, where necessary, additional information added later on. Placental samples were collected at site (immediately after giving birth) and analyses done later on. Metal analyses and steroid hormone analyses in the placental tissue samples are in progress. 17 consent procedures Informed consent of examined mothers (parturinets) have been obtained at site in the maternity hospital before inclusion in the study.

18 how is participation Initially, by detailed explanation of the aim of the study to the encouraged? participants in hospital ward including information that results of individual measurements will be available to participating subjects. Data collection 19 biomarkers of exposure Concentrations of toxic metals (lead, cadmium, mercury, arsenic) in placental tissue. 20 biomarkers of effect 1. Concentrations of essential trace elements (iron, zinc, copper, selenium) in placental tissue. 2. Concentrations of steroid hormone (primarily progesterone) in placental tissue. 21 biomarkers of susceptibility / Other data - By questionnaire and medical records from parturients

Croatia 02 - By assessment of metals in food and selected samples in the environment and wildlife 22 environmental data Questionnaire: Data on in-door and out-door sources of metal exposure: - Professional history––education, position, present employment; - Potential sources of recent environmental exposure: place of residence, relocation in the last 24 months, vicinity of factory, smelter, highway, street, road, large cross-road, or bus terminal with heavy traffic; - Assessment of metal food intake in Croatian population; Monitoring and/or assessment of the ratio of heavy metals in soil, plants (mushrooms), water, and wild life (isopodes, ground beetles, big game, sea turtles); 23 lifestyle data Detailed data on specific dietary habits (common and during pregnancy) to assess food metal intake. Dietary history: self- identification of the predominate diet type (mixed, vegetarian, vegetarian plus eggs, vegetarian plus eggs plus diary products, alcohol consumption); Detailed data on smoking habit (both active present and previous smoking data, ETS at home and at work). Smoking habit: self-classification as active smoker, former smoker, or nonsmoker. Active smoking: data on number of cigarettes, smoking during pregnancy; former smoking: data on exact time when stopped smoking in relation to last pregnancy. Passive smoking: data on active smokers in the family and at the workplace, average duration of exposure to passive smoking. 24 health data General personal data,age. Maternal general health status; general health status, reproductive health and data on the last pregnancy and delivery (parity, previous abortions or miscarriages, twins); data on the newborn (sex, weight and length at birth, health status including APGAR score at birth) 25 parental exposure Maternal exposure data during pregnancy serves also an indicator of foetal/newborn exposure (see also 22-24) 26 medication Records on vitamin, mineral and drug intake during pregnancy. 27 socio-economic factors Education level Analysis and quality control procedures 28 intra/interlaboratory testing Recommendations on quality assurance and standard procedures in tissue collection, sample preparation, and analytical techniques for metal analysis in human placentas are followed. Involved/responsible (our) Mineral Metabilism Unit laboratory regularly participates in inter/intra-laboratory testing within Croatia for toxic and essential metals and metalloids in surface and ground water. 29 external laboratory control Involved/responsible laboratory (in Mineral Metabilism Unit) also regularly participate in quality control programmes for metal and metalloid analyses in food and waters co-ordinated by the international institutions/agencies: IFA –Tulln, Austria; WHO/UNEP; IAEA, Wienna, Austria; National Food Administration

Croatia 02 (Sweeden) 30 accuracy, limit of Data for all these parameters in metal and metalloid analyses are detection/quantification, as expected in quantitative flame and electrothermal atomic reproducibility absorption spectrometry with deuterium correction. To assay steroid hormone progesterone so far, a specific radioimmunoassay (RIA Coat-A-Count® kit TKP25, Diagnostic Products Corp., Los Angeles, CA, USA) was used. Hormone standards were assayed in the media preparations using the method of standard additions. No deviation from linearity was found over the range of the standard curve for the hormone. The values determined by this procedure fell within the range reported in the literature for progesterone in term human placentas (Detailed data on analyses are available upon request). 31 data analysis (statistics, All statistical analyses are performed following preplanned power calculations) hypotheses. Both one-way and two-way analysis of variance (ANOVA by PROC GLM) is regularly used (using Statistical Analysis System or Statistica for Windows Programmes, latest versions available). When necessary numerical data are analysed after previuos logarithmical transformation to reduce heterogeneity of variance. Level of significance (P < 0.05) is tested using least-square means to determine the main effect of exposure source as a first independent variable (eg. smoking habit) and main effect of placental sample site location as a second independent variable. Correlations (PROC CORR) are also determined between biomarkers of exposure and biomarkes of effects.

Croatia 03 N° General data 1 type A.national; B.(a and b) international research studies 2 country Croatia 3 title Institute for Medical Research and Occupational Health, Zagreb 4 aim To investigate levels and distribution of persistent organic pollutants (POPs) in human milk and evaluate daily intakes by breast-fed children. To evaluate connection between children's diseases and levels in milk 5 beginning date A.1977; B.a.1978; B.b. 1987 6 ending date A.ongoing, ending date not defined; B.a.1982; B.b. Third round ended 2001 continuation not defined 7 contact person Dr. Blanka Krauthacker 8 initiator A. Institute for Medical Research and Occupational Health; B. WHO 9 involved/responsible organisations Institute for Medical Research and Occupational Health, Zagreb, Croatia; WHO; US EPA (1977- 1995) 10 budget available A. 3000 Euro B. Sampling covered by Institute. PCDD/PCDF analyses covered by WHO 11 who is financing A. Ministry of Science and Technology, Republic of Croatia; B.PCDD/PCDF analyses covered by WHO Description of the population 12 total number of mothers and children 700+700 so far 13 age groups and number of persons in each nursing mothers and children up to one year group 14 inclusion criteria, exclusion criteria A. Included: healthy mothers, general population, sampling: at least one week after delivery. Excluded: occupationally exposed mothers, mothers under medication. B. Included: healthy primiparae mothers nursing healthy baby, general population, sampling: one week to four months after delivery. 15 sampling strategy Random sampling: Mothers are recruited via maternity care or hospital and by privat contact 16 time schedule of biomonitoring A. Continuous sampling B. According to WHO schedule (app. every five years) 17 consent procedures Personal contact to every mother, written informed consent 18 how is participation encouraged? Results of individual measurements are offered to participating mothers Data collection 19 biomarkers of exposure Organochlorine pesticides, PCBs, PCDDs/PCDFs in human milk

Croatia 03 20 biomarkers of effect none 21 biomarkers of susceptibility none Other data 22 environmental data Air quality data: ambient air samples and pine needle samples 23 lifestyle data 1.Nutrition habits, smoking, occupation, number of breast-fed children (for multiparae mothers, contact with persistent organochlorine pesticides and PCBs, medication 24 health data Health status for mother and child, previous delivery and breast-feading duration 25 parental exposure Smoking during pregnancy, medication during pregnancy, use of pesticides 26 medication Medication during pregnancy and breast-feading 27 socio-economic factors Profession, employment, number of children Analysis and quality control procedures 28 intra/interlaboratory testing Intralaboratory testing (on each matrix); interlaboratory testing by participation to different proficiency testing programs 29 external laboratory control Accreditation for certain analyses 30 accuracy, limit of detection/quantification, Data presented in published papers reproducibility 31 data analysis (statistics, power Nonparametric statistics; long-term follow-up calculations) 32 representativity Depending on population. Analysis are ongoing Data protection and availability 33 privacy legislation Mothers and children are anonymus. Published data are anonymus. 34 intellectual property rights No patents 35 banking of biological samples Samples overleft after analysis are stored for further analyses. Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to Annual reports to Ministry of Science and general public, to participant Technology available on web cite; Institute report (in Croatian) published in journal annualy; articles in newspapers; individual data sent to participants 37 professionals involved, contacts between Scientists of entire programme, health care professionals and participants centre's nurses, pediatrics 38 role of media Attention was given via TV, newspapers and scientific articles 39 public debate Individual positive response was observed but in certain cases wrong interpretation of data was done and used for attraction of public attention particularly by non-governmental "green" organizations or individuals. 40 consequences of external communication 41 Problems Lack of money due to pure financing of projects and lack of qualified staff due to limitation of

Croatia 03 number of reserchers in scientific institution.

42 Experiences No problems with sample collection if mothers are informed. Pure collaboration with health centres in towns but excellent collaboration with health centres in small cities. Minorization of problems by governmental bodies (ministries for environmental protection, health, science and technology.

Croatia 04 N° General Data 1 type Regional ; Research study 2 country Croatia 3 title Inst.Med.Res.Occup.Health 4 aim To compare nicotine concentrations in children's hair with the reported smoking status within the households where children live 5 beginning date / 6 ending date March 2001 7 contact person Dr.sc. Ljiljana Skender Inst.Med.Res.Occup.Health Ksaverska c.2 10000 Zagreb Croatia [email protected] +385 1 4673188 8 initiator Inst.Med.Res.Occup.Health 9 involved/responsible / organisations 10 budget available / 11 who is financing Ministry of Science and Technology of the Republic of Croatia Description of the population 12 total number of children (and 33 parents) 13 age groups and number of 22 girls and 11 boys, aged 5-7 years persons in each group 14 inclusion criteria, exclusion Inclusion criteria were written informed consent of parents criteria 15 sampling strategy Children were recruited via kindergarten 16 time schedule of Once in March 2001 biomonitoring 17 consent procedures Written informed consent of parents 18 how is participation / encouraged? Data collection

19 biomarkers of exposure Nicotine in hair by gas chromatography/mass spectrometry (GC/MS) 20 biomarkers of effect / 21 biomarkers of susceptibility / Other data

22 environmental sampling / 23 lifestyle data Parents were asked to answer questions about the smoking habits, structure of the family, household

Croatia 04 crowding, education, socio-economic status 24 health data / 25 parental exposure / 26 medication / 27 socio-economic factors Structure of the family, educational level of parents, home- owning

Analysis and quality control procedures

28 intra/interlaboratory testing A tress of hair of about 5 mm in diameter was cut near the root from the rear of the scalp. Nicotine determination included alkaline dissolution of hair, ether extraction, evaporation and GC/MS analysis 29 external laboratory control /

30 accuracy, limit of Detection limit was 0.1 ng/mg hair, relative standard detection/quantification, deviations were 3.5-13.5% depending on nicotine reproducibility concentration

31 data analysis (statistics, t-test power calculations)

32 representativity Smoking and nonsmoking parents could be differentiated through analysis of nicotine in their children's hair

Data protection and availability

33 privacy legislation /

34 intellectual property rights /

35 banking of biological samples There was no hair for storage

Communication (individual level, group level, level (sub)population )

36 reporting results to public The written finding of nicotine concentration in the child's authority, to general public, to hair was given to the parents participant

37 professionals involved , / contacts between professionals and participants

38 role of media /

Croatia 04 39 public debate /

40 consequences of external / communication

41 Problems

42 Experiences

The difference in hair nicotine concentrations between children who lived with smokers (range 1.29 to 7.89 ng/mg hair) and those who did not live with smokers (range 0.27 to 4.42 ng/mg hair) was highly significant (t=5.456001; P<0.01

Czech Republic

Short summary to the questionnaires:

Two questionnaires were completed. Activities can be divided into two categories : surveillance and research Surveillance: The aims the project carried out between 1994-2004 were: a/ to assess environmental exposure to lead, cadmium, mercury, PCB’s and chlorinated pesticides (child population n = 4244; breast feeding women n=4142) in areas with different level of environmental pollution, b/ to obtain long term trends and c/ to establish reference values for the Czech population groups.

Research : The molecular epidemiology methods were used to analyze the impact of air pollution in pregnancy outcome studies in the Czech Republic. Organic compounds adsorbed to air particles (PM 10) induced DNA adducts and embryotoxicity in vitro and in vivo studies. The carcinogenic polycyclic aromatic hydrocarbons (carc-PAHs) were mostly responsible for the genotoxic activity, contributing to 45-50% of all DNA adducts induced by these complex mixtures. The placental bukly DNA adducts have been studied in relation to metabolic genotypes CYP1A1, EPHX, GSTM1 and NAT2, and plasma levels of continine and vitamins A,C,E. DNA adducts were determined by 32P-postlabeling assy. DNA adducts in placentas were affected by air pollution, smoking, genotypes, vitamin C levels. Higher DNA adducts were observed in nonsmoking mothers delivering children with IUGR (intrauterine growth retardation). CYP1A1 activity (by EROD assay) was enhanced in placentas of mothers from polluted district, children with IUGR and smokers. Using multiple regression analysis, GSTM1 null and CYP1A1 Ile/Val genotypes decreased newborn birth weight in polluted district. These results indicate that carc-PAHs act on fetal development as endocrine disruptors. In the Pregnancy Outcome Project, an increased risk of IUGR was established for mothers who were exposed to carc-PAHs > 15 ng/m3 during the first month of gestation. Carc-PAHs seem to be an important source of genotoxic and embryotoxic activities of organic mixtures associated with urban air particles.

Age of children : 8 –10 years in the surveillance study. Overall budget for all activities amounted to about 1 900 000 EURO. The laboratories participated in quality assuranace programmes .

Czech Republic 01 N° General data 1 type Nationalwide biomonitoring survey. Involves (1) newborns (mothers) (2) children 8-10 y (3) adults (not included to this table) 2 country Republic 3 title Environmental Health Monitoring System in the Czech Republic - 4 aim To monitor the exposure of the population to toxic environmental chemicals by means of biomarkers of exposure and effect (cytogenetic analysis). To obtain representative data for areas with different level of environmental pollution, to obtain long-term time trends, to establish reference values for the Czech population groups. 5 beginning date 1994 6 ending date 1. Etape 2004 7 contact person prof. Dr. Milena Cerna, Nat. Inst. Publ. Health, Srobarova 48, CZ-10042 Prague, Czech Rep., mcerna@szu-cz 8 initiator Czech Ministry of Health 9 involved/responsible Regional Institutes of Public Health organisations 10 budget available approximately 3 mil. Of Czech crowns each year 11 who is financing Czech Government

Description of the population 12 total number of children 4244 children aged 8-10 and 4142 breast-feeding women from four regions each year 13 age groups and number of persons in each group 14 inclusion criteria, exclusion Written informed consent, age, living in area for at least 1 criteria year. 15 sampling strategy Mothers are recruited via the maternity dept., children via school 16 time schedule of biomonitoring Each year from March till October 17 consent procedures Written informed consent, for children written informed consent of the parents. 18 how is participation Small present are given to each participants - vitamins, encouraged? nweborn kosmetict, chocolate etc.

Data collection 19 biomarkers of exposure 1. Lead, cadmium, mercury in cord blood and placenta in the period 1994-95 and 1998. 2. PCB, chlorinated pesticides in breast milk. 3. Cd, Pb, Hg, as toxic and Cu, Zn and Se as benefit elements in blood and urine and hair of children. 20 biomarkers of effect 4. Chromosomal aberration in blood of children. 21 biomarkers of susceptibility no

Czech Republic 01 Other data 22 environmental data Questionnaires (smoking, passive smoking, medication, viral infectio), air quality data, drinking water data and general dietary exposure are obtainable from other projects of Environmental Monitoring System. 23 lifestyle data 24 health data no 25 parental exposure 26 medication see questionnaire 27 socio-economic factors no

Analysis and quality control procedures 28 intra/interlaboratory testing internal QAQC system, interlaboratory 29 external laboratory control Accredited laboratory, use of certified reference material 30 accuracy, limit of detection/quantification, reproducibility 31 data analysis (statistics, power calculations) 32 representativity

Data protection and availability 33 privacy legislation Samples and questionnaires are coded and anonymised according to the Czech legislation. Ethical advice has been taken to determine the maximum necessary volume of blood. 34 intellectual property rights data will be published upon approval of the steering commitee. 35 banking of biological samples no long term storage.

Communication (individual level, group level, level (sub)population ) 36 reporting results to public The participants will be given individual results via their authority, to general public, to general practitionists. Each year Annual Summary reports in participant Czech and English mutations are edited. Each year a national conference in organised, where the reults are presented and discussed. Information are available on web sites www.szu.cz/chzpa/sumrep.htm 37 professionals involved, contacts a steering group has been established for the entire program between professionals and participants 38 role of media Media are periodically informed. Press conferences 39 public debate 40 consequences of external communication

41 Problems

42 Experiences Organisation of the Monitoring system is based on the close cooperation with Regional Institutes of Public Health. As the system of Hygiene Service has been changed since January this year, some organisational problems were generated

Czech Republic 02 N° General data 1 type national 2 country Czech Republic 3 title Pregnancy Outcome-biomarker study 4 aim Effect of air pollution on pregnancy outcomes 1994 5 beginning date 1994 6 ending date 2002 7 contact person R. J. Sram, [email protected], IEM AS CR 8 initiator Institute of Experimental Medicine AS CR, Videnska 1083, 142 20 Prague 4 9 involved/responsible organisations 10 budget available 900 000 EUR 11 who is financing Ministry of Enviroment of the Czech Republic

Description of the population 12 total number of children 2.400 13 age groups and number of newborns persons in each group 14 inclusion criteria, exclusion case : IUGR, LBW, birth defects criteria 15 sampling strategy 1 case/2 controls 16 time schedule of biomonitoring approx. 400/year allround 17 consent procedures informed consent by mother 18 how is participation encouraged? almost all mothersdelivering in two district hospitals (Teplice, Prachatice, later Prague 2) Data collection 19 biomarkers of exposure DNA adducts in placenta, cotinine in plasma 20 biomarkers of effect vitamins A, C, E, folic ac. 21 biomarkers of susceptibility GSTM1, NAT2, EPHX, CYP1A1 MspI, Ile/Val

Other data 22 environmental data PM10, PM2.5,carc.PAHs 23 lifestyle data questionnaire 24 health data questionnaire 25 parental exposure questionnaire 26 medication questionnaire 27 socio-economic factors questionnaire

Czech Republic 02 Data protection and availability 33 privacy legislation conf. Personal data identifiable 34 intellectual property rights no 35 banking of biological samples yes, Inst.Exp. Med. AS CR

Communication (individual level, group level, level (sub)population ) 36 reporting results to public to Min. of Environment, professional societies, public in both authority, to general public, to districts participant 37 professionals involved, contacts between professionals and participants 38 role of media results discussed in newspapers 39 public debate 40 consequences of external communication

41 Problems

42 Experiences The placental bulky DNA adducts have been studied in relation to metabolic genotypes CYP1A1, EPHX, GSTM1 and NAT2, and plasma levels of cotinine and vitamins A, C, E. DNA adducts were determined by 32P-postlabeling assay. DNA adducts in placentas were affected by air pollution, smoking, genotypes, vitamin C levels. Higher DNA adducts were observed in nonsmoking mothers delivering children with IUGR (intrauterine growth retardation). CYP1A1 activity (by EROD assay) was enhanced in placentas of mothers from polluted district, children with IUGR and smokers. Using multiple regression analysis, GSTM1 null and CYP1A1 Ile/Val genotypes decreased newborn birth weight in polluted district. These results indicate that carc- PAHs act on fetal development as endocrine disruptors. In the Pregnancy Outcome Project, an increased risk of IUGR was established for mothers who were exposed to carc-PAHs > 15 ng/m3 during the first month of gestation. Carc-PAHs seem to be an important source of genotoxic and embryotoxic activitie

Denmark

Short summary to the questionnaires:

Methodology

We have found 3 exposure studies from Denmark, one cohort study and two case-controls (one of these in co-operation among DK and Finland, see study Finland 01). The total population sample in the studies varies from 197 to 411 children. The studies are conducted with two objectives: research (to study the link between exposure and health outcome) or public health (to know the distribution in the population and to identify the groups at risk). The studies run from 1994 and ended in 2002. For further details about the methodology, please see the schemes added.

Country: Denmark Comments:

Reported biomonitoring 1. Exposure of Danish children to activities traffic exhaust fumes 2. Exposure- outcome relationships of male urogenital malformations with special reference to endocrine disrupters 3. Asthma in Childhood

Total number of children 888 children, 0.16o/ o o involved/ percentage of total population

Overall budget 2.3 million euro For two studies project information has not been presented 1. To assess exposure of Aims ad. 3. COPSAC studies Danish children to NO , 2 the interaction of benzene, toluene and environment and xylenes. To determine genetics in the levels of 1-Hydroxypyrene development of asthma, and beta-naphtylamine in allergy and eczema from their urine. delivery. Likewise an 2. To study the hypothesis that investigation of the foetal exposure to widely disease, influence on distributed endocrine growth and to disrupters may contribute to investigate if virus type the aetiology of urogenital and cytokine response disorders of boys. are specific for asthma 3. To receive knowledge of

the development of asthma and find methods to predict if a child will develop asthma and allergy. .

Specific age groups 4-12 year-old 1 study

0-3 year-old 1 study

from date of delivery – 15 year-old 1 study

Type of data identifiable in all three studies in one study : data deleted after ended study (about year 2018)

Time periods (shortest, 3 years, 4 years, 20 years average, longest)

Biomarkers of exposure 1. 1-Hydroxypyrene and beta- naphthylamine measured in urine. The environmental sampling is NO2, benzene, toluene and xylenes. 2. Dioxins, furans, PCB´s, polychlorinated diphenyl ethers and heavy metals. 3. Blood, urine, hair and aspiration samples and lung function, measurement of NO consent in exhaled air. Diary of lung symptoms and use of B 2 agonist. The biomarkers of susceptibility are blood samples and ultrasound measurement of bone density.

Biomarkers of effect blood samples, lung function tests, measurement of NO content in exhaled air. Diary of lung symptoms and use of B 2 agonist.

Additional data lifestyle data etc. all three studies

Denmark 01 N° General data 1 type Exposure study in relation to case-control study of childhood cancer 2 country Denmark 3 title Exposure of Danish children to traffic exhaust fumes. 4 aim To assess exposure of Danish children to NO2, benzene, toluene, xylenes. To determine levels of 1-Hydroxypyrene + beta-naphthylamine in their urine 5 beginning date october 1994 6 ending date 1997 7 contact person O. Raaschou-Nielsen, Division for Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, DK-2100, Copenhagen Ø, Denmark. +45-35257617. Email: [email protected] 8 initiator 9 involved/responsible organisations 10 budget available 11 who is financing Danish Environmental Research Program Description of the Children living in urban and rural areas, respectively population 12 total number of children 197 children

13 age groups and number of 4-12 years, Copenhagen: 56 boys and 42 girls. Rural districts: persons in each group 49 boys and 50 girls.

14 inclusion criteria, exclusion Inclusion criteria: criteria 1. Parental consent. 2. Residential area 3. Low presence of indoor sources 15 sampling strategy random sample from the Cental Population Register 16 time schedule of The measurements of the exposed children were carried out biomonitoring in 2 weeks in October 1994, 2 weeks in April 1995, 2 weeks in May 1995, and 1 week in June 1995. 17 consent procedures Parental consent. Invited via mail and questionnaire

18 how is participation They have received questionnaires and letters encouraged? Data collection 19 biomarkers of exposure 1-Hydroxypyrene + beta-naphthylamine is measured in urine 20 biomarkers of effect 21 biomarkers of susceptibility

Other data

22 environmental sampling NO2, benzene, toluene and xylenes 23 lifestyle data

Denmark 01 24 health data 25 parental exposure 26 medication 27 socio-economic factors

Analysis and quality control procedures

28 intra/interlaboratory testing

29 external laboratory control

30 accuracy, limit of detection/quantification, reproducibility 31 data analysis (statistics, Multiple regression analysis was based on 194 observations power calculations) without missing values, and the initial model included 13 explanatory variables and four interaction terms. 32 representativity Data protection and availability 33 privacy legislation 34 intellectual property rights Ref: Raaschou O. Exposure of Danish children to traffic exhaust fumes. The Science of the Total Environment. Elsevier Science, 1996; 189/190: 51-55 35 banking of biological samples Communication (individual level, group level, level (sub)population )

36 reporting results to public authority, to general public, to participant 37 professionals involved, contacts between professionals and participants 38 role of media 39 public debate 40 consequences of external communication

41 Problems 42 Experiences

Denmark 02 N° General data 1 type Prospective Cohorte Study 2 country Denmark 3 title Copenhagen Prospective Study on Asthma in Childhood 4 aim Receive knowledge of the development of asthma and find methods to predict if a child will develop asthma and allergy. COPSAC studies the interaction of environment and genetics in the development of asthma, allergy and eczema from delivery. Likewise an investigation of the disease, influence on growth and to investigate if virus type and cytokine response are specific for asthma. 5 beginning date autumn 1998 6 ending date results 2018 7 contact person Professor, dr. med. Hans Bisgaard Consultant at Peadiatrics dept. and in the COPSAC-clinic at Gentofte Amtssygehus. Email: [email protected] 8 initiator 9 involved/responsible Project Manager Cand.scient. Malene Stage organisations Senior research associate, MD Mette Hermansen Senior research associate, MD. Frederik Buchvald

Description of the population 10 total number of children (and 411 children and their parents parents) 11 age groups and number of The children are followed from date of delivery and once a year persons in each group until they are 15 years old.

12 inclusion criteria, exclusion Inclusion criteria: children who´s mothers suffer or have criteria suffered from asthma. Exclusion criteria: Children suffering from serious congenital malformations. 13 sampling strategy questionnaires and consent-letters sent to the pregnant women 14 time schedule of biomonitoring The children are followed from delivery through early childhood concerning early indications of asthma, ezcema and allergy. Blood samples from child, mother and father. The children are examined at the clinic when they have pulmonary symptoms. The secrete of the respiratory passages is examined for virus and cytokines. The children are tested every year for allergy.

15 consent procedures parental consent 16 how is participation free clinic, and free astma treatment. encouraged? 17 budget available 18 who is financing COPSAC is externally financed through private and public funds. Sponsored by the pharmaceutical industry

Data collection

Denmark 02 19 biomarkers of exposure Blood, urin, hair and aspirationsamples and lungfunction, measurement of NO content in exhaled air. Physical examination in the clinic. 20 biomarkers of effect blood samples, lungfunction tests, measurement of NO content in exhaled air. Diary of lungsymptoms and use of B 2 agonist. 21 biomarkers of susceptibility blood samples, ultrasound measurement of bone density, genotypes Other data 22 environmental sampling Measurement of NO and Carbonyl compounds in home enviroment. 23 lifestyle data from self-reported questionnaires and interviews 24 health data blood samples, self-reported lifestyle patterns 25 parental exposure from self-reported questionnaires and interviews 26 medication from self-reported questionnaires and interviews 27 socio-economic factors from self-reported questionnaires and interviews

Analysis and quality control procedures 28 intra/interlaboratory testing Measurement of bone density, lungfunction, NO content in expiration, hematology analysis/ Genotype, Mannan binding lechtine, immun.cap, etc. 29 external laboratory control 30 accuracy, limit of detection/quantification, reproducibility 31 data analysis (statistics, power calculations) 32 representativity

Data protection and availability 33 privacy legislation data is kept in data system at Gentofte Amtssygehus. Data are deleted when the study is completed. 34 intellectual property rights

35 banking of biological samples yes

Communication (individual level, group level, level (sub)population ) 36 reporting results to public yes. No individual reports to the participants authority, to general public, to participant

37 professionals involved, MD, laboratory technician, nurses, cand.scient and medical contacts between students professionals and participants

38 role of media 39 public debate 40 consequences of external communication

Denmark 02 41 Problems

42 Experiences

Finland

Short summary to the questionnaires:

Methodology

3 exposure studies from Finland exist. One of them is a case-control study in co-operation among DK and Finland and is already referred among Danish studies. The other two studies consist of a cohort study and another case-control study. The total population sample in the 3 studies varies from 280-465 children. They are conducted with two objectives: research (to study the link between exposure and health outcome or public health (to know the distribution in the population and to identify the groups at risk). The studies run from1987- 2002. The dioxins and risk of cleft palate-study is still going on. For further details about the methodology, please see the schemes added.

Country Finland Comments Reported 1. Exposure- outcome relationships of The first mentioned is biomonitoring male urogenital malformations with a co-operating study activities special reference to endocrine among Denmark and disrupters. Finland. Also 2. Dioxins in mothers´ milk mentioned in the 3. Dioxins and risk of cleft palate in Danish scheme. humans Total number of 1065 children children involved Overall budget 3,31 million euro Aims 1. To find POPs in mother milk 2. To look at the possible connection between cleft palate and POPs. 3. To study the hypothesis that foetal exposure to widely distributed endocrine disrupters may contribute to the aetiology of urogenital disorders of boys. Specific age newborn babies (two studies) groups 0-3 years-old (one study) Type of data Anonymised but identifiable Time periods 3 years (shortest, 6 years average, longest >16 years (longest) Biomarkers of Dioxins, furans, PCBs, and polybrominated exposure diphenyl ethers, polychlorinated diphenyl ethers and heavy metals. Biomarkers of effect Additional data Health data, etc reported in all three studies

Finland 01 N° General data 1 type International 2 country Finland and Denmark 3 title Exposure- outcome relationships of male urogenital malformations with special reference to endocrine disrupters 4 aim is to study the hypothesis that fetal exposure to widely distributed endocrine disrupters may contribute to the aetiology of urogenital disorders of boys. 5 beginning date 2000 6 ending date 2002 7 contact person Niels Skakkebaek 8 initiator Niels Skakkebaek and Jorma Toppari 9 involved/responsible Rikshospitalet Köbenhavn (RHC.DGR) organisations 10 budget available 2.3 million € 11 who is financing EU

Description of the population 12 total number of children 280 13 age groups and number of 0-3 years persons in each group 14 inclusion criteria, exclusion Boys having a genital malformation and their controls criteria 15 sampling strategy 140 boys from Finland and Denmark 16 time schedule of biomonitoring 17 consent procedures Yes, by the mothers 18 how is participation by no wise encouraged? Data collection 19 biomarkers of exposure Dioxins, furans, PCBs, polychlorinated diphenyl ethers, heavy metals 20 biomarkers of effect 21 biomarkers of susceptibility

Other data 22 environmental data yes 23 lifestyle data yes 24 health data yes 25 parental exposure yes 26 medication yes 27 socio-economic factors yes

Analysis and quality control procedures 28 intra/interlaboratory testing Yes, continuous participation to interlaboratory intercalibration tests in the field of POPs 29 external laboratory control Yes, every year, we are an accreditated testing laboratory No T077

Finland 01 30 accuracy, limit of 15%, 0.05-0.5 pg/g fat, 10% detection/quantification, reproducibility 31 data analysis (statistics, power Yes calculations) 32 representativity A case control study

Data protection and availability 33 privacy legislation Identifiable, follows KTL's policy 34 intellectual property rights Follows the legislation of Finland 35 banking of biological samples Mothers' milk and boys' fat samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to public We do not yet have the results authority, to general public, to participant 37 professionals involved, contacts between professionals and participants 38 role of media 39 public debate 40 consequences of external communication

41 Problems Problems to get fat samples from the boys

42 Experiences Mothers' milk samples were uasy to get but it has been difficult to get the fat samples from the children during the surgery

Finland 02 N° General data 1 type National 2 country Finland 3 title Dioxins and risk of cleft palate in humans 4 aim We look at the possible connection between cleft palate and POPs 5 beginning date 1994 6 ending date 1999 7 contact person Terttu Vartiainen 8 initiator National Public Health Institute (KTL) 9 involved/responsible KTL organisations 10 budget available 100000 € 11 who is financing EU and The Academy of Finland

Description of the population 12 total number of children 465 13 age groups and number of New born babies persons in each group 14 inclusion criteria, exclusion Babies with cleft palate and 4 parity matched controls for criteria every child 15 sampling strategy From 6 largest hospitals in Finland 16 time schedule of biomonitoring 17 consent procedures From the mothers 18 how is participation In no wise encouraged? Data collection 19 biomarkers of exposure Dioxins, furans, PCBs, polychlorinated diphenyl ethers, heavy metals 20 biomarkers of effect 21 biomarkers of susceptibility

Other data questionnaires 22 environmental data yes 23 lifestyle data yes 24 health data yes 25 parental exposure yes 26 medication yes 27 socio-economic factors yes

Finland 02 reproducibility 31 data analysis (statistics, Yes power calculations) 32 representativity All babys from the five largest hospitals between 1990-1999 were, included if the mother was willing to take part to the study

Communication (individual level, group level, level (sub)population ) 36 reporting results to public Individual results have been sent to the mothers authority, to general public, to participant 37 professionals involved, contacts between professionals and participants 38 role of media 39 public debate 40 consequences of external communication

41 Problems No

42 Experiences Hard work, good results

Finland 03 N° General data 1 type National 2 country Finland 3 title Dioxins in mothers' milk 4 aim Follow-up od POPs in mother milk 5 beginning date 1987 6 ending date Continues 7 contact person Terttu Vartiainen 8 initiator National Public Health Institute (KTL) 9 involved/responsible KTL organisations 10 budget available 8000€ 11 who is financing KTL

Description of the population 12 total number of children 320 13 age groups and number New born babies of persons in each group 14 inclusion criteria, Healthy, no twins exclusion criteria 15 sampling strategy WHO's strategy 16 time schedule of biomonitoring 17 consent procedures There are written consents from mothers 18 how is participation In no wise encouraged? Data collection 19 biomarkers of exposure Dioxins, furans, PCBs, polybrominated diphenyl ethers, heavy metals 20 biomarkers of effect 21 biomarkers of susceptibility

Other data questionnaires 22 environmental data yes 23 lifestyle data yes 24 health data yes 25 parental exposure yes 26 medication yes 27 socio-economic factors yes

Analysis and quality control procedures 28 intra/interlaboratory Yes, continuous participation to interlaboratory intercalibration testing tests in the field of POPs 29 external laboratory Yes, every year, we are an accreditated testing laboratory No control T077 30 accuracy, limit of 15%, 0.05-0.5 pg/g fat, 10% detection/quantification,

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Finland 03 reproducibility 31 data analysis (statistics, No power calculations) 32 representativity Random samples Data protection and availability 33 privacy legislation Identifiable, follows KTL's policy 34 intellectual property Follows the legislation of Finland rights 35 banking of biological Human milk samples samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to Individual results have been sent to the mothers, average public authority, to results have been published in international journals general public, to participant 37 professionals involved, contacts between professionals and participants 38 role of media Results have been published in news papers 39 public debate Yes 40 consequences of Nothing external communication

41 Problems No problems

42 Experiences We have had no problems with the mothers or in receiving the milk samples

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France

Short summary to the questionnaires

Biomonitoring in France

Though environmental health becomes more and more a matter of concern, biomonitoring is not yet well developed and organized. Biomonitoring will however be included in the public health policy strategy that is being defined and implemented.

Many children studies have recently been conducted or are now being conducted on environmental exposures and/or their health impact: more than 60 (see – not exhaustive – table of French studies). Among these studies, more than 35 have used biomarkers, but very few of them really concern biomonitoring.

Most of these studies are shared between two institutions, although involving more than 30 different teams: the InVS (National Institute of Public health Surveillance and its regional units (CIRE); www.invs.sante.fr) and Inserm (National Institute of Health and Medical Research; www.inserm.fr). Some universities and hospitals are also involved.

1/ Methodology

We have found 16 exposure studies, 6 cohorts and 6 case-control studies, 3 transversal surveys and one surveillance programme. Each of them includes from about 100 to 9000 children. They are conducted with two objectives: research (to study the link between exposure and health outcome) or public health (to know the distribution in the population, to follow trends and to identify the groups at risk). The methodology is very different from one study to another (see details about different key studies in annex).

Biomonitoring at the national scale was implemented with a view of surveillance in 4 studies: 2 on respiratory diseases and allergy (ISAAC, EGEA; Inserm), one lead exposure study, and one study on dioxins exposure via breast milk (InVS). The sample strategy was randomly conducted, but not from the census data. ISAAC was conducted in schools, EGEA in hospitals; the lead study was conducted in hospitals (infant surgery services for trauma) and the dioxin study in all lactariums (where mothers give their breast milk). Some were stratified by region.

A childhood lead poisoning surveillance system was set up at the national level in 1995 and modified in 2003. It is based on three sources of information: (i) Transversal surveys on blood lead level in the general population repeated every few years (ii) A monitoring system based on records of blood lead levels obtained by the laboratory’s, including evaluation of efficiency of prevention and screening programs (iii) mandatory reporting for each child (< 18 yrs) detected with a lead blood level over 100µg/l, in order to detect situations demanding intervention (declaration to do at the regional units of the ministry of Health and then centralised at InVS for epidemiologic purposes).

Biomonitoring at the regional scale: in French Guyana, InVS and the local CIRE have been conducting biomonitoring studies of methyl mercury exposure for about 10 yrs. The sample strategy has been randomly conducted from census data and stratified by territorial zones. In

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Brittany, a longitudinal study called PELAGIE is addressing endocrine disrupters. The recruitment is via gynaecologists or echographists

Several local studies exist on lead exposure. Also a cohort called EDEN (0-5yrs) has been implemented in two towns (Poitiers and Nancy) to identify factors (environmental ones also) associated to child’s development, with a particular attention for allergic and respiratory diseases.

2/ Biomarkers used / Health effects

Many studies address the four health priorities defined by EU. Among the studies reported 8 concern respiratory diseases, asthma and allergies, 19 psychomotor development, 3 cancers and leukaemias, and 2 congenital malformations and endocrine disrupting effects. The environmental factors studied are: lead (about 15 studies), indoor air and other housing factors (9), outdoor (urban) air pollution (5), passive smoking (8), pesticides (5), pets (5), radioactive substances and ionizing radiations (2), also mercury, benzene, dioxins and other endocrine disrupters (such as glycol ethers).

Respiratory diseases and allergies

For allergic and respiratory diseases, several biomarkers of effect (total and specific immunoglobulin E, etc) and clinical exams or tests (lung function and skin prick tests to common allergen) have been used, but few biomarkers of exposure. Recently, biomarkers of inflammation (exhaled NO and breath condensate) have been implemented. Biomarkers of exposure are basically biomarkers of passive and active (in teenagers) smoking. Furthermore, although genotypes of asthma and allergy have been identified, gene- environment interaction has been scarcely studied in the case of allergic and respiratory diseases. Such studies are necessary.

Neurological disorders

All the studies address biomarkers of exposure, except one that explores effect markers related to lead. Many studies have been conducted on lead in blood studies, on methyl mercury exposure are based on hair mercury. Recently, levels of PCBs (in serum), already studied in breast milk in the past, are studied in a cohort of newborns in Brittany. Cadmium, which is better known as a nephrotoxic compound than as a neurotoxic compound was also studied in urine of children during pollution investigations.

Cancer

Except DNA, no biomarker is commonly used in studies related to cancer. A national plan on cancer is now set up in France and reflection is been developed on cancer biomarkers (cf. NACRE network). Some carcinogenic pollutants have been explored, but are not widely used in biomonitoring: arsenic (inorganic As with MMA and DMA metabolites in urine), some pesticides (organochloride), dioxins, benzene (muconic acid, hydroquinone in urine). PAH are not yet easily measured, and there is the problem of enzymatic induction in the cancer pathology. Some biomarkers of genetic susceptibility have been explored.

Endocrine disrupting effects are not yet widely studied. PCBs, dioxin-like compounds, glycol ethers, some pesticides (organochlorides, organophosphorus) are measured.

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Other biomarkers of susceptibility studied are metabolized genes (CYP, GST), growth factors (TGF, etc) related to oral clefts.

3/ The studied population

Newborns: a perinatal study on about 30 000 births has been implemented every two years. This study is based on a questionnaire but a blood sample might be taken in a sub-sample of the population.

Neonatal life and infancy: recruitment via PMI (Maternal and Child protection) was often used for lead exposure screening in target population, but not for biomonitoring in general population.

Childhood: Children are contacted via physicians or via school. Recruitment via schools has been chosen in two studies (ISAAC, and pesticides study). Lead biomonitoring has been done from birth to 6 yrs, but usually from 1 to 6 yrs.

Adolescence: children are also contacted via physicians or via school.

See French studies detailed in the following annex

Country: Among the 35 studies with biomarkers: Comments FRANCE

Reported - 4 national scale biomonitoring - lead, dioxins, respir. diseases, biomonitoring allergies activities - 2 regional biomonitoring - methylmercury, endocrine - local studies, cohort studies disrupters

- lead, various environmental factors

Total* number of From 100 to 9000: In France about 760 000 births children involved/ each year percentage of - lead : 3445 (1-6 yrs) total population Children 0-5 yrs: 4,5 millions - respir. diseases: 2000 + 9000 + (2 x 3000) (7-16 yrs) (9-11 yrs) (0-5 yrs) children 1-6 yrs: 4,4 millions

- Dioxins : 244 children 9-11 yrs: 1,5 million

children 7-16 yrs: 7,5 millions

Overall budget* 200 000 (lead), 400 000 (dioxins) euros These 2 extreme numbers concern at the national scale, studies with only one pollutant. Other studies involving many 2 000 000 E (endocrine disrupters, biomarkers could be much more Britanny) expensive (cf. PELAGIE, EDEN).

The cost depends a lot of the sampling strategy, the biomarkers

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Country: Among the 35 studies with biomarkers: Comments FRANCE

Average : difficult to establish measured and the size of the population.

Aims - to assess lead exposure of the - public health: to know the population distribution of exposure or disease in the population, to follow trends - to assess the dioxins exposure in and to identify the groups at risk. France - research: to study the link - to assess mercury exposure in Fr. between environmental exposure Guiana and diseases (such as respiratory diseases and allergies) - to assess genetic and environmental factors of asthma and related traits - to determine health effects of indoor environment in childhood

- to identify factors associated to child’s development with a particular attention for allergic and respiratory diseases

- to study the impact of several environmental pollutions on pregnancy and postnatal development outcomes

- to search for the role of in utero exposure to tobacco smoke, alcohol, nutrients, maternal occupational exposure in the risk of oral clefs in their child

Specific age At birth, 0-5 yrs, 1-6 yrs, 7-16 yrs, 9-11 groups yrs (see above), 0-18 yrs (MeHg)

Type of data Statistical analysis is generally done on anonymous data. Identifiable data to give back individual results to participants and to allow follow-up in cohort studies.

Time periods From some weeks (transversal study) to (shortest, average, 16 years (follow-up of lead exposure and longest) its effets); 2 cohort studies during 5 years.

On average, biomonitoring in transversal

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Country: Among the 35 studies with biomarkers: Comments FRANCE

studies at national scale: 1 year

Biomarkers of Pb (15 studies/35 with biomarkers), exposure Dioxins (2), Mercury (2, in fact 4), pesticides (5), endocrine disrupters other than pesticides (such as glycol ethers, PCBs : 1), benzene (1), exhaled NO (1)

Biomarkers of Resp. dis., asthma and allergies: 6 (in all Resp. dis.: IgE, IgA, Interferon effect studies on resp. dis.) gamma, white blood cell count,

Neurodevelopmental disorders: 2, (but Other biomarkers (susceptibility): cognitive tests are more often used) Various genetic approaches: Cancer (DNA): 2, segregation analysis, linkages analyses, genotypes of asthma or allergies

Endocrine disrupting effects: 0 (but Metabolizing genes (CYP, GST), birth outcome, neurological and growth factors (TGF, etc) neuropsycholog.

Evaluation)

Additional data - Other exposure data: indoor air and other housing factors (9), outdoor (urban) air pollution (5), passive Individual characteristics: age, sex, smoking (8), pets (5), radioactive height, weight, gestational age for substances and ionizing radiations (2), newborns, tobacco consumption, etc) - individual characteristics: systematic medication : children, mothers - socioeconomic data: systematic during pregnancy

- life style data (house characteristics): medical tests: lung function test, skin prick tests, cognitive tests, - residence (place, rural…) diagnostic questionnaire (asthma, etc), clinical physical examination, - environmental data etc, - parental exposure

- medication

- food habits

- medical tests, examination,

* As the studies reported are probably not exhaustive and some data are sometimes lacking (such as

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size sample or budget), data concerning number of children and overall budget in the table are presented for the major biomonitoring activities (national and 3 important cohort studies: PELAGIE, EDEN and Asthma study).

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France 01 N° General data 1 type National biomonitoring. The biomonitoring involves adult and pediatric asthma cases, adult and pediatric controls and relatives of the asthma cases. 2 country France 3 title EGEA : Epidemiological study on the Genetics and Environnement of Asthma, bronchial hyperresponsiveness and atopy 4 aim To assess the genetic factors, the environmental factors of asthma and related traits. Environmental factors include smoking, indoor exposure, occupational exposures assessed through questionnaires. Biological factors include total IgE, white blood cell counts. Skin prick tests to 11 allergens have been performed. A DNA bank has been constituted. 5 beginning date 1991 (first survey) 6 ending date 1995 (first survey) 7 contact person Dr Francine Kauffmann INSERM U472-IFR69 16 avenue PV Couturier 94807 Villejuif cedex, France [email protected]

8 initiator Inserm 9 involved/responsible organisations Inserm, CNG, various hospitals 10 budget available 11 who is financing public and private funding

Description of the population 12 total number of children 2047 subjets, with around 600 in the pediatric range at the first survey 13 age groups and number of persons in children from 7 to 16, adults from 16 to 70 each group 14 inclusion criteria asthmatic cases, recruited in hospitals, controls recruited through electoral rolls (adults), surgery departments Minimum size of the family

15 sampling strategy Cases recruited in hospital over several years, group matched by center, sex, age range with controls 16 time schedule of biomonitoring 1991 –1995 17 consent procedures adults : written informed consents children : consent from parents, and if age appropriate also from children follow French Huriet law

18 how is participation encouraged? Brief report of results regarding lung function and skin

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France 01 tests sent to their physician

Data collection 19 biomarkers of exposure Not directly of exposure Measures of total IgE and white blood cell count

20 biomarkers of effect detailed standardised questionnaire on asthma and allergy, lung function test with methacholine challenge, IgE, skin prick tests 21 biomarkers of susceptibility Various genetic approaches (segregation analyses, linkages analyses with genome screen and candidate genes program)

Other data 22 environmental data none 23 lifestyle data Smoking, active and passive Indoor exposures (cooking fuel, heating fuel, exposures to pets and allergens) Country living Occupational exposure Drinking habits

24 health data Detailed questionnaire on asthma and allergy, based mostly on the ECRHS questionnaire and other international tools with extension on the severity of asthma 25 parental exposure See 23 26 medication Use of treatment for asthma

27 socio-economic factors Structure of the family, educational level of parents

Analysis and quality control procedures 28 intra/interlaboratory testing Replication measures for IgE (inter and intra assay determined) 29 external laboratory control 30 accuracy, limit of detection/quantification, reproducibility

31 data analysis (statistics, power classical methods calculations) 32 representativity It is a case control design. The subjects are not representative of the general population. An analysis of the potential biases limiting the comparability between cases and controls has been published and showed a good comparability.

Data protection and availability

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France 01 33 privacy legislation Follow the recommendations of the French regulations (CNIL). All computarised data and biological samples are anonymised. 34 intellectual property rights 35 banking of biological samples Long term storage of serum, plasma and DNA and cells lines is organised. The study is recognised as "a collection" by Inserm (potential preliminary step to a recognition as a biological ressource center)

Communication (individual level, group level, level (sub)population )

36 reporting results to public authority, to More than 20 scientific papers have been published. general public, to participant A public web site has been established. A web site devoted to the subjects has recently been set up in the context of a new examination of the cohort planned from 2003 onwards 37 professionals involved, contacts between Steering committee professionals and participants 38 role of media 39 public debate 40 consequences of external communication

41 Problems Long term storage conditions for serum samples were done according to knowledge in 1991/93. Possible unsufficient attention has been given to the rapidity of freezing the sample and the delay in moving samples from –20°C to –80°C. Traceability has been insured but without modern tools (no code barrs). International guidelines would be particularly useful.

42 Experiences Delays are always longer than anticipated, in great part related that insufficient staff for structuring such projects is classically available.

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France 02 N° General data 1 type Epidemiological survey involving pregnant mothers and newborns followed-up 5 years 2 country France 3 title EDEN 4 aim To identifiy factors associated to child's development with a particular attention for allergic and respiratory diseases 5 beginning date X. 2003 (first birth) 6 ending date 5 years later 7 contact person I Annesi-Maesano 8 initiator INSERM 9 involved/responsible INSERM organisations 10 budget available Difficult to establish 11 who is financing INSERM, Ministry of Health

Description of the population 12 total number of children 3000 13 age groups and number of Mothers: any; Child: 0 year persons in each group 14 inclusion criteria, exclusion At risk pregancy were excluded criteria 15 sampling strategy Mothers attending maternity hospitals in Poitiers and Nancy (up to n=3000) 16 time schedule of Birth biomonitoring 17 consent procedures YES, written informed consent 18 how is participation 1. Results of individual measurements and of the entire study are encouraged? offered to the participants

Data collection 19 biomarkers of exposure Heavy metals in cord blood, placenta and hair. Cotinine in cord blood and hair. 20 biomarkers of effect IgE, IgA, interferon gamma in the cord blood. Analysis of milk during the first 3 weeks of life, analysis of faeces of the infant at 3 weeks, 6 months and 1 year, lung function and allergy skin test at 3 years. 21 biomarkers of susceptibility Genotypes of asthma or allergies

Other data At birth, 4 months, 8 months, 1 year, 3 years and 5 years 22 environmental data YES, questionnaire on exposure to allergens, irritants, diet 23 lifestyle data YES, questionnaire on family habits 24 health data YES, mother's health during pregnancy and child's health and development (in general) up to 5 years 25 parental exposure YES, Mother's and father's alcohol use and smoking during pregnancy, mother's medication during pregnancy, medication during delivery. Asthma or allergy in the family. Home

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France 02 environment: traffic, construction works, decoration works, heating, use of pesticides in house/garden. Stress. 26 medication During pregnancy, delivery, birth and up to 5 years of life 27 socio-economic factors YES, 1. Structure of the family, educational level of parents, home-owning, educational level of child. Evolution of these between 0 and 5 years. Analysis and quality control procedures 28 intra/interlaboratory testing YES, as usually. An inventory of quality assurance programs used in the contracting laboratories is made. Identification of critical phases will be identified (collection, identification, transport, storage and preparation of the samples, sample preparation, analytical technique, reference materials, process control, calibrations, storage of samples and reporting of analytical data) 29 external laboratory control NO 30 accuracy, limit of Data for all parameters are available on request detection/quantification, reproducibility 31 data analysis (statistics, Power calculation was made to obtain the number of newborns power calculations) being informative to examine risk factors for the development 32 representativity Recruitment efficiency is monitored. Non-responder analysis is ongoing.

Data protection and availability 33 privacy legislation YES. Samples and questionnaires are maintained by the responsible medical doctor and subsequently anonymised in order to maintain confidentiality under secure conditions in accordance with the 1995 EC Data Protection Directive and data protection legislation. Measures are taken to ensure confidentiality and security of the data. 34 intellectual property rights Not applicable 35 banking of biological YES samples

Communication (individual This has still to be decided level, group level, level (sub)population ) 36 reporting results to public YES authority, to general public, to participant 37 professionals involved, YES contacts between professionals and participants 38 role of media Not yet established 39 public debate Not yet established 40 consequences of external Not yet established communication

112

France 02

41 Problems It is too early to talk about problems

42 Experiences

113

France 03 N° General data 1 type Epidemiological survey 2 country France 3 title ISAAC-II 4 aim To determine health effects of indoor environment in childhood 5 beginning date VI.2003 6 ending date VI.2005 7 contact person Isabella Annesi-Maesano 8 initiator INSERM 9 involved/responsible INSERM organisations 10 budget available 11 who is financing INSERM, Ministry of Health,

Description of the population 12 total number of children 1200 13 age groups and number of 10 years in mean persons in each group 14 inclusion criteria, exclusion 600 asthmatics and 600 controls matched on age, sex, criteria classrooms and school 15 sampling strategy Subsample of asthmatics and subsample of controls drawn from a representative population of almost 7000 children randomly selected 16 time schedule of At 10 years of age biomonitoring 17 consent procedures written informed consent 18 how is participation Results of individual measurements and of the entire study are encouraged? offered to the participants and also a small present

Data collection 19 biomarkers of exposure Blood and urine are available 20 biomarkers of effect Skin prick tests, bronchial hyperresponsiveness (run test), lung function, exhaled NO in a subsample 21 biomarkers of susceptibility Genotypes (asthma or allergy)

Other data 22 environmental data YES, questionnaire on exposure to allergens, irritants, diet and house characteristivcs (Home environment: traffic, construction works, decoration works, heating, use of pesticides in house/garden.) but also objective assessments of allergens (HDM, cat), air pollutants (PM2.5, benzene, NO2), mould and endotoxines 23 lifestyle data YES, questionnaire on family habits 24 health data YES, child's allergic and respiratory health 25 parental exposure YES, Mother's and father's alcohol use and smoking since the pregnancy, mother's medication during pregnancy,

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France 03 medication during delivery. Asthma or allergy in the family. Stress. 26 medication Asthma or allergy medications 27 socio-economic factors YES, Structure of the family, educational level of parents, home- owning, educational level of child. Evolution of these between 0 and 5 years.

Analysis and quality control procedures 28 intra/interlaboratory testing To be decided according to the type of analysis done 29 external laboratory control 30 accuracy, limit of Data for all parameters are available on request detection/quantification, reproducibility 31 data analysis (statistics, Power calculation was made to obtain the number of individuals power calculations) allowing variations in risk factors for asthma 32 representativity Recruitment efficiency is monitored. Non-responder analysis is ongoing.

41 Problems The recruitment is difficult

115

France 03 42 Experiences

116

France 04 N° General data 1 type Case-control study on oral clefts 2 country France 3 title Gene-environment interactions in the risk of oral clefts

4 aim Search for the role of in utero exposure to tobacco smoke, alcohol, nutrients, maternal occupational exposures in the risk of oral clefts in their child. 5 beginning date 2000 6 ending date 2003 7 contact person Dr Sylvaine Cordier, INSERM U435, University of Rennes I, 35 042 Rennes Cedex. 8 initiator Inserm 9 involved/responsible organisations Inserm, public and private hospitals in the regions where the study was conducted 10 budget available 250.000 € 11 who is financing Inserm, Ministry of Environment

Description of the population 12 total number of children 236 cases, 236 controls 13 age groups and number of persons children less than one year in each group 14 inclusion criteria, exclusion criteria cases: children treated for maxillofacial surgery; controls: children at hospital for "benign" disease. Written consent of the mother 15 sampling strategy all children whose family accepted participation within the study period in one of the hospitals in Lyon, Grenoble, Clermont-Ferrand, Paris. 16 time schedule of biomonitoring during hospitalisation 17 consent procedures approval from the Committee in charge of biomedical research 18 how is participation encouraged? information by the physician

Data collection 19 biomarkers of exposure maternal exposures during pregnancy collected by questionnaire 20 biomarkers of effect classification of the type of cleft lip and/or palate and associated malformations 21 biomarkers of susceptibility metabolizing genes (CYP, GST), growth factors (TGF…) : some drops of total blood

Other data 22 environmental data no available 23 lifestyle data of the parents 24 health data of the parents 25 parental exposure see point 4

117

France 04 26 medication of the mother during pregnancy 27 socio-economic factors of the parents

Analysis and quality control procedures 28 intra/interlaboratory testing validation of genotyping depending of the type of blood sample (venous blood, blood spots) buvard isocode PCR 29 external laboratory control 30 accuracy, limit of detection/quantification, reproducibility

31 data analysis (statistics, power calculations) 32 representativity

Data protection and availability 33 privacy legislation approval from the Commission Nationale Informatique et Libertés 34 intellectual property rights 35 banking of biological samples DNA Bank at Inserm SC7

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to general public, to participant

37 professionals involved, contacts between professionals and participants

38 role of media 39 public debate 40 consequences of external communication

41 Problems The participation of medical services was difficult. Moreover, it was also difficult to find control children to participate. Different services were not allowed to participate because of the Huriet law, so an agreement of the sanitary authorities was necessary, but was obtained at the end of the study ! This law should be changed.

42 Experiences

118

France 05 N° General data 1 type Cohort study on pregnant women 2 country France 3 title Endocrine disrupters: A longitudinal study on pregnancy and child (PELAGIE) 4 aim To study the impact of several environmental pollutions on pregnancy and postnatal development outcomes 5 beginning date 2002 6 ending date 2006 7 contact person Dr S Cordier INSERM U435, University Rennes I, 35 042 Rennes Cedex, France. 8 initiator Ministry of Labor, Ministry of Health 9 involved/responsible organisations INSERM 10 budget available 2 000 000€ approximately 11 who is financing Ministry of Labor, Ministry of Health, INSERM

Description of the population 12 total number of children 5 000 (expected) 13 age groups and number of persons in newborns each group 14 inclusion criteria, exclusion criteria written consent, women living in one of the three administrative departments in the study, before 16 weeks of gestation 15 sampling strategy recruted via 60 gynecologists or echographists at the beginning of pregnancy. In britanny, participation of 60 public or private gynecologists or echographists : 20 in Ile et Vilaine, 20 in Finistère, 20 in Côtes d'Armor. Recruitment based on willingness. 16 time schedule of biomonitoring first trimester of pregnancy, delivery 17 consent procedures written consent of the mother 18 how is participation encouraged? information through media

Data collection 19 biomarkers of exposure in urine : glycol ethers, trichloroacetic acid, atrazine ; in serum : PCBs, dioxin-like compounds 20 biomarkers of effect birth outcome (duration of gestation, birth weight, congenital malformation), neurological examination, neuropsychological evaluation at 6 months of age (Prechtl). 21 biomarkers of susceptibility not defined yet

Other data

119

France 05 22 environmental data food frequency questionnaire for the mother during pregnancy, monitoring of water quality at the residence from routine surveillance. 23 lifestyle data for the mother: tobacco smoking, alcohol drinking, physical exercise 24 health data for the mother: disease during pregnancy 25 parental exposure occupational exposures 26 medication during pregnancy 27 socio-economic factors education level

Analysis and quality control procedures 28 intra/interlaboratory testing not defined yet ; 20ml of maternal urine obtained at the 1rst trimester of pregnancy and 5-15 ml of total cord blood. Measurements of dioxin-like compounds via the Calux method. 29 external laboratory control 30 accuracy, limit of detection/quantification, reproducibility 31 data analysis (statistics, power calculations) 32 representativity

Data protection and availability 33 privacy legislation all necessary authorizations have been obtained. 34 intellectual property rights 35 banking of biological samples on site

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to Regular "Bulletins" informing the physicians and general public, to participant the participants of the state of the study 37 professionals involved, contacts between professionals and participants 38 role of media support from the local radios, TV and newspapers 39 public debate 40 consequences of external communication

41 Problems The participation of gynecologists was very difficult, particularly among the private gynecologists ; generally, mothers agreed to participate. How to improve the participation of gynecologists ?

42 Experiences

120

France 06 N° General data 1 type Regional Biomonitoring study 2 country French West Indies 3 title Persistent organic pollutants in delivering women and newborns 4 aim To evaluate the organochlorine levels in maternal and umbilical cord blood plasma 5 beginning date 2003 6 ending date 2004 7 contact person Luc MULTIGNER, INSERM U435, Campus de Beaulieu, Université Rennes 1, France, Email: [email protected] 8 initiator INSERM (National Institute of Medical Research) 9 involved/responsible organisations : CHU Pointe à Pitre,Guadeloupe, FWI ; CHGI Basse Terre, Guadeloupe, FWI ; CART, Université de Liège, Belgium 10 budget available € 60.000 11 who is financing INSERM, InVS, DSDS Guadeloupe

Description of the population 12 total number of children 100 13 age groups and number of persons in newborns each group 14 inclusion criteria, exclusion criteria: mothers should be living in the area for one year minimum written informed consent ; 15 sampling strategy consecutives delivering women are recruited via the maternity department 16 time schedule of biomonitoring: mothers-newborns are sampled in the period september 2003 -december 2003 17 consent procedures written informed consent 18 how is participation encouraged? The environmental pollution by organochlorine pesticides is a problem of public notoriety in this area Data collection 19 biomarkers of exposure Organochlorinated pesticides in blood plasma 20 biomarkers of effect 21 biomarkers of susceptibility Other data 22 environmental data places of residence (past and present) 23 lifestyle data nutrition of the mother (type and frequence) 24 health data duration of pregnancy, birth weight 25 parental exposure 26 medication 27 socio-economic factors: educational level

121

France 06 Analysis and quality control procedures 28 intra/interlaboratory testing: IAEA accreditation for PCBs analysis IAEA 29 external laboratory control 30 accuracy, limit of detection/quantification, reproducibility 31 data analysis (statistics, power calculations) 32 representativity

Data protection and availability 33 privacy legislation: samples and questionnaires are maintained by the medical coordinator and subsequently anonymised in order to maintain confidentiality 34 intellectual property rights: data will be published 35 banking of biological samples: no long term storage

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to general results will be communicated to the scientific public, to participant: community by publication in peer reviewed journals 37 professionals involved, contacts between professionals and participants

38 role of media : media attention will be important since the environmental pollution by organochlorine pesticides is a problem of public notoriety in this area 39 public debate 40 consequences of external communication

41 Problems

42 Experiences

122

France 07 N° General data 1 type National scale study 2 country France 3 title Dioxins and Furans in breast milk in France 4 aim 1/ to assess the exposure to dioxins in France via the concentration of dioxins in breast milk 2/ to "compare" this exposure within the Europen Union 3/ to identify the factors influencing the different levels in the population 4/ to give a reference basis for surveillance of the exposure to dioxins 5 beginning date 1998 6 ending date 1999 7 contact person Nadine Fréry, National Institute of Public Health Surveillance, Environmental Health Department, 12 rue du Val d'Osne, 94415 Saint Maurice, cedex, France. [email protected] - 00 331 41 79 67 58 ; 8 initiator Ministry of Health and Minsitry of Environment 9 involved/responsible National Institute of Public Health Surveillance (InVS), organisations Environmental and Energy Management Agency (ADEME), Rhônes-Alpes Center of Epidemiology and Public Health (CAREPS) 10 budget available euros 11 who is financing ADEME, InVS

Description of the population 12 total number of children 244 breastfeeding mothers

13 age groups and number mothers aged from 20 to 35 of persons in each group 14 inclusion criteria, primiparpus and healthy women, breastfeeding between the 4th exclusion criteria and 8th weeks after birth, ages less than 35, willing to participate to study 15 sampling strategy Selection of women in 18 French lactariums where they give their breast milk : about 30 mothers located in each of the 8 territorial zones 16 time schedule of see 4. biomonitoring 17 consent procedures written informed consent of parents 18 how is participation global results are given to each family ; seminar owith the whole encouraged? lactariums ; no financial compensation nor gifts ; less than 10 percent refused to be part of the study

Data collection

123

France 07 19 biomarkers of exposure individual breast milk : 350 ml for the quantification of the 17 PCDD/F 20 biomarkers of effect 21 biomarkers of susceptibility

Other data 22 environmental data place of residence (during the last 10 years (urban/rural, size of the population, proximity to different industries likely to release dioxins) 23 lifestyle data food habits : a semi-quantitative questionnaire (frequency and portion of food originated from animals), individual characteristics (age, height, weight, tobacco consumption,…) 24 health data birth weight, height, gestatiopnal age of the newborn 25 parental exposure occupational exposure 26 medication no 27 socio-economic factors educational level, professional occupation of parents

Analysis and quality control procedures 28 intra/interlaboratory HPGC/HRMS (cf. WHO method) ; vcomparison with the RIVM's testing laboratory (good quality of our French laboratory's data) 29 external laboratory control 30 accuracy, limit of Data for all parameters are available on request detection/quantification, reproducibility 31 data analysis (statistics, Power calculations were made according to available published power calculations) data. Non parametric multiple regression models (Generalized Additive Models, S-plus software) 32 representativity Not really representative of all the French mothers : mothers in the study are from higher socioeconomic classes, more often living in rural zones, but with similar food consumption as in national statistics

Data protection and availability 33 privacy legislation Samples and questionnaires have been maintained by the principal investigator and anonymised in order to maintain confidentiality under secure conditions. Measures have been taken to ensure confidentiality and security of the data. Authorizations of French ethics committees (CNIL) have been obtained. 34 intellectual property rights no patents 35 banking of biological no samples

Communication (individual level, group level, level (sub)population )

124

France 07 36 reporting results to public Global results have been communicated to each participating authority, to general family (8 pages) and a national report has been published and is public, to participant available on internet (InVS and ADEME web sites). A national seminar was held for the lactariums and a public press conference also. 37 professionals involved, Epidemiologists, lactariums directly in contact with families contacts between (medical doctors, nurses,...) , lab personnel, professionals and participants 38 role of media public press conference to give back the results to the population 39 public debate yes, at the press conference 40 consequences of external Mothers ask lots of questions about breastfeeding and the risk for communication their newborn

41 Problems No real problem. It took more time that we thought to include mothers in the study on the whole territory.

42 Experiences The need of a mature milk (between 4th and 8th weeks after birth) which is much more stable according to its composition in lipids than colostrum, and the big volume of milk, led us to use lactariums rather than obstetric departments. Mothers giving their milk to lactarium could be less representative than those in ob. departments, but the study in lactariums was more feasible. It is difficult to give back individual results concerning the exposure level of dioxins when the link to health risk remains unknown. At that time, it was decided not to give back the individual results because of the impossibility to interprete them (it was notified in the informed consent). This position is difficult according to the right of access to personal data and generally, parents appreciate to have personal results.

125

France 08 N° General data 1 type National scale study 2 country France 3 title Surveillance de la population française vis-à-vis du risque saturnin Surveillance of the French population to lead exposure 4 aim to assess lead exposure of the population in France (risk factors and geographical variations) 5 beginning date 1995 6 ending date 1997 7 contact person Guy Huel, Inserm, U 492, 16 avenue Paul-Vaillant Couturier, 94807 Villejuif cedex, France. [email protected] ; 00331 45 59 50 72 Nadine Fréry, National Institute of Public Health Surveillance, Environmental Health Department, 12 rue du Val d'Osne, 94415 Saint Maurice, cedex, France. [email protected] - 00 331 41 79 67 58 8 initiator Ministry of Health 9 involved/responsible National Institute of Public Health Surveillance (InVS), organisations National Institute of Health and Medical Research (Inserm) 10 budget available euros 11 who is financing InVS (at that time called Réseau National de Santé Publique)

Description of the population 12 total number of children 3445 chidren and 4208 young men 13 age groups and number of Children aged from 1 to 6, men aged from 18 to 26. persons in each group 14 inclusion criteria, exclusion children admitted in infant surgery services criteria 15 sampling strategy transversal study stratified by region ; 141 hospitals randomly selected in the whole territory. 16 time schedule of biomonitoring children were sampled once during 1995-1997 17 consent procedures written informed consent of parents 18 how is participation encouraged? individual results are given to each family ; no financial compensation nor gifts ;

Data collection 19 biomarkers of exposure 2 ml of total blood to quantify lead concentration 20 biomarkers of effect 21 biomarkers of susceptibility

Other data 22 environmental data place of residence, type of housing (built before or after 1948 ; paints ; house, building,...), traffic 23 lifestyle data drinking water intake, educational level of parents, professional occupation, sex of the child, ethnic origin, pica… 126

France 08 professional occupation, sex of the child, ethnic origin, pica…

24 health data 25 parental exposure occupational exposure 26 medication no 27 socio-economic factors level of education, professional occupation

Analysis and quality control procedures 28 intra/interlaboratory testing SAAE ; intra and interlaboratory control 29 external laboratory control Afssaps procedure ; EEC joint Research center at Ispra in Italy 30 accuracy, limit of Data for all parameters are available on request detection/quantification, reproducibility 31 data analysis (statistics, power Power calculations. Parametric multiple regression models calculations) (SAS software) 32 representativity This study is not based on census, but on children recruited in hospitals. Sociodemographic characteristics of these children were not particularly different from the national data.

Data protection and availability 33 privacy legislation Samples and questionnaires have been maintained by the responsible and anonymised in order to maintain confidentiality under secure conditions. Measures have been taken to ensure confidentiality and security of the data. Authorizations of French ethics committees (CNIL, CCPPRB) have been obtained. 34 intellectual property rights no patents 35 banking of biological samples no

Communication (individual level, group level, level (sub)population )

36 reporting results to public authority, to general individual results have been communicated to public, to participant each participating family and a national report and papers have been published. The results of the study have been presented in a scientific seminar and at a public press conference. 37 professionals involved, contacts between Epidemiologists, medical doctors, nurses professionals and participants directly in contact with families, lab personnel, 38 role of media 39 public debate no 40 consequences of external communication Awareness of the lead problem in France ; screening test among children ; law on housing

41 Problems Not really, nevertheless heavy study. It took time to include children in the study on the whole territory.

127

France 08

42 Experiences In each study when we need blood sample, the problem of participation is particularly important (more in children). Willingness and representativity via random sample are often contradictory. To collect blood for the study when blood is already obtained for an other reason is much more easier. But, it is important to avoid recrutment bias, confounding factors.

128

France 9 N° General data 1 type Regional scale study 2 country France (French Guiana : goldmining activities) 3 title Surveillance to methylmercury exposure 4 aim to assess the exposure to methylmercury of the population in French Guiana : - in the town of Sinnamary (end 2001-2002 - along the Maroni river (border with Surinam : end 2002-2003) - along the Oyapock river (border with Brazil : 2004-2005) 5 beginning date 2001 6 ending date 2005 7 contact person Nadine Fréry, National Institute of Public Health Surveillance, Environmental Health Department, 12 rue du Val d'Osne, 94415 Saint Maurice, cedex, France. [email protected] - 00 331 41 79 67 58 ; Mr Alain Blateau and Pascal Chaud, CIRE 8 initiator Ministry of Health 9 involved/responsible National Institute of Public Health Surveillance (InVS), Interregional organisations unit of epidemiology (French West Indies and Guiana ; CIRE) 10 budget available euros 11 who is financing CIRE, InVS

Description of the population 12 total number of children Sinnamary : 94 children less than 15 yrs and 191 adults Along the Maroni river : about 250 children and 550 adults Along the Oyapock river : not still determined 13 age groups and number of Children less than 15 yrs persons in each group 14 inclusion criteria, exclusion living from a minimum of 6 months in Sinnamary or along the criteria Maroni or Oyapock river 15 sampling strategy transversal study. Population randomly selected from the census data 16 time schedule of see 4. biomonitoring 17 consent procedures written informed consent of parents 18 how is participation information to media, to local authorities ; global results are given encouraged? by media, public conference ; no financial compensation nor gifts ;

Data collection 19 biomarkers of exposure Total mercury in hair (speciation in a subsample) 20 biomarkers of effect 21 biomarkers of susceptibility

Other data 22 environmental data place of residence (goldmining place) or goldmining activity

129

France 9 23 lifestyle data food habits : a semi-quantitative questionnaire (frequency and type of fish intake), individual characteristics (age, sex, type of hair and hair treatment…), ethnic origin, dental amalgams, use of cream to have a white skin 24 health data pregnancy, breastfeeding. Perception of the risk to mercury 25 parental exposure occupational exposure 26 medication no 27 socio-economic factors professional occupation of parents Analysis and quality control procedures 28 intra/interlaboratory testing SAAE and speciation (reference laboratory in Quebec) 29 external laboratory control 30 accuracy, limit of Data for all parameters are available on request detection/quantification, reproducibility 31 data analysis (statistics, power Power calculations were made according to available calculations) published data. Non parametric multiple regression models (Generalized Additive Models, S-plus software) 32 representativity a good representativity of the population

Communication (individual level, group level, level (sub)population )

36 reporting results to public authority, to Global results have been communicated in a public general public, to participant conference and a report has been published. 37 professionals involved, contacts between Epidemiologists, medical doctors, nurses directly in professionals and participants contact with families, lab personnel, 38 role of media public press conference to give back the results to the population 39 public debate yes, at the press conference 40 consequences of external Mothers ask questions about the health risk to eat such communication a fish and the type of clinical signs for their children.

41 Problems The problem was due to the accessibility to the villages (pirogues were necessary) and the difficulty to live there when there are not any hotel.

42 Experiences Hair mercury is a good indicator for the methylmercury exposure : easily available

130

France 10 N° General data 1 type Regional prospective birth cohort study + biomonitoring study 1. Children 18-months old 2. Children 6-years old

2 country France (Paris) 3 title Respiratory health, atopic status and environmental factors: follow-up of Parisian newborns from birth to the age of 6 years 4 aim 1. To assess incidence of respiratory and atopic disorders in a birth cohort population followed from birth up to the age of 6 years 2. To determine the relations between indoor and outdoor factors and respiratory health and atopic status among these children 5 beginning date february 2003 6 ending date 2012 7 contact person Prof. Isabelle MOMAS and Dr. Bénédicte CLARISSE, Environment and Public Health Laboratory, Faculty of Pharmacy, René Descartes University, 4 avenue de l’Observatoire 75270 Paris cedex 06 – France. Phone number : 33 1-53-73-97-28 Fax number : 33 1-43-25-38-76 e-mail : [email protected] 8 initiator Environment and Public Health Laboratory, Faculty of Pharmacy, René Descartes University

9 involved/responsible organisations Environment and Public Health Laboratory, Faculty of Pharmacy, René Descartes University; Paris Mayor offices, DASES -Department of Social Action, Childhood and Public Health- (Paris Hygiene Laboratory (LHVP), Research Office (SERD), St Marcel biological laboratory), French Agency of Environmental Health (AFSSE), Paris Hospitals (AP-HP) 10 budget available € 2 000 000 (approximately) 11 who is financing Paris municipality, French Agency of Environmental Health (AFSSE), René Descartes University

Description of the population 12 total number of children 3000 to 3500 children 13 age groups and number of persons 18-month old and 6-year old children: parents of each in each group child will be invited to consult a referent pneumopediatrician.

131

France 10 14 inclusion criteria, exclusion criteria Inclusion criteria are: 1. Full-term newborn 2. Birth weight between 10th and 90th percentiles 3. No intubation, no specialized reanimation 4. Apgar score = 10 at 5 minutes of life 5. No malformation nor chronic pathology involving a long-term treatment 6. No respiratory disease 7. Residence in Paris and its near suburbs 8. No plan to move in the next 2 years Exclusion criteria are: 1. Mother under 18 years 2. Multiple pregnancy 3. Known drug or alcohol abuse during pregnancy 4. Both parents unable to speak, read and write French 15 sampling strategy Infants are recruited in several Parisian maternity hospitals during childbirth hospitalization 16 time schedule of biomonitoring 1. When 18-months or 2-years old, children will be invited to a medical examination in a 2 years long period beginning in august 2003: they will be sampled and tested (skin princk) at the same time 2. When 6- years old, children will be invited to a medical examination in a 2 years period beginning in february 2009: they will be sampled and tested (lung function and skin prick) at the same time 17 consent procedures 1. Written informed consent of parents 2. Written informed consent of parents 18 how is participation encouraged? 1. Results of individual measurements and of entire study are offered to the participants, as well as greetings and birthday cards during the 6-year long follow-up period Data collection 19 biomarkers of exposure none 20 biomarkers of effect Apgar score at 1 minute of life, skin prick tests and total and specific serum IgE levels at 18 months and 6 years, lung function at 6 years, questionnaires on respiratory and atopic disorders during the first 6 years of life

21 biomarkers of susceptibility Genotypes (DNA) perhaps (not still defined)

Other data

132

France 10 22 environmental data Initial questionnaire on indoor parameters (type of dwelling, accomodation crowding, number of siblings, heating and cooking appliance, ventilation, wall and floor coverings, indoor smoking, home dampness, infant's bedding, pet ownership, coackrach), changes in these parameters all over the 6-year period follow-up; Modelled exposure index to traffic using local dispersion parameters and background air pollution ; Repeated environmental sampling in a small subset of the recruited population (150 children during their first year of life): house dust mite levels, endotoxin concentrations (air), fungal contamination (air and dust), passive samplers for nicotine, Volatile organic compounds, aldehydes, NOx, ambient parameters 23 lifestyle data Specific diet of mother during pregnancy, breast feeding or bottled feeding and changes in infant's diet during the first year of life, care attendance 24 health data Duration of pregnancy, prenatal complications, Apgar score at 1 minute, family history of asthma or atopic disorders, respiratory and allergic disorders all over the 6-year period follow-up, vaccinal injections

25 parental exposure smoking during pregnancy 26 medication use of medication during pregnancy, use of medication by each child all over the 6-year period follow-up

27 socio-economic factors housing renting, parental education levels, parental occupation, marital status

Analysis and quality control procedures

28 intra/interlaboratory testing All environmental analyses are performed in the Paris Hygiene Laboratory (LHVP). Field duplicates, field and laboratory blanks are made. 29 external laboratory control 30 accuracy, limit of Data for all parameters are available on request. detection/quantification, reproducibility 31 data analysis (statistics, power The expected number of subjets was calculated calculations) according to available published data. Variable distribution will be described and statistical analysis will be performed according to a stratified plan. 32 representativity Recruitement efficiency is calculated as recruitement progresses. Non-responder analysis is ongoing.

Data protection and availability

133

France 10 33 privacy legislation Questionnaires, environmental and blood samples are maintained by the responsible and anonymised in order to maintain confidentiality under secure conditions. Measures are taken to ensure confidentiality and security of the data. Authorizations of French committees (Ministry of Research and Education and CNIL) have been obtained. 34 intellectual property rights no patents 35 banking of biological samples not yet determined

Communication (individual level, group level, level (sub)population )

36 reporting results to public authority, to Personal biological results will be communicated to general public, to participant each participating parents; global results will be communicated to each maternity hospitals' team and will be published in peer-reviewed journals. They will be subject to 2 PhD Thesis. 37 professionals involved, contacts 2 PhD students, 2 Masters students, University between professionals and participants professors, Paris Hygiene Laboratory (LHVP) technicians and engineers and Research Office (DASES) staff. The students and the Research Office (SERD) are directly in contact with families. 38 role of media The start of the study was given attention in media (newspapers, TV, radio): because of the scale and the length of the study and the public opinion on pollutions problems in Paris and its suburbs, media attention is significant. 39 public debate no 40 consequences of external no communication

41 Problems Enrollment of infants during childbirth hospitalization need frequent visits of the recruiter. Language and educational levels are obvious parameters of non- participation. Lastly, the length of follow-up appears to be a constraint for parents. Physical examinations are sometimes a significant disincentive to participation. Recruitment of 3500 newborns in a 2- year period may be an ambitious objective.

42 Experiences Efforts should be made to incite parents of all socioeconomic status to participate and to go on participating all over the follow-up period.

134

Germany Short summary to questionnaires:

Biomonitoring has a long and successful tradition in Germany, not only for workers, but also for the general population where the aim is to characterise environmental exposures and their potential health effects.

Studies are carried out under two aspects. On the one hand, studies are being undertaken to generate survey-type information on the status of the population with regard to the internal exposure that results from the occurrence of numerous environmental pollutants and to the concentration of specific biomarkers of exposure. As, generally, these studies encompass a large number of individuals, there are only a few in the country. On the other hand, there are a larger number of smaller research projects that address specific aspects or test specific hypotheses with the aim to uncover the link between exposure and adverse health effects. An example of the former study type are the different rounds of the German Environmental Survey (GerES), which is a repetitive study to generate data that are representative for the German population. This study is carried out in conjunction with the National Health Survey.

Over the last 10 years there have been several dozens of studies carried out in Germany (see following questionnaires for detailed information on these studies, the number of which is however not exhaustive). There is wide variability among the studies with regard to the study type, the number and age of children involved, the duration of the study, the parameters investigated, and the cost of the study, to mention only a few variables that are important in characterising a study. Many studies are cross-sectional, only a few are cohort or intervention studies. The different studies include between about 100 and several thousand children of all age groups with an emphasis of those younger than 10 years. The study duration is generally between 1 and 3 years, with a few covering also longer periods of time, and some being even repetitive or ongoing. In most cases the investigations are directed toward children alone, although there are also a few where child/mother pairs are studied.

Studies that are of the survey-type character and include more than 1,000 up to several thousand participants are the GerES (as mentioned above), the breast milk data base (for organochlorine pesticides, PCB, and dioxins), and the ISAAC studies (to study allergy and asthma).

With regard to the study parameters, studies include biomarkers of exposure, e.g., heavy metals and metalloids, and organic compounds such as dioxins, PCB, PCP, PAH, flame retardants, or pyrethroids, as well as biomarkers of effect, such as different immunoglobulins, and DNA strand breaks. To analyse these parameters, different biological specimens are being taken, such as urine, blood including cord blood, breast milk, hair, saliva, and toenails. Generally, the information obtained by experimental analysis is complemented by information gathered via questionnaires.

Studies are financed in different ways. Some rely on intra muros funding, others depend totally on external funding be it from national or international bodies. Clearly, the amount of money involved depends on the size of the study. Total costs range from about 100,000 Euro to several million Euro for GerES activities.

135

Germany 01 N° General Data 1 type Regional biomonitoring study Intervention study cohort of Kindergarten children in different burdened industrial areas 2 country Germany 3 title Kindergarten Studies in industrial regions (KIGA-IND) 4 aim To clarify, if remediation processes can improve the health status of Kindergarten children in different polluted regions as base for the estimation of remediation success 5 beginning date 1995 6 ending date 1999 7 contact person Prof. Dr. O. Herbarth Centre for Environmental Research , Department of Human Exposure Research and Epidemiology Permoser Str. 15 04318 Leipzig, Germany Tel. ++49 341 235 2365, Fax ++49 341 235 2288 [email protected] 8 initiator Prof. P. Krumbiegel Centre for environmental Research , Department of Human Exposure Research and Epidemiology

9 involved/responsible Centre for Environmental Research , Department of Human organisations Exposure Research and Epidemiology 10 budget available 140 000 DM 11 who is financing EU and German Research Foundation

Description of the population

12 total number of children (and parents) 144 children

13 age groups and number of persons in 4-6 years old each group

14 inclusion criteria, exclusion criteria - written informed consent - age 15 sampling strategy - children were recruited via Kindergarten - children from different different industrial studies 16 time schedule of biomonitoring

17 consent procedures - written informed consent 18 how is participation encouraged? - results of individual measurements and of the entire study are offered to the participants

136

Germany 01

Data collection

19 biomarkers of exposure - Measurement of S-phenyl and S-benzyl mercapturic acid (SPMA, SBMA) in urine - Measurement of pentachlorphenol in urine - Measurement of TCA (urine) 20 biomarkers of effect - [13C]Methacetin-Test (liver function test), - Measurement of δ-ALA 21 biomarkers of susceptibility

Other data 22 environmental sampling - Measurement of traffic and domestic fuel specific and gases (NOx, SO2) - Measurement of volatile organic compounds (VOC) in indoor air - active sampling for outdoor measurements - passive sampling for VOC measurements 23 lifestyle data - questionnaire on living conditions, life style habits 24 health data - investigation of health status by medical doctor 25 parental exposure assessed using questionnaire 26 medication asked using questionnaire 27 socio-economic factors - structure of the family - educational level of parents

Analysis and quality control procedures

28 intra/interlaboratory testing 29 external laboratory control 30 accuracy, limit of - data for all parameters are available on detection/quantification, reproducibility request

31 data analysis (statistics, power - statistical analyses were performed by calculations) Statistica for Windows

32 representativity

Data protection and availability

33 privacy legislation - samples and questionnaires are maintained by the responsible scientists

137

Germany 01 - data were made anonymous subsequently in order to maintain confidentiality under secure conditions

34 intellectual property rights - data were published by the responsible scientists - no patents 35 banking of biological samples - urine samples

Communication (individual level, group level, level (sub)population )

36 reporting results to public authority, to - the parents of participants was given general public, to participant individual results

- the results are summarized in scientific journal and a final report - parent-teacher-conference/year 37 professionals involved , contacts between professionals and participants

38 role of media 39 public debate 40 consequences of external communication

41 Problems

42 Experiences

138

Germany 02 N° General Data 1 type Regional biomonitoring study cross sectional study cohort of Kindergarten children in Leipzig and different burdened industrial areas 2 country Germany 3 title Exposure associated Airway diseases and Allergies in Kindergarten-children (KIGA) 4 aim To clarify the role of different exposure types (domestic fuel vs traffic) at the development of respiratory tract diseases and allergies in a little mobile population (Kindergarten children). It was connected with question if the effects are exposure specific and so urban structure dependent. 5 beginning date 1993 6 ending date 1999 7 contact person Prof. Dr. O. Herbarth Centre for Environmental Research , Department of Human Exposure Research and Epidemiology Permoser Str. 15 04318 Leipzig, Germany Tel. ++49 341 235 2365, Fax ++49 341 235 2288 [email protected] 8 initiator Prof. Dr. O. Herbarth Centre for environmental Research , Department of Human Exposure Research and Epidemiology 9 involved/responsible Centre for Environmental Research , Department of Human organisations Exposure Research and Epidemiology 10 budget available 161.789 DM (promoted) 11 who is financing Federal Ministry of Education and Research UFZ - Centre for scientific-technical cooperation

Description of the population

12 total number of children (and parents) 736 children 13 age groups and number of persons in each 5 – 6 years old children (mainly) group 14 inclusion criteria, exclusion criteria - written informed consent - age - children from different urban areas (city linked studies) 15 sampling strategy - children were recruited via Kindergarten 16 time schedule of biomonitoring 17 consent procedures - parent: written informed consent 18 how is participation encouraged? - results of individual measurements and of the entire study are offered to the participants

139

Germany 02

Data collection 19 biomarkers of exposure - Measurement of S-phenylmercapturic acid (SPMA), (benzene) and S-benzylmercapturic acid (SBMA), (toluene) in urine - Measurement of TCA (tri- and tetrachloro- ethylene) in urine - Measurement of pentachlorphenol (pentachlorphenol) in urine 20 biomarkers of effect 21 biomarkers of susceptibility

Other data 22 environmental sampling - Measurement of traffic and domestic fuel specific and gases (NOx, SO2) - Measurement of volatile organic compounds (VOC) in indoor air - Measurement of Pentachlorphenol in house dust (pentachlorphenol) - active sampling for outdoor measurements - passive sampling for VOC measurements 23 lifestyle data - questionnaire on living conditions, life style habits 24 health data - with focus on respiratory tract, allergies and family anamnesis, health diaries 25 parental exposure not considered 26 medication considered via questionnaire 27 socio-economic factors - structure of the family - educational level of parents

Analysis and quality control procedures

28 intra/interlaboratory testing 29 external laboratory control - round robin test 30 accuracy, limit of detection/quantification, - data for all parameters are available on reproducibility request 31 data analysis (statistics, power - statistical analyses were performed by calculations) Statistica for Windows 32 representativity - representative for a city with changing environmental conditions

Data protection and availability 33 privacy legislation - samples and questionnaires are maintained by the responsible scientists - data were made anonymous subsequently in

140

Germany 02 order to maintain confidentiality under secure conditions 34 intellectual property rights - data were published by the responsible scientists - no patents 35 banking of biological samples - urine

38 role of media 39 public debate - debate within the kindergarten communities and city representatives 40 consequences of external communication

41 Problems

42 Experiences

141

Germany 03 N° General Data 1 type Regional biomonitoring study prospective cohort study with nested case control in newborns 2 country Germany 3 title Leipzig`s Allergy Risk Study (LARS) 4 aim To clarify, if different indoor air exposures have an association to respiratory tract diseases and allergies in children with children with an higher allergy risk 5 beginning date 1995 6 ending date 1999 7 contact person Prof. Dr. O. Herbarth Centre for Environmental Research , Department of Human Exposure Research and Epidemiology Permoser Str. 15 04318 Leipzig, Germany Tel. ++49 341 235 2365, Fax ++49 341 235 2288 [email protected] 8 initiator Prof. Dr. O. Herbarth Centre for environmental Research , Department of Human Exposure Research and Epidemiology Dr. med. M. Borte, Dipl.-Med. H.Wetzig Childrens Hospital of the Leipzig`s University 9 involved/responsible Centre for environmental Research , Department of Human organisations Exposure Research and Epidemiology and Childrens Hospital of Leipzig`s University, maternity clinics of Leipzig, Institute for clinical immunology and transfusion medicine of the university of Leipzig 10 budget available 489.140 DM 11 who is financing Ministry of Science and Arts of Saxony

Description of the population 12 total number of children (and parents) 475 children 13 age groups and number of persons in 0-6 years each group 14 inclusion criteria, exclusion criteria - written informed consent - inclusion criteria 1. born between March 1995-1996 2. cord blood Ig E> 0.9 kU/L 3. children with a double positive allergy history 4. children with a birth weight between 1500- 2500g 15 sampling strategy - newborns were recruited in maternity clinics 16 time schedule of biomonitoring 17 consent procedures - parent: written informed consent

142

Germany 03 18 how is participation encouraged? - results of individual measurements and of the entire study are offered to the participants

Data collection 19 biomarkers of exposure - Measurement of S-phenyl and S-benzyl mercapturic acid (SPMA, SBMA) in urine (specific metabolites of benzene and toluene) - Measurement of urine samples for Cotinine (nicotine), TCA (tri- and tetra chloro ethylene), Phenol (benzene), 2-methylphenol (toluene), 4- methylphenol (toluene), 2-ethylphenol (ethylbenzene), 2,4-dimethylphenol (m-xylene), 2,3-dimethylphenol (o-xylene), 3,4- methylphenol (o-xylene) and pentachlorophenol (pentachlorphenol) 20 biomarkers of effect - Measurement of IgE and IgE specific, - Measurement of immune globulines (IgG, IgM, IgD, IgA and immune globuline subclasses - T cell function (cytokines) 21 biomarkers of susceptibility

Other data 22 environmental sampling - Measurement of outdoor carbon monoxide, NOx, ozone, sulfur dioxide, airborne particle - Measurement of volatile organic compounds (VOC) Indoor air - Measurement of the Indoor mould burden and the burden with house dust mites - Measurement of pyrethroides and pentachlorophenol in house dust samples - active sampling for outdoor measurements - home visits for sampling of biological exposures - passive sampling for VOC measurements 23 lifestyle data - questionnaire on living conditions, life style habits 24 health data - investigation of health status by medical doctor - questionnaire 25 parental exposure - questionnaire 26 medication - questionnaire 27 socio-economic factors - structure of the family - educational level of parents

Analysis and quality control procedures

143

Germany 03 28 intra/interlaboratory testing 29 external laboratory control - participation on round robin tests 30 accuracy, limit of - data for all parameters are available on detection/quantification, reproducibility request

31 data analysis (statistics, power - statistical analyses were performed by calculations) Statistica for Windows

32 representativity - representative for children at risk for allergic diseases

Data protection and availability 33 privacy legislation - samples and questionnaires are maintained by the responsible scientists - data were made anonymous subsequently in order to maintain confidentiality under secure conditions 34 intellectual property rights - data were published by the responsible scientists - no patents 35 banking of biological samples - urine

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to - the parents of participants was given general public, to participant individual results - the results are summarized in scientific journal and a final report 37 professionals involved , contacts - the parents of participants was given between professionals and participants individual results during consultation hours role of media - presentation of a parents information paper 39 public debate 40 consequences of external communication

41 Problems - the relative big drop out rate (over 6 years)

42 Experiences

144

Germany 04 N° General Data 1 type National biomonitoring study prospective cohort study 2 country Germany 3 title Influence of behaviour on allergy disposition in early childhood under urban living conditions (EVA) embedded in the project Influence of life style factors and behaviour on the development of the immune system and allergies in East-West settlement (LISA) 4 aim To clarify the role of lifestyle, especially of combined indoor exposures (biological and chemical) on children and the associated characterization of allergic diseases. The different influence can be shown on the level of the immune regulation. 5 beginning date 1998 6 ending date 2007 (phase 3: starting 2004) 7 contact person Prof. Dr. O. Herbarth Centre for Environmental Research , Department of Human Exposure Research and Epidemiology Permoser Str. 15 04318 Leipzig, Germany Tel. ++49 341 235 2365, Fax ++49 341 235 2288 [email protected] 8 initiator Dr. med. M. Borte Childrens Hospital of the Leipzig`s University Prof. Dr. O. Herbarth Centre for Environmental Research , Department of Human Exposure Research and Epidemiology 9 involved/responsible Centre for environmental Research , Department of Human organisations Exposure Research and Epidemiology and Childrens Hospital of Leipzig`s University, maternity clinics of Leipzig, Institute for clinical immunology and transfusion medicine of the university of Leipzig 10 budget available 11 who is financing Research Network Public Health ,Saxony Federal Ministry of Education and Research

Description of the population

12 total number of children (and parents) Subpopulation of the LISA cohort (n=976) 13 age groups and number of persons in each 6 – 9 years group 14 inclusion criteria, exclusion criteria 15 sampling strategy

145

Germany 04 16 time schedule of biomonitoring 17 consent procedures - parent: written informed consent 18 how is participation encouraged? - results of individual measurements and of the entire study are offered to the participants

Data collection 19 biomarkers of exposure - Measurement of S-phenyl and S-benzyl mercapturic acid (SPMA, SBMA) in urine (metabolites of benzene and toluene) and cotinine (metabolite of nicotine) in urine 20 biomarkers of effect - Measurement of IgE and IgE specific, - Measurement of immune globulines (IgG, IgM, IgD, IgA and immune globuline subclasses - T cell function 21 biomarkers of susceptibility

Other data

22 environmental sampling - Measurement of PM10, PM2.5 (outdoors) - Measurement of volatile organic compounds (VOC) and microbial volatile organic compounds (MVOC) in indoor air - Measurement of the indoor mould burden and the burden with house dust mites - active sampling for outdoor measurements - home visits for sampling of biological exposures - passive sampling for VOC/MVOC measurements 23 lifestyle data - questionnaire on living conditions, life style habits 24 health data - investigation of health status by medical doctor - winning of the blood and urine samples 25 parental exposure - questionnaire 26 medication - questionnaire 27 socio-economic factors - structure of the family - educational level of parents

Analysis and quality control procedures 28 intra/interlaboratory testing 29 external laboratory control - participation on round robin tests 30 accuracy, limit of detection/quantification, - data for all parameters are available on reproducibility request

146

Germany 04 31 data analysis (statistics, power calculations) - statistical analyses were performed by Statistica for Windows 32 representativity

Data protection and availability 33 privacy legislation - samples and questionnaires are maintained by the responsible scientists - data were maked anonymous subsequently in order to maintain confidentiality under secure conditions 34 intellectual property rights - data were published by the responsible scientists - no patents 35 banking of biological samples - urine

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to - the parents of participants was given general public, to participant individual results - the results are summarized in scientific journal and a final report 37 professionals involved , contacts between - the parents of participants was given professionals and participants individual results during clinical investigation hours role of media - presentation of a parents information paper 39 public debate 40 consequences of external communication

41 Problems - the relative big drop out rate

42 Experiences

147

Germany 05 N° General Data 1 type Regional biomonitoring study + research project The biomonitoring study involves - children attending a PCB-contaminated school building (age 7 – 16 years, median age 12 years) - a control group of children attending a non- contaminated school building (age 6 – 16 years, median age 11 years)

2 country Germany 3 title Biological monitoring of low-level exposure to lower chlorinated PCBs in children attending a contaminated school building 4 aim To evaluate differences in the internal exposure to PCBs in children attending a contaminated school building and a control group of children by determination of 6 WHO-PCBs in plasma samples. To investigate whether health complaints may be attributed to the exposure to PCBs in the contaminated school building. 5 beginning date 08/2001 6 ending date 09/2002 7 contact person Prof. Dr. Jürgen Angerer Institute and outpatient clinic of occupational, social and environmental medicine Schillerstraße 25

91054 Erlangen Germany Tel.: ++49 9131 26131 [email protected] 8 initiator Bavarian State Ministry of Health, Munich, Germany 9 involved/responsible Institute and outpatient clinic of occupational, social and organisations environmental medicine; Bavarian State Ministry of Health, Munich, Germany 10 budget available € ?? 11 who is financing Bavarian State Ministry of Health, Munich, Germany

Description of the population 12 total number of children (and parents) 595 children 13 age groups and number of persons in each 1) 377 children (202 male, 175 female) group attending a PCB-contaminated school (age 7 – 16 years, median 12 years)

2) 218 children (101 male, 117 female) attending a non-contaminated school building

148

Germany 05 of the same region (age 6 – 16 years, median 11 years) 14 inclusion criteria, exclusion criteria Inclusion criteria are: - Written informed consent - Attendance of the contaminated school and the control school building, respectively - collection of at least 2 ml plasma

15 sampling strategy Biological monitoring was offered to the attendants of the school buildings, participance in the study was voluntarily. 16 time schedule of biomonitoring - Children of the contaminated building were sampled between August and September 2001 - Children of the control school were sampled in October 2001 17 consent procedures Written informed parental consent, Study protocol was approved by local medical ethics committee 18 how is participation encouraged? Results of individual measurements and of the entire study are offered to the participants

Data collection 19 biomarkers of exposure Highly sensitive GC/µECD-analysis of 6 WHO- PCBs in childrens plasma samples. 20 biomarkers of effect Not measured 21 biomarkers of susceptibility Not measured

Other data 22 environmental sampling Analysis of PCBs in indoor air samples of the contaminated school building. 83 individual measurements of 16 different rooms sampled between August 1999 and July 2001. 23 lifestyle data Nutrition: type/frequency/amount of fish and meat consumption or vegetarian diet. Active/passive smoking Place of birth, duration of residence in Germany, hobbies; Duration of attendance in the building 24 health data Assessment of health complaints using a standardized questionnaire. 25 parental exposure Not acquired 26 medication Not acquired 27 socio-economic factors Occupation and hobbies of the parents; Year of construction of the habitation, duration of occupancy; heating installation

149

Germany 05 Analysis and quality control procedures 28 intra/interlaboratory testing Reagent blank values as well as a certified quality control plasma sample were included in every analytical series. 29 external laboratory control Regular and successful participation in the external quality assurance program of toxicological analysis in biological materials offered by the German Society for Occupational and Environmental Medicine. (‘Round robin test’ for PCBs) 30 accuracy, limit of detection/quantification, Data for all parameters are available on reproducibility request 31 data analysis (statistics, power Statistical calculations were performed with the calculations) program SPSS for Windows (Version 11.0). As level of significance, a value of p<0.05 was established. 32 representativity Both collectives matched excellent concerning age and sex distribution and can be considered representative.

Data protection and availability 33 privacy legislation Plasma samples were blinded prior to analysis under supervision of a notary. The final interpretation of the results was done after the analysis of all samples was finished. Questionnaires were maintained by the responsible medical doctor in order to maintain confidentiality under secure conditions in accordance with the 1995 EC Data Protection Directive and data protection legislation. Measures are taken to ensure confidentiality and security of the data. 34 intellectual property rights No patents. 35 banking of biological samples No long term storage is foreseen

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to A project group “PCB” met six times during the general public, to participant proceeding of the study in order to discuss the current data and future actions. To satisfy the need for information and advice for the concerned children and parents as well as for the public, a special PCB information center was established at the Institute and Outpatient Clinic for Occupational, Social and Environmental medicine. Furthermore, a

150

Germany 05 website with special informations about PCB was created and accessed for the public. The results of biological monitoring were first presented on a parent-teacher conference and a few days later on a press conference. After the final report has been prepared and notified to the involved Bavarian ministry of health, the participants has been given individual results as far as they are interpretable, as well as the respective group results in a letter. Results of the study will be communicated to the scientific community preferentially by publication in peer reviewed journals. 37 professionals involved , contacts between Representatives of the parents collaborated in professionals and participants a project group in order to ensure a high degree of transparency in the study. The information center provided for the contact between participants and professionals. 38 role of media Due to several reports about the contaminated school building prior to the start of the study, the media interest in the study was very high (local newspapers, TV, radio…). 39 public debate During a parent-teacher-conference, where the final results were presented, the participants was given the opportunity to debate with the scientists and local authorities. Our results raised a great public debate about the health concerns of indoor PCB exposure and especially about the consequences public authorities may draw when a PCB-exposure in a public building is discovered. 40 consequences of external communication Our results were the basis for a general statement of the Federal Environmental Agency about the excess uptake of PCB from indoor sources.

41 Problems

Despite the good collaboration in the project group, risk communication with the parents turned out to be difficult and has to be prepared carefully.

42 Experiences Due to the study design (blind analysis of the samples) and the good collaboration between the participants and the responsible organizations, our results found excellent acceptance both in the public and the scientific

151

Germany 05 community. Participation in the study was very high, probably because of the high concern that has been raised in the media.

152

Germany 06 N° General data 1 type National survey 2 country Germany 3 title Data bank for residues in human milk 4 aim 1) To summarize data on residues and contaminants in human milk as well as individual, environmental and exposure factors possibly influencing the individual concentrations 2) To calculate the intake of residues and contaminants by breast-fed babies 3) To evaluate possible health risks of intake of contaminants and residues to breast-fed infants 4) To observe time trends of residues and contaminants in human milk as an bioindicator of the background body burden 5) To identify possible sources and path ways of contamination 6) To propose specific measures und to control the efficiency of measures and regulations to minimize environmental and human exposure to residues and contaminants 5 beginning date 1993 6 ending date permanent project 7 contact person Dr. Bärbel Vieth, Federal Institute for Risk Assessment (BfR), Thielallee 88-92, D-14195 Berlin, Germany, e-mail: [email protected], phone: ++49 1888 412-3212 8 initiator Federal Ministry of Consumer Protection Food and Agriculture of Germany(BMVEL); Federal Institute for Risk Assessment (BfR); Federal States of Germany 9 involved/responsible Federal Office of Consumer Protection and Food Safety (BVL), organisations Food Control Laboratories and Health Offices of the Federal States of Germany 10 budget available no special budget, because it is a permanent task of the BfR

11 who is financing Federal Ministry of Consumer Protection, Food and Agriculture (BMVEL)

Description of the population 12 total number of children population: breast-feeding mothers 13 age groups and number of without limitations, up to the present milk samples from about persons in each group 35000 mothers have been analysed 14 inclusion criteria, exclusion samples from mothers living in Germany criteria 15 sampling strategy no sampling strategy, every interested mother can send a sample to the responsible food control laboratory of the federal states of Germany 16 time schedule of biomonitoring continounsly 17 consent procedures Mothers: written informed consent

153

Germany 06 18 how is participation 1) The analysis of samples are free of charge to the mothers 2) encouraged? The results of the individual sample are offered to the mothers, 3) Evaluation of the individual results in relation to the german background levels, 4) Evaluation and recommendation concerning breast feeding to the participating mothers Data collection 19 biomarkers of exposure POP's (organochlorine pesticides, PCB, dioxins) synthetic musk compounds, PBDE 20 biomarkers of effect 21 biomarkers of susceptibility

Other data collection of personal, environmental and exposure data by a questionnaire 22 environmental data possible environmental/industrial sources of exposure near by the habitation, occupational exposure of the mother to POP's, PBDE 23 lifestyle data kind of nutrition (vegetarian diet or not) frequency of fish consumption, smoking habits(active/passive) 24 health data age, body weight, size, 25 parental exposure 26 medication 27 socio-economic factors 1) age of the mother, 2)number of breast-fed-infants, 3) educational level and profession of the mother, 4) native country of the mother Analysis and quality control procedures 28 intra/interlaboratory testing 29 external laboratory control the laboratories participate in proficiency tests organized by different institutions, the labs are accredited 30 accuracy, limit of data for these parameters are available in all labs detection/quantification, reproducibility 31 data analysis (statistics, power calculations) 32 representativity althought the samples are analysed on request of the mothers the data can be considered as representative because of the high number of samples Data protection and availability 33 privacy legislation Personal data are made anonymous. The procedure has been proven and accepted by the Federal Data Protection Commissioner of Germany 34 intellectual property rights No patents. Data are published in scientific papers with the collaboration of the Federal states of Germany and the scientists of the laboratories 35 banking of biological samples no banking of the samples Communication (individual level, group level, level (sub)population )

154

Germany 06 36 reporting results to public 1) The participating mothers are given the individual results by authority, to general public, to the laboratory. 2) Data on time trends and current levels of participant, residues and contaminants in human milk as well as intake data of breast-fed infants have been evaluated together with the National Committee for the Promotion of Breast-Feeding of Germany, these data are the basis of general breast-feeding recommendations. 3) The data on dioxins and PCBs in human milk are summarized and evaluated in reports of the German Bund-Länder working group "Dioxins" under the leadership of the Federal Ministry for the Environment, Nature Conservation and Nuclear Safety of Germany (BMU). 4) Results are reported to the Federal Ministry of Consumer Protection Food and Agriculture of Germany (BMVEL) and to the EU (for instance SCOOP-Report Task 3.2.5) on demand. 37 professionals involved, The participants contact the scientists of the food control contacts between professionals laboratories or the health office of the federal states of and participants Germany. 38 role of media Media are informed by press releases of the BfR. 39 public debate Because of the public interest on environmental pollution problems and on safe nutrition of babies, there is a general public attention. 40 consequences of external communication

41 Problems 1)Most of the laboratories analyse the organochlorine pesticides, PCB's and nitro musk compounds only. But addionally, "new" residues (polycyclic musk compounds, triclosane, PBDE, Phthalates) should be analysed in human milk. 2) The questionnaire is very extensive, not all data are given by the mothers.

42 Experiences Human milk is a very useful non-invasive available bioindicator for internal exposure of persistent and lipophilic residues and contaminants. Future activities should also include "new" residues. The conjunction of exposure data and residue levels by a data bank is a useful instrument to identify relevant exposure factors and to propose specific measures for minimizing human exposures. The cooperation with the National Committee for the Promotion of Breast-Feeding is important

155

Germany 07 N° General data 1 type Regional environmental health survey for children (10 years old) in 4 regions including a biomonitoring program 2 country Baden-Württemberg / Germany 3 title Beobachtungsgesundheitsämter Baden-Württemberg, Belastungs- und Wirkungsmonitoring (Sentinel health departments in Baden-Württemberg, body burden monitoring and effect monitoring) 4 aim To generate valid data about the body burden of heavy metals and organochlorine compounds in children - in different regions of Baden-Württemberg which differ with regard to environmental pollution (2 urban regions, 1 industrial area in a rural setting, 1 rural area), - at different times to estimate the time trend of the body burden. To identify influencing factors and confounders for the intake/body burden of the compounds. 5 beginning date 1992 6 ending date not defined 7 contact person Dr. Bernhard Link Landesgesundheitsamt Baden-Württemberg Wiederholdstr. 15 70174 Stuttgart Germany [email protected] Tel. 0049 711-1849 309 Fax 0094 711-1749 369 8 initiator Ministry of Social Affairs Baden-Württemberg 9 involved/responsible Ministry of Social Affairs Baden-Württemberg organisations State Health Agency (Landesgesundheitsamt) Baden- Württemberg Health Department (Gesundheitsamt) Stuttgart, Health Department (Gesundheitsamt) Mannheim, Health Department (Gesundheitsamt) Ortenaukreis, Health Department (Gesundheitsamt) Ravensburg 10 budget available 1.000.000 € (since 1992) for the biomonitoring programs 11 who is financing Government of Baden-Württemberg Description of the population 12 total number of children 10.000 (from 1992 to 2003) 13 age groups and number of All children are in the age group of 10 years (fourth-graders) persons in each group 14 inclusion criteria, exclusion Inclusion criteria: criteria written informed consent, living in the region for at least 2 years Exclusion criteria: acute infections

156

Germany 07 15 sampling strategy All 4th-graders living in the investigation areas (300 - 600 pupils) are asked for participation. From the participating children samples (blood, urine) for the determination of different biomonitoring parameters were selected randomly. For analyses of PCDD/PCDF and dioxin-like PCB blood samples of several pupils were pooled. 16 time schedule of biomonitoring Samples were drawn in the winter periods (Oct. to March) of 1992/93, 1993/94, 1994/95, 1996/97, 1998/99, 2000/01 and 2002/03 17 consent procedures Written informed consent by the parents and the participating child 18 how is participation The children and the parents were asked for participation with encouraged? an information letter, which was handed out to the children in the schools. The participants received the results of their individual measurements with an interpretation as well as mean results of the entire study. Data collection 19 biomarkers of exposure Cadmium, lead, DDE, HCB, PCB-138, PCB-153, PCB-180 in blood; arsenic and mercury in urine; selenium in serum; PCDD/PCDF and dioxin-like PCB in pooled blood samples 20 biomarkers of effect Specific IgE (inhalation allergens, nutrition allergen) in serum 21 biomarkers of susceptibility Other data 22 environmental data Air quality data (outdoor concentrations of SO2, NO2, CO, PM10) are available for different sites of the investigation areas (Environmental Agency of Baden-Württemberg). 23 lifestyle data Breastfeeding by the mother, nutrition at home (meat, fish, vegetarian), passive smoking, numbers of amalgam fillings, exposure to traffic, heating conditions at home by questionnaire. 24 health data Frequency / prevalence of diseases with special emphasis on airway diseases and allergies (asthma, eczema, hay fever) by questionnaire. 25 parental exposure 26 medication Medication of the children by questionnaire 27 socio-economic factors Education level of the parents, health problems of parents and siblings, number of siblings, nationality and colloquial language by questionnaire. Analysis and quality control procedures 28 intra/interlaboratory testing Development of a laboratory quality control program, use of reference materials. Contracting laboratory (analysis of PCDD/PCDF, Dioxin-like PCB) is accredited. 29 external laboratory control Participation on measurements of interlaboratory comparison (Deutsche Gesellschaft für Arbeitsmedizin) 30 accuracy, limit of According to common criteria of the analytical laboratory. Data detection/quantification, are available for all parameters on request reproducibility

157

Germany 07 31 data analysis (statistics, power Results were initially presented by descriptive statistics. Multiple calculations) regression models for biomonitoring parameters were performed considering independent variables as well as confounders and influence factors. Time trends were analyzed. 32 representativity The participation response is > 70 % Data protection and availability 33 privacy legislation Personal data were only maintained by the Sentinel Health Department. Analyses and calculations were performed after anonymization of personal data by coding of all samples. The examination design was coordinated with the agency of data security of Baden-Württemberg and approved by the ethics committee of the medical council of Baden-Württemberg. 34 intellectual property rights No patents.

35 banking of biological samples Long term storage of biological samples for analytical purpose is not foreseen.

Communication (individual level, group level, level (sub)population ) 36 reporting results to public The results of each investigation period are published on a authority, to general public, to group level in special reports by the State Health Agency. The participant parents of the participating children get the individual results in a personal letter from the Sentinel Health Departments. Some results are published in scientific journals. 37 professionals involved, An advisory board (12 scientists from different universities) contacts between professionals discusses the results of the survey every second year. The and participants survey is coordinated by the "Sentinel Health Department Office" of the State Health Agency. The scientific employees of this office and of the Sentinel Health Departments are contact persons for the participants. 38 role of media The regional journals and the regional broadcast report on the activities and results of the survey. 39 public debate In 2002 on the occasion of the 10th anniversary of the survey a public workshop was arranged by the Ministry of Social Affairs of Baden-Württemberg 40 consequences of external External communication is important for the maintenance of the communication survey.

41 Problems The two-year repetition of the examinations appears not necessary for all parameters. For some parameters therefore longer periods are planned. This may cause considerable problems in organization. Due to the declining body burden of environmental. pollutants the relevancy of the examinations decreases in the public debate. One has to face the common problems of scientific project management.

158

Germany 07 42 Experiences The teamwork between the State Health Agency and the Sentinel Health Departments and the good contact with the schools is an advantage of the survey. The implementation of an advisory board was helpful.

159

Germany 08 N° General data 1 type Regional study on indoor and outdoor particle exposure of children in Baden-Württemberg and monitoring of health effects in children 2 country Baden-Württemberg / Germany 3 title Indoor and outdoor particle exposure of children in Baden- Württemberg and health effects

4 aim 1.) To characterise the particle load (PM2,5, particle number concentration, coarse particles) indoors and outdoors of dwellings and schools in different polluted areas of South-West- Germany (Baden-Württemberg). 2.) To study health effects possibly associated to particle load (lung function tests, measurements of exhaled nitric oxide and determination of complement C3c in serum) in children. Prevalences of airway diseases and allergies were recorded in a parents questionnaire. Atopic status was monitored by specific IgE in serum. 5 beginning date November 2001 6 ending date March 2004 7 contact person Dr. Bernhard Link Landesgesundheitsamt Baden-Württemberg Wiederholdstr. 15 70174 Stuttgart Germany [email protected] Tel. 0049 711-1849 309 Fax 0094 711-1749 369 8 initiator Ministry of Social Affairs Baden-Württemberg State Health Agency Baden-Württemberg 9 involved/responsible Ministry of Social Affairs Baden-Württemberg organisations State Health Agency (Landesgesundheitsamt) Baden- Württemberg Health Department (Gesundheitsamt) Stuttgart, Health Department (Gesundheitsamt) Mannheim, Health Department (Gesundheitsamt) Ortenaukreis, Health Department (Gesundheitsamt) Ravensburg Deutscher Wetterdienst Freiburg, UMEG Karlsruhe 10 budget available 179.000 € (financial support by BWPLUS) 11 who is financing Ministry of Environment and Traffic Baden-Württemberg (Program BWPLUS), Government of Baden-Württemberg

Description of the population 12 total number of children 160

13 age groups and number of All children are in the age group of 10 years (fourth-graders) persons in each group

160

Germany 08 14 inclusion criteria, exclusion Inclusion criteria: criteria written informed consent, participation in a questionnaire on traffic volume at home Exclusion criteria: acute infections 15 sampling strategy All 4th-graders living in the investigation areas (300 - 600 pupils in each area) are asked for participation. Out of the children offering their participation 160 children were selected according their traffic volume at home (80 children with high traffic, 80 children with low traffic). The selected children were examined (lung function test, measurement of exhaled nitric oxide, determination of complement C3c and specific IgE in serum). Prevalence of airway diseases and allergies were recorded in a

parents questionnaire. Particle exposure (PM2,5, coarse particles) was measured for one week at home and in the school. 16 time schedule of biomonitoring Biomonitoring of the children (lung function test, exhaled NO, C3c and IgE) and ambient monitoring (particle exposure) were carried out from November 2001 to April 2002. Measurements of exhaled NO were repeated in May and June 2002. 17 consent procedures Written informed consent by the parents and the participating child 18 how is participation The children and the parents were asked for participation with encouraged? an information letter, which was handed out to the children in the schools. The participants received the results of their individual measurements. Data collection 19 biomarkers of exposure exposure was only measured by ambient monitoring

20 biomarkers of effect Lung function test (VFC, FEV1, PEF, MEF50), exhaled nitric oxide, complement C3c in serum. 21 biomarkers of susceptibility Specific IgE (inhalation allergens) in serum as a marker for atopic status.

Other data

22 environmental data Outdoor PM2,5 and PM10 (daily average) at different sites of the investigation areas (UMEG); outdoor and indoor PM2,5 and coarse particles (average for one week) at home and at school, particle number concentrations at home and at school (10 hours). 23 lifestyle data Passive smoking, exposure to traffic, heating conditions at home, personal activities by questionnaire. 24 health data Frequency / prevalence of diseases with special emphasis on airway diseases and allergies (asthma, eczema, hay fever), health problems of parents and siblings by questionnaire. 25 parental exposure 26 medication Medication of the children by questionnaire

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Germany 08 27 socio-economic factors Education level of the parents, number of siblings, nationality by questionnaire.

Analysis and quality control procedures 28 intra/interlaboratory testing Effect monitoring: Calibration by volume (lung function), use of calibration gas (exhaled NO), standard calibration curve (C3c); Ambient monitoring: intralaboratory comparison of particle sampling instruments 29 external laboratory control interlaboratory comparison of particle sampling measurements

30 accuracy, limit of According to common criteria of the analytical laboratory. Data detection/quantification, are available for all parameters on request reproducibility

31 data analysis (statistics, power Power calculations were based by the assumption of PM2,5- calculations) differences more than 15 µg/m³ for low and high pollution areas and a participant rate of 200 children. Statistical analysis will be performed according to a stratified plan 32 representativity Selection of participants according high and low traffic load is inadequate for representative measurements

Data protection and availability 33 privacy legislation Personal data were only maintained by the Sentinel Health Department. Analyses and calculations were performed after anonymization of personal data by coding of all samples. The examination design was coordinated with the agency of data security of Baden-Württemberg and approved by the ethics committee of the medical council of Baden-Württemberg. 34 intellectual property rights No patents.

35 banking of biological samples No long term storage of biological samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to public Results of the study were reported at scientific meetings (INIS authority, to general public, to 2003, GHU/ISEM 2003) and will be published in a special report participant by the State Health Agency and in scientific journals. Preliminary results are available in the internet (http://bwplus.fzk.de/ -> Publikationen -> Zwischenberichte 2003). The parents of the participating children got the results concerning their child and their dwelling in a personal letter from the Sentinel Health Departments. 37 professionals involved, The study is supported by the program BWPLUS (Ministry of contacts between professionals Environment and Traffic Baden-Württemberg). In connection and participants with this, the study was subjected to a scientific evaluation process. 38 role of media The regional journals report on the activities and results of the survey.

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Germany 08 39 public debate The public debate is limited to the scientific society (see Nr. 36 and 37) 40 consequences of external The external communication is emphasizing the relevancy of communication further indoor air measuring.

41 Problems The regional differences of outdoor particle pollution in Baden- Württemberg are relatively small. Meteorological variations from day to day are more relevant than regional differences. Therefore health effects due to outdoor particle load were not detectable in our study. Indoor particle pollution shows a high variation. Therefore further measuring is needed for representative recording of indoor particle pollution and individual particle exposure of children.

42 Experiences In South West Germany indoor particle pollution seems to be more relevant than outdoor particle concentrations. Important sources for fine particles in dwellings are tobacco smoke and domestic activities like cooking and frying. Due to the different chemical composition of these particles it seems of interest to differentiate the health effects according to their exposure.

163

Germany 09 N° General data 1 type Regional case control study - children with atopy and without atopy in 4 regions (two industrial regions, an industrial area in rural setting and rural area) 2 country Baden-Württemberg / Germany 3 title Relationship between biological agents in indoor air and allergies and respiratory diseases 4 aim To investigate the degree of exposure to biological agents, to determine regional differences, if any, and to uncover the correlation between exposure and symptoms. 5 beginning date 1997 6 ending date 2000 7 contact person Dr. Snezana Jovanovic Landesgesundheitsamt Baden-Württemberg Wiederholdstr. 15 70174 Stuttgart Germany [email protected] Tel. 0049 711-1849 310 Fax 0094 711-1749 369 8 initiator Ministry of Social Affairs Baden-Württemberg 9 involved/responsible Ministry of Social Affairs Baden-Württemberg organisations State Health Agency (Landesgesundheitsamt) Baden- Württemberg Environmental health surveillance system consisted of 4 sentinel health departments: Health Department (Gesundheitsamt) Stuttgart, Health Department (Gesundheitsamt) Mannheim, Health Department (Gesundheitsamt) Ortenaukreis, Health Department (Gesundheitsamt) Ravensburg 10 budget available running budged resources (ca. 40.000 €/a) 11 who is financing Government of Baden-Württemberg

Description of the population 12 total number of children 776

13 age groups and number of 4th-graders school children (age 9 to 11 years) persons in each group 14 inclusion criteria, exclusion written informed consent criteria Cases and controls were selected on the basis of the answers in the parents questionnaire, regarding allergy and respiratory diseases. Children were defined as atopic (cases) if the parents reported in questionnaire at least one of the following atopic disorders: asthma, asthmoid-spastic or obstructive bronchitis, hay fever, atopic eczema. According to the number of cases a comparable number of controls was selected for every investigation area. In controls none of the disorders were reported.

164

Germany 09 15 sampling strategy Children were recruited via schools. Environmental samples (single, spot measurement) for the determination of biological agents were taken in the children’s bedroom. IgE-antibodies against moulds and mites were determined in the serum of the children. 16 time schedule of biomonitoring Samples were drawn in the winter periods (Oct. to March) 1997/98 and 1999/00. 17 consent procedures Written informed consent by the parents and the participating child 18 how is participation The children and the parents were asked for participation with encouraged? an information letter, which was handed out to the children in the schools. The participants received the results of their individual measurements with an interpretation as well as mean results of the entire study.

Data collection 19 biomarkers of exposure Viable culturable mould spores in indoor air, outdoor air, household dust from floors and mattresses. Allergens of house dust mite (Der p1, Der f1, Gr2) and cat (Fel d1) in household dust from floors and mattresses. 20 biomarkers of effect IgE in serum against a mixture of moulds (Test MX2: Penicillium notatum, Cladosporium herbarum, Aspergillus fumigatus, Candida albicans, Alternaria alternata, Helminthosporium halodes), against a mixture of mites (Test HX2: home dust with allergens of Dermatophagoides pteronyssinus, Dermatophagoides farinae und Blatella germanica), against single house dust mites and against cat. 21 biomarkers of susceptibility

Other data 22 environmental data The indoor and outdoor relative humidity and temperature were measured. 23 lifestyle data Specific home characteristics were assessed by standardised questionnaire. A special checklist on building and occupant characteristics with 49 items was developed to obtain information on type and age of home, size of the dwelling, type of the heating, signs of dampness, age of carpets and mattresses, tightness of windows, ventilation and cleaning habits in the home.

165

Germany 09 24 health data An inquiry with parents questionnaire based on International Study on Asthma and Allergies in Childhood (ISAAC) questionnaire has been performed in order to acquire data regarding the allergies and respiratory diseases of the child. The questionnaire comprised respiratory diseases with a component of infection and asthmatic diseases to provide information concerning symptoms and complaints as well as diagnosis confirmed by a physician. Furthermore, several questions about environmental exposure (such as exposure to cigarette smoke, pet ownership), parental history of atopy, social status, number of siblings were asked. 25 parental exposure 26 medication Medication of the children by parents questionnaire 27 socio-economic factors Education level of the parents, health problems of parents and siblings, number of siblings, nationality by questionnaire.

Analysis and quality control procedures 28 intra/interlaboratory testing The State Health Agency co-ordinated these investigations and conducted the analysis with uniform methods. Quality criteria were of special importance in the conduction of the project. In the sentinel health departments, survey teams were established and specially trained by the State Health Agency in order to standardise the procedure which was described in a survey manual. Laboratory work was improved by development of Internal Quality Control (IQC) system with following steps: routine checking and calibrating of equipment and instruments to ensure adequate performance routine checking of culture media, water, and analytical reagents for appropriate sterility, microbial growth, and analytical purity maintenance of a microbial/fungal culture collection data quality assurance, quality assurance records, and documentation of deficiencies and corrective actions housekeeping, cleanliness, and appropriate waste treatment and disposal practices

29 external laboratory control Participation in measurements of interlaboratory comparison. Since 2001 the State Health Agency Baden-Württemberg is carrying out an Inter-Laboratory Test entitled ‘Identification of indoor fungi’. 30 accuracy, limit of According to common criteria of the analytical laboratory. Data detection/quantification, are available for all parameters on request reproducibility 31 data analysis (statistics, power Results are presented by descriptive statistics. Multiple calculations) regression models were performed considering independent variables as well as confounders and influence factors. 32 representativity The participation response is about 50 %

Data protection and availability

166

Germany 09 33 privacy legislation Personal data were only maintained by the Sentinel Health Department. Analyses and calculations were performed after anonymization of personal data by coding of all samples. The examination design was coordinated with the agency of data security of Baden-Württemberg and approved by the ethics committee of the medical council of Baden-Württemberg. 34 intellectual property rights No patents.

35 banking of biological samples No

Communication (individual level, group level, level (sub)population )

36 reporting results to public The results of each investigation period are published in special authority, to general public, to reports by the State Health Agency, available also in participant www.landesgesundheitsamt.de. The parents of the participating children get the individual results in a personal letter from the Sentinel Health Departments. Some results are published in scientific journals and presented at scientific meetings. 37 professionals involved, The study was evaluated by a scientific advisory board which contacts between professionals consisted of experts for the different fields of the study. and participants

38 role of media The regional journals and the regional broadcast report on the activities and results of the survey. 39 public debate None 40 consequences of external External communication is important for the maintenance of the communication survey.

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Germany 09 41 Problems Statistical evaluations didn’t show any significant associations between the indoor concentration of biological agents and allergological parameters (prevalence of allergic diseases and sensitisation). The lack of associations in this study may be influenced by the following reasons: Between the current exposure to allergens and the situation during the development of an allergy no causal connection must exist. exposure assessment was done on the basis of single (spot) measurement. with current methods for assessing exposure it remains difficult or impossible to determine causality and attributable risk mould exposure assessment was based on the determination of culturable spore concentrations in samples. Total spore concentrations and its potentially health affecting agents, e.g. the fungal cell wall components, (ergosterol, extracellular polysaccharides EPS, β-glucan), metabolites and allergens, might be more suitable for epidemiological studies the sensitisation rates to mould was performed with mixture MX-2 This mixture does not include the fungal allergens that are typical for wet indoor environments small sample size for moulds: a) only 2,5% of buildings were classified as mould- contaminated, b) 9,2% among the cases and 4,4% among the controls were sensitised to moulds.

42 Experiences The Sentinel Health Departments in our health surveillance system are suitable instrument for conducting of special studies. Specially trained teams are an important element for good contact with the schools, successful recruitment of study population and for conduction of field investigation. Quality criteria were of special importance in the conduction of the project. For the teams the procedure was described in a survey manual in order to standardise investigation. We trained with our teams al steps in the project (contact to study population, home visit, sampling of specimens). The implementation of an advisory board was helpful.

168

Germany 10 Number General Data 1 type Representative health examination survey 2 country Germany 3 title German National Health Interview and Examination Survey for Children and Adolescents 4 aim To provide representative national data on the health status of children and adolescents from 6 months to 17 years of age. 5 beginning date May 2003 6 ending date April 2006 7 contact person Dr. Bärbel-Maria Kurth Robert Koch Institute Seestr. 10 D-13353 Berlin Germany [email protected] 8 initiator Robert Koch Institute 9 involved/responsible Robert Koch Institute organisations

10 budget available € 5.000.000 (approximately) 11 who is financing Federal Ministry of Health and Social Security Federal Ministry of Education and Research Federal Ministry of Consumer Protection, Food and Agriculture Robert Koch Institute

Description of the population 12 total number of children and 18.000 adolescents 13 age groups and number of persons in All ages between 0 and 17 years. 1.000 each group persons in each age-group (18 x 1.000 = 18.000) 14 inclusion criteria, exclusion criteria not applicable 15 sampling strategy Stratified random sample via population registries in 150 selected towns 16 time schedule of biomonitoring Biological samples are collected once when proband is being examined 17 consent procedures Written informed consent of parents 18 how is participation encouraged? Results of individual measurements are sent to the participants. In addition, a present is handed out after examination

Data collection 19 biomarkers of exposure None

169

Germany 10 20 biomarkers of effect Red blood cell count Folic acid (in red cells and in plasma) Ferritine Vit. B12 TSH, fT3, fT4 Anti HAV, anti HBs, anti HBc, HBsAg Homocysteine Specific inhalation allergenes (20 different) Helicobacter pylori antibodies Glucose Uric acid Cholesterol (total, hdl, ldl) Tryglycerides Protein (total) ggt CRP and others 21 biomarkers of susceptibility None

170

Germany 11 N° General Data 1 type National survey in cooperation with the National Health Interview and Examination Survey for Children and Adolescents. The biomonitoring study involves children between 3 and 14 years of age. Cross sectional study. 2 country Germany 3 title German Environmental Survey for Children (GerES IV) 4 aim One of the main aims of GerES is to generate, update, and evaluate representative data. These data facilitate an environmental health related observation and the reporting of information at the national level. They are also useful: • as a basis to establish reference values with regard to the levels of noise and environmental pollutants children and teenagers are exposed to; • to indicate over time trends and regional differences in contaminant levels; • to identify and quantify contamination routes; • to evaluate influences on children's health; • to design and evaluate preventive, interventive and control strategies within the framework of policy measures related to health and environment.

5 beginning date 2003 (field work) 6 ending date 2006 (field work) 7 contact persons Christine Schulz / Bernd Seifert Federal Environmantal Agency (Umweltbundesamt) Bismarckplatz 1 14191 Berlin Germany [email protected] +49 30 8903-1739 [email protected] +49 30 8903-1320 8 initiator Federal Environmental Agency 9 involved/responsible Federal Environmental Agency (UBA) organisations Robert Koch Institute (RKI) German Aerospace Center (DLR) 10 budget available € 4 200 000 (approximately) 11 who is financing Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU) Federal Ministry of Education and Research (BMBF)

Description of the population 12 total number of children 1.800 children, 600 selected for substudies 13 age groups and number of persons in each 150 children selected from each of the 12 age- group groups (3 to 14 years); subsample: 150 children selected from each of the four age groups (3 to 5; 6 to 8, 9 to 11; 12 to14)

171

Germany 11 14 inclusion criteria, exclusion criteria Inclusion criteria: sufficient knowledge of German 15 sampling strategy Randomly selected children from the cross- sectional sample of the National Health Interview and Examination Survey for Children and Adolescents, representatively chosen for age, gender, community size and region (East and West Germany), drawn in a multistage random sampling. Recruited via registrations offices from 150 sampling locations. 16 time schedule of biomonitoring May 2003 to May 2006 17 consent procedures Written informed consent 18 how is participation encouraged? Results of individual measurements are offered to the parents and incentives/gifts with a value of 12,50€ (environmental survey) and 15 -€ (health survey). .

Data collection 19 biomarkers of exposure • Lead, cadmium and mercury in whole blood (N=1800) • PCBs, DDE, HCB and HCH in whole blood (N=1800) • Arsenic, cadmium, mercury, nickel and creatinine in morning urine (N=1800). • Nicotine and cotinine in morning urine (N=1800) • Cortisol, adrenalin, noradrenalin (N=1050, 8 to 14 years) in morning urine • PCP and other chlorophenols, metabolites of pyrethroides, of PAHs and of organic esters of phosphoric acid in morning urine (N=600). 20 biomarkers of effect • Atopy Panel 20, SX1-Test: specific IgE in serum samples (N=1800) • hearing test (N=1050, 8 to 14 years) • questionnaire on asthma, allergy, irritation of skin, eyes and the respiratory system 21 biomarkers of susceptibility

Other data

22 environmental data • Household drinking water: first draw samples analyzed for lead, cadmium, copper, nickel (N=1800). • House dust: dust from vacuum cleaner bags analyzed for biocides such as pyrethroides, methoxychlorine, chorpyrifos, propoxur, eulane and DDT, HCH, HCB, PBCs, PCP, PAHs, flame retardants and plastizisers such as DEHP, as well as arsenic, lead and cadmium (N=600).

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Germany 11 • Chemical pollutants in indoor air: volatile organic compounds such as benzene and carbonyl compounds such as form aldehyde (N=600, passive collectors). • Biological pollutants: active measurement of air and dust for mould spores, house dust mites and allergens on pet hairs (N=600). • Measurement of noise • Questionnaires on lifestyle and the home environment 23 lifestyle data • Nutrition: consumption of grilled or smoked food items and other fish consumption prior sampling, frequency of consumption of grilled or smoked food, fish, chewing gum, mushrooms, wild game, offal, consumption of fruits bought in supermarkets. • Home environment: traffic in the neighbourhood, type of house, rural/urban area, garden belonging to the house, industry around the house, age of the house, kind of domestic heating, use of biocides and other chemical products in the home, floor, wall and ceiling covering, age of the furniture, kind of upholstered furniture, break of a clinical thermometer in the past twelve months, rooms with mold. • Dental status: number of teeth with amalgam fillings, crowns, use of braces. • Clothing: leather clothes, piercing. • Use of drinking water: material of the water pipe system, use of filters, amount consumed. • Behaviour patterns: time spent in- and outdoors, in other countries, in traffic, in smoky rooms, on farms, duration of playing on the floor, contact to soil. • Noise: disturbance during the day and at night, noise exposure. • ETS exposure • • Data from the National Health Survey Nutrition: type/frequency/amount of milk and dairy products, other beverages, bread, butter, eggs, soups, meat, fish, fruit, vegetables, salads, noodles, rice, potatoes, fast food, cakes and sweets, nuts, supplements, special diet. Home: rooms with mold, number of pets. • Behaviour: Smoking and alcohol consumption. 24 health data Ear diseases, hearing problems, irritation of the skin, eyes and the respiratory system.

Data from the National Health Survey:

173

Germany 11 Duration of the pregnancy, pregnancy, breastfeeding, medical history of the child, accidents, physical and psychical well-being, health care utilization. Health examination: blood pressure, visual acuity, akathisia, biometry, skin status, status of the thyroid gland, beginning of puberty, urine analyses with Combur-9 test, blood analyses to detect a lack of nutrients, parameters to detect the risk of cardiovascular diseases and protection provided by vaccination. 25 parental exposure Data from the National Health Survey: Alcohol use and smoking during pregnancy, neurodermatitis, eczema, hey fever, asthma and other allergies of one of the family members. 26 medication Use of medication by the child. 27 socio-economic factors Household members, educational level of parents, home-owning, educational level of the child, family income, nationality, country of birth.

Analysis and quality control procedures 28 intra/interlaboratory testing Contractors are required to meet special standards in terms of precision and accuracy. The laboratories of the Federal Environmental Agency, which did the analytical work in previous GerES, will take part in the quality control. 29 external laboratory control Commercial ‘round robin test’ as far as available 30 accuracy, limit of detection/quantification, Data for all parameters are available and will reproducibility be published

31 data analysis (statistics, power Power calculations are based on former calculations) GerESs and on the pilot study. Statistical analysis will be performed according to a stratified plan. 32 representativity Recruitment efficiency is monitored. Non- responder analysis is ongoing.

174

Germany 11 be taken in order to minimize distress to the participant. 34 intellectual property rights 35 banking of biological samples Blood and urine samples will be stored frozen

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to The steering group including ministerial general public, to participant representatives is half-yearly informed on the progress/problems of the study. One year after the final recruitment the results of GerES will be described in a status report and communicated to the public. The participant will be given individual results compared to guideline values. Local authorities (health and environmental offices) were informed when GerES started, results will be communicated. The results of GerES are available to the general public by the web site http://www.umweltbundesamt.de/survey- e/index.htm. Results of GerES are communicated to the scientific community by publication in peer reviewed journals. 37 professionals involved , contacts between A steering group including scientists and professionals and participants ministerial representatives for the entire programme. Hot line for questions of the participants. Expert advice for the participants after getting their results is available. 38 role of media Press releases on the start of GerES and on results 39 public debate 40 consequences of external communication

41 Problems Emphasis should be laid on the recruitment of persons belonging to lower social classes as well as single working mothers. Problems to recruit immigrants are particularly dealt with. Recruitment of laboratories that perform chemical analyses is time consuming and special attention must be given to analytical control measurements.

42 Experiences

A one year pilot study on 550 randomly selected children and teenagers in four towns and villages/sampling locations was conducted in 2001. The emphasis was to get information on parameters influencing the response rate and test the suitability of the different instruments

175

Germany 11 intended to be used for the main study. This pilot study gave valuable indications for the implementation of the main phase of the survey. Internal and external quality control of the field work is essential. External quality control should be performed by a consultant. It is essential to inform public representatives in the sampling locations: the police, hospitals, public health and environmental offices.

176

Germany 12 N° General Data 1 type Pilot study for the German Environmental Survey for Children (GerES IV). Conducted in cooperation with the pilot study of the German National Health Interview and Examination Survey. Cross sectional study. 2 country Germany 3 title German Environmental Survey for Children (GerES IV) - Pilot Study 4 aim to test the practicability and compliance of the experimental methodology to be used and to find factors that might influence response rate 5 beginning date March 2001 (field work) 6 ending date March 2002 (field work) 7 contact persons Christine Schulz / Bernd Seifert Federal Environmantal Agency (Umweltbundesamt) Bismarckplatz 1 14191 Berlin Germany [email protected] +49 30 8903-1739 [email protected] +49 30 8903-1320 8 initiator Federal Environmental Agency 9 involved/responsible Federal Environmental Agency (UBA) organisations Robert Koch Institute (RKI) 10 budget available € 1 600 000 (approximately) 11 who is financing Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU)

Description of the population 12 total number of children 560 children from 4 sampling points age groups and number of 13 10 children from the age groups 0 to 8, 11, 14 and persons in each group 17 years per sampling point, chosen via registration

office 10 children from the age groups 8, 11 and 14 years per sampling point, recruited from their schools. 14 inclusion criteria, exclusion Inclusion critera: sufficient knowledge of German criteria

15 sampling strategy Subsample of children recruited for the pilot study of the German National Health Interview and Examination Survey. Recruited via registrations offices and schools. Four sampling locations in East and West Germany and in rural and urban areas. 16 time schedule of biomonitoring March 2001 to March 2002 17 consent procedures Written informed consent

177

Germany 12 18 how is participation encouraged? Results of individual measurements were offered to the parents and different incentives/gifts were tested.

Data collection 19 biomarkers of exposure - Lead, cadmium and mercury in whole blood - PCBs, DDE, HCB and HCH in whole blood - Arsenic, cadmium, mercury and creatinine in morning urine - Nicotine and cotinine in morning urine - Cortisol, adrenalin, noradrenalin in morning urine - PCP and other chlorophenols, metabolites of pyrethroides, of PAHs and of organic esters of phosphoric acid in morning urine. 20 biomarkers of effect hearing test 21 biomarkers of susceptibility

Other data 22 environmental data - Household drinking water: first draw samples analyzed for arsenic, lead, cadmium, copper, zinc, iron. - House dust: dust from vacuum cleaner bags analyzed for biocides such as pyrethroides, methoxychlorine, chorpyrifos, propoxur, eulane and DDT, HCH, HCB, PBCs, PCP, PAHs, flame retardants and plastizisers such as DEHP, as well as metals (As, B, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mn, Ni, P, Pb, Sr, Zn) - Chemical pollutants in indoor, outdoor and personal air: volatile organic compounds such as benzene and carbonyl compounds such as formaldehyde (N=112). - Biological pollutants: active measurement of air (indoors and outdoors) and dust for mould spores, house dust mites and allergens on pet hairs (homes: N=50; schools: N=10). - Measurement of noise - Questionnaires on lifestyle and the home environment 23 lifestyle data - Nutrition: consumption of grilled or smoked food items and other fish consumption prior sampling, frequency of consumption of grilled or smoked food, fish, chewing gum, mushrooms, wild game, offal. - Home environment: traffic in the neighbourhood, type of house, rural/urban area, garden belonging to the house, industry around the house, age of the house, kind of domestic heating, use of biocides and other chemical products in the home, floor, wall and ceiling covering, kind of upholstered furniture, break of a clinical thermometer in the past twelve months, rooms with mold.

178

Germany 12 - Dental status: number of teeth with amalgam fillings, crowns, use of braces. - Clothing: leather clothes, piercing. - Use of drinking water: material of the water pipe system, use of filters, amount consumed. - Behaviour patterns: time spent in- and outdoors, in other countries, in traffic, in smoky rooms, on farms, duration of playing on the floor, contact to soil. - Noise: disturbance during the day and at night, noise exposure. - ETS exposure

Data from the National Health Survey Nutrition: type/frequency/amount of milk and dairy products, other beverages, bread, butter, eggs, soups, meat, fish, fruit, vegetables, salats, noodles, rice, potatoes, fast food, cakes and sweets, nuts, supplements, special diet. Home: rooms with mold, number of pets. Behaviour: Smoking and alcohol consumption. 24 health data Ear diseases, hearing problems.

Data from the National Health Survey: Duration of the pregnancy, pregnancy, breastfeeding, medical history of the child, accidents, physical and psychical well-being, health care utilization. Health examination: blood pressure, visual acuity, akathisia, biometry, skin status, status of the thyroid gland, beginning of puberty, urine analyses with Combur-9 test, blood analyses to detect a lack of nutrients, parameters to detect the risk of cardiovascular diseases and protection provided by vaccination. 25 parental exposure Data from the National Health Survey: Alcohol use and smoking during pregnancy, neurodermatitis, eczema, hey fever, asthma and other allergies of one of the family members. 26 medication Use of medication by the child.

27 socio-economic factors Household members, educational level of parents, home-owning, educational level of the child, family income, nationality, country of birth.

Analysis and quality control procedures

28 intra/interlaboratory testing Contractors were required to meet special standards in terms of precision and accuracy. 29 external laboratory control Commercial ‘round robin test’ as far as il bl 179

Germany 12 available 30 accuracy, limit of Data for all parameters are available detection/quantification, reproducibility

31 data analysis (statistics, power Statistical analysis was performed according to calculations) a stratified plan. 32 representativity Recruitment efficiency was monitored. Non- responder analysis was performed.

Data protection and availability 33 privacy legislation Data anomymised to maintain confidentiality in accordance with the 1995 EC Data Protection Directive and the data protection legislation. Ethical advice has been taken to determine the maximum volume of blood samples that may be taken in order to minimize distress to the participant. 34 intellectual property rights 35 banking of biological samples Blood and urine samples were stored frozen

Communication (individual level, group level, level (sub)population )

36 reporting results to public authority, to The results of the pilot study will be described general public, to participant in a status report. The participant were given individual results compared to guideline values. 37 professionals involved , contacts Hot line for questions of the participants. between professionals and participants Expert advice for the participants after getting their results was available. 38 role of media Press releases on the start of the pilot study. 39 public debate 40 consequences of external communication

41 Problems The Response rate was lower than in earlier GerES with adults, lowest with teenagers. The reduced response rate went along with the level of education and the material status of the mother. 42 Experiences Age dependant incentives increased response rate. Recruitment via registrations should be preferred. In contact with migrants emphasis should be put on specific cultural aspects. It is essential to inform public representatives in the sampling locations: the police, hospitals, public health and environmental offices.

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Germany 13 N° General Data 1 type National survey in cooperation with the German National Health Examination Survey. The biomonitoring study involved adults aged 25 to 69 as well as children between 6 and 14 years of age Cross-sectional study 2 country Germany 3 title German Environmental Survey 1990/92 (GerES II) 4 aim One of the main aims of GerES was to generate, update, and evaluate representative data. These data facilitate an environmental health related observation and the reporting of information at the national level. They were also useful: • as a basis to establish reference values with regard to the levels of environmental pollutants adults and children are exposed to; • to indicate over time trends and regional differences in contaminant levels; • to identify and quantify contamination routes; • to design and evaluate preventive, interventive and control strategies within the framework of policy measures related to health and environment.

5 beginning date 1990 (field work) 6 ending date 1992 (field work) 7 contact persons Dr. Bernd Seifert, MSc Christine Schulz Federal Environmantal Agency (Umweltbundesamt) Bismarckplatz 1 14191 Berlin Germany [email protected] +49 30 8903-1320 [email protected] +49 30 8903-1739 8 initiator Federal Environmental Agency 9 involved/responsible Institute for Water, Soil and Air Hygiene of the Federal organisations Health Office, since 1994 of the Federal Environmental Agency (UBA) Robert Koch Institute (RKI) Infratest Health Research, Munic; Epidemiological Research, Berlin, Center of Epidemiology and Health Research, Zepernick 10 budget available DM 5,5 Mio. (approximately) 11 who is financing Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU)

Description of the population 12 total number of children 812 children 13 age groups and number of persons in 453 children from West-Germany aged 6 to 14 each group and 359 children/teenager from East-Germany

181

Germany 13 aged 6 to 17 (6 to 14 years: 283). 14 inclusion criteria, exclusion criteria Inclusion criteria: living in the household of the participating adults exclusion criteria: migrants 15 sampling strategy Adults: Randomly selected from the cross- sectional sample of the German National Health Examination Survey, representatively chosen for age, gender, community size and region (East and West Germany), drawn in a multistage random sampling. Recruited via registrations offices from 150 sample points Children: Living in the household of the participating adult subjects. 16 time schedule of biomonitoring October 1990 to May 1992 17 consent procedures Written informed consent 18 how is participation encouraged? Results of individual measurements were offered to the parents. Incentives (20,--DM) for the children

Data collection 19 biomarkers of exposure - Lead, cadmium, copper, and mercury in whole blood (N=784) - Arsenic, cadmium, chromium, copper, mercury, and creatinine in morning urine (N=785). - Nicotine and cotinine in morning urine (N=785) - PCP in morning urine (N=695) - Scalp hair (100 mg occipital, 4 cm proximal): samples analyzed for trace elements (Al, Ba, B, Cd, Ca, Cr, Cs, Cu, Mg, P, Pl, Pt, Pb, Sr, Tl, U, Zn, V, nicotine and cotinine) 20 biomarkers of effect FEP in whole blood 21 biomarkers of susceptibility

Other data

22 environmental data - Household drinking water: spontaneous and first draw; samples analyzed for lead, cadmium, calcium, copper, iron, magnesium, sodium, zinc (N=720 children). - Samples from the waterworks serving the households surveyed: aluminium, barium, boron, manganese, nickel, phosphorus, potassium, strontium, chloride, nitrate, sulphate. - House dust: dust from vacuum cleaner bags analyzed for trace elements (Al, As, B, Ba, Cd, Ca, Cr, Cu, Fe, Li, Ni, Mg, Mn, P, Pb, Sr, Zn, (N=3900 adults households), γ-HCH and PCP (N=850 adults households)

182

Germany 13 biocides such as permethrine, PBO (N=1200 adults households) - House dust: deposited dust during one year in the room where children (and adults) spent most of their time during the day; samples analyzed for trace elements (Al, As, B, Ba, Pb, Cd, Ca, Cr, Cu, Fe, Li, Mg, Mn, Ni, Na, P, Sr, Zn) (N=600 children) - Dust fall outdoors (Bergerhoff-gauge); samples analyzed for trace elements ( As, B, Pb, Cd, Ca, Cr, Cu, Fe, Mg, P, Zn) 23 lifestyle data - Nutrition: frequency of the consumption of several foodstuffs and beverages (milk and dairy products, bread, butter, eggs, soups, meat, fish, fruit, vegetables, salads, noodles, rice, potatoes, fast food, cakes and sweets, nuts,) supplements, special diet. - Home environment: traffic in the neighbourhood, type of house, rural/urban area, garden belonging to the house, industry around the house, age of the house, kind of domestic heating, use of biocides and other chemical products in the home, floor, wall and ceiling covering, number of pets - Dental status: number of teeth with amalgam fillings - Use of drinking water: material of the water pipe system, use of filters, - Behaviour patterns: time spent in- and outdoors, in traffic, in smoky rooms, contact to soil, hobby activities - ETS exposure 24 health data Diseases, frequency of unspecific and specific health complaints (headache, deficiency of concentration, absence of appetite, allergies, bronchitis)

BMI, Combur-9 and micral test in morning urine of the children living in East Germany contacts to medical institutions 25 parental exposure 26 medication use of the medication by the child 27 socio-economic factors Household members, educational level of parents, home-owning, educational level of the child, family income, nationality, country of birth.

Analysis and quality control procedures 28 intra/interlaboratory testing Contractors are required to meet special standards in terms of precision and accuracy. 29 external laboratory control Commercial ‘round robin test’ as far as available

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Germany 13 30 accuracy, limit of Data for all parameters are available and detection/quantification, reproducibility published 31 data analysis (statistics, power Statistical analysis will be performed according calculations) to a stratified plan. 32 representativity Recruitment efficiency was monitored.

Data protection and availability 33 privacy legislation Data anomymised to maintain confidentiality in accordance with the data protection legislation. Ethical advice was taken to determine the maximum volume of blood samples that was taken in order to minimise distress to the participant. 34 intellectual property rights 35 banking of biological samples Whole blood and morning urine samples were stored frozen

Communication (individual level, group level, level (sub)population) 36 reporting results to public authority, to The ministerial representatives was half-yearly general public, to participant informed on the progress/problems of the study. Results of GerES IIt were communicated to the scientific community by publication of 13 reports of the Institute of Water, Soil and Air Hygiene and in several articles in scientific and peer reviewed journals. The participant were given individual results compared to guideline values. Local authorities (health and environmental offices) were informed when GerES started and results were communicated The results of the monitoring campaigns were available to the general public by the web site http://www.umweltbundesamt.de/survey- e/index.htm. 37 professionals involved , contacts For scientific experts had evaluated the entire between professionals and participants survey.

Expert advice for the participants after getting their results were available. 38 role of media Press releases on the start of the study and on the results 39 public debate 40 consequences of external communication

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Germany 13 41 Problems Emphasis was laid on the recruitment of persons belonging to lower social classes.

42 Experiences Internal and external quality control of the field work was essential. External quality control was performed by a consultant. It was essential to inform public representatives in the sampling locations: the police, hospitals, public health and environmental offices.

185

Germany 14 N° General Data 1 type Regional biomonitoring study + survey The biomonitoring study involves 3 age groups - 5 - 7 years - 8 - 10 years - 11 – 14 years

2 country Germany, Sachsen-Anhalt 3 title Bitterfeld Study 4 aim 1. Regional comparisons of internal burden with heavy metals in three East German areas including a smelter area 2. Temporal changes of body burden with heavy metals 3. To identify potential sources of heavy metal body burden. 5 beginning date 1992 6 ending date 1999 7 contact person Dr. Joachim Heinrich GSF- National Research Center for Environment and Health Institute of Epidemiology Unit of Environmental Epidemiology Ingoslstädter Landstraße 1 D-85764 Neuherberg Tel. +49-89-3187 4150 Fax +49-89-3187 3380 Email: [email protected] 8 initiator GSF- National Research Center for Environment and Health Institute of Epidemiology 9 involved/responsible WaBoLU of Umweltbundesamt, organisations Berlin, Federal Environmental Office 10 budget available € 500 000 (approx.) 11 who is financing Federal Environmental Office (Umweltbundesamt)

Description of the population 12 total number of children 5000 13 age groups and number of persons in each Age groups: group 1. 5 – 7 years: 20 % 2. 8 – 10 years: 35 % 3. 11 – 14 years: 45 %

14 inclusion criteria, exclusion criteria Inclusion criteria are: Written informed consent 15 sampling strategy - Total sampling of all children from Hettstedt & Zerbst - Random cluster sampling (by school) in Bitterfeld area 16 time schedule of biomonitoring All the year 17 consent procedures - Parents - Child’s consent

186

Germany 14 18 how is participation encouraged? - Results of individual measurements and of the entire study are offered to the participants and also a small present

Data collection 19 biomarkers of exposure Cadmium, lead and mercury in blood, cadmium and arsenic in urine, nicotine and cotinine in urine (in a subset of 1000 children only). 20 biomarkers of effect no 21 biomarkers of susceptibility no

Other data 22 environmental sampling - Content of heavy metals in settled house dust (subset of 450 children), and measurements of lead in tape water. - Monitoring data of ambient air quality 23 lifestyle data Home grown vegetables intake Passive smoking of the mother, contact with chemicals, hobbies, pets (questionnaire), time spent outdoors/indoors, exposure to traffic. 24 health data - Birth weight, preterm birth - Allergies, eczema, respiratory problems, illnesses in the past 14 days and past year - Allergic sensitization (SPT, RAST) - Lung function data - WBC, RBC 25 parental exposure - Asthma or allergy in the family. Home environment: traffic intensity, heating, occupational exposure to heavy metals - idem 26 medication - Use of antibiotics by the infant 27 socio-economic factors - Structure of the family, educational level of parents

Analysis and quality control procedures 28 intra/interlaboratory testing An inventory of quality assurance programs used in the contracting laboratories is made. 29 external laboratory control ‘Round robin test’ 30 accuracy, limit of detection/quantification, Data for all parameters are available on reproducibility request 31 data analysis (statistics, power calculations) Results were published 32 representativity High Response also for blood sample availability (> 75 %)

187

Germany 14 Data protection and availability 33 privacy legislation Samples and questionnaires are maintained by the responsible medical doctor and subsequently anonymised in order to maintain confidentiality under secure conditions in accordance with the 1995 EC Data Protection Directive and data protection legislation. Measures are taken to ensure confidentiality and security of the data.

34 intellectual property rights No patents. Data were published. 35 banking of biological samples Yes

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to general Results are reported to parents and children, public, to participant local authorities and funding agency. 37 professionals involved , contacts between professionals and participants 38 role of media 39 public debate Several public presentations before and after investigations. 40 consequences of external communication

41 Problems

42 Experiences 43 References:

Trepka MJ, Heinrich J, Krause C, Schulz C, Lippold U, Meyer E, Wichmann HE. The internal burden of lead among children in a smelter town - a small area analysis. Environ. Res. 72, 118- 130 (1997). Trepka MJ, Heinrich J, Krause C, Schulz C, Wjst M, Popescu M, Wichmann HE. Factors Affecting Internal Mercury Burdens among Eastern German Children. Arch. Environ. Health 52, 134-138 (1997).

Meyer I, Heinrich J, Trepka MJ, Krause C, Schulz C, Meyer E, Lippold U. The effect of lead in tap water on blood lead in children in a smelter town. Sci. Total Environ. 209, 255-271 (1998). Ritz B, Heinrich J, Wjst M, Wichmann HE, Krause, C. Effect of cadmium body burden on immune response of school children. Arch. Environ. Health 53, 272-280 (1998). Meyer I, Heinrich J, Lippold U. Factors affecting lead, cadmium, and arsenic levels in house dust in a smelter town in Eastern Germany. Environ. Res. Section A 81, 32-44 (1999). Meyer I, Becker K, Lippold U, Meyer E, Wichmann HE, Heinrich J. Biomonitoring von Blei und

188

Germany 14 Cadmium bei Frauen aus industriellen Regionen Sachsen-Anhalts. Umweltmed Forsch Prax 2003; 8(4):227-236. Meyer I, Hoelscher B, Frye C, Becker K, HE Wichmann, J Heinrich. Temporal changes in blood lead levels of children in East Germany. Int J Hyg Environ Health 2003; 206:181-192.

189

Germany 15 N° General Data 1 type biomonitoring study – exposure assessment The biomonitoring study involves 4 age groups - 0-<6 y - 6-<12 y - 12-<20 y - Adults (nonsmoker and smoker)

2 country Germany, City of Frankfurt on the Main 3 title Internal exposure to PAHs of children and adults living in homes with parquet flooring containing high levels of PAHs in parquet glue. 4 aim To evaluate internal exposure to PAHs in a urban population – living in homes with PAH containing parquet glue and elevated levels of PAHs in household dust, compared with persons living in homes without PAH in parquet glue or in household dust – evaluation of the impact of PAH in the home on internal PAH exposure of the inhabitants 5 beginning date 1998 6 ending date 1998 7 contact person Dr. Ursel Heudorf Public Health Department of the City of Frankfurt Braubachstrasse 18-22 D-60311 Frankfurt Germany Tel: 0049-69-21236980 Fax: 0049/69-21230475 e-mail: [email protected] 8 initiator Public Health Department of the City of Frankfurt 9 involved/responsible Institute for occupational, Social and Environmental organisations Medicine, University Erlangen-Nürnberg, Germany 10 budget available - 11 who is financing City of Frankfurt

Description of the population 12 total number of children (and parents) About 10 000 persons total living in the former US-housing; 1213 had their urine tested for PAH metabolites; i.e. > 10 % of the total population; 27 % of the children < 6 y of age, 22 % of the children 6-12 y of age 13 age groups and number of persons in each 0-<6 y: 347 group 6-<12 y:261 12-<20 y: 110 adults: 495 14 inclusion criteria, exclusion criteria Inclusion criteria were: Written informed consent (by their parents)

190

Germany 15 living in the former US-housing of Frankfurt/M 15 sampling strategy Voluntary participation, no exclusion criteria 16 time schedule of biomonitoring February 1998 – December 1998 17 consent procedures - Children: written informed consent by mother or father - Adults: written informed consent by themselves 18 how is participation encouraged? - Information via mass media - Leaflets in post boxes - Information evenings

Data collection 19 biomarkers of exposure Levels of hydroxypyrene und monohydroxylated phenanthrenes in urine specimen 20 biomarkers of effect - 21 biomarkers of susceptibility - Questionnaire for symptoms and diseases Other data 22 environmental sampling - Assessment of indoor exposure via analyses of household dust samples and parquetglue for BaP 23 lifestyle data - 24 health data - Children: standardised questionnaire – modified ISAAC-questionnaire - Adults: standardised questionnaire, modifies Düsseldorf-questionnaire 25 parental exposure - 26 medication - 27 socio-economic factors -

Analysis and quality control procedures 28 intra/interlaboratory testing Quality control according to German Society of Occupational and Environmental medicine 29 external laboratory control Internal and external quality assurance sceme according to the guidelines of the chamber of the physicians in Germany 30 accuracy, limit of detection/quantification, Data for all parameters are available on reproducibility request

31 data analysis (statistics, power SPSS Version 8 calculations) 32 representativity Not representative – but no hints for bias

Data protection and availability 33 privacy legislation Data are stored after anonymisation, PC;

191

Germany 15 34 intellectual property rights No patents. Data are published , i.e. Heudorf U, Angerer J: Internal exposure to PAHs of children and adults living in homes with parquet flooring containing high levels of PAHs in parquet glue. Int Archives of Occupational and Environmental Medicine (2001) 74: 91-101. Heudorf U, Angerer J: Humanbiomonitoring auf PAK-Metaboliten im Urin von Kindern aus Wohnungen mit PAK-haltigem Parkett-kleber – Ergebnisse aus der umweltmedi-zinsichen Sprechstunde des Frankfurter Gesundheitsamtes. Umweltmed Forsch Prax (2000) 5: 218-226. 35 banking of biological samples -

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to Individual data have been given to the general public, to participant participants (or their parents), anonymised data have been used for reports to the local politics scientific data have been published: (See 34) 37 professionals involved , contacts between Physicians on the Public Health services in professionals and participants Frankfurt an Pediatricians of the families; Scientist in Human-Biomonitoring (university Erlangen) 38 role of media The study was given attention in newspapers, radio 39 public debate The study results have been discussed on various congresses and have been published (s. 34) 40 consequences of external communication According to the data – showing no increment in internal exposure of PAHs– even in small children playing on the floor – no “danger for health” could be detected and thus no regulations could be published forcing the owners to redevelop homes with PAH containing parquet glue. 41 Problems 42 Experiences Results: Though high levels of PAHs were detected in parquet glue an increment in internal exposure of the inhabitants was not to be seen, even in small children playing on the floor.

192

Germany 16 N° General Data 1 type biomonitoring study – exposure assessment The biomonitoring study involves one age group 0-<6 y 2 country Germany, City of Frankfurt on the Main 3 title Exposure to environmental tobacco smoke in children and its impact on urinary levels of metabolites of polycyclic aromativ hydrocarbons (PAHs) 4 aim To evaluate the impact of passive smoking at home on internal exposure of children to PAHs 5 beginning date 1998 6 ending date 1998 7 contact person Dr. Ursel Heudorf Public Health Department of the City of Frankfurt Braubachstrasse 18-22 D-60311 Frankfurt Germany Tel: 0049-69-21236980 Fax: 0049/69-21230475 e-mail: [email protected] 8 initiator Public Health Department of the City of Frankfurt 9 involved/responsible Institute for occupational, Social and Environmental Medicine, organisations University Erlangen-Nürnberg, Germany 10 budget available - 11 who is financing City of Frankfurt

Description of the population

12 total number of children (and parents) 101 children 13 age groups and number of persons in each 0-<6 y: 101 group 14 inclusion criteria, exclusion criteria Inclusion criteria were: Written informed consent (by their parents) living in the former US-housing of Frankfurt/M data on exposure to environmental tobacco smoke at home 15 sampling strategy Voluntary participation 16 time schedule of biomonitoring February 1998 – December 1998 17 consent procedures Children: written informed consent by mother or father 18 how is participation encouraged? 3. Information via mass media 4. Leaflets in post boxes 5. Information evenings

Data collection

193

Germany 16 19 biomarkers of exposure Levels of hydroxypyrene und monohydroxylated phenanthrenes in urine specimen 20 biomarkers of effect -

21 biomarkers of susceptibility - Questionnaire for symptoms and diseases Other data 22 environmental sampling - 23 lifestyle data - 24 health data Children: standardised questionnaire – modified ISAAC-questionnaire 25 parental exposure - 26 medication - 27 socio-economic factors -

Analysis and quality control procedures 28 intra/interlaboratory testing Quality control according to German Society of Occupational and Environmental medicine

29 external laboratory control Internal and external quality assurance sceme according to the guidelines of the chamber of the physicians in Germany 30 accuracy, limit of detection/quantification, Data for all parameters are available on reproducibility request 31 data analysis (statistics, power SPSS Version 8 calculations) 32 representativity Not representative – but no hints for bias Data protection and availability 33 privacy legislation Data are stored after anonymisation, PC; 34 intellectual property rights No patents. Data are published , i.e. Heudorf U, Letzel S, Angerer J, Drexler H: Exposure to environmental tobacco smoke in children and its impact on urinary levels of metabolites of polycyclic aromatic hydrocarbons (PAHs) Umweltmed Forsch Prax (2001) 6: 336-342 (German)

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to anonymised data have been used for reports to general public, to participant the local politics scientific data have been published: (See 34) 37 professionals involved , contacts between Physicians on the Public Health services in professionals and participants Frankfurt an Pediatricians of the families; Scientist in Human-Biomonitoring (university

194

Germany 16 Erlangen) 38 role of media -

39 public debate The study results have been discussed on the congress of the International Society of Environmental Medicine (ISEM) and have been published (s. 34) 40 consequences of external communication 41 Problems 42 Experiences Exposure to environmental tobacco smoke (i.e. level of urinary cotinine) in young children is associated to a significant increase in the level of 1-hydroxypyrene, but not to the levels of monohydroxylated phenanthrenes

195

Germany 17 N° General Data 1 type Regional biomonitoring study The biomonitoring study involves 3 age groups - 0-<6 y - 6-<12 y - 3.12-<18 y - (4. Adults )

2 country Germany, City of Frankfurt on the Main 3 title Internal exposure to pesticides in a urban population 4 aim To evaluate internal exposure to pesticides in a population living in former US forcing houses, where in former times chlorpyrifos (an organophosphorous insecticide) might have been used. There were no hints for increased external exposure to pyrethroids in the homes. 5 beginning date 1998 6 ending date 1998 7 contact person Dr. Ursel Heudorf Public Health Department of the City of Frankfurt Braubachstrasse 18-22 D-60311 Frankfurt Germany Tel: 0049-69-21236980 Fax: 0049/69-21230475 e-mail: [email protected] 8 initiator Public Health Department of the City of Frankfurt 9 involved/responsible Institute for occupational, Social and Environmental Medicine, organisations University Erlangen-Nürnberg, Germany 10 budget available - 11 who is financing City of Frankfurt

Description of the population 12 total number of children (and parents) About 10 000 persons total living in the former US-housing; > 1100 had their urine tested for organophosphorous and pyrethoid metabolites; i.e. > 10 % of the total population; > 25 % of the children < 6 y of age, > 20 % of the children 6-12 y of age 13 age groups and number of persons in each 0-<6 y: 331 group 6-<12 y:247 12-<20 y: 108 adults: 483 14 inclusion criteria, exclusion criteria Inclusion criteria were: Written informed consent (by their parents) living in the former US-housing of Frankfurt/M 15 sampling strategy Voluntary participation, no exclusion criteria

196

Germany 17 - Children are recruited via schools 16 time schedule of biomonitoring February 1998 – December 1998 17 consent procedures - Children: written informed consent by mother or father - Adults: written informed consent by themselves 18 how is participation encouraged? - Information via mass media - Leaflets in post boxes - Information evenings

Data collection 19 biomarkers of exposure Urinary metabolites of organophosphorous and pyrethroid insecticides 20 biomarkers of effect - 21 biomarkers of susceptibility - Questionnaire for symtoms and diseases Other data 22 environmental sampling Assessment of indoor exposure via analyses of household dust samples for different pesticides 23 lifestyle data - 24 health data - Children: standardised questionnaire – modified ISAAC-questionnaire - Adults: standardised questionnaire, modified Düsseldorf-questionnaire 25 parental exposure - 26 medication - 27 socio-economic factors -

Data protection and availability 33 privacy legislation Data are stored after anonymisation, PC; 34 intellectual property rights No patents. Data are published 1 Heudorf U, Angerer J, Drexler H: Current internal exposure to pesticides in children and

197

Germany 17 adolescents in Germany:- II. Urinary levels of metabolites of pyrethroid and organophosphorous insecticides. Int Arch Occup Environ Med, in press 2. Heudorf U, Angerer J: Metabolites of pyrethroid insecticides in urine specimens: current exposure in an urban population in Germany. Environmental Health Perspectives (2001) 109: 213-217. 3. Heudorf U, Angerer J: Metabolites of organophosphorous insecticides in urine specimens from inhabitants of a residential area. Environmental Reasearch (2001) 86: 80- 87. 4. Heudorf U, Angerer J, Drexler H: Abschätzung der Exposition gegenüber Organophosphaten und Pyrethroiden in einer Großstadtbevölkerung in Deutschland. Umweltmedizin in Forschung und Praxis (2003) 8: 79-85

35 banking of biological samples

41 Problems

42 Experiences Participation was voluntary, the population was very much interested. With regard to the great public interest, redevelopment of the flats had been done – in spite

198

Germany 17 of the fact, that there were no hints for an impact of the external exposure (indoor exposure, as assessed via analysing household dust samples). Data on current background exposure of an urban population – children and adults – are obtained. Data are useful for exposure assessment to pesticides of an urban population in Germany

199

Germany 18 Number General Data 1 type Regional biomonitoring study The biomonitoring study involves 3 age groups - 0-<6 y - 6-<12 y - 12-<18 y - (4. Adults )

2 country Germany, City of Frankfurt on the Main 3 title Internal exposure to pesticides in a urban population 4 aim To evaluate internal exposure to pesticides in a population living in former US forcing houses, where in former times DDT might have been used. There were no hints for increased external exposure to PCP or lindane in the homes. 5 beginning date 1998 6 ending date 1998 7 contact person Dr. Ursel Heudorf Public Health Department of the City of Frankfurt Braubachstrasse 18-22 D-60311 Frankfurt Germany Tel: 0049-69-21236980 Fax: 0049/69-21230475 e-mail: [email protected] 8 initiator Public Health Department of the City of Frankfurt 9 involved/responsible Institute for occupational, Social and Environmental organisations Medicine, University Erlangen-Nürnberg, Germany 10 budget available - 11 who is financing City of Frankfurt

Description of the population

12 total number of children (and parents) 130 children and adolescents, 13 age groups and number of persons in 0-<6 y: 30 each group 6-<12 y: 60 12-<20 y: 40 20-<30 y: 59 30-<40 y: 255 40-<50y: 138 > 50y: 33 14 inclusion criteria, exclusion criteria Inclusion criteria are: Written informed consent (by their parents) living in the former US-housing of Frankfurt/M 15 sampling strategy Voluntary participation, no exclusion criteria - Mothers-newborns are recruited via the

200

Germany 18 maternity department - Children are recruited via schools 16 time schedule of biomonitoring February 1998 – December 1998 17 consent procedures - Children: written informed consent by mother or father - Adults: written informed consent by themselves 18 how is participation encouraged? - Information via mass media - Leaflets in post boxes - Information evenings

Data collection 19 biomarkers of exposure PCP, lindane, DDE/T in blood plasma 20 biomarkers of effect - 21 biomarkers of susceptibility - Questionnaire for symptoms and diseases Other data 22 environmental sampling Assessment of indoor exposure via analyses of household dust samples for different pesticides 23 lifestyle data - 24 health data - Children: standardised questionnaire – modified ISAAC-questionnaire - Adults: standardised questionnaire, modifies Düsseldorf-questionnaire 25 parental exposure - 26 medication - 27 socio-economic factors -

Analysis and quality control procedures 28 intra/interlaboratory testing Quality control according to German Society of Occupational and Environmental medicine

29 external laboratory control Internal and external quality assurance sceme according to the guidelines of the chamber of the physicians in Germany 30 accuracy, limit of Data for all parameters are available on detection/quantification, reproducibility request 31 data analysis (statistics, power SPSS Version 8 calculations) 32 representativity Not representative – but no hints for bias

Data protection and availability 33 privacy legislation Data are stored after anonymisation, PC; 34 intellectual property rights No patents .Data are published Heudorf U, Angerer J, Drexler H: Current

201

Germany 18 internal exposure to pesticides in children and adolescents in Germany. Blood plasma levels of pentachlorophenol (PCP), lindane (g-HCH), and dichloro-diphenyle-ethylene (DEE), a biostable metabolite of dichloro-diphenyl- trichloroetheane (DDT) Int J Hyg Environ Med (2003) 206: 485-491

Stadtgesundheitsamt: Umweltmedizinische Sprechstunde für Bewohner der ehema-ligen US-Housing in Frankfurt am Main. Ergebnisse der Blut- und Urinunter-suchungen auf PAK, PCB und Pestizide oder deren Stoffwechselprodukte. Frankfurt, im Oktober 1999. 35 banking of biological samples

41 Problems 42 Experiences Participation was voluntary, the population was very much interested. With regard to the great public interest, redevelopment of the flats had been done – in spite of the fact, that there were no hints for an impact of the external exposure (indoor exposure as assesses via analysing household dust samples) to internal exposure. With regard to PCP, a decrease in internal exposure of the adult population during the 1990s could be demonstrated; regarding children, for the first time analyses had been published for internal exposure to PCP, DDE/T, and lindane during the whole childhood (newborns – adolescents)

202

Germany 19 N° General Data 1 type Regional biomonitoring study The biomonitoring study involves 8 age groups - 0-<6 y - 6-<12 y - 12-<18 y - 18-25 y - 26-35 y - 36-45 y - 46-55 y - > 55 y

2 country Germany, City of Frankfurt on the Main 3 title Internal exposure to PCB in a urban population without any hints for increased inhalatory exposure in their homes 4 aim To evaluate internal exposure to PCBs in a population living in former US forcing houses, where indoor air levels of PCB were low and within the national guidelines (<< 300 ng/m3) 5 beginning date 1998 6 ending date 1998 7 contact person Dr. Ursel Heudorf Public Health Department of the City of Frankfurt Braubachstrasse 18-22 D-60311 Frankfurt Germany Tel: 0049-69-21236980 Fax: 0049/69-21230475 e-mail: [email protected] 8 initiator Public Health Department of the City of Frankfurt 9 involved/responsible Institute for occupational, Social and Environmental Medicine, organisations University Erlangen-Nürnberg, Germany 10 budget available - 11 who is financing City of Frankfurt

Description of the population 12 total number of children (and parents) 624 13 age groups and number of persons in each 0-<6 y: 30 group 6-<12 y: 60 12-<18 y: 40 18-25 y: 28 26-35 y: 205 36-45 y: 200 46-55 y: 50 > 55 y: 11

14 inclusion criteria, exclusion criteria Inclusion criteria are: Written informed consent (by their parents)

203

Germany 19 living in the former US-housing of Frankfurt/M 15 sampling strategy Voluntary participation, no exclusion criteria 16 time schedule of biomonitoring February 1998 – December 1998 17 consent procedures - Children: written informed consent by mother or father - Adults: written informed consent by themselves 18 how is participation encouraged? - Information via mass media - Leaflets in post boxes - Information evenings

Data collection 19 biomarkers of exposure PCB in blood plasma 20 biomarkers of effect - 21 biomarkers of susceptibility - Questionnaire for symptoms and diseases Other data 22 environmental sampling Assessment of indoor exposure via analyses of household dust samples and – partly for PCB levels in the indoor air 23 lifestyle data - 24 health data - Children: standardised questionnaire – modified ISAAC-questionnaire - Adults: standardised questionnaire, modifies Düsseldorf-questionnaire 25 parental exposure - 26 medication - 27 socio-economic factors -

31 data analysis (statistics, power SPSS Version 8 calculations) 32 representativity Not representative – but no hints for bias

Data protection and availability 33 privacy legislation Data are stored after anonymisation, PC;

34 intellectual property rights No patents. Data are published

204

Germany 19 Heudorf U, Angerer J, Drexler H: Polychlorinated biphenyls in the blood plasma: Current exposure of the population in Germany. Reviews on Environmental Health (2002) 17: 123-134

Heudorf U, Angerer J: Polychlorierte Biphenyle (PCB) im Blutplasma von Kindern und Jugendlichen. Montasschrift Kinderheilkunde (2003) 151: 293-300. 35 banking of biological samples

41 Problems

42 Experiences For the first time data were obtained on current PCB levels in blood plasma in an urban population in Germany in 1998 – through all ages, from newborns to old persons. The data show, that during childhood PCB levels in blood plasma are decreasing (especially in formerly breastfed infants) and that they are increasing with age in adults. The data show a decrease in PCB levels in adults since the years 1991-4.

205

Germany 20 N° General Data 1 type Regional survey and human biomonitoring study The survey involved three follow-up studies over three years of the same group of children. Start first survey: children 7-10 years , second-grade school children . 2 country Germany 3 title Human-biomonitoring around the hazardous waste incinerator “SVA Biebesheim” (South of the Federal State of Hesse) 4 aim Waste incinerators and their emissions of hazardous compounds into the ambient air play an important role and are of great public concern. The potential risks to the health of the surrounding population are often discussed. Most notably the exposures caused by of organic chlorine substances and heavy metals are of interest. In this context the government of Hesse caused an extensive monitoring program surrounding a hazardous waste incinerator. These program contained an ecosystem monitoring, measurements of emissions and immissions loads and a human-biomonitoring. The aim of the human-biomonitoring was directed at school-children (second-level) lived near by and far away the hazardous waste incinerator. The purpose was to assess the internal body burden of heavy metals and organochlorine compounds and to study the prevalence and incidence of respiratory health and some biological markers. Specific objectives were: to obtain evidences of regionaly differences to body burden and health status; to describe and to get more informations on possible routes and sources of exposure; to identify whether subgroups of the children was at higher risk to health effects from exposure to emissions from the hazardous waste incinerator. 5 beginning 1994 date 6 ending 1999 date 7 contact Dr. Hermann Kruse person Klinikum der Christian-Albrechts-Universität Kiel Institut für Toxikologie Brunswiker Str. 10 24105 Kiel Germany Tel.: +49 (0)431- 5973540 Email: [email protected]

Nadia Obi-Osius Epidemiological Working Group Winterhuder Weg 29 22085 Hamburg Germany

206

Germany 20 Tel.: +49 (0)40-428636069 Email: [email protected] 8 initiator Ministry of Health, Hesse, Germany 9 involved/re Staatliches Medizinal-, Lebensmittel- und Veterinäruntersuchungsamt sponsible Mittelhessen, Abtlg. Humanmedizin, Dillenburg; organisatio Fakultät für klinische Medizin der Universität Heidelberg Institut für klinische Chemie am Klinikum Mannheim; ns Hessische Landesanstalt für Umwelt, Wiesbaden; Hessisches Ministerium des Innern und für Landwirtschaft, Forsten und Naturschutz; Laborgemeinschaft Kramer und Partner, Geesthacht; GQH-Geschäftsstelle Qualitätssicherung Hessen Gesundheitsämter der Kreise Groß-Gerau, Bergstraße, Darmstadt, Odenwaldkreis Kommunale Arbeitsgemeinschaft „SAV Biebesheim“; Regionale Ärzteschaft; Regionale Umweltinitiativen 10 budget € 1 900 000 (approximately) available 11 who is Government of Hesse, Germany financing

Description of the population 12 total number of children 671 children 13 age groups and number of persons in Age groups: each group 1.survey: 7-10 years (second-grade school children) 671 children; the identical children were monitored again: 2.survey follow-up: 9-11 years 609 children; 3.survey follow-up: 10-13 years 567 children.

Number of persons: 1. exposed group living nearest the incinerator: 1.survey 362 children; 3.survey follow-up 293 children. 2. control group living 20 km north of the incinerator: 1.survey 126 children; 3.survey follow-up 110 children 3. control group living in low mountains 50 km east of the incinerator: 1.survey 183 children; 3.survey follow-up 142 children 14 inclusion criteria, exclusion criteria Inclusion criteria are: school-children of the communities child participate in blood sampling if passive smoking did not exceed 10 cigarettes in the previous 12 months (parents were asked).

207

Germany 20 15 sampling strategy - local schools and parents were asked for participation - Children were recruited via local schools 16 time schedule of biomonitoring - survey oktober 1994 - january 1995 - 2.survey january - march 1996 - 3.survey january - march 1997 17 consent procedures - permission from the Data Protection Ageny of the state of Hamburg, Germany - informed consent was obtained from the local school committees - informed consent was obtained from parents 18 how is participation encouraged? T-shirts offered in the 2. and 3.survey

Data collection

19 biomarkers of exposure

Heavy metals and organic compunds 1. Survey 1994/95 2. Survey 1996 3. Survey 1997 urine whoole blood hair urine urine whoole blood Mercury Hg Hg Hg Hg Chromium total Cr Cr Cr Lead Pb Pb Cadmium Cd Cd Arsenic As As Selenium Se PCB (Kongenere) 8 PCB 11 PCB DDT / DDE DDE DDT/DDE Hexachloro-benzene HCB HCB Hexachloro-cyclohexane Isomere α, β, γ-HCH α, β, γ-HCH Chlorophenols 10 chlorophenols

20 biomarkers of effect

1. Survey 1994/95 2. Survey 1996 3. Survey 1997 urine blood/serum urine urine blood/serum δ-ALS, porphobilinogen, porphyrin albumin calcium phosphate creatinine creatinine creatinine creatinine creatinine

208

Germany 20 blood count red/white Leukozyten, Erythrozyten, MCV, MCH, MCHC platelet Ferritin lymphocyte- subset immunglobuline M, G, A, E C-reactive protein iodine TSH, FT3, FT4 TSH, FT3, FT4 cholesterol triglyceride cholesterol triglyceride liver enzyme: GGT, GPT albumin calcium sodium potassium potassium iron

21 biomarkers of susceptibility

Other data 22 environmental sampling self-administered questionnaires were used in the survey: the living conditions, traffic,home environment, building constructions, heating, use of pesticides in house/garden 23 lifestyle data self-administered questionnaires were used in the survey: nutrition of the families, see also no. 22 24 health data 3. self-administered questionnaires were used in the survey: anamnestical data of the child (allergies, eczema) 4. self-administered questionnaires were used in the survey: respiratoy health and 5. tests of lung function (FEV, bronchial hyperreactivity) 25 parental exposure self-administered questionnaires were used in the survey: a. demographic and anamnestical data of the mother and father b. reproductive interview (duration of the pregnancy, number of birth, breastfeeding) 26 medication self-administered questionnaires were used in the survey, see also no.24 27 socio-economic factors self-administered questionnaires were used in the survey: 1. demographic data, education of the familiy. 2. occupational situation 3. the school situation

Analysis and quality control procedures 28 intra/interlaboratory testing certificated analysis of certificated standards of the international bureau of standards

209

Germany 20 29 external laboratory control Interlaboratory control (certification) 30 accuracy, limit of accuracy, limit of detection, reproducibility detection/quantification, reproducibility according to GLP

31 data analysis (statistics, power calculations) 32 representativity

Data protection and availability 33 privacy legislation 34 intellectual property rights 35 banking of biological samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to general public, to participant 37 professionals involved , contacts between professionals and participants 38 role of media 39 public debate 40 consequences of external communication

41 Problems

42 Experiences

210

Germany 21 N° General data 1 type regional cross-sectional study on asthma and allergies with three centres (Dresden, Leipzig and Munich) 2 country Germany 3 title German ISAAC Phase two Study 4 aim 1) Investigation of prevalence differences between East- and West- Germany 2) Identification of determinants of asthma and allergies and the prevalence differences in East- and West-Germany: • Association of occurrence and severity of symptoms of asthma, allergic rhinitis and atopic eczema with skin prick test reactivity, serum IgE levels, signs of flexural dermatitis, and bronchial responsiveness within and between centres • Association of known and suspected risk factors, as assessed by parental questionnaire and measurements of indoor exposure, with symptoms and other markers of asthma, allergic rhinitis and atopic eczema within and between centres • Extent to which the above risk factors can explain the observed variation in the prevalence between East and West Germany • Association of genetic factors and asthma and allergies, including their interaction with environmental exposures 5 beginning date 1995 6 ending date 1997 7 contact person Prof. Stephan Weiland Abteilung Epidemiologie Universität Ulm Helmholtzstr.22 D-89081 Ulm

E-mail: [email protected] Tel: ++49 731 50 31060 Fax: ++49 731 50 31069 8 initiator Institute of Epidemiology and Social Medicine, University of Münster 9 involved/responsible Institute of Epidemiology and Social Medicine, University of Münster; organisations Dept. of Epidemiology, University of Ulm; Munich University Children's Hospital; Children's Clinic, Technical University Dresden; Leipzig University Children's Hospital; Institute of Clinical Chemistry and Biochemistry, University of Berlin; 10 budget available project has been concluded 11 who is financing German Ministry of Education and Research

Description of the population 12 total number of children Questionnaires: 14200 IgE, Skin prick test, DNA, Lungfunction and bronchial challenge: 3650-8100

211

Germany 21 13 age groups and number 5-7 yrs old: Questionnaires: 8600; IgE, Skin prick test, DNA: 1750- of persons in each 2900 group 9-11 years old: 5600; IgE, Skin prick test, DNA, lungfunction and bronchial challenge: 1900-5200 14 inclusion criteria, inclusion criteria: pupils of 1st and 4th grade exclusion criteria 15 sampling strategy random sample of schools, all pupils within the sampled schools; partly random subsamples for IgE, Skin prick test, DNA, lung function and bronchial challenge, dust samples. 16 time schedule of Dresden: 5-7 yrs: 07/1995-03/1996; 9-11yrs: 09/1995 - 06/1996 biomonitoring Munich: 5-7 yrs: 04/1996-07/1996; 9-11yrs: 09/1995 - 12/1996 Leipzig: 5-7 yrs: 08/1995-05/1996; 9-11yrs: 09/1995 - 05/1996 17 consent procedures written informed consent by one of the parents 18 how is participation invitation by schools encouraged? Data collection 19 biomarkers of exposure

20 biomarkers of effect IgE, Skin prick test, lung function and bronchial challenge 21 biomarkers of DNA susceptibility

Other data 22 environmental data data on SO2, NO2 and suspended particulate matter were provided by regional authorities and collected by additional measurement stations questionnaire on living conditions such as crowding, bedding, exposure to animals, indoor pollution, outdoor environment; dust samples 23 lifestyle data nutrition, breastfeeding 24 health data asthma, allergic rhinitis, atopic dermatitis, birth weight, diseases and immunizations 25 parental exposure parental asthma and allergies 26 medication management of asthma, allergic rhinitis, atopic dermatitis 27 socio-economic factors parental education

Analysis and quality control procedures

28 intra/interlaboratory training according to a detailed study manual, announced and testing unannounced field visits of field supervisors; comparisons between laboratories. 29 external laboratory control 30 accuracy, limit of detection/quantification, reproducibility

212

Germany 21 31 data analysis (statistics, Power calculations were performed to ensure sufficient sample size power calculations) according to the international study design. For details see the ISAAC II study protocol. Statistical analysis of the stratified subsamples will be done by using a weighting scheme. 32 representativity average participation rates are 46.7% for IgE, 59.9% for skin prick test, 54.4% for bronchial challenge and 64.4% for lung function

Data protection and availability 33 privacy legislation National legislation on data confidentiality and ethical approval has been followed. 34 intellectual property rights

35 banking of biological Yes samples

Communication (individual level, group level, level (sub)population )

36 reporting results to Publication in peer reviewed journals public authority, to general public, to participant 37 professionals involved, A steering group, a coordination and data centre, principal contacts between investigators for each centre, all consisting of scientists. professionals and Medical doctors and nurses performing the field work participants Teachers are the in-between professionals 38 role of media 39 public debate 40 consequences of external communication

41 Problems

42 Experiences

213

Germany 22 N° General data 1 type international cross-sectional study on asthma and allergies 2 country Albania, Estonia, France, Italy, Germany, Greece, Iceland, Latvia, Netherlands, Norway, Sweden, Spain, Turkey, United Kingdom 3 title Phase two of the International Study on Asthma and Allergies in Childhood (ISAAC Phase II) 4 aim 1) Further investigation of the internationally observed prevalence patterns (in ISAAC I and III) 2) Identification of determinants of asthma and allergies: • Association of occurrence and severity of symptoms of asthma, allergic rhinitis and atopic eczema with skin prick test reactivity, serum IgE levels, signs of flexural dermatitis, and bronchial responsiveness within and between centres • Association of known and suspected risk factors, as assessed by parental questionnaire and measurements of indoor exposure, with symptoms and other markers of asthma, allergic rhinitis and atopic eczema within and between centres • Extent to which the above risk factors can explain the observed variation in the prevalence across Europe • Association of genetic factors and asthma and allergies, including their interaction with environmental exposures

5 beginning date 2000 6 ending date 2004 7 contact person Prof. Stephan Weiland Abteilung Epidemiologie Universität Ulm Helmholtzstr.22 D-89081 Ulm

E-mail: [email protected] Tel: ++49 731 50 31060 Fax: ++49 731 50 31069 8 initiator Institute of Epidemiology and Social Medicine, University of Münster 9 involved/responsible Dept. of Epidemiology, University of Ulm, Germany; organisations Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; University of Utrecht, Environmental and Occupational Health Group, Utrecht, The Netherlands; Asthma Genetics Group, University of Oxford, Wellcome Trust Centre for Human Genetics, Oxford, UK; Munich University Children's Hospital, Germany; Department of Public Health Sciences, St George's Hospital Medical School, London, UK

10 budget available approx. 1 000 000 €

214

Germany 22 11 who is financing European Union

Description of the population 12 total number of children Questionnaire data: 28900 IgE-data: 3400 (stratified subsample) Skin prick test: 18000 Lungfunction and bronchial challenge: 6200 (stratified subsample) DNA-data: 2160 (stratified subsample) 13 age groups and number all 9-11 years old of persons in each group 14 inclusion criteria, inclusion criteria: children in the school year in which the majority exclusion criteria of children are aged 10 years 0 months to 10 years 11 months

15 sampling strategy Questionnaires, Skin prick test: random sample of schools, all pupils within the sampled schools; IgE, lung function and bronchial challenge, DNA, dust samples: stratified subsample of 100 wheezers and 100 non-wheezers 16 time schedule of not specified, therefore different in each country biomonitoring 17 consent procedures written informed consent by one of the parents

18 how is participation invitation by schools; encouraged? Data collection 19 biomarkers of exposure

20 biomarkers of effect IgE, Skin prick test, Lungfunction and bronchial challenge

21 biomarkers of DNA susceptibility

Other data 22 environmental data questionnare on living conditions such as crowding, bedding, exposure to animals, indoor pollution, outdoor environment; dust samples 23 lifestyle data nutrition, breastfeeding 24 health data asthma, allergic rhinitis, atopic dermatitis, birth weight, diseases and immunizations 25 parental exposure parental asthma and allergies

26 medication management of asthma, allergic rhinitis, atopic dermatitis 27 socio-economic factors parental education

Analysis and quality control procedures 28 intra/interlaboratory all samples are analysed in the same certified laboratory, quality testing controls according to the ISAACII Manual

215

Germany 22 29 external laboratory control 30 accuracy, limit of detection/quantification, reproducibility

31 data analysis (statistics, Power calculations were performed to ensure sufficient sample power calculations) size according to the international study design. For details see the ISAAC II study protocol. Statistical analysis of the stratified subsamples will be done by using a weighting scheme. 32 representativity average participation rates are 64% for IgE, 69% for skin prick test, 74% for bronchial challenge and 66% for DNA

Data protection and availability

33 privacy legislation Privacy legislation of the individual countries is applied. The coordinating and data centre in Ulm and the laboratories only receive anonymized data. 34 intellectual property No patents. rights Data will be published upon approval of the ISAAC Steering Group 35 banking of biological yes samples

Communication (individual level, group level, level (sub)population )

36 reporting results to public Publication in peer reviewed journals authority, to general public, to participant 37 professionals involved, A steering group, a coordination and data centre, national contacts between coordinators, principal investigators for each centre, all consisting professionals and of scientists. participants Medical doctors and nurses performing the field work Teachers are the in-between professionals 38 role of media 39 public debate 40 consequences of external communication

41 Problems

42 Experiences

216

Germany 23 N° General Data 1 type Regional cross-sectional study The study involves 2 age groups 4. Children (school starters) and 5. their mothers 2 country Germany 3 title Human medical effect research in small-scaled impact areas with defined impact emphasis (Hot Spot research) 4 aim To define immission-related impacts and eventual health risks of the population living in the direct vicinity of several industrial locations in a cross-sectional human medicinal study 5 beginning date 1999 6 ending date 2003 7 contact person Dr. Georg Krause North Rhine-Westphalia State Environment Agency (LUA NRW) Wallneyer Str. 6 45133 Essen +49-201-79951215 [email protected] 8 initiator Ministry for Environment, Nature Protection, Agriculture and Consumer Protection of North Rhine-Westphalia (MUNLV NRW) North Rhine-Westphalia State Environment Agency (LUA NRW) 9 involved/responsible Supervision: North Rhine-Westphalia State Environment Agency organisations (LUA NRW) Investigator: Department for Hygiene, Social and Environmental Medicine at the Ruhr-University Bochum, Medical Institute for Environmental Hygiene at the Heinrich-Heine- University Düsseldorf Subcontractors: Medical College Hannover, TU Munich, University Erlangen-Nuremberg, Others: The Health Departments of Borken, Dortmund and Duisburg, Department of Local Environment Protection Duisburg, North Rhine-Westphalia State Surveying Agency (LVA NRW) 10 budget available € 700 000 (approximately) 11 who is financing Ministry for Environment, Nature Protection, Agriculture and Consumer Protection of North Rhine-Westphalia (MUNLV NRW)

Description of the population 12 total number of children (and 949 children parents) 886 mothers 13 age groups and number of persons Children: 5 - 6 years in each group Mothers: 21 - 51 years 14 Inclusion/exclusion criteria Inclusion criteria are: Written informed consent Age (for children) Mother of a participating child Chronic health effects: Mothers and children should be living in the area for 2 years minimum.

217

Germany 23 Work related exposition in mothers If possible concurrent factors of influence have been recognized in the MRA 15 sampling strategy Mothers and children are recruited via the local health department 16 time schedule of biomonitoring Specimen of mothers and children are sampled once in the period February - June 2000 17 consent procedures Mothers and child: written informed consent 18 how is participation encouraged? Results of individual measurements and of the entire study are offered to the participants Press conferences, TV and radio interviews Incentives for the children

Data collection 19 biomarkers of exposure Metals: cadmium and lead in blood, cadmium, chromium, nickel in urine. Confounder: nickel, lead and chromium in drinking water. PAH-metabolites: 1-OH-pyrene, hydroxylated phenanthrenes in urine Benzene metabolites: s-phenylmercapturic acid and tt-muconic acid in urine. 20 biomarkers of effect DNA exposition: Comet assay on whole blood, 8-OhdG-adducts in blood Nephrotoxicity markers: total protein, albumin, alpha-1- microglobuline, HMW- and LMW-proteins, NAG in urine Immunological parameters: Serum: C3c, IgA, IgG, IgM, IgE, small and differential haemogramme, neopterine, CRP Nasal parameters: interleukin 8, proliferation marker Ki 67, 8- OhdG-adducts, uric acid Lung function (only children) Allergological tests: skin-prick test, contact allergy test, specific IgE 21 biomarkers of The differentiation by means of allergological tests can be seen susceptibility as a differentiation into susceptible subgroups

Other data 22 environmental Routinely monitored air quality data was analysed and modelled to sampling calculate individual exposure (mothers and children) according to their home address 23 lifestyle data Nutrition of the mother: type/frequency/amount of bread, cereals, fats, fish, meat, wild meats, poultry, sauces, pastries, coffee, tea, milk products, vegetables, fruit, soup, drinks, barbecue, vegetarian, alcohol use (frequency/amount before and during pregnancy). Active/passive smoking of the mother (starting age, amount, frequency, exposure), contact with chemicals, drug-use (frequency, type), hobbies, pets (questionnaire), exposure to traffic Nutrition of the child: type/frequency/amount of bread, cereals, fats, fish, meat, wild

218

Germany 23 meats, poultry, sauces, pastries, coffee, tea, milk products, vegetables, fruit, soup, drinks, barbecue, vegetarian Passive smoking (frequency, exposure), contact with chemicals, pets (questionnaire), exposure to traffic 24 health data Mothers: Biometry, allergies, eczema, medical history, illnesses in the past year and on the day of examination Children: Biometry, allergies, eczema, respiratory problems, illnesses in the past year and on the day of examination 25 parental exposure Mothers: Asthma or allergy in the family. Home environment: traffic ‘pressure’, heating, use of pesticides in house/garden, use of gas for heating/cooking. Children: Asthma or allergy in the family. Home environment: traffic ‘pressure’, heating, bedroom sharing, use of gas for heating/cooking. 26 medication Asked in detail and categorized in relevant groups and time periods 27 socio-economic Structure of the family, educational level of parents, nationality factors

Analysis and quality control procedures 28 intra/interlaboratory testing Atomic-absorption-spectrometry (metals), HPLC + fluorescence detector (1-OH-pyrene, hydroxylated phenanthrenes), HPLC + UV detector (tt-muconic acid), HPLC + mass spectrometry (s-phenylmercapturic acid), Comet Assay (blood), HPLC/UV + electrochemical detector (8-OhdG), standard laboratory methods (nephrotoxicity, haemological and immunological markers) 29 external laboratory control Yes 30 accuracy, limit of Data for all parameters are available on request detection/quantification, reproducibility 31 data analysis (statistics, power Statistical analysis is based on SAS. The indexes were calculations) calculated for the specific areas as for the total random sample. The connection between immissions/internal impact and the target parameters were calculated in multivariate regression models. 32 representativity Population based study design Non-responder analysis based on socio-economic factors and health related items

Communication (individual level, group level, level (sub)population)

219

Germany 23 36 reporting results to public authority, to Individual result report for the participants general public, to participant Printed report Publication on the internet 37 professionals involved, contacts between Scientific advisory board, civic action groups professionals and participants 38 role of media Press conferences, TV and radio interviews 39 public debate Occasional symposia were organized which included debates between different stakeholders. 40 consequences of external communication Can not be judged at the moment

41 Problems Quantity and quality of response, logistic and organisatory problems (coordination between laboratory examination, on site examination, questionnaires, immission modelling) The limit for the strain put on the participants was reached 42 Experiences Positive influence of the multiplicators (advisory bureaus) The cooperation of Health and Environment Department improves the efficiency of research, this has a positive effect on the image with the general public

220

Germany 24 N° General Data 1 type Regional cohort study (biomonitoring and health effects) The biomonitoring study involves newborn and their mothers 2 country Germany 3 title Correlation between the pre- and postnatal PCB and PCDD/F exposition and neurological and neuropsychological development parameters as well as thyroid parameters of infants and toddlers 4 aim To find out - to which extent PCB and PCDD/F are detectable in blood of pregnant women - to which extent these substances are detectable in the milk of breast feeding mothers - if there is a correlation between infantile neurological and neuropsychological development parameters at the age of 2 weeks, 12 and 18 months and these substances in dependence of their concentration - to which extent the confounders lead, mercury, alcohol consume of the mother, home environment and the thyroid hormone status of the mother affect the infantile neurological an neuropsychological development - to which extent cadmium is detectable in the urine of mothers - to which extent mothers and their newborns are provided with the essential trace element selenium 5 beginning date 2000 6 ending date 2004 (may be continued) 7 contact person Dr. Georg Krause North Rhine-Westphalia State Environment Agency (LUA NRW) Wallneyer Str. 6 45133 Essen +49-201-79951215 [email protected] 8 initiator Ministry for Environment, Nature Protection, Agriculture and Consumer Protection of North Rhine-Westphalia (MUNLV NRW) North Rhine-Westphalia State Environment Agency (LUA NRW) 9 involved/responsible Supervision: North Rhine-Westphalia State Environment Agency organisations (LUA NRW) Investigator: Department for Hygiene, Social and Environmental Medicine at the Ruhr-University Bochum, Medical Institute for Environmental Hygiene at the Heinrich- Heine-University Düsseldorf 10 budget available € 720 000 (approximately) 11 who is financing Ministry for Environment, Nature Protection, Agriculture and Consumer Protection of North Rhine-Westphalia (MUNLV NRW)

Description of the population 12 total number of children 231 Newborns and their mothers

221

Germany 24 13 age groups and number of persons in Newborns/infants: 0-18 months and follow up each group 14 inclusion criteria, exclusion criteria Inclusion criteria are: Written informed consent German or Turkish nationality Extended inclusion criteria are: No serious complications during pregnancy or birth First or second born in the family Newborns of 38th to 42th week of pregnancy No congenital anomalies Apgar-score minimum 8 15 sampling strategy Recruiting of pregnant women via hospital, doctors, midwifes, press calls from the ministry, civic action groups 16 time schedule of biomonitoring Prenatal and perinatal

17 consent procedures Written informed consent 18 how is participation encouraged? Insentives (infants) Information about personal exposition (mothers)

Data collection 19 biomarkers of exposure PCB, PCDD/F, lead, cadmium, selenium and CDT in blood of pregnant women. Mercury and cadmium in urine of mothers PCB, lead and selenium in cord blood PCDD/F and PCB in breast milk 20 biomarkers of effect thyroid parameters in blood of pregnant women thyroid parameters in cord blood 21 biomarkers of susceptibility None

Other data 22 environmental sampling Planned exposition estimation 23 lifestyle data Nutrition of the mother: type/frequency/amount of bread, cereals, fats, fish, meat, wild meats, poultry, sauces, pastries, coffee, tea, milk products, vegetables, fruit, soup, drinks, barbecue in the past few days, vegetarian, eating outdoors, alcohol use (frequency/amount before and during pregnancy). Active/passive smoking of the mother (starting age, amount, frequency, exposure), drug use (frequency, type). Nutrition of the baby: breastfeeding or powdered milk 24 health data Duration of the pregnancy, apgar score, medical history, breastfeading 25 parental exposure Alcohol use and smoking during pregnancy, medication during pregnancy, medication during delivery. Amalgam filling of teeth. Home environment: use of pesticides in house/garden, use of gas for heating/cooking (standardised interviews and questionnaires) 26 medication Use of medication during pregnancy or during delivery.

222

Germany 24 27 socio-economic factors Motherly vocabulary, educational level of parents, nationality.

Analysis and quality control procedures 28 intra/interlaboratory testing mass spectrometry and gas chromatography (PCB, PCDD/F in blood), atomic absorption spectrometry (lead, mercury, cadmium), CDT- Assay, immunoassay (thyroid parameters) standard laboratory methods (creatinine in urine) 29 external laboratory control Yes 30 accuracy, limit of detection/quantification, Data for all parameters are available on reproducibility request 31 data analysis (statistics, power Power calculation on the basis of existing calculations) studies (minimum of 180 children) Various regression models 32 representativity Population based (all infants in a defined region and timeframe)

Data protection and availability 33 privacy legislation Samples and questionnaires are maintained by the responsible medical doctor and subsequently anonymised in order to maintain confidentiality under secure conditions in accordance with national Data Protection Directive and data protection legislation. Measures are taken to ensure confidentiality and security of the data. Ethical advice has been taken to determine the maximum volume of blood samples that may be taken in order to minimise distress to the participant. 34 intellectual property rights No patents. 35 banking of biological samples Yes, if specimen sufficient

Communication (individual level, group level, level (sub)population)

36 reporting results to public authority, to Individual result report for the participants general public, to participant Printed report Publication on the internet 37 professionals involved, contacts between Scientific advisory board, civic action groups professionals and participants 38 role of media Press conferences, TV and radio interviews

39 public debate Occasional symposia were organized which included debates between different stakeholders. 40 consequences of external communication Can not be judged at the moment

223

Germany 24 41 Problems Great difficulties concerning recruiting and response (sufficiently long timeframe should be calculated)

42 Experiences

224

Germany 25 N° General Data 1 type Regional biomonitoring study + survey The biomonitoring study involves children aged 9-10 2 country Germany 3 title Epidemiological study on health effects of traffic-related immissions to children 4 aim To achieve sound indications on connections between adverse health effects and the exposition to urban traffic-related immissions 5 beginning date 1995 6 ending date 1997 7 contact person Prof. U. Ranft Medical Institute for Environmental Hygiene Auf’m Hennekamp 50, 40225 Düsseldorf +49-211-3389287+ [email protected] 8 initiator Ministry for Environment, Nature Protection, Agriculture and Consumer Protection of North Rhine-Westphalia (MUNLV NRW) North Rhine-Westphalia State Environment Agency (LUA NRW) 9 involved/responsible Supervision: North Rhine-Westphalia State Environment Agency organisations (LUA NRW). Principal investigator: Medical Institute for Environmental Hygiene, Heinrich-Heine-University of Düsseldorf Subcontractors: RWTH Aachen, TU Munich, University of Hamburg 10 budget available 11 who is financing Ministry for Environment, Regional Development and Agriculture of North Rhine-Westphalia

Description of the population 12 total number of children 317 children 13 age groups and number of 9-10 persons in each group 14 inclusion criteria, exclusion Inclusion criteria are: criteria Written informed consent Age Children should be living in the area for more than 2 years 15 sampling strategy Children are recruited via the distance of their home address to main roads 16 time schedule of biomonitoring Children were sampled in February-March 1996 and in October to December 1996 17 consent procedures Parents: written informed consent 18 how is participation encouraged?

Data collection 19 biomarkers of exposure Lead, benzene, ethyl benzene, xylene and toluene in blood.

225

Germany 25 Gold, palladium, platinum, phenanthrene and anthracene in morning urine. Napthaline, acenaphtylene, acenaphthene and fluorene in 24h-urine. Immunological parameters: Serum: C3c, IgA, IgG, IgM, cortisol, neopterin, CRP; saliva: IgA, IgG, IgM, cortisol, total protein, albumin 20 biomarkers of effect Lung function and allergy skin-prick test, questionnaire on asthma and allergy, symptom diary 21 biomarkers of susceptibility none

Other data 22 environmental sampling Air quality data was analysed and modelled to calculate individual exposure. Ambient air quality in the living/school area of the children were monitored. 23 lifestyle data Nutrition: type/frequency/amount of fish (+ own caught fish), vegetables and fruit (+ garden-grown vegetables and fruit). Passive smoking of the mother during pregnancy, passive smoking of the child, exposure to traffic and exhaust. Home environment: heating, bedroom sharing, lead water pipes 24 health data Biometry, allergies, eczema, respiratory problems, illnesses on the day of examination and in the past year 25 parental exposure Alcohol use and smoking, asthma or allergy in the family, lead contamination of parents. Home environment: heating 26 medication Intake of medicaments during biomonitoring period or always, amalgam or plastic filling of teeth 27 socio-economic factors Structure of the family, educational level of parents, nationality

Analysis and quality control procedures 28 intra/interlaboratory testing Atomic absorption spectrometry (lead), headspace capillar gas chromatography (BTXE), magnet sector ICP-MS (gold, platinum, palladium), solid phase extraction (PAH), standard laboratory methods (immunology, lung function) 29 external laboratory control Yes 30 accuracy, limit of Data for all parameters are available on request detection/quantification, reproducibility 31 data analysis (statistics, power Statistic programme SAS calculations) Various regression models

32 representativity Non-responder analysis.

Data protection and availability

226

Germany 25 33 privacy legislation Samples and questionnaires are maintained by the responsible medical doctor and subsequently anonymised in order to maintain confidentiality under secure conditions in accordance with national Data Protection Directive and data protection legislation. Measures are taken to ensure confidentiality and security of the data. Ethical advice has been taken to determine the maximum volume of blood samples that may be taken in order to minimise distress to the participant. 34 intellectual property rights No patents. 35 banking of biological samples No long term storage is foreseen

Communication (individual level, group level, level (sub)population) 36 reporting results to public The participants were regularly given individual results as authority, to general public, to far as they are interpretable, as well as group results. participant Printed report for the general public Results of the studies were partly communicated to the scientific community by publication in journals after approval by the management committee and according to specifications mentioned in the call. 37 professionals involved, contacts between professionals and participants 38 role of media Focused attention on the study 39 public debate Conference on the results 40 consequences of external communication

41 Problems Great difficulties with recruiting and response

42 Experiences

227

Germany 26 N° General data 1 type regional biomonitoring, schoolbeginners and their mothers

2 country Germany, NRW 3 title Humanmedizinische Wirkungsuntersuchungen innerhalb kleinräumiger Belastungsareale mit umschriebenen Belastungsschwerpunkten 4 aim health effects (genetic, nephrotoxic, immunmodulatory, respiratory and allergic) at different groups (children, mothers) caused by industrial plants and confirmed by levels of biomarkers in blood and urine 5 beginning date 2000 6 ending date 2002 7 contact person Prof. Dr. U. Ranft, MIU, email: [email protected], Prof. M.Wilhelm, email:[email protected] bochum.de 8 initiator Ministry of Environment (MUNLV) of North Rhine Westphalia, Environmental Agency (LUA) of North Rhine Westphalia 9 involved/responsible Ruhr University Bochum, Dept. Hygiene, Social- and organisations Environmental Medicine, Universitätsstr. 150 44801 Bochum, Medical Institute for Environmental Hygiene, Dept. Epidemiologiy, Auf'm Hennekamp 50, 40225 Düsseldorf 10 budget available 800.000 € (approx.) 11 who is financing Ministry of Environment (MUNLV) of North Rhine Westphalia, Environmental Agency (LUA) of North Rhine Westphalia

Description of the population 12 total number of children ca. 550 13 age groups and number of ca. 6 yrs old schoolbeginners (550) and mothers (550) persons in each group 14 inclusion criteria, exclusion written informed consent, living time at their residence for criteria at least 2 yrs, mothers: occupational exposure to the substance monitored 15 sampling strategy all schoolbeginners and their mothers from schools in four investigation areas 16 time schedule of biomonitoring one investigation at the time of schoolbeginner's examination (Feb.- Jun. 2000) at the local health office

17 consent procedures written informed consent for child and mother 18 how is participation information of the aim of the study and offering individual encouraged? results of investigations Data collection

228

Germany 26 19 biomarkers of exposure metals in blood, urine (Pb, Cd, Cr, Ni) and nasal lavage (V, Cr, Pt), metabolites from benzene and PAK in urine (OH-phenanthrene, OH-pyrene, mucone acid, S- phenylmercapto-acid) 20 biomarkers of effect DNA strand breaks (comet assay) and 8-OHdG adducts in white blood cells, proteins in urine(albumine, high and low molecul. proteins, alpha-1-mikroglobulin, N-Acetyl- Glucosaminidase), immune parameter in serume (immunoglobulins, C3c, neopterine, CRP), inflammatory and proliferatory markers in nasal lavage 21 biomarkers of susceptibility none

Other data 22 environmental data In ambient air: Pb, Cd, Ni, Cr, TSP, B(a)P, benzene, in drinking water: Pb, Ni, Cr. Questions about ETS, drinking tap water, eating products from private garden, questions about exposition to traffic exhaust 23 lifestyle data questions about nutrition and home setup, smoking

24 health data respiratory and allergic symptoms and diseases (life-time prevalence and during the last 12 months) by questionaire, allergic diagnoses and sensitisations (skin examination, RAST, Prick, Epicutane test), respiratory function, acute infections, immunisations, differential haemogram, anthropometric and birth data 25 parental exposure ETS, occupational or home- and hobby-derived chemical burdens 26 medication permanent and acute mediaction of respiratory and allergic diseases, free text of all used medicaments

27 socio-economic factors educational level

Analysis and quality control procedures

28 intra/interlaboratory testing accredited laboratories 29 external laboratory control round-robin tests 30 accuracy, limit of data are available at request detection/quantification, reproducibility

31 data analysis (statistics, power estimation of odds ratios adjusted for possible calculations) confounders by regression models 32 representativity nonresponder analysis

Data protection and availability 33 privacy legislation names and adresses are stored at the regional health authorities, only numbers and coordinates from the home are stroraged together with data

229

Germany 26 34 intellectual property rights data are owned by Ministry of Environment (MUNLV) of North Rhine Westphalia/Environmental Agency (LUA) of North Rhine Westphalia 35 banking of biological samples none

Communication (individual level, group level, level (sub)population )

36 reporting results to public authority, to reports and meetings with Environmental Agency general public, to participant (LUA) of North Rhine Westphalia and citizen's action committees, publication for layman, technical report will be set in the internet, individual results reported to participants 37 professionals involved, contacts scientific advisory board, steering group including between professionals and scientists of the co-operating institutes participants 38 role of media - 39 public debate - 40 consequences of external - communication

41 Problems -

42 Experiences -

230

Germany 27 N° General Data 1 Type Regional biomonitoring study 2 Country Germany 3 Title Prevalence of respiratory symptoms in school children and salivary IgA – an epidemiological study in a rural area of Northrhine-Westphalia, Germany 4 Aims 1.To compare the prevalence and severity of children´s wheezing in Ochtrup 1998 to the study of 1996 2. To compare the questionnaire data on wheezing to objective measurements of bronchial hyperreactivity and putative risk factors of wheezing 3. To compare the results on wheezing with levels of salivary IgA, IgM, IgG 5 Study period 1998-99 6 Contact persons Prof. Dr. Michael Wilhelm, Dr. Jürgen Hölzer Dept. Hygiene, Social and Environmental Medicine Ruhr-Universität Bochum Universitätstsr. 150 44801 Bochum Germany [email protected] +49 234 32 22365 7 Initiator and support City of Ochtrup and the Steinfurt District 8 Number, age of children 1161, 6-8 and 12-15 years 9 Sampling period Saliva samples, 1998-1999 10 Biomarkers of effect IgA, IgM, IgG in saliva 11 Other data Questionnaires (including ISAAC), Lung function 12 More details see Hoelzer et al.: Prevalence of respiratory symptoms in school children and salivary IgA – an epidemiological study in a rural area of Northrhine-Westphalia, Germany Int J Hyg Environ Health 205, 309-319, 2002

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Germany 28 Number General Data 1 Type Regional biomonitoring study, cross-sectional 2 Country Germany 3 Title Mercury concentrations in urine, scalp hair, and saliva in children from Germany 4 Aims To compare mercury levels in urine, hair and saliva 5 Study period 1996 6 Contact person Prof. Dr. Michael Wilhelm Dept. Hygiene, Social and Environmental Medicine Ruhr-Universität Bochum Universitätstsr. 150 44801 Bochum Germany [email protected] +49 234 32 22365 7 Initiator and support Ministry of Environment, Northrhine-Westphalia, Germany 8 Number, age of children 245, 8-10 years 9 Sampling period 1996 10 Biomarkers of exposure Hg in urine, hair, saliva 11 Other data Questionnaires 12 More details see Pesch et al.: Mercury concentrations in urine, scalp hair, and saliva in children from Germany J Expo Anal Environ Epidemiol 12, 252-258, 2002

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Germany 29 Number General Data 1 Type Regional biomonitoring study, cross-sectional 2 Country Germany 3 Title Concentrations of lead in blood, hair, and saliva in children from Germany living in three different areas of traffic density 4 Aims 1.To compare lead levels in urine, hair and saliva 2. To study the influence of traffic density on lead exposure 5 Study period 1996 6 Contact person Prof. Dr. Michael Wilhelm Dept. Hygiene, Social and Environmental Medicine Ruhr-Universität Bochum Universitätstsr. 150 44801 Bochum Germany [email protected] +49 234 32 22365 7 Initiator and support Ministry of Environment, Northrhine-Westphalia, Germany 8 Number, age of children 245, 8-10 years 9 Sampling period 1996 10 Biomarkers of exposure Lead in blood, hair, saliva

11 Other data Questionnaires, area related NO2 levels 12 More details see Wilhelm et al.: Concentrations of lead in blood, hair, and saliva in children from Germany living in three different areas of traffic density Sci Total Environ 297, 109-118, 2002

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Germany 30 N° General Data 1 Type Regional biomonitoring study, cross-sectional, follow-up 2 Country Germany 3 Title Cadmium, copper, lead, and zinc concentrations in hair and toenails of young children and family members: a follow-up study 4 Aims 1. To study time trend in cadmium, copper, lead, and zinc concentrations in hair and toenails of children 5 Study period 1987-88 6 Contact person Prof. Dr. Michael Wilhelm Dept. Hygiene, Social and Environmental Medicine Ruhr-Universität Bochum Universitätstsr. 150 44801 Bochum Germany [email protected] +49 234 32 22365 7 Initiator and support Ministry of Health, Germany 8 Number, age of children 47, 5-9 years 9 Sampling period 1987-88 10 Biomarkers of exposure Cadmium, copper, lead, zinc in hair and toenails 11 Other data Questionnaires 12 More details see Wilhelm et al.: Cadmium, copper, lead, and zinc concentrations in hair and toenails of young children and family members: a follow-up study. Sci Total Environ 141, 275-280, 1994

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Germany 31 N° General Data 1 Type Regional biomonitoring study, cross-sectional 2 Country Germany 3 Title Humanbiomonitoring study with children and their mothers in hot spot regions. 4 Aims To study influence of local emissions on exposure and health status of populations living close to emitters. 5 Study period 2000-2003 6 Contact persons Prof. Dr. Michael Wilhelm Dept. Hygiene, Social and Environmental Medicine Ruhr-Universität Bochum Universitätstsr. 150 44801 Bochum Germany [email protected] +49 234 32 22365

And Prof. Dr. Ulrich Ranft IUF Düsseldorf [email protected] 7 Initiator and support Ministry of Environment, Northrhine-Westphalia, Germany 8 Number, age 866 pairs of children (6 years) and their mothers 9 Sampling period 2000 10 Biomarkers of exposure Lead in blood, cadmium in blood and urine, chromium, nickel in urine, PAH- and benzene metabolites in urine 11 Biomarker of effect Comet-assay, 8-OHdG, nephrological and immunological markers 12 Other data Questionnaires, air qualitiy data modelled to calculate individual exposure, clinical examination (skin, lung function) 13 More details Will be available in the final report which will be put into the internet probably at the end of 2003

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Germany 32 Number General Data 1 Type Regional biomonitoring study, cohort-study 2 Country Germany 3 Title Cohort-study on the influence of POP exposure on the neurobehavioral development of children 4 Aims To study influence of POP exposure on the neurobehavioral development of children 5 Study period 2001-2004 (2006) 6 Contact persons Prof. Dr. Michael Wilhelm Dept. Hygiene, Social and Environmental Medicine Ruhr-Universität Bochum Universitätstsr. 150 44801 Bochum Germany [email protected] +49 234 32 22365

And Prof. Dr. Gerhard Winneke MIU Düsseldorf [email protected]

7 Initiator and support Ministry of Environment, Northrhine-Westphalia, Germany 8 Number, age 230 mothers and their newborns 9 Sampling period 2002 10 Biomarkers of exposure Lead in blood, cadmium in blood and urine, PCDD/F and PCB in blood 11 Biomarker of effect TSH, iodine 12 Other data Questionnaires, air qualitiy data modelled to calculate individual exposure, neurobehavioral and psychological tests 13 More details Will be available in the final report at the end of 2004

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Germany 33 N° General Data 1 type Biomonitoring study The biomonitoring study involves only samples of breast milk taken after 2 weeks and 12 weeks post partum 2 country Germany 3 title Polybrominated diphenyl ethers (PBDEs) in human breast milk 4 aim 1) To analyse the levels of PBDEs in breast milk at 2 and 12 weeks post partum to obtain data on dynamics within this period 2) To identify the influence of normal and of vegetarian food of the mother on the corporal burden with PBDEs 3) To assess the risk of the breast-fed newborn by PBDEs 5 beginning date 2002 6 ending date 2004 7 contact person Dr. Thomas Rüdiger Bundesinstitut für Risikobewertung Thielallee 88 – 92 Germany [email protected] 8 initiator Federal Institute of Risk Assessment (Bundesinstitut für Risikobewertung, BfR) 9 involved/responsible BfR, Federal Environmental Agency (Umweltbundesamt, organisations UBA) 10 budget available € 60.000 (approximately) 11 who is financing Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (Bundesministerium für Umwelt, Naturschutz und Reaktorsicherheit, BMU), BfR

Description of the population 12 total number of children (and parents) No children 13 age groups and number of persons in each Women in the period of lactation group Age: reproductive age Circa 80 mothers at 2 weeks post partum Circa 40 mothers at 12 weeks post partum ratio of normal to vegetarian nutrition: ca. same number of individuals 14 inclusion criteria, exclusion criteria Inclusion criteria are: Written informed consent Women in the period of lactation, no sectio caesarea 15 sampling strategy Mothers are recruited via maternity department,

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Germany 33 via advertisement on the homepage of BfR and in several magazines 16 time schedule of biomonitoring Breast milk samples were collected in the period September 2002 – December 2003 at 2 and 12 weeks post partum 17 consent procedures Mothers: written informed consent 18 how is participation encouraged? Results of individual measurements and of the entire study will be offered to the participants.

Data collection 19 biomarkers of exposure 3-, 4-, 5-,6- and 10-BDE (brominated biphenyl ethers) 20 biomarkers of effect No 21 biomarkers of susceptibility No Other data 22 environmental sampling No 23 lifestyle data Questionnaires on nutrition of the mother: type/frequency/amount of meat, sausage, ham, fish (+ own caught fish), milk and milk products, eggs, vegetarian with eggs or without eggs, smoking of the mother (starting year, amount, frequency, exposure), contact with chemicals, inclusion criteria :breastfeeding 24 health data Duration of the pregnancy, biometry 25 parental exposure Smoking during pregnancy 26 medication No 27 socio-economic factors Educational level of mother Analysis and quality control procedures 28 intra/interlaboratory testing An inventory of quality assurance programs used by the contracting laboratory is applied. 29 30 accuracy, limit of detection/quantification, Data for all parameters are available on reproducibility request 31 data analysis (statistics, power Power calculations were based on a feasibilty calculations) biomonitoring study involving atotal of circa 120 breast milk samples. Statistical analysis will be performed according to a stratified plan 32 representativity No

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Germany 34 N° General Data 1 type Regional biomonitoring study and survey, cross-sectional study 2 country Germany / Saxony-Anhalt 3 title Studying school beginners in Saxony- Anhalt 4 aim To investigate the impact of changing environment on the health of school beginners in industrial centres and in non- industrial areas of Saxony-Anhalt 5 beginning date 1991 6 ending date Ongoing 7 contact person Dr. med. Hanna Oppermann Landesamt für Verbraucherschutz Sachsen-Anhalt Fachbereich Gesundheit/Hygiene/Epidemiologie Wallonerberg 2-3 39104 Magdeburg Germany [email protected] 0391 5377-106 8 initiator Ministry of health and social affairs Saxony -Anhalt 9 involved/responsible Local health departments: Magdeburg, Halle, Salzwedel, organisations Stendal, Merseburg-Querfurt; Medical Institute of Environmental Hygiene Düsseldorf; Institute of Hygiene Saxony- Anhalt 10 budget available 11 who is financing Ministry of health and social affairs Saxony- Anhalt

Description of the population 12 total number of children 26.433 13 age groups and number of 5-6 year old children persons in each group 14 inclusion criteria, exclusion Children should be living 2 years in the region criteria 15 sampling strategy All children, who are school beginners 16 time schedule of In the spring of 1991, 1994,1997,2000, 2003 biomonitoring 17 consent procedures Written informed consent 18 how is participation Results of individual measurements are offered to the encouraged? participants

Data collection 19 biomarkers of exposure Heavy metals (cadmium and mercury) in urine 20 biomarkers of effect Allergological parameters in serum (RAST), skin-prick-test 21 biomarkers of susceptibility

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Germany 34 Other data 22 environmental data Biological and chemical pollution of indoor spaces (dust mite infestation and mould fungi of mattresses of children's bed or house dust or indoor air, VOC in the indoor air) 23 lifestyle data Active/passive smoking, pets, exposure to traffic, breastfeeding, attendence at day care, vaccinations, bedroomsharing, 24 health data Duration of pregnancy, allergies, eczema, respiratory problems, illnesses in the past year, childhood infections, atopy, hay fever, 25 parental exposure Smoking during pregnancy, 26 medication 27 socio-economic factors Structure of the family, educational level of parents,

Analysis and quality control procedures 28 intra/interlaboratory testing Use of commercial standards in each series 29 external laboratory control `Round robin tests` for VOC, heavy metals, mould fungi 30 accuracy, limit of Data for all parameters are available on request detection/quantification, reproducibility 31 data analysis (statistics, power calculations) 32 representativity

Data protection and availability 33 privacy legislation 34 intellectual property rights 35 banking of biological samples No long term storage

Communication (individual level, group level, level (sub)population )

36 reporting results to public authority, to conferences and publications general public, to participant

37 professionals involved, contacts between professionals and participants

38 role of media 39 public debate 40 consequences of external communication

41 Problems

42 Experiences

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Greece Short summary to the questionnaires

A one year study monitoring DNA damage repair, apoptosis and necrosis in children in comparison to adults will start in 2003. A total of 100 healthy children (age 5-10) and their parents will be studied. Exposure assessment will focus on environmental pollution using questionnaires. Social habits (smoking, alcohol use, nutrition patterns) will be collected also.

The Institute of Child Health Programme 1. This longitudinal study compared pregnancy characteristics and outcomes between a community close to industrial activities and one which is not. A subgroup of 260 was re- examined when 12-13 years. The study started in 1981 and included 1260 newborns. No individual markers of exposure were collected, environmental measurements in air, soil and surface dust (not specified) were conducted. Results were reported to Greek funding agency and parties involved.

The Institute of Child Health Programme 2. This case-control study of 1169 children studied the relation between air pollution in the Greater Athens area in the early nineties. Children’s age was between 1 month and 14 years. Children admitted for respiratory complaints were compared with age matched controls admitted to the sample hospital for another reason. Daily air pollution data (SO2, black smoke, CO, NO2 and O3) were collected. Questionnaires were used to collect family medical history and other relevant information. Report was submitted to the Greek Ministry of the Environment.

The Institute of Child Health Programme 3. This study from 1996/8, investigated socioeconomic factors which might in conjunction with air pollution, may have negative health effects. 1000 Athens households, 100 from each of the districts where air pollution data are generated, were interviewed. Information was obtained on respiratory or heart diseases. One of the age categories was persons younger than 20 years. Daily air pollution data (SO2, black smoke, CO, NO2 and O3) were collected. The report was submitted to the Hellenic Ministry of the Environment.

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Greece 01 N° General data 1 type Longitudinal epidemiological research project, regional, comparing an industrial and a non-industrial community in the same region and with otherwise similar access to health care facilities. 2 country Greece 3 title Study of the effect of industrial pollution on the health of children: Comparative study of the outcome of pregnancy in a community with industrial pollution (Elefsina) and a non- industrial community. 4 aim Monitoring of the women in the two study areas who became pregnant in a specific 2-year period. Comparison of the pregnancy complications, the outcome of pregnancy and the health of the babies in the immediate neonatal period and at the age of 2 years. A sub-sample of about 25%, comprising adolescent mothers and their children and matched controls, was re-examined when the children were aged 12-13 years. 5 beginning date 1981 6 ending date End of entry of subjects 1984, end of first follow-up 1986, end of sub-sample follow-up 1998 7 contact person Dr.Sheena Nakou, Institute of Child Health, Athens 11527, Greece. [email protected] 8 initiator Hellenic Ministry of Health and Welfare 9 involved/responsible organisations Institute of Child Health, Athens: Borough Councils of the communities of Elefsina, Koropi and Spata in the Nomos of Attiki 10 budget available terminated 11 who is financing Hellenic Ministry of Health and Welfare

Description of the population 12 total number of children 1260 newborn infants (1187 mothers) 13 age groups and number of 1187 mothers, 1385 pregnancies, 1260 births, 1146 infants persons in each group at 2 years (the aim was at least 600 births in each of the 2 study areas), sub-group of 250 children at 12-13 years. 14 inclusion criteria, exclusion criteria Mothers were resident in the study areas for the whole duration of the pregnancy and gave their informed consent. 15 sampling strategy Pregnant women recruited through antenatal facilities and private obstetricians, births confirmed at the maternity hospitals. Re-location at the age of 12 years was effected partly through the local schools. 16 time schedule of biomonitoring Pregnant women sampled between 1981 and 1983 17 consent procedures Each mother given a written description of the aims and procedure, consent oral

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Greece 01 18 how is participation encouraged? Introduction by personal obstetricians and antenatal department personnel. Active support and promotion from the borough councils. Questionnaire administration and examination of the children conducted in the homes. Data collection 19 biomarkers of exposure No individual biomarkers. Environmental measurements in communities. 20 biomarkers of effect At each phase, questionnaires were administered by personal interview in the mothers’ homes, where the neonatal and 2-year paediatric examinations were conducted. Time to pregnancy, conception difficulties, pregnancy complications, fetal death, labour complications, premature rupture of membranes, perinatal problems, birth weight, congenital malformations, complete paediatric assessment in the first month, history of health problems and medication in first and second years of life, Griffith’s testing of a 1 in 5 sample. On sub-sample at age 12 years, health history, maturation, school performance, Achenbach scale. 21 biomarkers of susceptibility Chromosomal study on a sub-sample of mothers in the postnatal period

Other data 22 environmental data Study of local soil and surface dust pollution data (Forest Research Institute) and borough air pollution monitoring 23 lifestyle data An extensive questionnaire elicited details of lifestyle, living conditions, socio-economic information, parental smoking and drinking habits, illnesses and medication, employment and possible workplace exposures, unemployment, etc. both study populations included a proportion of internal immigrants, whose lifestyle differed from that of the local population. Further details were collected at each contact, recording changes. Nutrition history of the infants. Breastfeeding, start of solid foods, feeding problems. 24 health data Maternal and paternal health problems, including allergy, mother’s health during pregnancy, baby’s health problems, hospital admissions and medications during the first and the second years of life. 25 parental exposure Possible workplace exposures (including pesticides) parental medication in the periconceptual period, maternal medication during pregnancy, parental smoking and alcohol intake. Home cooking and heating means. 26 medication For parental medication see 25. History of infants’ medication and immunizations. 27 socio-economic factors Family make-up, presence of extended family in home, home ownership, car ownership, household size, crowding, household equipment, garden, pets, dampness, cooking and heating facilities. Parental education and occupation.

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Greece 01 Child care facilities.

Analysis and quality control procedures 28 intra/interlaboratory testing Not applicable - epidemiological study 29 external laboratory control Not applicable 30 accuracy, limit of Data available detection/quantification, reproducibility 31 data analysis (statistics, power Number of subjects decided by power calculation prior to calculations) study. Statistical analysis carried out by Statistics Section of the Institute of Child Health, according to epidemiological principles 32 representativity Non-responders were minimal, and did not differ from the study population Data protection and availability 33 privacy legislation Questionnaires are maintained by the chief researcher under secure conditions to ensure confidentiality in accordance with the 1995 Data Protection Directive. Data were analysed under conditions of anonymity 34 intellectual property rights The study complied with all the procedures of the scientific and deontological committees of the Athens Institute of Child Health and is considered the intellectual property of that Institute. Publications were made with permission of the Institute. 35 banking of biological samples The only biological samples, from the chromosomal testing, were not stored Communication (individual level, group level, level (sub)population ) 36 reporting results to public The Hellenic Ministry of Health and Welfare was kept authority, to general public, to informed of the progress and findings of the study via the participant, annual report of the Institute of Child Health, which is financed by that Ministry. The local authorities of the communities participating in the study were provided with a relevant reports, and in the case of Elefsina, organized a variety of events for informing the public, the school representatives, etc. of the findings. Individual families in which a specific problem was identified were informed and referred to the appropriate source of help (family doctor, paediatrician, psychology dept. etc.). 37 professionals involved, contacts In addition to the research team and the Scientific and between professionals and Deontological Committees of the Institute of Child Health, participants the local antenatal clinic staff and the mothers’ obstetricians were involved. 38 role of media There was some coverage following presentation of findings at professional meetings

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Greece 01 39 public debate Presentation of findings at professional conferences and meetings in Greece (medical, sociological, environmental) provided a forum for debate. 40 consequences of external There has been an increase in public awareness of communication environmental health hazards, and particular interest in the schools 41 Problems Continued funding of a long-term study was a major problem. This kind of study does not produce the quick results which the funding agencies like to see. The follow- up at 12 years was only possible because of the willingness of a young researcher to conduct the study at her own expense as her doctoral thesis. 42 Experiences This kind of study requires long-term commitment, and is only possible when a concerted investment in preparation and informing of the populace is made in advance. An extended pilot phase proved invaluable in smoothing out the problems at all levels, from the questionnaire to the cooperation of the services to the recruitment procedures. Continuity of research personnel helped to ensure continued participation of the families. Personal interview and examination of the children in their homes was time- consuming, but ensured cooperation and provided reliable information.

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Greece 02 N° General data 1 type Regional, research study 2 country Greece 3 title Geographical distribution of socio-economic factors in the Greater Athens basin in conjunction with air pollution levels 4 aim The levels of air pollution which have been shown to be associated with morbidity of the adult and child population vary widely between the various districts, and according to the season. The socio-economic characteristics which influence the health status of the residents also show wide variation between districts, but with a different distribution. The study aimed to investigate the factors which, in conjunction with air pollution, may have negative health effects 5 beginning date 1996 6 ending date 1998 (Report submitted) 7 contact person Dr.Sheena Nakou, Institute of Child Health, Athens 11527, Greece. [email protected] 8 initiator Hellenic Ministry of the Environment 9 involved/responsible organisations Athens Institute of Child Health, Laboratory of Hygiene and Epidemiology of the University of Athens Medical School, National Statistical Service of Greece 10 budget available terminated 11 who is financing Hellenic Ministry of the Environment

Description of the population 12 total number of children The study population was 1000 Athens households, 100 in each of the 10 districts where the Ministry of the Environment air pollution monitoring stations is located. General data was collected about each household, then one household member was selected, in accordance with the census data for that district for population distribution ratios, for a more detailed study. This gave a total study population of 1000, of whom less than 200 were aged 19 and under. 13 age groups and number of The age and sex distribution of the population and the persons in each group household size varied between districts, with some having more old people and others having larger, younger families, so the sample composition varied between districts. For analysis purposes, the target sample was divided into 3 groups, those under 20 years, those aged 20-60 (corresponding roughly to working age), and those aged over 60 years. 14 inclusion criteria, exclusion criteria 15 sampling strategy The study area around each monitoring was defined, using anonymous census data from the National

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Greece 02 Statistical Service, to cover 1000-2000 households. Families were located using a door-to-door search, and inclusion was based on permanent residence and agreement to participate. Within each household the specific study member was selected in order according to the population sex-age distribution for that district. The interview was conducted on the spot, unless the household members preferred a later date. 16 time schedule of biomonitoring The questionnaires were completed in a period of less than one year in 1997. 17 consent procedures The families were given a written account of the aims of the study and the contact phone numbers of the chief researcher, and gave their oral consent. In the case of reluctance to participate, the next household in the area was approached. 18 how is participation encouraged? Participation was encouraged by assurance of anonymity, and by careful selection and training of the interviewers who were all health professionals or paramedical personnel. Data collection 19 biomarkers of exposure Questionnaire covered history of hospital admission for respiratory or heart disease ever, and during the preceding year, history of asthma, bronchitis, sinusitis, pneumonia ever, and during the preceding year, history of medication for respiratory problems during the previous year (all with dates). Symptomatology during the previous week: cough, dyspnoea, runny nose, headache, itching eyes. 20 biomarkers of effect 21 biomarkers of susceptibility

Other data 22 environmental data The daily recordings of the air pollution monitoring stations in each of the 10 study districts were supplied by the Ministry of the Environment (CO, SO2, black smoke, NO2 and O3). The questionnaire covered details on possible indoor exposures from cooking and heating devices and passive smoking, as well as mold and house dust, and possible workplace exposures, individual or parental in the case of children.

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Greece 02 23 lifestyle data Extensive details were collected on lifestyle, individual habits, history of holidays away from the city, and time activity patterns from the most recent week day and the most recent weekend day, concentrating on time spent indoors and outdoors, use of transport, time spent away from the place of residence, physical activity, in an attempt to individualize exposures. Details of past places of residence other than the study district were included. Attention was paid to the proximity of the home to busy roads and to the level of residence in the case of an apartment. 24 health data Personal health history was recorded, along with family history of malignancy, respiratory disease, asthma and allergies. 25 parental exposure 26 medication History of medication for respiratory problems in the past year. 27 socio-economic factors A full socio-economic record was made for each household, including educational level and occupation of household head and of study individual, total number of persons in household, number of employed, size and type of home, home ownership, car ownership, household equipment, etc. For the purposes of analysis, a ‘crowding index’ and an ‘affluence index’ were derived.

Analysis and quality control procedures 28 intra/interlaboratory testing 29 external laboratory control 30 accuracy, limit of detection/quantification, reproducibility 31 data analysis (statistics, power The data were analysed according to recognised calculations) epidemiological procedures 32 representativity The representativity was confirmed by comparing the sex-age-household size and distribution of each district with that of the census data.

Data protection and availability 33 privacy legislation The questionnaires were anonymous and no names were recorded. The study was approved by the Scientific and Deontological Committees of the Institute of Child Health. 34 intellectual property rights The report of the results was presented to the Hellenic Ministry of the Environment who have the rights. The Institute of Child Health may publish parts at the discretion of the Ministry. 35 banking of biological samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to general public, to participant,

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Greece 02 37 professionals involved, contacts between professionals and participants 38 role of media 39 public debate 40 consequences of external communication

41 Problems The recent symptomatology proved difficult to correlate with air pollution ‘episodes’ in districts where there was an epidemic of respiratory virus. The collection and management of time-activity patterns continues to pose problems.

42 Experiences The recruitment technique was successful in the study period, but the recent influx of immigrants and the pressure of door-to-door advertising have made people reluctant to open their doors.

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Greece 03 number General data 1 type Cross-sectional epidemiological study. Regional 2 country Greece 3 title Air pollution and child morbidity. Epidemiological study of the extent and type of effects of air pollution on the respiratory system of children living in the Greater Athens basin.4. The study aimed to identify factors associated with the admission to hospital of children with respiratory problems, and specifically to investigate the relationship of admissions with the air pollution levels recorded by the pollution monitoring network of the Ministry of the Environment. 4 aim The study aimed to identify factors associated with the admission to hospital of children with respiratory problems, and specifically to investigate the relationship of admissions with the air pollution levels recorded by the pollution monitoring network of the Ministry of the Environment.

5 beginning date 01.06.1992 6 ending date 31/5/93 was the end date of the recruiting period. 7 contact person Dr.Sheena Nakou, Institute of Child Health, Athens 11527, Greece. [email protected] 8 initiator Hellenic Ministry of the Environment 9 involved/responsible Laboratory of Hygiene and Epidemiology of the University of organisations Athens, ‘Aghia Sophia’ Children’s Hospital, Athens, ‘Aglaia Kyriakou’ Children’s Hospital, Athens 10 budget available terminated 11 who is financing Hellenic Ministry of the Environment

Description of the population 12 total number of children 1,169 children 13 age groups and number of Of the total 1,169 children, 411 (35.2%) were aged 1<=12 persons in each group months, 211 (18%) were aged 12-24 months, 275 (23.5%) were aged 2-4 years and 272 (23.3%) were aged 4-14 years. 14 inclusion criteria, exclusion The children were a 1 in 3 sample of all the children aged over criteria one month admitted to the two major Athens children’s hospital for a respiratory problem over a one year period, who were permanent residents of the Greater Athens area. In a parallel study, a matched control sample for the school-age children was selected from the children admitted the same day, but with no respiratory symptoms. 15 sampling strategy The children’s names and admission symptoms and hour of admission were derived from the admissions list. All children’s ages and place of residence were recorded, and for each third child the accompanying parent or guardian of each child was approached on the day following admission. If the family did not wish to participate, the next child on the list was selected.

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Greece 03 16 time schedule of A full year was used as the sampling period in order to take biomonitoring into account seasonal variations 17 consent procedures Each parent/guardian was provided with a written account of the aims of the study and told of the time completion of the questionnaire would take, and oral consent was obtained. 18 how is participation Participation was encouraged by ensuring cooperation of all encouraged? the staff in the paediatric clinics included in the study. Hospital routine was interrupted as little as possible Data collection by questionnaire completed on personal interview 19 biomarkers of exposure 20 biomarkers of effect The exit diagnosis allocated to each child by the hospital paediatric team was used as the ‘effect’, classified into diagnosis categories, e.g., asthma, acute laryngitis, pneumonia, etc. 21 biomarkers of susceptibility

Other data 22 environmental data Daily air pollution data (SO2, black smoke, CO, NO2 and O3) from the Athens network of monitoring stations of the Hellenic Ministry of the Environment. 23 lifestyle data The study questionnaire included details of location, type and size of home (including level in the case of apartments) and of living conditions, size of household, means of cooking and heating, smoking of household residents, dampness of the rooms, household pets. It also detailed daily habits and activities of the child, with a detailed time activity pattern of the periods just before the onset of symptoms and immediately before admission, including hours spent out of doors and in places other than the home. 24 health data The family medical history was recorded, with particular reference to asthma and allergies, and the child’s medical history, with particular attention to the pregnancy, including maternal smoking and medication in pregnancy, birth, breastfeeding, neonatal respiratory problems, wheezing, asthma and allergies and previous hospital admissions. The symptomatology leading to admission was recorded. 25 parental exposure Parental smoking habits and potential workplace exposure to toxic materials were recorded. 26 medication The children’s history of medication was included. 27 socio-economic factors The socio-economic background of the family, parental education and occupation, type of home and home and car ownership and household equipment were recorded.

Analysis and quality control procedures 28 intra/interlaboratory testing 29 external laboratory control 30 accuracy, limit of detection/quantification, reproducibility

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Greece 03 31 data analysis (statistics, power The study aimed to include at least 1000 admissions calculations) (final number 1,169). Statistical analysis was performed according to epidemiological principles by the Statistics Section of the Institute of Child Health. 32 representativity Analysis of the 2 in 3 admissions not included showed no statistical difference in the age, and place of residence between the sample and the children not included

Data protection and availability 33 privacy legislation The name of the children was not entered in the final record, the address was not used (only the district) and the questionnaires were handled according to the 1995 EC Data Protection Directive. Both parts of the study were approved by the Scientific and Deontological Committees of the Institute of Child Health 34 intellectual property rights The data belong to the Hellenic Ministry of the Environment to which the final report was made, and the results may be published by the Institute of Child Health at the discretion of the Ministry. 35 banking of biological samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to public The final report of the study was submitted to the Ministry authority, to general public, to of the Environment to be publicised at their discretion. participant, The cooperating hospitals were notified of the findings, some of which were presented to the local Paediatric Association to which the paediatricians of the cooperating hospitals belong 37 professionals involved, contacts Approval was granted by the Scientific Committees and between professionals and the Clinic heads of the two participating hospitals. participants 38 role of media There was no external publicity, but the study was the subject of discussion amongst the paediatric community, and in particular it drew attention to the importance of home factors. 39 public debate 40 consequences of external communication

41 Problems The main problems concerned the analysis of the multiplicity of data derived from the study, and in particular the use of time activity information. The question of the relative impact of pollution during a respiratory virus epidemic is difficult to handle. In many ways the study raised more questions than it answered

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Greece 03 42 Experiences The intensive preparation for the study – informing the hospital staff, piloting, etc., were well worth the effort. The major role played by a family history of asthma and other allergies in the presentation of children’s respiratory illness was striking, as was the contribution of ‘poverty’.

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Greece 04 Number General Data 1 type Children 5-10 years 2 country Greece 3 title Monitoring DNA damage-repair, apoptosis and necrosis in children in comparison to adults 4 aim To study children’s DNA repair efficiency in comparison to adults. To find out whether the mechanisms of apoptosis and necrosis in children are similar to the one’s in adults. 5 beginning date 2003 6 ending date 2004 7 contact person Dr. S. Piperakis E-mail: [email protected] Tel/Fax: +30 210 8075978

8 initiator DNA Repair Lab, Institute of Biology, NCSR Demokritos 9 involved/responsible DNA Repair Lab, Institute of Biology, NCSR Demokritos organisations 10 budget available € 3000 11 who is financing NCSR Demokritos

Description of the population 12 total number of children (and parents) 100 children 13 age groups and number of persons in Age groups: each group 5-10 healthy children 14 inclusion criteria, exclusion criteria Inclusion criteria are: Informed consent Age 15 sampling strategy Children are recruited via hospitals 16 time schedule of biomonitoring Children will be sampled once in the period between May 2003 - May2004 17 consent procedures parent informed consent 18 how is participation encouraged? ------

Data collection

19 biomarkers of exposure ------20 biomarkers of effect - Comet assay on lymphocytes to estimate DNA damage-repair. - measurement of apoptosis and necrosis 21 biomarkers of susceptibility ------

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Greece 04 Other data 22 environmental sampling Questionnaires on place of residence to determine whether they leave in air polluted area. 23 lifestyle data - Nutrition of the family on: type/frequency/amount of bread, cereals, fats, fish, meat, poultry, sauces, pastries, coffee, tea, milk products, vegetables, fruit, drinks, etc. - Active/passive smoking of the parents, drug- use (frequency, type), hobbies, contact with chemicals etc.

24 health data Health of participating child, any genetic or inherited disease. 25 parental exposure Alcohol use and smoking, exposure to chemicals etc. 26 medication Use of any medication by child 27 socio-economic factors Structure of the family, educational level of parents

Analysis and quality control procedures 28 intra/interlaboratory testing Critical phases are been monitored (collection, identification, transport, storage and preparation of the samples, etc) 29 external laboratory control ------30 accuracy, limit of Data for all parameters are kept. detection/quantification, reproducibility

31 data analysis (statistics, power Suitable statistical analysis is been performed. calculations) 32 representativity Recruitment efficiency is monitored.

Data protection and availability 33 privacy legislation Samples and questionnaires are kept confidential. Measures are taken to ensure confidentiality and security of the data. Ethical advice has been taken to determine the maximum volume of blood samples that may be taken in order to minimise distress to the participant. 34 intellectual property rights No patents. Data will be published. 35 banking of biological samples No long term storage is foreseen

Communication (individual level, group level, level (sub)population )

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Greece 04 36 reporting results to public authority, to Results of the study will be communicated to general public, to participant the scientific community by publication in peer reviewed journals and presentation in international conferences. 37 professionals involved , contacts Biologists and GP’s. between professionals and participants

38 role of media ------

39 public debate ------

40 consequences of external ------communication

41 Problems

Collection of blood samples is a significant disincentive to participation

42 Experiences

A lot of energy has to be spent in communication for organising participation of children.

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Short summary to the questionnaires:

The first study (Childhood leukaemia and road traffic: a population-based case-control study) and the Setil Project (an Italian multicentric case-control study) investigate the association of selected childhood neoplasms with environmental risk factors to assess children’s exposure to benzene.

The first study provides further evidence of a relationship between exposure to traffic exhausts and childhood leukaemia. Benzene is an established cause of leukaemias in humans and benzene and other carcinogens, such as polycyclic aromatic hydrocarbons, emitted by motor vehicles are inhaled as gases or adsorbed on particulate matter which is also inhaled. The data of the present study and other available evidence are in favour of the hypothesis that exposure to traffic exhausts is a factor in the aetiology of childhood leukaemia.

The Project SETIL also characterize the relation between benzene intake and excretion of some urinary metabolites;

The others studies evaluate the effects and the relation between respiratory disease and air pollution in asthmatic children, in the association between levels of pollutants monitorated by urban stations.

Country: ITALY Comments

Reported biomonitoring 1. Childhood leukaemia and road activities traffic: a population-based case- control study 2. Associations between levels of polluttants and wheezing in ER 3. AIRE (Asthmatic children in the Emilia-Romagna region) 4. Exposure to benzene among children participating in the SETIL Project

Total number of children Italy 40000 / 0,027% involved/ percentage of total population

Overall budget About € 161.000 For one project information has not been presented

Aims 1. investigate association between benzene exposure and childhood leukaemia

2. to study the associations

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Country: ITALY Comments between levels of polluttants monitorated by urban stations and Emergency Room visits in hospital in 6 cities of Italy

3. to study the relation between respiratory disease and air pollution in asthmatic children.

4. to assess children’s exposure to benzene; to characterize the relation between benzene intake and excretion of some urinary metabolites;

Specific age groups 0 – 14 years (1 project) 0 – 2 years (1 project) 6 – 11 years (1 project) 0 – 10 years (1 project

Type of data X% anonymous y % identifiable (code)

Time periods (shortest, 3 years; 3 years; 4 years; 21years; average, longest)

Biomarkers of exposure urinary excretion of biological indicators of exposure [t-t muconic acid (MA) , S-phenylmercapturic acid (S-PMA), cotinine, and sorbic acid].

Biomarkers of effect /

Additional data Life style data (1 project)

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Italy 01 N° General data 1 type Time series 2 country Italy 3 title Associations between levels of polluttants and wheezing in ER 4 aim To study the associations between levels of polluttants monitorated by urban stations and Emergency Room visits in hospital in 6 cities of Italy 5 beginning date 1 1 1996 6 ending date 31 12 2000 7 contact person F Orazzo via A Manzoni n 157 C Naples Italy 0039 081 7692557 0039 3288250327 [email protected] 8 initiator F Orazzo via A Manzoni n 157 C Naples Italy 0039 081 7692557 0039 3288250327 [email protected] 9 involved/responsible organisations 10 budget available 11 who is financing Nobody

Description of the population 12 total number of children for 1996-1998 29554 wheezing visted in ER age0- 2 years 13 age groups and number of persons in each group 14 inclusion criteria, exclusion criteria Low respiratory disease , cardiopaties 15 sampling strategy daily number of ER visits for wheezing and daily levels of polluttants 16 time schedule of biomonitoring 17 consent procedures 18 how is participation encouraged? Pubblications Data collection 19 biomarkers of exposure 20 biomarkers of effect 21 biomarkers of susceptibility

Other data 22 environmental data levels of PTS, NO2, ozone, Co So , and aeroallergens graminacae , urticariacae 23 lifestyle data 24 health data 25 parental exposure 26 medication 27 socio-economic factors

Analysis and quality control procedures 28 intra/interlaboratory testing 29 external laboratory control 30 accuracy, limit of detection/quantification, reproducibility

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Italy 01 31 data analysis (statistics, power calculations) 32 representativity

Data protection and availability 33 privacy legislation 34 intellectual property rights 35 banking of biological samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to general public, to participant 37 professionals involved, contacts between professionals and participants 38 role of media nothing 39 public debate nothing 40 consequences of external communication

41 Problems founds for paing the associations by temporal series

42 Experiences

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Italy 02 N°r General data 1 type Provincial study 2 country Province of Varese 3 title Childhood leukaemia and road traffic: a population-based case-control study 4 aim A case-control study to investigate association between benzene exposure and childhood leukaemia 5 beginning date 1978 6 ending date 1997 7 contact person Paolo Crosignani, MD, e-mail:[email protected] Fax: +39.02.23902762 8 initiator 1 Lombardy Cancer Registry, National Cancer Institute, Via Venezian 1, 20133 Milano , 2 Varese Environmental Agency Unit (ARPA), Via Caretti 5, Varese, Italy, 3 Varese Health Unit (Saronno District), Via Manzoni 23, Saronno, (VA), Italy 9 involved/responsible Paolo Crosignani1, Andrea Tittarelli1, Alessandro Borgini1, organisations Tiziana Codazzi1, Adriano Rovelli2 , Emma Porro2, Paolo Contiero1, Nadia Bianchi2, Giovanna Tagliabue1, Rosaria Fissi1, Francesco Rossitto3, Franco Berrino1

Description of the population 10 total number of children (and 120 cases and 480 controls parents) 11 age groups and number of aged 0 to 14 years persons in each group 12 inclusion criteria, exclusion diagnosed with leukaemia according to codes 204.0 to 208.9 criteria inclusive of ICD IX 13 sampling strategy For the cases, The Province of Varese has been covered by the population-based Lombardy Cancer Registry (LCR) since 1976, for Controls were obtained from Health Service archives established in 1987 14 time schedule of biomonitoring 15 consent procedures 16 how is participation Questionaire encouraged? 17 budget available 18 who is financing

Data collection 19 biomarkers of exposure 20 biomarkers of effect 21 biomarkers of susceptibility

Other data 22 environmental sampling outdoor pollution (benzene) 23 lifestyle data

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Italy 02 24 health data leukaemia 25 parental exposure 26 medication 27 socio-economic factors

Data protection and availability 33 privacy legislation anonymous data 34 intellectual property rights 35 banking of biological samples no

41 Problems

42 Experiences

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Italy 03 N° General data 1 type Regional (research study) 2 country Italy 3 title AIRE (Asma Infantile nella regione Emilia-Romagna)(Asthmatic children in the Emilia-Romagna region) 4 aim To study the relation between respiratory disease and air pollution in asthmatic children. 5 beginning date 1999 6 ending date 2002 7 contact person Dr. Andrea Ranzi, Environmental Epidemiology Unit of ARPA Emilia- Romagna, tel: +39+59433625, FAX: +39+59241312, e-mail: [email protected] 8 initiator Environmental Epidemiology Unit of ARPA Emilia-Romagna 9 involved/responsible ARPA Emilia-Romagna, Regional sanitary agency, Paediatric organisations Department of local health authority in Modena, Paediatric Department of local health authority in Reggio Emilia 10 budget available 50.000 € 11 who is financing Emilia-Romagna Region and ARPA Emilia-Romagna

Description of the population 12 total number of children Screening: 5787; Panel: 118 13 age groups and number of 6-11 years-old persons in each group 14 inclusion criteria, exclusion Screening: school-aged children, Panel: included on the basis of 4 criteria questions in the screening questionnaire 15 sampling strategy Screening: randon sampling of schools, Panel:selection of cases on the basis of a questionnaire 16 time schedule of 10 weeks of winter-spring follow-up with questionnaire and a daily biomonitoring diary of activities, PFR, Atopy test, daily personal PEF measurements. 17 consent procedures written informed consent by parents of children 18 how is participation encouraged? Data collection 19 biomarkers of exposure 20 biomarkers of effect 21 biomarkers of susceptibility

Other data 22 environmental data outdoor level concentrations of PM2.5, TSP, SO2, NO2, CO 23 lifestyle data parents/passive smoking, daily activities, presence of animals (daily diary) 24 health data respiratory disease, PEF (daily diary), general respiratory health status, familiarity (questionnaires), Allergy (Prick test) 25 parental exposure smoking (daily diary) 26 medication medicine consumption (daily diary) 27 socio-economic factors type of house, study level of parents, number of brother/sister (initial

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Italy 03 questionnaire)

Analysis and quality control procedures 28 intra/interlaboratory testing 29 external laboratory control 30 accuracy, limit of according to diagnostic test guidelines detection/quantification, reproducibility 31 data analysis (statistics, descrpitive statistics, time series analysis, linear mixed models power calculations) 32 representativity children population at local level

Data protection and availability 33 privacy legislation data presented in aggregated form 34 intellectual property rights None 35 banking of biological No samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to public Research paper in press, short scientific comunications authority, to general public, to participant 37 professionals involved, Physicians, Epidemiologists, Statisticians, Chemists contacts between professionals and participants 38 role of media Not yet 39 public debate Not yet 40 consequences of external Not yet communication

41 Problems 42 Experiences

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Italy 04 General data 1 Type National activity – Research study 2 Country Italy 3 Title Exposure to benzene among children participating in the SETIL Project 4 Aim SETIL is an Italian multicentric case-control study, investigating the association of selected childhood neoplasms with environmental risk factors. Dr. Corrado Magnani (Turin, Italy) is the national coordinator. The study involves 15 Italian regions and is conducted by an ad hoc unit in each region. Cases are children aged 0 to 10 years diagnosed with acute leukemia (~ 800 cases), non-Hodgkin lymphoma (~ 75 cases), and neuroblastoma (~ 200 cases) in 1998-2001. Incident cases are notified by the national registry run by the Association of Pediatric Hematology and Oncology (AIEOP) and the Italian Task Force for Pediatric Oncology (FONOP). Controls, individually matched to leukemia cases (ratio 2:1) on sex, date of birth and region, are randomly selected from population lists. Trained interviewers administer a structured questionnaire to the parents of cases and controls. Parental occupational exposure to chemicals and radiation will be estimated via expert assessment from data collected at interview. Exposure of children to 50 Hx magnetic fields are estimated based on indoor measurements. Measures of indoor γ radiation and personal exposure to benzene are being collect for a subset of leukemia cases and their matched controls. We described herein the side study “Exposure to benzene among children participating in the SETIL Project”, which is the only research line involving biomonitoring activities. This side-study involve a subset of SETIL children, from 7 italian provinces (Cagliari, Catania, Florence, Milan, Palermo, Rome, and Turin). The study is aimed to assess children’s exposure to benzene; to characterize the relation between benzene intake and excretion of some urinary metabolites; to evaluate the role of outdoor concentration and environmental tobacco smoke on the exposure profile; to gain insights about the possible confounding effect of benzene exposure on the associations between leukemia risk and other risk factors. The study is based on repeated measurements (4 series in 1 year, each lasting 1 week) of: (i) benzene concentrations in breathing zone air samples; (ii) outdoor benzene concentrations in proximity of the child’s residence; (iii) urinary excretion of biological indicators of exposure [t-t muconic acid (MA) , S-phenylmercapturic acid (S-PMA), cotinine, and sorbic acid]. However, the side study lacks the statistical power required to evalutate the association between incidence of childhood leukemia and exposure to benzene per se 5 Beginning date Samplings began between March 2002 and January 2003, depending on the province.

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Italy 04 6 Ending date Ending dates vary between October 2003 and July 2004, again, depending on the province. 7 Contact person Dr. Susanna Lagorio ([email protected]; tel and fax +39 06 49903180). 8 Initiator Istituto Superiore di Sanità – National Center for Epidemiology, Surveillance and Health Promotion. 9 Involved/responsible The research group involved is a subset of the full SETIL study group. The organisations list of investigators is enclosed at the end of this form. 10 Budget available About € 81000,00 (covering essentially costs of passive samplers and sample analyses). 11 Who is financing Italian Ministry of Health. Other costs (i.e. personnel, travels, consumables, computing, etc) have been covered by other national funding agencies (AIRC, MURST, ISPESL). Description of the population 12 Total number of children Eligible for this side-study are cases of childhood leukemia included in SETIL Study, diagnosed between 1 August 2000 and 31 December 2001 and resident in 7 italian provinces (Cagliari, Catania, Florence, Milan, Palermo, Rome, and Turin), along with their matched controls. Each province includes both urban and rural areas. Within the above defined boundaries, however, each local study group choose an eligible diagnostic period compatible with the available resources. In principle, 324 children (108 cases and 216 controls) were eligible for the Benzene side-study (Table 1), and 143 had at least one week of benzene exposure indexes collected by the end of June 2003 (Table 2).

Table 1. Distribution of eligible children by province of residence

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Italy 04 11 Province Cases Controls Total Cagliari 9 18 27 Catania 10 20 30 Florence 8 16 24 Milan 27 54 81 Palermo 12 24 36 Rome 27 54 81 Turin 15 30 45 Totale 108 216 324

Table 2. Children included in the benzene side-study up to June 2003, by province of residence

Province Cases Controls Total Cagliari 4 5 9 Catania 5 10 15 Florence 3 2 5 Milan 10 14 24 Palermo 4 6 10 Rome 18 37 55 Turin 8 17 25 Totale 52 91 143

Please note that figures in table 2 are provisional, as the benzene side-study is still in progress. 13 Age groups and number of The following table describes the age distribution of eligible cases and persons in each group controls, at diagnosis (or corresponding reference date).

Table 3. Age distributon of children eligible for the benzene side-study

Age group Cases Controls Overall 0-2 41 82 123 3-5 41 82 123 6-10 26 52 78 Total 108 216 324

The mean age at diagnosis is 3.97 years (SD 2.78), with a median of 3 and a modal value of 2 years. Families of cases are approached at least 6 months after diagnosis (during a remission phase). A further delay occurs between the parents’ interview and the start of the biomonitoring of the child’s exposure to benzene. As the Benzene exposure study is still in progress, the exact age distribution of participating and non-participating children (at diagnosis and at entering the Benzene Exposure side- study), will only be available once completed the data collection phase.

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Italy 04 14 Inclusion criteria, exclusion Children, whose parents were not approached (following the advice of the criteria attending physician), or refused to participate in the SETIL Project, were not asked to participate in the Benzene exposure study. No other restriction was applied. We are measuring ambient concentrations of benzene in the near proximity of the homes of non-participating children, in order to detect possible differential participation rates and the impact of such bias on the study findings 15 Sampling strategy Due to the high day-to-day variability of ambient benzene concentrations, the study is based on repeated individual measures of exposure biomarkers and environmental data, i.e. 4 weeks of sampling, 1 week for season, during 1 year. 16 Time schedule of At each of the 4 seasonal monitoring surveys, daily urine samples (10 ml, biomonitoring from the last micturition before sleep) are collected for 7 subsequent days (70 ml per week). The daily urine samples are pooled in a single container (case), kept in the freezer compart of the home refrigerator. This sampling strategy is due to the low concentrions of benzene exposure biomarkers expected under “average” exposure conditions among children. Weekly urine samples are collected at the end of each week, transported to local SETIL unit in thermic bags, and stored at –5 °C until they are sent (usually in 2 weeks), packed in dry ice, to the laboratory for the analyses.. 17 Consent procedures We decided a-priori to rely on biological indicators not requiring invasive sampling procedures. The members of Piedmont Ethical Commitee, who approved the Benzene exposure study on 14 January 2002, considered this decision an appropriate measures to protect the frialty of the involved subjects. Parents of children willing to participate in the SETIL project are invited to sign an informed consent form. The request concerning the Benzene exposure study is submitted either as a specific letter, or as an addendum to the invitation letter for the main study, depending on the local coordinator choice and on the delay between the interview date (including measures of 50 Hz magnetic fields) and the beginning of the benzene exposure biomonitoing. In the first case, there is a Benzene specific consent form to be signed by the parents; in the second instance, the general consent form include a separate question concerning the willingness to participate in the Benzene exposure study. Therefore, subjects who agree to participate in the SETIL main study, are free of refusing participation in the Benzene exposure study. 18 How is participation We expected parents to be reluctant to engage in a survey involving 4 encouraged? repeated monitoring weeks in 1 year. Furthermore, we were afraid that the involved children might be uneasy while wearing the benzene passive sampler at school, in front of their friends. Therefore, we produced a leaflet addressed to the involved children, their schoolmates, parents and teachers. The title is “How much benzene does a child breath?”. The brochure opens with a poem by Gianni Rodari, entitled “The glass-men”. We then explain that, as in the real world human beings are not made of glass, we cannot “see” the intake of substances assumed when breathing. We clarify, in a question-and-answer format, why we were asking them to wear the

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Italy 04 passive sampler, its functioning, and what we are going to do of it after withdrawal (i.e. its trip to the laboratory for the analyses). In most cases, we have asked the parents of the involved child to deliver the leaflet to their child’s nursery-school or primary-school teachers. In some instances however, for example in Florence, local coordinators have directly met teachers and schoolmates of participant children. Data collection 19 Biomarkers of exposure Average weekly exposure to benzene from any source is assessed by monitoring urinary excretion of t-t muconic acid (t-tMA) and S- phenylmercapturic acid (S-PMA) – two benzene metabolites. Urinary concentration of sorbic acid will be determined, as this compound may confound the relationship between benzene exposure and MA excretion. Cotinine excretion will be used as indicator of exposure to environmental tobacco smoke (a relevant source of indoor benzene exposure among children). All these analyses are performed with an HPLC system (Alliance 2690, Waters) equipped with a SM detector (ZQ, Waters).

The analyses are divided in two steps: the purification of the sample with SPE cartridges and the analyses with the chromatographic system. In the first step each urine sample is loaded on a pre-activated cartridge; the cartridges are then washed and finally eluted: an aliquot is injected in the HPLC system. This step is necessary to clean the urine sample from the substance that could obstruct the analyses in HPLC. The volume of the solutions used to realize the purification depends on the chemical-physical characteristic of the analyte and so it is specific for each method. In the second step the chromatographic column is able to separate the substance to detect from the other substance. The different substance are detected from a spectrometric detector: with a single ion monitoring method we obtain a series of peaks through the areas of which is possible to determinate the concentration of the urine samples. The determination of this concentration is based on a calibration curve obtained adding known amount of standard to a pool of no-smokers subjects: these samples are purified and analysed in the same condition used for unknown samples. 20 Biomarkers of effect None. 21 Biomarkers of None. susceptibility Other data 22 Environmental data Personal exposure to benzene will be determined by repeated measures of benzene concentrations in breathing zone air samples, collected by passive samplers (Radiello; 1 week sampling – 1 week for season = 4 weeks in 1 year). Ambient benzene concentrations in proximity to the child’s home, will be measured concurrently with each weekly biomonitoring session. For the measurements of front-door benzene concentrations, diffusive samplers will be placed near (within 1 meter) the entrance of the index residence, at a vertical distance from the ground suitable to avoid infringements (2-2.5 m). In both personal and ambient air samples, concentrations of benzene,

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Italy 04 toluene, xylenes (o-, m-, p-) and ethyl benzene will be determined by capillary GC after thermal desorption. The interview includes questions about the smoking habits of the parents. The residential section of the questionnaire collects information on the traffic intensity in the surroundings of the child’s home. 23 Lifestyle data The interview administered to the parents includes many lifestyle-related questions (indicators of socio-economic status of the family, number of siblings, life-long residential history with characteristics of the different dwellings; school history; time spent by the child in proximity to sources of electromagnetic fields). Moreover, during the benzene biomonitoring periods, parents are required to fill in a diary, recording time spent in different microambients (indoor at home, indoor at school, outdoor, in commuting, etc.). 24 Health data The Benzene exposure side-study involves leukemia cases and their matched controls. 25 Parental exposure Parental occupational exposure to chemicals and radiation will be estimated via expert assessment from data collected at interview. 26 Medication No information gathered. 27 Socio-economic factors The interview includes questions about the occupation and educational level of the parents.

Analysis and quality control procedures 28 Intra/interlaboratory testing Urine samples are analysed by a single laboratory (Centro Ricerche Labs MEIA - Fondazione Salvatore Maugeri; Pavia - Dr. Segio Ghittori and Dr. Luciano Maestri). All personal and ambient air samples are analysesed by a single laboratory (Centro Ricerche Ambientali – Fondazione Salvatore Maugeri, Padova – Dr. Vincenzo Cocheo (until his recent premature death) and Dr. Paolo Sacco). 29 External laboratory control A small numer of urine samples will be analysed in duplicate, using different methods, at the Istituto Superiore di Sanità (Dr. Luigi Turrio Baldassarri and Dr. Cinzia Leone). 30 Accuracy, limit of BIOLOGICAL INDEXES OF EXPOSURE. detection/quantification, The conditions used for the analyses of each metabolite are summarized in reproducibility the following scheme. S-Phenyl mercapturic acid analyses (SPMA) Pre-treatment of the urine sample Calibration curve concentrations: 0, 5, 10, 50 µg/L; Acidification of urine (5 mL) with HCl; Centrifugation : 10 minutes at 3500 rpm; Purification on SPE (Isolute C18 500 mg/3mL). Chromatographic conditions Mobile Phase: :60% acetic acid 1%; 40% methanol; Flow: 0.3 mL/min; Column: Symmetry C18 3.0 x 150 mm, 3.5 µm (Waters); Column temperature = 29°C; Run time = 45 min; Volume injected = 21 µL. MS Method: Single Ion Recording of mass 238.0 in ESI neg. LR = 0.3 µg/L; LOD = 1 µg/L; CV % = (1.22)-(1.10); Accuracy % = (- 2.39)-(3.36). Muconic acid analyses (MA) Pre-treatment of the urine sample

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Italy 04 Calibration curve concentrations: 0, 50, 200, 500,1000 µg/L; Centrifugation on 2 mL of urine : 10 minutes at 3500 rpm; Purification on SPE ( Isolute SAX 500 mg/3mL). Chromatographic conditions: Mobile Phase: 78 % formic acid 0.2 %; 22 % methanol; Flow: 0.3 mL/min; Column: Symmetry C18 3.0 x 150 mm, 3.5 µm (Waters); Column temperature = 30°C; Run time = 30 min; Volume injected = 21 µL. MS Method: Single Ion Recording of mass 141.0 in ESI neg. LR = 7 µg/L; LOD = 20 µg/L; CV % = (1.33)-(1.06); Accuracy % = (- 2.18)-(3.27). Sorbic acid analyses (SA) Pre-treatment of the urine sample Calibration curve concentrations: 0, 20, 100, 500, 2000 µg/L; Acidification of urine (2 mL) with 1 mL HCl 8N; For 30 min. a 100°C; Centrifugation : 10 minutes at 3500 rpm; Purification on SPE ( Isolute ENV+ 50 mg/3mL). Chromatographic conditions: Mobile Phase:72 % ammonium acetate 5 mM; 28 % methanol; Flow: 0.3 mL/min; Column: Symmetry C18 3.0 x 150 mm, 3.5 µm (Waters); Column temperature = 30°C; Run time = 35 min; Volume injected = 21 µL. MS Method: Single Ion Recording of mass 111.1 in ESI neg. LR = 4 µg/L; LOD = 12 µg/L; CV % = (1.18)-(1.14); Accuracy % = (- 2.28)-(3.32). Cotinine analyses Pre-treatment of the urine sample Calibration curve concentrations: 0, 10, 50, 250, 1000, 3000 µg/L; Basification of urine (2 mL) with Ammonium Hydroxide ACS Reagent; Centrifugation : 10minutes at 3500 rpm; Purification on SPE ( Isolute ENV+ 50 mg/3mL). Chromatographic conditions: Mobile Phase:75 % ammonium acetate 3.7mM; 25 % methanol; Flow: 0.3 mL/min; Column: Symmetry C18 3.0 x 150 mm, 3.5 µm (Waters); Column temperature = 30°C; Run time = 33 min; Volume of sample injected = 21 µL MS Method: Single Ion Recording of mass 177.2 in ESI pos. LR = 0.3 µg/L; LOD = 1 µg/L; CV % = (1.25)-(1.09); Accuracy % = (- 2.29)-(3.33).

Personal and ambient air samples For diffusive sampling measurements the extended uncertainty (EU) is a better estimate of the performance of the method, with respect to accuracy. The EU at 5 µg/m3 concentration is 29%. For 1 week of exposure, the limit of detection is 0,05 µg/m3 and the limit of quantification is 0,1 µg/m3. In the same conditions the reproducibility can be estimated to be around 14 %. 31 Data analysis (statistics, Due to the limited size, this study does not have adequate power to power calculations) investigate the epidemiologic relationship between exposure to benzene and the occurrence of childhood leukemia. The main goal of the analyses will be

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Italy 04 to separate out factors affecting the variability of ambient and personal exposure data, and their derived indices, while adjusting for potential confounders. Linear mixed-effects models will be used to account for the repeated-measures design. The output of the analysis will provide a basis for the design of future epidemiologic studies based on monitoring data. 32 Representativity Due to study design, children involved in the SETIL Benzene exposure side- study are not a representative sample of the children resident in the 7 Italian provinces where the Benzene exposure side-study is based. In particular, the sex- and age-distribution of the control sample reflects that of incident childhood leukemia cases. However, control children are randomly sampled from population lists. The possibility of differential participation of cases and controls (i.e. participation rates associated with both caseness and probability/intensity of exposure to benzene) does exist. Data protection and availability 33 Privacy legislation Data are collected, stored, and analysed in accordance with the Italian Privacy Law requirements (L 675/1996) and subsequent amendaments for research projects of relevant public health interest (DLgs 135/1999 e 318/1999). 34 Intellectual property rights Data belongs to the SETIL Research Group (whose national coordinator is Dr. Corrado Magnani..The PI for the Benzene exposure side-study is Dr. Susanna Lagorio (Rome, Italy) and the list of scientists involved is enclosed at the end of this form. 35 Banking of biological Urine samples will not be stored after the analyses. samples Communication (Individual level, group level, level (sub)population ) 36 Reporting results to public Result of the SETIL project, as well as of the Benzene exposure side-study, authority, to general public, will be submitted for publication to peer-reviewed journals. Participants (in to participant facts, the parents of the children) will receive a letter illustrating results of all the measures taken at their home or from their children. 37 Professionals involved, The professional background of personnel responsible for direct contact contacts between with participants in not homogeneous in the 7 local study centres professionals and (epidemiologists,pediatricians, interviewers, social workers). However, one participants only professional in each centre is in charge of the repeated contacts with participants during the whole study period. 38 Role of media - 39 Public debate - 40 Consequences of external - communication Problems 41 Problems encountered in the planning phase of the project consisted of: (i) difficulties in convincing local coordinators to carry out the Benzene Exposure side-study, given the extra-efforts required; (ii) funds obtained for the SETIL project did not cover the costs of the Benzene Exposure side- study, so that we had to apply for extra-funding; (iii) when funds were finally obtained, they were inadequate to cover the full range of costs. Problems encountered in the implementation phase of the project consisted mainly of (i) difficulties in obtaining and sustaining subject participation, due to the long period of the study; (ii) heavy burden of work for the local

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Italy 04 centre; (iii) difficulties in assuring a proper level of coordination and support to local centres (again due to inadeguate funding). Experiences 42 For the PI, this is the first experience of biomonitoring of children (she has previously carried out similar studies on adult population, professionally exposed), in the context of a case-control study (which implies the inclusion of diseased children) centered in 7 different Italian regions (which makes extremely difficult to assure homogeneous procedure of data collection, sample storage and transport; and problem solving). A full appreciation of this experience will only be possible after completion of the study.

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“EXPOSURE TO BENZENE AMONG CHILDREN PARTICIPATING IN THE SETIL PROJECT”

LIST OF Participating institutions and investigators

Affiliation Investigator e-mail Telephone Fax National Center for Dr. Susanna [email protected] 0649903180 0649387083 Epidemiology Lagorio (PI) Istituto Superiore di Sanità Viale Regina Elena 299 00161 ROMA Istituto Analisi Sistemi e Dr. Alberto [email protected] 067716423 067716461 Informatica "A. Ruberti" Salvan CNR Viale Manzoni 30 00185 ROMA LabS MEIA Dr. Sergio [email protected] 0382562341 0382592072 Fondazione Salvatore Ghittori Maugeri IRCCS Dr. Luciano Via Severino Boezio, 26 Maestri 27100 PAVIA Istituto Superiore di Dr. Luigi Turrio [email protected] 0649902653 Sanità Baldassarri Laboratorio Dr. Cinzia Leone Tossicologia Comparata Viale Regina Elena 299 00161 ROMA Fondazione Salvatore Dr. Vincenzo [email protected] 0498064511 0498064555 Maugeri IRCCS Cocheo Centro di Ricerche Dr. Paolo Sacco Ambientali Via Svizzera 16 35127 PADOVA Servizio di Dr. Corrado [email protected] 0116336968 0116336963 Epidemiologia dei Magnani 0116336965 0116706692 Tumori Sig.ra Vanda 0116706531 Dip. Scienze Macerata Biomediche e Oncologia Umana Via Santena 7 10126 TORINO Servizio di Dr. Luigi Bisanti [email protected] 0285782114 0285782128 Epidemiologia Sig.ra Maria [email protected] ASL Città di Milano Sciacca Corso Italia 19 20100 MILANO

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CSPO Istituto Dr. Lucia Miligi [email protected] 0556268348 055679954 Scientifico della Regione Toscana U.O. Epidemiologia Ambientale- Occupazionale Via S. Salvi 12 50135 FIRENZE Dipartimento Dr. Francesco [email protected] 0683060484 0683060463 Epidemiologia Forastiere ASL RME Dr. Paola Via Santa Costanza 53 Michelozzi 00198 ROMA Dr. Ursula Kirchmayer Lega Tumori Onlus di Prof. Lorenzo [email protected] 0932 229128 0932/229128 Ragusa Gafà [email protected] Via Transpontino, 1 Dr. Santina 97100 RAGUSA Cannizzaro Dr. Giuliana Buscema Istituto di Medicina del Dr. Luigi Cocco [email protected] 0706028528 070654350 Lavoro Università di Cagliari Via S. Giorgio 12 09100 CAGLIARI Dip. Igiene e Prof. Maria [email protected] 0916553603 0916553641 Microbiologia Valeria AOUP (Policlinico) Torregrossa Via del Vespro, 133 90127 PALERMO

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Lithuania

Lithuania 01 N° General data 1 Type National surveys on: 1. Nutrition status among newborns (breast feeding and artificial feeding) 2. Nutritional status among schoolchildren (8-17 years of age) 2 Country Lithuania 3 Title National Nutrition Center: the surveys were performed according to the provisions of Lithuanian Health program (improvement quality of life) 4 Aim 1. Improvement on newborns and child’s health and nutritional status 2. Improvement on schoolchildren health and nutritional status 5 Beginning date 1. 1998 (survey among newborns) 2. 1994 (survey among schoolchildren) 6 Ending date 1. 1999 (survey among newborns) 2. 1996 (survey among newborns) 7. Contact person Albertas Barzda, Director National Nutrition Center Ministry of Health Kalvariju 153 2042 Vilnius, Lithuania [email protected] 8 Initiator National Nutrition Center Ministry of Health 9 Involved / National Nutrition Center Ministry of Health Responsible Ministry of Education and Science organisations Ministry of Agriculture Minister of Social Security and Labor Kaunas Medical University Medical Faculty of Vilnius University National UNICEF committee Institute of Biochemistry Regional Public Health Centres State Public Health Service Ministry of Health 10 Budget available No data 11 Who is financing Funds were allocated from the budget of Lithuanian ministries and institutions Description of the population

12 Total number of About 3500 children (and parents) 13 Age groups and 1994-1996: 2513 schoolchildren’s were interviewed (11, 13 and 15 years number of persons in of age) each group 1998-1999:1500 mothers were investigated about breast - feeding 14 Inclusion criteria, Age; exclusion criteria Mother mast be have children 0-12 mouth of age 15 Sampling strategy Mothers and newborns were recruited via the hospitals; the method – interview of mothers; Children were recruited via schools; the method – 24 dietary questionnaire (filled by children and parents according to the age).

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Lithuania 01 16 Time schedule of Mothers – newborns were sampled 1998-1999 biomonitoring Children were sampled 1994-1996 17 Consent procedures Mothers: written informed consent Children: written informed consent by parents 18 How is participation Results of individual measurements and of the entire study are offered to encouraged the participants; Schools are offered an educational package on environment and health Data collection 19 Biomarkers of No biomarkers were monitored exposure 20 Biomarkers of effect No biomarkers were monitored 21 Biomarkers of No biomarkers were monitored susceptibility Other data 22 Environmental No environmental sampling was done sampling 23 Lifestyle data No collected 24 Health data on Data on breastfeeding terms; nutrition questionnaire (24 hour recal) mothers and children 25 Parental exposure No collected 26 Medication No collected 27 Socio – economic Structure of the family, education level of parents factors Analysis and quality control of procedures 28 Intra/ interlaboratory No biomarkers were monitored testing 29 External laboratory No biomarkers were monitored control 30 Accuracy, limit of All investigation were performed according to the standard methodology detection etc. 31 Data analysis Statistical analysis were performed according to the common (statistics, power requirements calculations) 32 Representativity Representative sample was selected and it represents national population in schoolchildren as well as in breastfeeding women. Data protection and availability 33 Privacy legislation Questionnaires were anonymised in order to maintain confidentiality under secure conditions according to Lithuanian law 34 Intellectual property No patents. Data was published upon approval of the steering rights committee. 35 Banking of biological No biomarkers were monitored . samples Communications 36 Reporting results to The results of above mentioned studies were published in the national public authority, to medical journals, national and international conferences, presented in general public, to the Lithuanian Health Programme (1998), also the reports of National participant Health Board (1999), as well as in the National Food and Nutrition Strategy (2003), adopted by the Lithuanian Government

277

Lithuania 01 37 Professionals A steering group including the scientists of Kaunas Medical Academy involved, contacts and Medical Faculty of Vilnius University was established. between professionals and participants 38 Role of media The start of the studies was given to the attention in many media (TV, newspapers…) 39 Public debate Occasionally symposia and scientific conferences were organized 40 Consequences of No external communications were developed external communications Problems 41 Problems Lack of money and human resources Experiences 42 Experiences Reporting results to public authority, to general public, to participant were useful;

278

Lithuania 02 N° General data 1 type Regional biomonitoring study. The biomonitoring study involves children aged 0,2 – 15 years 2 country Lithuania 3 title Cytogenetic effects of environmental exposures and medical treatment 4 aim To study chromosome aberrations and sister chromatid exchanges (SCEs) in children living in a polluted area of Lithuania and environmentally exposed to chemical substances. To study chromosome aberrations and SCEs in children suffering from urinary tract infection (UTI), exposed to diagnostic X-ray examination, and long-term antibacterial therapy. 5 beginning date The research was completed 6 years ago. 6 ending date 1997 7 contact person Dr. Grazina Slapsyte Department of Botany and Genetics Vilnius University 21 Ciurlionis St. 2009 Vilnius, Lithuania [email protected], +370 2398258 8 initiator Vilnius University 9 involved/responsible Vilnius University Children’s Hospital organisations 10 budget available 11 who is financing

Description of the population 12 total number of children 183 13 age groups and number of Age groups: persons in each group 1. Environmentally exposed children: 11-15 years. 2. Control group: 11-15. 3. Children with UTI: 0.2-13 years. 14 inclusion criteria, exclusion Inclusion criteria: criteria 1. Parental consent. 2. Children living 10-25 km downwind from the chemical plant. 3. Diagnosis and therapy schedule. 15 sampling strategy Sampling was random. 1. Environmentally exposed and control children were recruited via schools. 2. Children with UTI were hospitalized in Vilnius University Children’s Hospital. 16 time schedule of 1. Environmentally exposed and control children were sampled biomonitoring once in the period 1989-1990. 2. Children with UTI were sampled in 1993-1997. Blood sampling was done at the diagnosis (before or after X-ray examination), and after antibacterial therapy (1, 6 or 12 months). 17 consent procedures Parental oral consent. 18 how is participation Results of individual measurements are offered to the parents.

279

Lithuania 02 encouraged? Data collection 19 biomarkers of exposure 20 biomarkers of effect 1. Chromosome aberrations in lymphocytes. 2. Sister chromatid exchanges in lymphocytes. 21 biomarkers of susceptibility

Other data 22 environmental sampling Air quality data in the place of residence of environmentally exposed children. 23 lifestyle data 24 health data The blood urea nitrogen and creatinine levels for children with UTI. 25 parental exposure 26 medication Previous medication for children with UTI. 27 socio-economic factors

Analysis and quality control procedures 28 intra/interlaboratory testing 29 external laboratory control 30 accuracy, limit of detection/quantification, reproducibility 31 data analysis (statistics, Statistical methods were used according to the nature of data and power calculations) type of analysis needed. Calculatios were performed using InStat and SPSS/PC+ statistical packages. 32 representativity

Data protection and availability 33 privacy legislation Individual data are maintained by the responsible researcher and subsequently coded to maintain confidentiality. 34 intellectual property rights No patents. Data were published in Mutation Research, Mutagenesis. 35 banking of biological No samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to public Results of the studies were published in: authority, to general public, Mutation Research 445 (1999) 225-239; to participant Mutation Research 491 (2001) 25-30; Mutagenesis 17 (2002) 31-35 37 professionals involved, contacts between professionals and

280

Lithuania 02 participants 38 role of media 39 public debate 40 consequences of external communication

41 Problems

42 Experiences

281

Luxembourg

Short summary to the questionnaires:

1. Impact of heavy metals ands moulds on environmentally burden patients children 12-16 (number?) Date: 1999 – ongoing Will be published Aim: establishment of validated and standardized chemical and immunological analytical tools. Biomarkers of exposure: various heavy metals, moulds. In peripheral blood Biomarkers of effect: Activation of Lymphocytes, biomonitoring of cytokine production by memory vs non-memory CD4 cells. Direct assessment of heavy metals in serum and/or hair samples. Biomarkers of susceptibility: CD4 memory cells, cytokine production

2. National survey on dioxins (PCDFs + PCDPs) Aim: to monitor exposure in different geographic areas to find out if differences in exposure exist 2000-2001 number of children: 22

3. Part of international survey (WHO) Monitoring of PCBs, PCDFs and PCDDs in breastmilk same cohort as 2

282

Luxembourg 01 N° General data

1 type National Biomonitoring survey and study.The biomonitoring involves 2 age groups: 1) children 12-16 years 2) Adults 2 country Luxembourg 3 title LNS/ALMEN/CST/AKUT: Impact of heavy metals and moulds on environmentally burdened patients 4 aim Establishment of validated and standardized chemical and immunological analytical tools. 5 beginning date 1999 6 ending date 7 contact person Dr Sc. J-M MICHELS Laboratoire de Cytométrie de la Clinique Ste Thérèse 36, rue Zithe, L-2763 Luxembourg Tél: + 352.49.776-4574, Fax: + 352.49.776-5912, E-mail: [email protected] 8 initiator Ministère de la Santé LNS (Laboratoire National de Santé): Division Laboratoire d'Hygiène du Milieu et de Surveillance Biologique/ALMEN 9 involved/responsi LNS, CST (Clinique Ste Thérèse), ALMEN (Association ble organisations Luxembourgeoise de Médecine de l'Environnement), AKUT asbl 10 budget available 11 who is financing Sécurité Sociale

Description of the population 12 total number of variable children 13 age groups and variable number of persons in each group 14 inclusion criteria, general medical care exclusion criteria 15 sampling strategy general medical care 16 time schedule of biomonitoring 17 consent procedures 18 how is medical consultation, interests of patients participation encouraged?

Data collection 19 biomarkers of various heavy metals, moulds. In peripheral blood exposure 20 biomarkers of Activation of Lymphocytes, biomonitoring of cytokine production by effect memory vs non-memory CD4 cells.Direct assessment of heavy metals in serum and/or hair samples

283

Luxembourg 01 21 biomarkers of CD4 memory cells, cytokine production susceptibility

Other data 22 environmental Questionnaires on general health state of patient and "house-visitng" if data judged necessary 23 lifestyle data Nutrition, smoking, general lifestyle practices of patient 24 health data Presence of dental or other prothesis, allergies, eczema, auto-immune disorders, etc. 25 parental exposure Smoking, alcohol, allergies, asthma, home environment (decoration, pesticides, construction materials…) 26 medication 27 socio-economic Family structure, educationnal level,… factors

Analysis and quality control procedures 28 intra/interlaborator Standardisation of methods used. Confrontation of laboratory and clinical y testing data. 29 external National Quality Control (COQULUX) laboratory control 30 accuracy, limit of detection/quantification, reproducibility 31 data analysis A strategy is curently being elaborated for statistical evaluation (statistics, power calculations) 32 representativity Recruitment strategies are currently re-evaluated

Data protection and availability 33 privacy legislation Results are maintained by the responsible medical doctor and the Laboratory. A database containing all data available (clinical, analytical results, therapy & results of) is being discussed with respect to patient security and anonymity. This is done in a group formed by represantative persons of the different Laboratories and Medical doctors. 34 intellectual No patents. Data will be published. property rights 35 banking of No long term storage possible biological samples

Communication (individual level, group level, level (sub)population ) 36 reporting results A steering group meets every 5 weeks for discussion of problems and to public authority, progress to general public, to participant 37 professionals Steering group composed of medical doctors, laboratory scientists and involved, contacts representatives of patients for the entire program. between professionals and

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Luxembourg 01 participants 38 role of media TV, newspapers and radio were informed of the availability for patients to be medically treated by medical doctors trained in environmental care. 39 public debate Via occasional symposia 40 consequences of Public manifests great interest in seeing the disorders due to external environmemtal stress being taken care of. Visits to specialized medical communication doctors and laboratories are are growing in number

41 Problems Mostly Nomenclature problems involving recognition of the various new medical and laboratory acts by the Sécurité Sociale 42 Experiences Development of new approaches in immunology testing. Collaboration with various dicsiplines in the field. Extension of collaboration with foreign laboratories as is the case for us (CST) is very helpful.

285

The Netherlands

Short summary to the questionnaires:

Country The Netherlands Comments Reported 1. Longitudinal cohort study on 10000 mother-infant The response biomonitoring pairs on development and growth including rate to the activities biomarkers of exposure, effect and susceptibility questionnaires 2. Longitudinal cohort study on later health effects of was very low: perinatal dioxin exposure in small group of there are children several 3. Longitudinal observational study on exposure to studies fine particulate air pollution and respiratory health ongoing that in 670 school children were not 4. Cohort study on (neuro)development, endocrine reported and immunological effects on children due to exposure to PCBs, brominated flame retardants and other halogenated compounds. 5. Cohort study on development of allergies in response to household factors (dust mites, smoking, endotoxins etc.) 6. Cohort study on development of allergies due to prebiotica in food. Total number Perinatal to adult: > 10.000 of children School age (7-10 years old): 67 involved Perinatal to school age (0-4 years old) 200 Perinatal to 8 years old: 3500 Overall Data not available budget Aims 1. Description of (ab)normal growth and development and identification of its biological, social and environmental determinants to examine utilisation and effectiveneness of current strategies for prevention and early identification of groups at risk 2. Assessment of (long-term) health effects of perinatal exposure to background dioxin levels, PCBs, PCP, brominated flame retardants and/or other halogenated substances Specific age All ages: from 1st trimester of pregnancy until adulthood High groups participation rates (from 65% for large studies to virtually complete participation in small studies)

286

Country The Netherlands Comments Type of data Anonymised but identifiable Time periods Shortest 4 years (shortest, Longest >20 years average, longest Biomarkers Various pesticides, phthalates, bisphenol A, cotinin (cord of exposure bloods, urine sampling from birth onwards); particulate matter (PM2.5 and PM10); various PCBs, PCP, halogenated organic chemicals; dust mite, endotoxins Biomarkers Neurodevelopmental assessments; lung, liver and kidney of effect function tests; pulmonary complaints; endocrine functions (thyroid, reproductive, stress, glyco); haematology; immune status (incl. respiratory allergies and various IgEs; serum lipids, cytokines. Additional Extensive questionnaires on housing conditions, diets, data allergens, life style, and environmental contaminations based on area codes Biomarkers of maternal exposure (3 times during pregnancy) Extensive fetal data (ultrasounds), anthropometrics, neurocognitive and motorical development (incl. school data), glucose tolerance, vaccination response; dental, GP and pharmacy data Parental exposures (questionnaire data), incl. smoking. Socio-economic factors (incl. Ethnicity, daycare, family composition, educational levels, work status, income, acculturation)

287

Netherlands 01 N° General data 1 type Regional research study, longitudinal cohort from 1st trimester of pregnancy till adulthood among 10.000 mother-infant pairs. 2 country The Netherlands 3 title Generation R: The Rotterdam Study into Growth, Development and Health. 4 aim To describe normal and abnormal growth and development, to identify its biological, social and environmental determinants, and to examine the utilisation and effectiveness of current strategies for prevention and early identification of groups at risk. 5 beginning date 2002 6 ending date 2025? 7 contact person Dr Rosalinde FM Snijders, Generation R, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands, [email protected] 8 initiator Prof dr Albert Hofman, Department of Epidemiology & Biostatistics; Erasmus MC 9 involved/responsible Main research groups: Depts. of Epidemiology & Biostatistics, organisations Public Health, Pediatrics and Child Psychiatry, Erasmus MC. Collaborators:Stichting Trombosedienst & Artsenlaboratorium Rijmond, Rotterdam; Municipal Health Service Rotterdam area, Rotterdam; Rotterdam Homecare Foundation Rotterdam; Erasmus University Rotterdam, School of Law; Erasmus University Rotterdam, Faculty of Social Sciences; Midwives in Rotterdam; General practitioners in Rotterdam; Pharmacies in Rotterdam; Hospitals in Rotterdam: Sint Fransiscus Gasthuis, Medical Centre Rijnmond-Zuid, Ikazia Hospital, Haven Hospital, IJsselland Hospital. 10 budget available 11 who is financing Erasmus Medical Centre, Rotterdam / Erasmus University Rotterdam / Dutch Diabetic Research Foundation / Dutch National Epilepsy Fund / Netherlands Asthma Foundation / Netherlands Organization for Health Research and Development (Zon Mw) / Sint Laurensinstituut / Sophia Foundation for Medical Research / Stichting Bevordering Volkskracht / Stichting K.F. Heinfonds / Stichting Physico / Unilever Health institute / Vereniging Trustfonds Erasmus Universiteit / US National Institute of Environmental Health Sciences (NIEHS-NIH) / Department of Environmental Health, Harvard School of Public Health, Boston, US

Description of the population 12 total number of children 10000 children from a multi-ethnic population-based cohort, of whom 1000 from Dutch origin are studied in depth (focus-group) 13 age groups and number of longitudinal study from 1st trimester of pregnancy with

288

Netherlands 01 persons in each group follow-up until age 20 14 inclusion criteria, exclusion inclusion: mother is legal resident of Rotterdam, and criteria delivery expected in Rotterdam; exclusion: illegal residents 15 sampling strategy prospective inclusion of all consecutive births in Rotterdam through midwives and obstetricians 16 time schedule of biomonitoring maternal blood and urine pre- en postnatal, paternal blood prenatal, cord blood, children's blood postnatal 17 consent procedures IRB has approved; participants are asked for their written informed consent for the four consecutive phases of the study (prenatally, 1 to 4 years, 4 to 12 years, 12 to 20 years 18 how is participation Generation R newsletters & website, birth(day) encouraged? congratulation cards, participation feedback, additional health monitoring mother & child (e.g. prenatal ultrasound which is not standard in NL), Data collection 19 biomarkers of exposure urine and blood products are available for biomonitoring of e.g. pesticides, phthalates, bisphenol A, cotinin, etc. (maternal: 3 repeats during pregnancy) 20 biomarkers of effect e.g. endocrine (thyroid, reproductive, stress, glyco), immunological, kidneyfunction, serum lipids, etc. 21 biomarkers of susceptibility e.g. polymorphisms related to insulin, DNA available for further polymorphisms, e.g. detoxification enzymes)

Other data 22 environmental data questionnaire on e.g. housing conditions, diet, allergens. Databases on environmental contamination based on area code 23 lifestyle data smoking, alcohol, sports, fruit, and (determinants) of health behaviour, dietstyle (e.g. vegetarianism) 24 health data Examinations: fetal ultrasound (body proportions, placental function, organ development such as brain, hart, kidney), anthropometrics, blood pressure, heart rate, clinical chemistry (e.g. Hb, electrolytes), medical consumption, endocrinology, birth defects (e.g. urogenital, heart, kidney), neurocognitive and motorical development, glucose tolerance, vaccination response, serology (immune), immunophenotyping, lung function, screening for hip, scoliosis eye and hearing disorders. Health questionnaire (e.g. general health, infectious diseases, quality of life, ) Professional health data (dentist, GP, pharmacists) 25 parental exposure questionnaire on e.g. occupational exposures, housing conditions, diet, allergens. Databases on environmental contamination based on area code 26 medication self-reported and medical records 27 socio-economic factors civil state, ethnicity, family income, daycare, family

289

Netherlands 01 composition, level of education, work status and level, social support, social network, level of acculturation, cultural activities

Analysis and quality control procedures 28 intra/interlaboratory testing in place 29 external laboratory control in place 30 accuracy, limit of decribed in detail elsewhere detection/quantification, reproducibility 31 data analysis (statistics, power described per substudy calculations) 32 representativity population-based study; anticipated response rate 65%

Data protection and availability 33 privacy legislation in conformance with national and international conventions (eg separation of personal details and other data; confidentiality) 34 intellectual property rights primary ownership of all materials and information remains with the Generation R Study Group 35 banking of biological samples yes, urine and blood products and -20 or -80C at a central location with powerfailure backup and temperature alarm

Communication (individual level, group level, level (sub)population ) 36 reporting results to public newsletter to participants and professionals (health care, authority, to general public, to research), annual report to collaborators and supporting participant organisations 37 professionals involved, contacts see 9 between professionals and participants 38 role of media strictly adherence to hospital procedures 39 public debate n.a. 40 consequences of external strict devision between research and policy communication

41 Problems Lack of financial support for infrastructure / Limited resources for biomonitoring / Long-term follow-u research not accomodated by funding agencies

42 Experiences Participation 65-70% / Urine collection started recently, high response (>90%) / high costs of biomarkers of exposure

290

Netherlands 02 N° General Data 1 type Long-term longitudinal study on later health effects of perinatal dioxin exposure 2 country The Netherlands 3 title Zaandam/Amsterdam Perinatal Dioxin Study Cohort 4 aim To assess (long-term) health effects of perinatal exposure to background dioxin levels. The cohort is assessed at various ages and developmental stadiums

5 beginning date 1987 6 ending date Ongoing (aim: far into adulthood) 7 contact person Dr. G.W. ten Tusscher Emma Children’s Hospital Academic Medical Centre University of Amsterdam P.O. Box 22660 1100 DD Amsterdam The Netherlands [email protected] +31 (0)229 278627 8 initiator Prof. Dr. J.G. Koppe Emma Children’s Hospital Academic Medical Centre University of Amsterdam 9 involved/responsible Emma Children’s Hospital Academic Medical Centre organisations University of Amsterdam 10 budget available No sponsoring. 11 who is financing No sponsoring.

Description of the population 12 total number of children (and parents) 41 children 13 age groups and number of persons in each Longitudinal cohort followed since birth group (recruited prenatally). Assessed at various developmental stages. Now aged 12-16 years. 14 inclusion criteria, exclusion criteria Inclusion criteria are: Written informed consent Documented perinatal dioxin exposure. 15 sampling strategy Pregnant mothers recruited by midwives and obstetricians. 16 time schedule of biomonitoring The children are called up at various intervals for new assessments. 17 consent procedures Parents and children give written informed consent for each investigation. 18 how is participation encouraged? The group is highly motivated and few subjects have been lost to follow-up during the years.

Data collection 19 biomarkers of exposure Perinatal dioxin exposure has been documented. Health and developmental

291

Netherlands 02 assessment outcomes are correlated with the perinatal exposures. 20 biomarkers of effect Neurodevelopmental assessments, lung function testing, liver and thyroid function testing, haematology and immunology testing. 21 biomarkers of susceptibility Disturbances in above mentioned organ systems.

Other data

22 environmental sampling Breastmilk postnatally tested. 23 lifestyle data Already documented 24 health data Extensively documented (and published) health parameters of the mothers and children. 25 parental exposure Extensively documented (and published) health parameters of the mothers. 26 medication Medication usage is re-evaluated and documented at each follow-up. 27 socio-economic factors Structure of the family, educational level of parents, home-owning, educational level of child, school achievements of the children.

Analysis and quality control procedures 28 intra/interlaboratory testing Standard testing outcomes are assessed using standard testing apparatus in routine use in our academic hospital. 29 external laboratory control Not necessary. 30 accuracy, limit of detection/quantification, Data for all parameters are available on reproducibility request. Routinely used academic hospital apparatus is used. 31 data analysis (statistics, power calculations) Standard statistical tests are performed. 32 representativity Reliable representation of Dutch children. Data protection and availability 33 privacy legislation Measures are taken to ensure confidentiality and security of the data. Medical Ethics Committees approve the tests. 34 intellectual property rights No patents. Results are published in peer-reviewed respected international (medical) journals. 35 banking of biological samples No long term storage is foreseen. Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to Results are published in peer-reviewed general public, to participant respected international (medical) journals. 37 professionals involved , contacts between Paediatricians and other medical specialists professionals and participants and environmental scientists are involved. Dr. G.W. ten Tusscher is the co-ordinator. 38 role of media The study has received much media coverage over the years, and continues to do so.

292

Netherlands 02 39 public debate Not officially organized but encouraged via publications and presentations. 40 consequences of external communication Governmental legislation has been improved as a result of increased public opinion and knowledge, helped by the scientific outcomes seen, and publicized in the media. 41 Problems The biggest problem is finding financing for the testing. The Dutch government declines to sponsor such research (fear of the outcomes?).

42 Experiences

Much new knowledge and original ideas have resulted from the longitudinal study and it would be an enormous loss should the study stop because of lack of funding. This cohort is one of a handful worldwide with such a long follow-up period (now 12-16 years).

293

Netherlands 03 N° General data 1 type Regional observational longitudinal research study 2 country the Netherlands 3 title Association between chemical features of fine particulate air pollution and respiratory health of school children 4 aim 1)To investigate if transition metals content, radical generating capacity and blackness of particulate air pollution are associated with airway inflammation, reduced lung function, reduced lung function increase after two years, and increased prevalence of respiratory complaints in school children? 2) In a pilot study of children within the city of Maastricht we obtained indications that overall lung function of children in Maastricht may be low compared to lung function in other areas in the Netherlands. We want to investigate if we can reproduce this result and if lung function in rural areas outside Maastricht and outside the Maas Valley (in which Maastricht is situated) is similarly low. Through this it will be assessed if lung function measurements are a useful (sensitive) biomarker of effect for exposure to air pollution 3) In our pilot study (2002) radical generating capacity was associated with reduced lung function. Furthermore, where PM levels varied only to a small extent within the city, radical 5 beginning date 01.01.2002 6 ending date 01.01.2007 7 contact person Drs. Janneke Hogervorst, department of General Practice, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands. 0031-433882985 [email protected] 8 initiator Prof. Dr. Jos Kleinjans (Department of Health Risk Analysis and Toxicology, Maastricht University) and Prof. Dr. Onno van Schayck (Department of General Practice, Maastricht University) 9 involved/responsible Maastricht University organisations 10 budget available €100 000, more financial means are needed 11 who is financing Maastricht University, Province of Limburg, Maastricht City Council

Description of the population 12 total number of children 670 13 age groups and number of Primary school children aged 7-10 years. 335 children will be persons in each group recruited at schools inside the city of Maastricht, and 335 children at schools in rural areas will be recruited. 14 inclusion criteria, exclusion Written informed consent by the parents, children aged 7-10 criteria years 15 sampling strategy Children are recruited at their schools. We will contact as many schools within and without the city of Maastricht as needed to achieve the number of 670 participants, but we estimate that we will need to contact six schools both inside and outside the city. 16 time schedule of 1. Measuring round 1 starts in the spring of 2004. 2. Round 2 biomonitoring starts in the spring of 2006 and will involve the same study

294

Netherlands 03 participants 17 consent procedures Written informed consent by one of the parents 18 how is participation If parents indicate that they want to be informed if their child has encouraged? a lower-than-normal lung function or respiratory allergy, they will be contacted. Every participating child will receive a small present. One bicycle will be given away by lottery to a child that participates in all of the measurements in each of the two measuring rounds. Data collection 19 biomarkers of exposure Exposure to particulate matter of different sizes (PM10 and PM2.5) and of different chemical composition will be estimated by collecting particulate matter outside the children's schools with High Volume Samplers. Of this particulate matter we will determine the amount present in the air outside the schools, the blackness (as a marker of exposure to particulate matter from diesel vehicles), the amount of reactive oxygen species generated by the particulate matter (through Electron Spin Resonance spectroscopy), the transition metal content and the LPS content. 20 biomarkers of effect Lung function (through standardised spirometric tests), pulmonary complaints (through questionnaire to be completed by the parent(s)), exhaled nitrogen oxide level (as a marker of pulmonary inflammation), and lung function increase in two years time (through a second round of spirometric testing two years after the initial testing). 21 biomarkers of Respiratory allergy (blood from finger prick will be analysed for susceptibility specific IgE for the most prevalent aero-allergens (cat, dog, rodent, house dust mite, grasses, trees and fungi)

Other data 22 environmental data Exposure to particulate matter of different sizes (PM10 and PM2.5) and of different chemical composition will be estimated by collecting particulate matter outside the children's schools with High Volume Samplers. Of this particulate matter we will determine the amount present in the air outside the schools, the blackness (as a marker of exposure to particulate matter from diesel vehicles), the amount of reactive oxygen species generated by the particulate matter (through Electron Spin Resonance spectroscopy), the transition metal content and the LPS content. 23 lifestyle data Intake of fruit and vegetables, socio-economic status, indoor sources of air pollution (gas stove, fire place, moist, heating system, environmental tobacco smoke, pets). All these data will be obtained by questionnaire to be completed by the parent(s). 24 health data Length and weight (and BMI) of the children will be assessed, doctor diagnosed asthma, respiratory disease or other disease of the child, familiy anamnesis for asthma and atopy (questionnaire) 25 parental exposure Parental smoking (amount of cigarettes/cigars/pipes smoked in

295

Netherlands 03 the house, smoking of the mother during pregnancy) 26 medication Medication for respiratory disease (general and in the week before the testing) (questionnaire) 27 socio-economic factors Education level and profession of the parents (questionnaire)

Analysis and quality control procedures 28 intra/interlaboratory testing Transition metals, blackness and LPS are analysed by accredited laboratories 29 external laboratory control 30 accuracy, limit of Data for all parameters, except for radical generating capacity, detection/quantification, since this is still a very new method, are available on request reproducibility 31 data analysis (statistics, Sample size calculation was based on the combined detrimental power calculations) effect of particulate matter radical generating capacity (we observed a negative association between this PM characteristic and lung function in a pilot study) and presence of respiratory allergy. We then performed a sample size calculation for two independent means: one group of children inside the city (high PM characteristics) with respiratory allergy and one group of children outside the city free from respiratory allergy.The number obtained from this calculation was multiplied by 1/prevalence of respiratory allergy in children, to obtain a sufficient number of allergic children in the city-group (which automatically ensures a sufficient number of non-allergic children in the rural group). Power was set at 80%, type-1-error at 5%. Associations between PM (characteristics) and lung function, exhaled NO, and lung function growth will be evaluated through multiple linear regression analysis, correcting for relevant covariates. Associations between 32 representativity Non-response (and non-participation) will be analysed Data protection and availability 33 privacy legislation 34 intellectual property rights No patents. Data will be published in relevant scientific journals upon approval of the study researchers (all from Maastricht University) 35 banking of biological Finger prick and exhaled breath samples will not be stored. samples Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to general public, to participant 37 professionals involved, contacts between professionals and participants 38 role of media 39 public debate 40 consequences of external communication

41 Problems

42 Experiences

296

Norway

Short summary to the questionnaires:

Den norske Mor-barn undersøkelsen. (Norway). Cohort study. Built in case control design. The aim is to recruit 100.000 pregnant women, follow these during pregnancy and after delivery follow mother and child for an indefinite period. Then the aim is to estimate the coherence of potential exposures with illness of mother or child. The study was initiated in 1999 and will probably run until 2006. The total sample is 100.000 mothers, 100.000 children and 70.000 fathers. The inclusion criteria is pregnant women who have filled out the first questionnaire and have given one blood sample. The exclusion criteria are women who are not able to read the questionnaire. Time schedule of biomonitoring: 3 large questionnaires are sampled during pregnancy and again 3 during the first 5 years after birth. One questionnaire is sampled from the father. There is blood sample from the mother and father early in pregnancy. Another one is sampled at time of birth from the mother and newborn child (umbilical cord). All this implies informed consent from mother and father. Blood samples are collected and blood tests are frozen down to minus 83 degrees Celsius. Data is kept in tracking system and blood and urine sample kept in biobank

297

Norway 01 N° General data 1 type cohort study. Built-in case-control design 2 country Norway 3 title Den norske Mor og barn undersøkelsen 4 aim Recruiting 100.000 pregnant women, follow these during pregnancy and after delivery follow mother and child for an indefinite period. The aim is to estimate the coherence of potential exposures with illness of mother or child 5 beginning date autumn 1999 6 ending date running until 100.000 women are collected. Probably 2006 7 contact person Kjell Haug M.D., Dr.Med.Sc., professor Department of Public Health and Primary Health Care, Division for Social Medicine, University of Bergen, Norway Email: [email protected] 8 initiator National Institute of Health 9 involved/responsible National Institute of Health organisations

Description of the population

10 total number of children (and 100.000 women ,100000 children, 70000 fathers parents) 11 age groups and number of persons in each group

12 inclusion criteria, exclusion Inclusion criteria: Pregnant women who have filled in the criteria first questionnaire and have given one blood sample.Exclusion criteria: Women who are not able to read the Norwegian questionnaires 13 sampling strategy Invitation send by post - mostly in the 14.Th week of pregnancy 14 time schedule of biomonitoring 6 large questionnaires are sampled. 3 during pregnancy and 3 during the first 5 years after birth. One questionnaire from the father, too. Blood sample from the mother and father early in pregnancy and at the time of birth from the mother and the child (umbilical cord). 15 consent procedures Informed consent from mother and father 16 how is participation Brochures and letters for mother and father encouraged? 17 budget available 3 million Euro (25 million NKr) per year 18 who is financing Health- and Social Department

Data collection 19 biomarkers of exposure blood samples

20 biomarkers of effect blood samples 21 biomarkers of susceptibility blood samples

Other data

298

Norway 01 22 environmental sampling

23 lifestyle data from self-reported questionnaires' 24 health data blood sample, self-reported lifestyle patterns (smoking habits, etc) 25 parental exposure from self-reported questionnaires' 26 medication from self-reported questionnaires' 27 socio-economic factors from self-reported questionnaires'

Analysis and quality control procedures

28 intra/interlaboratory testing

29 external laboratory control the blood tests are frozen down at minus 83 degrees Celcius 30 accuracy, limit of detection/quantification, reproducibility

31 data analysis (statistics, power data kept in a tracking system (particular database) calculations) 32 representativity

Data protection and availability

33 privacy legislation Data kept in tracking system and blood and urine sample kept in biobank 34 intellectual property rights

35 banking of biological samples yes

Communication (individual level, group level, level (sub)population ) 36 reporting results to public yes.No individual reports to the participants authority, to general public, to participant

37 professionals involved, contacts between professionals and participants 38 role of media 39 public debate Yes. 40 consequences of external communication

41 Problems

42 Experiences

299

Poland Short summary to the questionnaires:

Sixteen questionnaires are summarized. In one of them, environmental aspects were not included. Activities can be divided into two categories : surveillance and research

Surveillance: four projects were carried out. The aim of the first project was to assess environmental exposure to lead and cadmium in child population ( n =1260) in seven regions of Poland. Within the three other projects exposure to lead was evaluated in the contaminated areas of Upper Silesia ( 6000 children, period 1992-1996; 14 000 children, period 1993-1998) and in Lower Silesia (77 000 children, period 1991-1999 ). All laboratories participated in external quality control programmes . The obtained results revealed decreasing trends of exposure. Individual results of determinations were made available to parents. In Lower and Upper Silesia prophylactic and rehabilitation programmes were organized.

Research : concerned early health effects of exposure to heavy metals , polycyclic aromatic hydrocarbons and mixed environmental factors.

The investigated effects of exposure to lead included: psychological functions impairment, school abilities and social functioning ( 400 children) hearing , posture and EEG (337 children). The results of the studies on the influence of long-term environmental exposure to cadmium ( 136 children) revealed that children who were born and grew up in cadmium-contaminated areas are potentially more susceptible to kidney dysfunction than adults. The evaluation of health risks associated with non-ferrous smelter activities in Eastern Europe ( 212 children in Poland) was carried out within the EU Inco-Copernicus program. The determinations concerned environmental factors including Cd-B, Cd-U, Pb- B, As-U and Hg-U. The possible influence on kidney function (β2M, RBP, NAG, Alb,CC16 BBA in urine ) and lung function ( spirometry, CC16 in serum ). Analysis of health risk of child population in Bytom (Upper Silesia) (150 children) encompassed measurements of environmental factors (dust, SO2, biomonitoring of exposure to metals , mutagens, 1-HP ) and effects ( birth -weight, heigh, Apgar score, upper respiratory system, hematological parameters). Two other projects carried out in the Upper Silesia ( 560 children) concerned evaluation of exposure to PAH’s ( 1-HP in urine) and heavy metals and the possible effects on the cytogenetic damage, taking into account genetic polymorphism (SCE, micronuclei, DNA damage and repair ). One project concerned health survey of the jealth status in population living close to the big municipal waste landfill near Warsaw ( 33 children).

Age of children : 3-5 years ( 2 projects), 6-8 years ( 8 projects ), 8-12 years( 4 projects) , 12-22 years ( follow-up study). Overall budget for research activities amounted to about 580 000 EURO. The laboratories participated in quality assuranace programmes for determination of metals in biological material. Research activities have been carried out by two Institutes : Nofer Institute of Occupational Medicine in Lodz and Institute of Occupational Medicine and Environmental Health in Sosnowiec.

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Table: Environment and health – Biomonitoring of children Poland

Country Poland Comments Reported 1. Evaluation of psychological functions Project No 78 has biomonitoring impairment in children environmentally exposed been not Activities to lead. included due to 2. School abilities and social functioning in the lack of the children environmentally exposed to lead. environmental 3. Study on children exposure to lead (Upper date. Silesia) Project 13 started 4. Study on children exposure to lead (Lower 2003. Silesia) 5. Evaluation of the health risk resulting from environmental exposure to lead and cadmium in selected regions in Poland. 6. Health risk for the general and working population associated with nonferrous smelter activities in Eastern Europe: an assessment based on biomarkers of internal dose and early non- genotoxic effects. 7. The influence of long-term environmental exposure to cadmium on the kidney function. 8. Level of proinflammatory cytokines in children with type 1 DM. 9. Effects of environmental lead exposure effects on children’s hearing and posture. 10. Evaluation of intra- and interindividual variation of urinary 1-hydroxypyrene, a biomarker of exposure to polycyclic aromatic hydrocarbons. 11. Analysis of childrens risk in the town of Bytom with respect to environmental pollution. 12. Urinary 1-hydroxypyrene as a biomarker of environmental exposure to polycyclic aromatic hydrocarbons. 13. Assessment of early cytogenetic effects in children population exposed to lead and PAH’s. 14. DNA damage in children environmentally exposed to lead with the assessment of individual susceptibility for toxic effect of lead, and genetic polymorphism of lead biotransformation and mechanism of DNA repair. 15. Prevention of childhool lead poisoning in

301

Country Poland Comments urban children, Silesia. 16. Biological monitoring of exposure to environmental hazards in population living close to the municipal waste landfill. Total number of 100180/0,27% children involved/percentage of total population Overall budget About 580 000 Euro For six projects information has not been presented Aims 1. Evaluation of the environmental exposure to lead and cadmium. Organization of prophylactic program in Lower Silesia. 2. Evaluation of lead exposure on psychological and Upper function and school performance in children. 3. Early health effects (kidney, haematopoietic system, lungs) in children exposed to lead and cadmium. 4. Influence of environmental lead exposure on children’s hearing, posture and central nervous system. 5. 1-Hydroxypyrene as a biomarker of environmental exposure to PAH’s. 6. DNA damage in children environmentally exposed to lead. 7. Biological monitoring of exposure in population living close to landfill. Specific age groups 3-5 years (2 projects) 6-8 years (8 projects) 8-12 years (4 projects) 12-22 years (1 follow up study ) Type of data 14 projects anonymous. Physicians could persent results to parents (92%), 1 project – no data Time periods 1; 2.8; 5 years (shortest, average, longest) Biomarkers of Pb-B (80%); Cd-B (33%); Cd-U (33); 1-HP-U In % of projects

302

Country Poland Comments exposure (40%); Se-S (20%); mutagenic substances in urine (27%); cotinine (13%); aromatic DNA adducts (13%); As-U (7%); Hg-U (13%); Acetylocholinesterase activity (7%) Phenol-u (7%) Hippuric acid – u (7%) Trichloroautic acid –u (7%) Biomarkers of Β2M-U (26%); RBP-U (20%); Alb-U (20%); In % of projects effect general parameters of urine (20%); psychological testing (13%); β2M-S (13%); NAG-U (20%); micronuclei (13%); SCE (15%); haematological blood indicators (15%); ZPP (7%); Cystatin C (7%); CC-16-S (7%); CC-16-U (7%); BBA-U (7%); glutathione peroxidase (7%); cytological changes in expectorations from the upper respiratory system (7%) ; audiometry 8%); otoacoustic emissions (7%); posturography (7%); EEG (7%); MetHb (7%); IgE (7%) Additional data Life style data (12 projects) External quality (9 projects) (11)

303

Poland 01 N° General data 1. type Analysis of GH, GHBP, GHR, IGF, IGFBP concentrations, molecular structure and activity in children and adolescent with growth retardation 2. country Poland 3. title Endocrinology Clinic, regional centre for Great Poland district with cooperative University of Poznań, Molecular Biology Department 4. aim Our centre diagnoses the causes for growth disturbances in children and adolescent in the whole region. We treat patients with growth hormone therapy diagnosed with growth hormone deficiency and girls with Turner syndrome. Also, another goal of our studies is diagnosis of patients with excluded hormonal deficiencies (GH and others). We study further stages of growth signal transduction. We measure the values of GHBP, IGF, IGFBP. We also analyze the molecular structure for growth hormone receptor (GHR), IGF-I (together with promoter sequence). 5. beginning date 1995 6. ending date open 7. contact person Andrzej Kędzia MD, PhD 8. initiator Committee of Science Study (KBN) 9. involved/responsible KBN, University of Poznań, University Medical School of Poznań organizations 10. budget available 120 000 PLN (30 000 euro-approximately) 11. who is financing KBN Description of the population 12. total number of children 2000 analyzed patients 13. age groups and number 4-18 years old, 2000 patients of persons each group 14. inclusion criteria, Inclusion criteria: growth deficiency less 3 percentile, bone age less 2 exclusion criteria year comparison with calendar age, growth velocity less 4 cm/year, Exclusion criteria: growth hormone deficiency, other hormonal deficiency, mpSDS-low then (-) 0,5 SDS (medium maternal and paternal height) 15. sampling strategy We are take sample in time of visit in hospital 16. time schedule of We are sampled only once biomonitoring 17. consent procedures Older patients and 1 or 2 parent take consent 18. how is participation -- encouraged Data collection 19. biomarkers of exposure GH-normal or height concentration in two other stimulatory tests, GHBP-low concentration, IGF I-low concentration 20. biomarkers of effect Auxological parameters of growth 21. biomarkers of -- susceptibility Other data

304

Poland 01 22. environmental sampling -- 23. lifestyle data -- 24. health data Duration of pregnancy, biometry, apgar, medical history, illnesses. 25. parental exposure Illnesses in family, low height case in family 26. medication Early use of medication 27. socio-economic factors --

Analysis and quality control procedures 28. intra/interlaboratory Our laboratory working according to KITs producent norms. testing Identification of critical phases will be identified (collection samples, identification, storage of the samples, analytical technique, reference materials, process control, calibrations). 29. external laboratory Audit will be made by Central Laboratory Radiation Control control 30. accuracy, limit of Data for all parameters are available on request detection/quantification, reproducibility 31. data analysis (statistics, Statistical analysis will be performed power calculations) 32. representativity Recruitment efficiency is monitored Data protection and availability 33. privacy legislation Samples and questionnaires are maintained by the responsible medical doctor and subsequently anonymised in order to maintain confidentiality under secure conditions in accordance with the 1995 EC Data Protection Directive and data protection legislation. Measures are taken to ensure confidentiality and security of the data. Ethical advice has been taken to determine the determine the maximum volume of blood samples that may be taken in order to minimise distress to the participant. 34. intellectual property No patents. Data will be published. rights 35. banking of biological Short term storage samples

Communication 36. reporting results to Each new findings are publication in medical press. public authority, to The participant will be given individual results. general public, to participant 37. professionals involved, The contacts between professionals and participants is all time made. contacts between professionals and participants 38. role of media -- 39. public debate Symposia are organized. 40. consequences of -- external communication

305

Poland 01 41. Problems -- 42. Experiences --

306

Poland 02 Number General data 1. Type Regional study 2. Country Poland 3. Title Level of proinflammatory cytokines in children with type 1 DM 4. Aim Role of proinflammatory cytokines in beginning of DM 5. Beginning date 2003 6. Ending date 2006 7. Contact person Marek Wdowiak M.D Department of Pediatric Nursery University of Medical Sciences Poznan Poland Szpitalna Str. 27/33 Tel +48618491265 8. Initiator None 9. Involved/responsible None organizations 10. Budget available € 15.000 11. Who is financing Poznan University of Medical Sciences, private founds Description of the population 12. Total number of children 600 13. Age groups and number of Age groups: persons in each group - 0-3 years – 15 - 3-6 years – 15 - 6-8 years – 45 - 8-10 years 150 - 10-14 years - 195 - 14-18 years – 180 14. Inclusion criteria Age of beginning of DM, written informed consent 15. Sampling strategy - Children treated in Clinic of Childhood Endocrinology and Diabetology Poznan University of Medical Sciences - Children during routine visits in diabetological outpatients clinic 16. Time schedule of - Newly diagnosed patients from January 2003 to biomonitoring December 2004 - Next measurements after 6, 12, 18 and 24 months after diagnosis from June 2003 to December 2006 17. Consent procedures Parents written informed consent 18. How is participation None encouraged? Data collection 19. Biomarkers of exposure In all points: weight, height, nutritional status, sexual maturation, skin fold measurements, doses of insulin counting on body weight, blood tests: lipids management, routine biochemical tests, serum level of proinflammatory cytokines, interleukins. Effect of cytokines activity – C reactive protein, diet. Information about quality of life

307

Poland 02 20. Biomarkers of effect HbA1c, c-peptide, presence of glucose and/or ketones bodies in urine analysis, average serum level during 24 h 21. Biomarkers of susceptibility Genotype, family history of DM Other data 22. Environmental sampling Data’s from patient’s history: chemical factors which can start pancreas islets destruction. 23. Lifestyle data Nutritional habits: smoked meat, short time of breast feeding 25. Parental exposure None 26. Medication None 27. Socio-economic factors Structure of the family, educational level of parents, Analysis and quality control procedures 28. Intra/interlaboratory testing Basic and routine laboratory tests are made in Hospital’s laboratory, which have all certificates and accreditations. 29. External laboratory control None 30. Accuracy, limit of Data for all parameters are available by request detection/quantification, reproducibility 31. Data analysis (statistics, In statistic analysis we use the most common statistic power calculations) tests 32. representavity Our group is representative, recruitment is monitored Data protection and availability 33. Privacy legislation All data’s from patient’s history are confidential, including laboratory tests, anthropometric measurements. 34. Intellectual property rights No patents.. 35. Banking of biological No long term storage samples Communication 36. Reporting results to public Results are present on endocrinological, and authority, to general public, diabetological conferences to participant 37. Professionals involved, Every doctor who work with diabetic patients let us use contacts between history data’s. Patients agree on blood tests. professionals and participants. 38. Role of media None 39 Public debate None 40. Consequences of external None communication 41. Problems None 42. Experiences Children and youth suffered by DM like to talk about their dissease. Usually there is no problem with permission for tests. Parents need to know what a sense of tests is.

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Poland 03 N° General data 1. Type Regional study 2. Country Poland 3. Title Children with chronic disease – perspectives, quality of life 4. Aim Biomonitoring of children with chronic diseases. Possibilities of future work, barrier in school, society barrier. Diseases: DM, CF, asthma, leukaemia 5. Beginning date 2004 6. Ending date 2006 7. Contact person Boguslaw Pawlaczyk Prof. Ph.D. Department of Pediatric Nursery University of Medical Sciences Poznan Poland Szpitalna Str. 27/33, Tel +48618491265 Elzbieta Pawlaczyk – Wróblewska M.D Department of Pediatric Nursery 3ewUniversity of Medical Sciences Poznan Poland Szpitalna Str. 27/33, Tel +48618491481 8. Initiator None 9. Involved/responsible None organizations 10. Budget available € 40.000 11. Who is financing Poznan University of Medical Sciences, and private foundations Description of the population 12. Total number of children 1000 13. Age groups and number of Age groups: persons in each group - 0-3 years – 50 - 3-6 years – 50 - 6-8 years – 200 - 8-10 years 200 - 10-14 years - 300 - 14-18 years – 200 14. Inclusion criteria Written informed consent, age 15. Sampling strategy Children suffered by chronic diseases during routine visits in outpatients clinic 16. Time schedule of biomonitoring From Jan. 2004 to Jun. 2006, than statistic analysis 17. Consent procedures Parents written informed consent 18. How is participation encouraged? None Data collection 19. Biomarkers of exposure Diagnosis, treatment, weight, height, nutrition, vital signs, toleration of physical activity, questionnaire 20. Biomarkers of effect Routine laboratory tests 21. Biomarkers of susceptibility Genotype, family history of chronic diseases Other data 22. Environmental sampling Data’s from patient’s history: toxic chemical factors. 309

Poland 03 23. Lifestyle data Nutritional habits: smoked meat, short time of breast feeding 24. Health data Other diseases present or occurring after diagnosis 25. Parental exposure None 26. Medication None 27. Socio-economic factors Structure of the family, educational level of parents, of patient. Analysis and quality control procedures 28. Intra/interlaboratory testing Basic and routine laboratory tests are made in Hospital’s laboratory, which have all certificates and accreditations. 29. External laboratory control None 30. Accuracy, limit of Data for all parameters are available by request detection/quantification, reproducibility 31. Data analysis (statistics, power In statistic analysis we use the most common statistic calculations) tests 32. representavity Our group is representative, recruitment is monitored Data protection and availability 33. Privacy legislation All data’s from patient’s history are confidential, including laboratory tests, anthropometric measurements. 34. Intellectual property rights No patents.. 35. Banking of biological samples No long term storage Communication 36. Reporting results to public Results are present on endocrinological, and authority, to general public, to diabetological conferences participant 37. Professionals involved, Every doctor who work with patients let us use history contacts between professionals data’s. Patients agree on using this data. and participants. 38. Role of media None 39 Public debate None 40. Consequences of external None communication 41. Problems None 42. Experiences We do not have any experiences. We start this project next year.

310

Poland 04 N° General Data 1 Type Regional biomonitoring study

2 Country Poland 3 Title Evaluation of the health risk resulting from environmental exposure to lead and cadmium in selected regions in Poland.

4 Aim The aim of project was to assess environmental exposure on lead and cadmium in children and adults populations of different regions in Poland. The study allowed comparing the results obtained from investigated populations inhabiting areas in the vicinity of nonferrous mills and with no industrial emitters. The subjects were adults with no history of occupational exposure to metals, and children under 10 years old of age. The examined population was divided on two groups, the one living five urban areas without a direct influence of big industrial emitters Krakow, Lodz, Walbrzych, Legnica, Wloclawek located in the central, south-western and southern parts of Poland and the second citizens of neighborhood of two nonferrous mills, a zinc mill in Miasteczko (Upper Silesia) and a copper mill in Glogow (Lower Silesia).

5 Beginning date 01. 10. 1991 6 Ending date 30. 09. 1994 7 Contact person Prof. Marek Jakubowski, Nofer Institute of Occupational Medicine Department of Chemical and Dust Hazard 8 Sw. Teresy St., 90-950 Lodz e-mail [email protected] tel: (+48) 42 63 14 801 fax: (+48) 42 63 14 813 8 Initiator This study was supported by the Polish Committee for Scientific Research 9 Involved/responsible Nofer Institute of Occupational Medicine (NIOM) organizations Department of Chemical and Dust Hazard 8 Sw Teresy St., 90-950 Lodz 10 Budget available 57,000.00 Euro 11 Who is financing The Polish Committee for Scientific Research supported this study (grant PB 2472/4/91).

Description of the population 12 Total number of children 1262 children below 10 years old and 1106 adults – total 2368 (and parents) persons. 13 Age groups and number of Legnica – 69 children, Lodz – 211 children, Krakow - 99 children, person in each group Walbrzych – 48 children, Wloc ławek – 128 children, Miasteczko – 425 children: <6 years old – 79 children 6-8 years old – 148 children, 8-10 years old – 198 children, Glogów – 282 children. 14 Inclusion criteria, Inclusion criteria – Persons living the areas with and with out

311

Poland 04 exclusion criteria environmental exposure, distance from home to smelter, housing conditions.

Exclusion criteria – the subjects with a history of occupational exposure to cadmium were excluded from the study, based on questionnaire data. 15 Sampling strategy Children were recruited via schools located in the contaminated and control (choice for examination) areas. The group of adult consisted of the parents. The subjects were asked to complete data questionnaires. The samples from investigated persons were taken in schools or public health clinics. Blood samples were collected by venipuncture using vacutainers Becton-Dickinson (Li- Heparine). Spot urine samples were collected in polyethylene tubes. The urine sample used for cadmium determination (5 ml) was acidified with 50 0 µl 50% nitric acid (Merck) and stored at –20 C. For the β2M-U, RBP- U and Alb-U determination 0.5 ml of 0.4 mol phosphate buffer, pH 7.4, containing 1% sodium azide, was added to 4.5 ml urine. This sample was stored at -200 C. 16 Time schedule of The samples were collected within May-June as well as October – biomonitoring November. The subjects were sampled once in this period. 17 Consent procedures The participants: written informed consent. 18 How is participation The inhabitants living in the vicinity of zinc smelter are interested in a encouraged? medical survey and different forms of biomonitoring. The subjects were encouraged on short meetings organized by the leaders of program with the peoples who would be going to take part in the study. At that time the people were informed about the aim of the investigation and advantages connected with its realization.

Data collection 19 Biomarkers of exposure Cadmim in blood (Cd-B), cadmium in urine (Cd-U), lead in blood (Pb-B) • Pb-B. In the areas without large industrial emitters (group 1), in the children group, the mean geometric Pb-B concentrations range from 29.9 to 62.5 µg/l. In the group of children living in the vicinity of smelters (group 2), the geometric mean of Pb-B were significantly higher and ranged from 73.7 to 114 µg/l, the values decreasing as the distance from the source of emission increased. A significantly correlations was noted between Pb-B concentrations in mothers and children. • Cd-U, Cd-B. The geometric means of Cd-U and Cd-B concentrations in group 1 for the children were from 0.28 to 0.62 µg/l (adjusted for specific gravity) and 0.28 to 0.37 µg/l respectively, in group 2 from 0.60 to 1.16 µg/l (adjusted for specific gravity) and 0.36 to 0.57 µg/l.

20 Biomarkers of effects β2M-U (β2 microglobulin), RBP-U (retinol binding protein), Alb-U (albumin) and ZPP (zinc- protoporphyrin). Biomarkers of effect were

312

Poland 04 determined only in adult’s group. 21 Biomarkers of susceptibility

Other data 22 Environmental sampling Over the period of 1968-1993 the data on atmospheric emission of cadmium from the zinc smelter was collected. The concentrations of cadmium and lead in the air and soil were analyzed as well as concentrations of suspended dust and gaseous contaminants such

as SO2 and NO2. 23 Lifestyle data Where living, how long in the same place, distance from smelter, active/passive smoking (starting age, amount, frequency), alcohol use (frequency, amount) hobbies, time spent outdoor/indoor. 24 Health data Kidney disease, diabetics, current illnesses and in the past 7 days. 25 Parental exposure Alcohol use and smoking habit 26 Medication Educational level of parents, educational level of children 27 Socio-economic factors Structure of the family, educational level of parents, educational level of children

Analysis and quality control procedures

28 Intra/interlaboratory testing The using methods have been always tested by internal and external quality assurance scheme. For internal quality control Seronorm – Nycomed, BCR, lyophilized blood and urine samples were used. The determination of the references materials was carried out every 20 samples; Shewhart Charts were constructed. The following references materials were used • Pb-B, B1=413 µg/l; B2=745 µg/l; BCR 194=124 µg/l; 195=416 µg/l; 196=772 µg/l; N1=42 µg/l; N2=380 µg/l; N3=671 µg/l • Cd-B, B1=5.2 µg/l; B2=29.7; BCR 194=0.5 µg/l; 195=5.37 µg/l; 196=12.4 µg/l; N1=2.7 µg/l; N2=8.1 µg/l; N3= 13.2 µg/l. • Cd-U, B1=2.9 µg/l; N1=5.5 µg/l.

313

Poland 04 quantification=0.33 µg/l; BIAS=2.2%(for N1=5.2 µg/l); repeatability (as a precision) = 3.8 (for N2=8.1 µg/l); precision in the working range=6.6% • Lead in blood was established with Stoeppler, Brandt, Rains method (1978) where blood samples were deproteinized by the addition of 5% HNO3. Linearity = 50-500 µg/l; limit of detection = 2.7 µg/l; limit of quantification = 5.5 µg/l; BIAS=1.1% (for N1 = 42 µg/l); repeatability (as a precision) = 8.1% (for N1 = 42 µg/l); precision in the working range=4.4% • Cadmium in urine was determined according to the Recommendation Condition for cadmium published by Perkin- Elmer: Publication B 3210, 7-12, 1992. Urine samples were diluted 1+1 with the mixed matrix modifier (NH4)2 HPO4 and Mg (NO3)2 Linearity = 18 µg/l; limit of detection = 0.1 µg/l; limit of quantification = 0.2 µg/l; BIAS=2%(for N1 = 5.1 µg/l); repeatability (as a precision) = 6.1% (for N1 = 5.5 µg/l); precision in the working range=6.8%

31 Data analysis (statistics, The differences between geometric means were tested by the power calculations) analysis of variance and multiple comparison tests. The parameters with a skew distortion were transformed logarithmically. Relationship between continuous variables was examined by linear regression.

32 Representativity The recruitment was very efficient (especially on contaminated regions) whether about 95% of children (above 6 year old) chosen for this study, took part in this program. Also many adults (frequently mothers and sometimes fathers) participated in this program.

Data protection and availability 33 Privacy legislation The full names of participants were available only for the leader of program. Each of participants was coded with an identification number and during all steps of samples analysis, only these numbers were recognized. Confidence procedure was agreement with the Polish low on the protection of personnel data. The local Biomedical Ethics Committee approved the study protocol. 34 Intellectual property rights There are no patents. The obtained data was published in 1) Int. Arch Occup Environ Health, 68, 193-198, 1996 and was entitled “Blood lead in the general population in Poland” by Jakubowski M., Trzcinka- Ochocka M., Razniewska G., Christansen J. M., Starek A. and 2) Medycyna Pracy 44, 15-34, 1993, “Blood cadmium in the general population in Poland” (in Polish) by Jakubowski M. 35 Banking of biological samples Always samples that had been taken for participants were stored in the Laboratory of Biomonitoring at NIOM, during 5 years.

314

Poland 04 Communication (individual level, group level, level (sub) population) 36 Reporting results to public The results were passed to the medical service in schools and authority, to general public, to policlinic cooperated with the organizers. participant 37 Professional involved, contacts During the meeting the discuses with participants about between professionals and results, problems and purposes was realized. participant 38 Role of media The study was given attention in local media: radio, newspaper. 39 Public debate In the end of study, meeting was organized for the inhabitants participated in this research. At that time the results of investigations were presented and the participants were informed in details about all aspects of exploration. Results of the individual measurements and of the entire study were offered to the participants. 40 Consequences of external communication 41 Problems The problem was with the children selection and encourages them for the examination as well as with obtaining agreement from children’s parents on the partaking in this study.

42 Experiences

Close collaboration with the local authorities, personnel of polyclinic as well as managers and medical workers of schools, helped persuade participants to take part in the study.

315

Poland 05 N° General Data 1 Type International 2 Country France, Poland, Czech Republic, Belgium, Italy 3 Title Health risks for the general and working population associated with nonferrous smelter activities in eastern Europe: an assessment based on biomarkers of internal dose and early non-genotoxic effects. 4 Aim The main objectives of the study in Poland were:

1. Evaluation of the health risk connected with the environmental and occupational exposure in the copper mill and its vicinity. 2. Getting acquaintance with the techniques of determination of biological markers of early health effects in the laboratories responsible for the analysis during the study in Belgium (nephro- and pneumotoxicity) and France (oxidative). Implementation of these methods in the Institute of Occupational Medicine in Lodz. 3. Intercalibration of the laboratories for metal analysis and spirometry. Tasks of the Institute of Occupational Medicine in Lodz (NIOM), Poland. 1. Recruitment of the cohort of adults and children living in the vicinity of the copper smelter and in non polluted control area. 2. Questioning of the investigated population. Delivery of the translated questionnaires to the coordinator. 3. Collection of blood and urine samples. Delivery of the frozen samples to the laboratories in Belgium, Italy and France. 4. Determination of inorganic arsenic (sum of As-I, MMA and DMA), cadmium and mercury in urine samples of Polish cohort. 5. Determination of cadmium and lead in whole blood and selenium in serum in the Polish cohort. 6. Determination of the standardised spirometry in the Polish cohort. 5 Beginning date 14. 04. 1997 6 Ending date 14. 04. 2000 7 Contact person Prof. Marek Jakubowski, Nofer Institute of Occupational Medicine Department of Chemical and Dust Hazard 8 Sw Teresy St., 90-950 Lodz e-mail [email protected] tel: (+48) 42 63 14 801 fax: (+48) 42 63 14 813 8 Initiator Coordinator: prof. J. M., HAGUENOER Cereste – Laboratoire de Mediciné du Travail

316

Poland 05 Faculté de Mediciné, Place de Verdun, 59045 LILLE Cédex - France tel: 33 03 20 62 69 65 (secretariat) fax: 33 03 20 88 36 64 e-mail: [email protected] e-mail: [email protected] This study was supported by the EU Inco-Copernicus Program (PL 96 32 40) (I.C. 15 CT 96 – 0311).

9 Involved/responsible Polish partner: organizations ∗ Nofer Institute of Occupational Medicine (NIOM) Department of Chemical and Dust Hazard Laboratory of Biomonitoring 8 Sw Teresy St., 90-950 Lodz Polish Committee for Scientific Research 10 Budget available 120,000 Euro 11 Who is financing ∗ EU Inco-Copernicus Program (PI 96 32 40) (I.C. 15 CT 96 – 0311), ∗ Polish Committee for Scientific Research, ∗ Nofer Institute of Occupational Medicine (NIOM) in Lodz.

Description of the population 12 Total number of children (and In Polish part of research, 212 children and 169 adult parents) males were investigated.

13 Age groups and number of The population under study comprised 212 children. person in each group Group (I) of 106 children recruited from the inhabitants of non-polluted regions of north-western Poland, and group (II) included 106 children was living in the vicinity of a copper smelter. The group of adult’s subjects included 93 persons from control area and 76 exposed male employees of copper mill. The mean age of children was 10.2 years (9-12) and for adults 40.7 years (22-61) respectively. 14 Inclusion criteria, exclusion Inclusion criteria – Persons living in the areas with and criteria without environmental exposure. The contaminated area was near a copper mill in Legnica in the south-western part of Poland. The control group of children was recruited from the Gorzow area. This area is located in the northwestern part of Poland free of heavy industry

Exclusion criteria – children with kidney diseases, diabetic diseases were excluded from the study, based on

317

Poland 05 questionnaire data. 15 Sampling strategy Children were recruited via schools. The samples from investigated persons were taken in schools or public health clinics. The subjects were asked to complete data questionnaires. Blood samples for determination of ● Cd, Pb were collected by venipuncture using Venoject (Li-Heparine, Oxford) and stored at -200C until determination, for ● Se-

S, CC16, cystatin C and prolactin in serum as well as β2M- S determination, blood samples were collected using Venoject with no additive. They were left in a vertical position at room temperature for approx. 1 h and then centrifuged at 3500 r.p.m. for 15 min. Serum samples were transferred to clean tubes and stored at –18 or –200 C in refrigerated, as required. Spot urine samples were collected in polyethylene tubes. The urine sample used for ● cadmium, arsenic determination (Cd-U, As-U) 5 ml was acidified with 50 µl 50% nitric acid (Merck) and stored at –200 C, ● mercury in urine (Hg-U), 30 ml of urine was acidified with 20 µl

H2SO4. For ● the β2M-U, RBP-U, Alb-U, CC16 determination 0.5 ml of 0.4 mol phosphate buffer, pH 7.4, containing 1% sodium azide, was added to 4.5 ml urine. This sample was stored at -200 C. For ● Brush Border Antigen to sterile container 4.5 ml of urine was added and next 0.5 ml PBS 10% and freeze immediately. The samples were stored at -200 C not longer than two months. For the ●HVA and DOPAC to 8 ml of the urine samples 50 µl of 37% HCl was added, froze immediately and stored in dark in –200C. For the ● NAG-U and creatinine determination, spot urine samples were stored without any preservation.

The concentrations of Cystatin C, CC16, β2M in

serum samples and β2M, RBP, Alb, CC16, creatinine, NAG in urine samples were determined at the Université Catholique de Louvain, Bruxelles 1200-Belgium. The determinations of serum Prolactin and urine brush border antigen (BBA), HVA and DOPAC concentrations were led in laboratory in Parma, Universita Degli Studi di Parma. Laboratory in Poland (NIOM) in France and Czech Republic (National Institute of Public Health) determined blood lead, cadmium and serum selenium concentrations as well as cadmium, arsenic, mercury in urine. Laboratory in France additionally determined levels of SOD, GPX, GSH and GSSG.

16 Time schedule of biomonitoring The study was carried out during the period of seven th f A il t O t b 1998 Child 318

Poland 05 months, from April to October 1998. Children were sampled once in this period. 17 Consent procedures The children’s parents: written informed consent. 18 How is participation The adults/children parents were encouraged on short encouraged? meetings organized by the leaders of program with the peoples who would be going to take part in the study. At that time the people were informed about the aim of the investigation and advantages connected with it’s realization. During collecting samples, the children received chocolates and sweets. Data collection 19 Biomarkers of exposure Cadmium in blood (Cd-B), cadmium in urine (Cd-U), lead in blood (Pb-B), selenium in serum (Se-S), arsenic in urine (As-U), mercury in urine (Hg-U). • Pb-B. In children, in the areas without industrial emitters (group 1), the mean geometric Pb-B concentration was 35.5 µg/l (range from 14.6 to 115.6 µg/l). In the group of investigation children living in the vicinity of smelters (group 2), the geometric mean of Pb-B was significantly higher and amounted 59.1 µg/l, within range 16.0 to 252.1 µg/l, the values decreasing as the distance from the source of emission increased. • Cd-U, Cd-B. The geometric means of Cd-U and Cd-B concentrations (in group 1) in children group were 0.50 µg/g creatinine (0.07 to 3.5 µg/g creatinine) and 0.13 µg/l (from 0.1 to 0.8 µg/l) respectively. The geometric means of Cd-U and Cd-B in children group amounted (in group 2) 0.70 µg/g creatinine (the range 0.07 – 3.5 µg/g creatinine) and 0.22 µg/l (0.1 to 1.0 µg/l) respectively. • As-U, In group I the geometric mean was 6.24 (0.9 – 51.8 µg/g creatinine) significantly lower than in group II, for the children living on polluted area 8.35 µg/g creatinine (1.8 – 58.8 µg/g creatinine). • Hg-U, the concentrations were below detection limit for the method using in laboratory.

20 Biomarkers of effects ∗ The concentrations of Cystatin C, CC16, β2M in serum samples and β2M, RBP, Alb, CC16, creatinine, NAG in urine samples were determined at the Université Catholique de Louvain, Bruxelles 1200-Belgium. ∗ The determinations of serum Prolactin and urine brush border antigen (BBA), HVA and DOPAC concentrations were led in laboratory in Parma, Universita Degli Studi di Parma.

21 Biomarkers of susceptibility Other data 22 Environmental sampling Questionnaires on contaminant intake via food in children. Data about environmental exposure in the vicinity of

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Poland 05 copper mills and control area were collected. The concentrations of cadmium and lead in the air and soil were analyzed as well as concentrations of suspended

dust and gaseous contaminants such as SO2 and NO2. 23 Lifestyle data Living: where, how long in the same place, frequently of changing the living place, owning flat/house, garden, distance from smelter, exposure to traffic, housing condition: renovation of flat/house, kind of using chemicals e.g. xylophen, active/passive smoking of the parents (starting age, amount, frequency), hobbies, pets, time spent outdoors/indoors. Nutrition: eating outdoor, how many meals were eating per day, fishes, meat, wild meat, vegetables, fruits, drinks (amount), alcohol use (frequency, amount). 24 Health data Kidney disease, diabetics, allergies, eczema, respiratory problems, asthma, current illnesses and in the past 7 days, drugs use (frequency, type) during past 4 weeks, teethes fillings. 25 Parental exposure Occupational exposure, alcohol use and smoking habit, home environment, traffic (pressure), constructions works, decorating works, heating, use of chemicals, use of pesticides in house/garden. 26 Medication Educational level of parents, educational level of children

27 Socio-economic factors Structure of the family, educational level of parents, home/flat – owning, educational level of children.

Analysis and quality control procedures 28 Intra/interlaboratory testing Since laboratory received an accreditation (EN ISO/IEC 17025), clear and distinct quality system is described. The quality system structure provides control and assurance overall processes and actions, which may affect the quality of the service. The quality manual includes all elements of laboratory structure involved collection, identification, transport, storage and preparation samples furthermore via analytical technique, use reference materials, process control, calibrations and reporting of analytical data. The methods have been always tested by internal and external quality assurance scheme. For internal quality control Seronorm – Nycomed, BCR, lyophilized blood and urine samples were used. The determination of the references materials was carried out every 20 samples; Shewhart Charts were constructed. The following references materials were used: • Pb-B, BCR 194; 195; 196; Seronorm – Nycomed (N): level 1, level 2, level 3

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Poland 05 • Cd-B, BCR 194; 195; 196; Seronorm – Nycomed: level 1, level 2, level 3 • Se-S, Seronorm – Nycomed • Cd-U, Seronorm – Nycomed • As-U, Recipe - ClinCheck®

29 External laboratory control The laboratory has been taking part in the U.K. National External Quality Assessment Schemes for lead and cadmium in blood since 1983. It has also been taking part in the External Quality Control according to the Guidelines of the German Federal Medical Council and has been certified to perform cadmium and lead determinations in blood and cadmium and arsenic in urine, selenium in serum in the fields of occupational medicine and environmental health. 30 Accuracy, limit of detection/ Cadmium and lead concentration in blood and urine quantification, reproducibility cadmium, concentration was determined by graphite furnace atomic absorption spectrometry (GF-AAS) Perkin Elmer 4100 ZL; arsenic in urine using technique of HG- AAS and selenium in serum – GF-AAS on a Unicam Solar 989 QZ apparatus. • Blood cadmium levels were determined using Stoeppler and Brandt method (1980) following by the procedure based on deproteinization of blood sample by the addition of 5% HNO3. Linearity = 1-8 µg/l; limit of detection = 0.16 µg/l; limit of quantification = 0.33 µg/l; BIAS = 2.2% (for N1 = 5.2 µg/l); repeatability (as a precision) = 3.8 (for N2 = 8.1 µg/l); precision in the working range = 6.6% • Lead in blood was established with Stoeppler, Brandt, Rains method (1978) where blood samples were deproteinized by the addition of 5% HNO3. Linearity = 50-500 µg/l; limit of detection = 2.7 µg/l; limit of quantification = 5.5 µg/l; BIAS = 1.1% (for N1 = 42 µg/l); repeatability (as a precision) = 8.1% (for N1 = 42 µg/l); precision in the working range = 4.4% • Cadmium in urine was determined according to the Recommendation Condition for cadmium published by Perkin-Elmer: Publication B 3210, 7-12, 1992. Urine samples were diluted 1+1 with the mixed matrix modifier (NH4)2HPO4 and Mg (NO3)2 Linearity = 1-8 µg/l; limit of detection = 0.1 µg/l; limit of quantification = 0.2 µg/l; BIAS = 2% (for N1 = 5.1 µg/l); repeatability (as a precision) = 6.1% (for N1 = 5.5 µg/l); precision in the working range = 6.8% • Arsenic in urine was determined following by Angerer and Schaller: Arsenic: Analyses of hazardous substances in biological materials. 1991 vol 3, 69-80, DFG. Arsenic is determined by means of hydride atomic absorption spectrometry.

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Poland 05 Linearity = 25-100 As (DMA) µg/l; limit of detection = 3 µg/l; limit of quantification = 6 µg/l; BIAS (Trueness) = 2.9% (for Recipe = 72.5 µg/l); repeatability (as a precision) = 10.3%, precision in the working range = 6.3% • Serum selenium was determined according to the method of Neve and Molle (1986). The serum sample was diluted with matrix modifier: Cu (CH3COO)2 and Mg (NO3)2. Linearity = 20-120 µg/l; limit of detection = 3.4 µg/l; limit of quantification = 6.7 µg/l; BIAS (Trueness) = 0.64% (for Seronorm-Nycomed = 78 µg/l); repeatability (as a precision) = 6.5%, precision in the working range = 7.3 31 Data analysis (statistics, power The differences between geometric means were tested by calculations) the analysis of variance and multiple comparison tests. The parameters with a skew distortion were transformed logarithmically. Relationship between continuous variables was examined by linear regression. 32 Representativity All children under 10 years old from contaminated areas were supposed to the participation. Control group was matched with the investigation group. Data protection and availability 33 Privacy legislation The full names of participants were available only for the leader of program. Each of participants was coded with an identification number and during all steps of samples analysis, only these numbers were recognized. Confidence procedure was agreement with the Polish low on the protection of personnel data. (Dz. U Nr 133 poz. 883 z 1997r.). The local Biomedical Ethics Committee approved the study protocol. 34 Intellectual property rights There are no patents. The part of obtained data was published in Trace Elements and Electrolytes, Vol. 17. No.3/2000, 147-153 and was entitled “Blood serum selenium levels in children and adults in Poland” by Trzcinka-Ochocka M., Razniewska G., Jakubowski M. 35 Banking of biological samples Always samples that had been taken for participants were stored in the Laboratory of Biomonitoring at NIOM during 5 years.

Communication (individual level, group level, level (sub) population) 36 Reporting results to public Results were delivered to the Foundation for Children from authority, to general public, to Copper Basin, Legnica, Poland. participant 37 Professional involved, contacts Once a year, for all the partners of program, the meetings between professionals and were organized where the cooperators discussed about participant results, problems and purposes

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Poland 05 38 Role of media The study was given attention in local media: radio, newspaper. 39 Public debate In the end of study, meeting was organized for the inhabitants participated in this research. At that time the results of investigations were presented and the participants were informed in details about all aspects of exploration. Results of the individual measurements and of the entire study were offered to the participants. 40 Consequences of external communication 41 Problems The major problem was with: ∗ International standardization of the obtained data in questionnaires. ∗ Delivery of the thousands frozen samples to the laboratories in Belgium, Italy and France. The samples were transported in dry ice by car. The minor problem was with: ∗ Choice of suitable areas for examination the children selection and with obtaining agreement from children’s parents as well as encouraging them for the examination.

42 Experiences ∗ Standardization of the methods for determinations of metals in blood and urine as well as adaptation of the method for the determination of arsenic in urine, comprising selective determination in urine of inorganic arsenic and its methyl derivatives separately from arsenic compounds found in urine as a result of marine food products intake, after training for developing the techniques in Laboratory in Brussels. ∗ Standardization of spirometry method after training in Lille.

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Poland 06 N° General Data 1 Type Regional biomonitoring study

2 Country Poland 3 Title The influence of long-term environmental exposure to cadmium on the kidney function.

4 Aim The study aimed at assessing the possible influence of long- term environmental exposure to cadmium as well as age during exposure on the renal function. The study concerned a cadmium-contaminated area in the vicinity of zinc smelter (Miasteczko-Upper Silesia). This factory was built in late 1950s and operated since 1968 and therefore part of inhabitants was not exposed to cadmium during childhood. The study population for the present study was recruited based on the results of the 1991-1994 project when about 2000 inhabitants of the contaminated areas were examined. Eventually, 308 persons who in 1993 presented Cd-U levels ≥ 0.5 µg/g adjusted for specific gravity 1.020 were selected in 2000. This group consisted of 172 persons ‘former adults’ - non-exposed, and 136 persons ‘former children’ - exposed, during childhood. 5 Beginning date 01. 03. 2000 6 Ending date 28. 02. 2003 7 Contact person dr Malgorzata Trzcinka – Ochocka, Nofer Institute of Occupational Medicine (NIOM) Department of Chemical and Dust Hazard Laboratory of Biomonitoring 8 Sw Teresy St., 90-950 Lodz e-mail: [email protected] tel: (+48) 42 63 14 807 fax: : (+48) 42 63 14 813 8 Initiator This study was supported by the Polish Committee for Scientific Research 9 Involved/responsible Nofer Institute of Occupational Medicine organizations Department of Chemical and Dust Hazard Laboratory of Biomonitoring 8 Sw Teresy St., 90-950 Lodz 10 Budget available 60,000 Euro 11 Who is financing The Polish Committee for Scientific Research supported this study (grant No 0718 /P05/2000/18).

Description of the population 12 Total number of children (and The investigated group consisted of 172 persons ‘former parents) adults’, and 136 persons ‘former children’, non-exposed and exposed during childhood.

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Poland 06 13 Age groups and number of ‘Former children’ group consisted of 64 girls and 72 boys, person in each group ‘former adults’ of 128 women and 44 men. During the second investigation carried out in 2000 the mean age of the ‘former children’ group was 18 years (12 – 22 years) and the ‘former adults’ group 46 years (35 – 71 years). 14 Inclusion criteria, exclusion Inclusion criteria. For the study performed in 2000, criteria persons who in 1993 presented Cd-U levels ≥ 0.5 µg/l adjusted for specific gravity 1.020 were selected. The selected persons were living in the vicinity a zinc mill and they consisted from 2 groups: subjects without and with environmental exposure during childhood (‘former adults’ and ‘former children’). The oldest person of the ‘former children’ group was 22 years old and was born in 1978, when the emission from the smelter decreased but was still high, and the youngest one in 1988, before the emission was substantially reduced. In the second group of ‘former adults’, the oldest person was born in 1929 and the youngest one in 1965, before the smelter started operating. Exclusion criteria. The subjects with kidney diseases, diabetic disease or those with a history of occupational exposure to cadmium were excluded from the study, based on questionnaire data. 15 Sampling strategy Children were recruited via schools. The samples from investigated persons were taken in schools or at a polyclinic located outside the smelter. Blood samples were collected by venipuncture using Venoject vacutainers (Li-Heparine, Oxford) and stored at 0 -20 C until determination. For β2M-S determination, blood samples were collected using venoject with no additive. They were left in a vertical position at room temperature for approx. 1 h and then centrifuged at 3500 r.p.m. for 15 min. Serum samples were transferred to clean tubes and stored at < 60 C or refrigerated, as required. Spot urine samples were collected in polyethylene tubes. The urine sample used for cadmium determination (5 ml) was acidified with 50 µl 50% nitric acid (Merck) and stored at –200 C. For the NAG-U and creatinine determination, spot urine samples were stored without any preservation. For the

β2M-U, RBP-U and Alb-U determination 0.5 ml of 0.4 mol phosphate buffer, pH 7.4, containing 1% sodium azide, was added to 4.5 ml urine. This sample was stored at -200 C. 16 Time schedule of biomonitoring The study was carried out during the period of eight months, from May to December 2000. The subjects were sampled once in this period. 17 Consent procedures The participants: written informed consent.

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Poland 06 18 How is participation encouraged? The inhabitants living in the vicinity of zinc smelter are interesting in a medical survey and different forms of biomonitoring. The subjects were encouraged on short meetings organized by the leaders of program with the peoples who would be going to take part in the study. At that time the people were informed about the aim of the investigation and advantages connected with its realization. Results of investigation were provided to the local polyclinic.

Data collection 19 Biomarkers of exposure Cadmim in blood (Cd-B), cadmium in urine (Cd-U), lead in blood (Pb-B) • Pb-B - concentrations were found to be significantly lower in 2000 than in 1993, both in the group of ‘former children’ (54.4 vs. 99.4 µg/g creatinine) and ‘former adults’ (56.4 vs. 71.0 µg/g creatinine). • Cd-B - during the period of 1993-2000, the mean geometric Cd-B concentrations in ‘former children’ increased from 0.60 to 0.87 µg/l while in ‘former adults’ from 1.37 µg/l to 1.60 µg/l. These differences were not statistically significant. • Cd-U - between 1993 and 2000 the mean geometric concentrations increased both in the group of ‘former adults’ (from 1.28 to 2.23 µg/g creatinine) and ‘former children’ (from 0.86 to 0.97µg/g creatinine).

20 Biomarkers of effects The markers of renal tubular dysfunction (β2M-U, RBP-U, NAG, NAG-A, NAG-B) and glomerular dysfunction (Alb-U

and β2M-S) were measured. 21 Biomarkers of susceptibility

Other data 22 Environmental sampling Over the period of 1968-2002 the data on atmospheric emission of cadmium from the zinc smelter was collected. 23 Lifestyle data Where living, how long in the same place, distance from smelter, active/passive smoking (starting age, amount, frequency), alcohol use (frequency, amount) hobbies, time spent outdoors/indoors 24 Health data Kidney disease, diabetics, current illnesses and in the past 7 day 25 Parental exposure Alcohol use and smoking habit. 26 Medication Educational level of parents, educational level of children 27 Socio-economic factors Structure of the family, educational level of parents, educational level of children

Analysis and quality control procedures

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Poland 06 28 Intra/interlaboratory testing Since laboratory received an accreditation (EN ISO/IEC 17025), clear and distinct quality system is described. The quality system structure provides control and assurance overall processes and actions, which may affect the quality of the service. The quality manual includes all elements of laboratory structure involved collection, identification, transport, storage and preparation samples furthermore via analytical technique, use reference materials, process control, calibrations and reporting of analytical data.

The methods have been always tested by internal and external quality assurance scheme.

For internal quality control Seronorm – Nycomed, BCR, lyophilized blood and urine samples were used. The determination of the references materials was carried out every 20 samples; Shewhart Charts were constructed. The following references materials were used • Pb-B, BCR 194; 195; Seronorm – Nycomed: level 1, level 2 • Cd-B, BCR 195; Seronorm – Nycomed: level 1, level 2, level 3 • Cd-U, Seronorm – Nycomed 29 External laboratory control The laboratory has been taking part in the U.K. National External Quality Assessment Schemes for lead and cadmium in blood since 1983. It has also been taking part in the External Quality Control according to the Guidelines of the German Federal Medical Council and has been certified to perform cadmium and lead determinations in blood and cadmium in urine, in the fields of occupational medicine and environmental health. 30 Accuracy, limit of detection/ Cadmium (Cd-B) and lead concentration (Pb-B) in blood and quantification, reproducibility urine cadmium (Cd-U), concentration was determined by graphite furnace atomic absorption spectrometry (GF-AAS) Perkin Elmer 4100 ZL. • Blood cadmium levels were determined using Stoeppler and Brandt method (1980) following by the procedure based on deproteinization of blood sample by the addition of 5% HNO3. Linearity = 1-8 µg/l; limit of detection = 0.16 µg/l; limit of quantification = 0.33 µg/l; BIAS = 3.4%, repeatability (as a precision) = 3.8%, precision in the working range = 6.6% • Lead in blood was established with Stoeppler, Brandt, Rains method (1978) where blood samples were deproteinized by the addition of 5% HNO3. Linearity = 50-500 µg/l; limit of detection = 2.7 µg/l; limit of quantification = 5.5 µg/l; BIAS = 1.1%; repeatability (as a precision) = 8.1%; precision in the working range = 4.4% • Cadmium in urine was determined according to the

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Poland 06 Recommendation Condition for cadmium published by Perkin-Elmer: Publication B 3210, 7-12, 1992. Urine samples were diluted 1+1 with the mixed matrix modifier (NH4)2HPO4 and Mg (NO3)2 Linearity = 1-8 µg/l; limit of detection = 0.1 µg/l; limit of quantification = 0.2 µg/l; BIAS = 2%, repeatability (as a precision) = 6.1%, precision in the working range = 6.8% 31 Data analysis (statistics, power All biologic test data were log-transformed for statistical calculations) analysis to approximate normality. The measurements of cadmium in blood and urine, lead in blood and all values of urinary markers are presented as geometric means. For a simultaneous comparison of the mean values for three study groups, one-way analysis of variance (Scheffe, 1959) with multiple comparisons T-Tukey test (Spjøtvoll et al, 1973) was applied. For a comparison of mean values adjusted for gender, covariance analysis was used (Scheffe, 1959). Student t-test was applied for homogeneous or heterogenous variances to compare the means for two groups (Fisher et al, 1993). Pearson correlation coefficient (r) and linear regression were calculated to assess the relationships between different indices of kidney dysfunction and urinary cadmium (Jobson, 1991). All the statistical tests were applied at the significance level of α = 0.05. 32 Representativity Out of 386 people enrolled for the study 56 refused to cooperate. Persons with kidney diseases (5), diabetic disease (6) or those with a history of occupational exposure to cadmium (11) were excluded from the study, based on questionnaire data. Eventually, 308 persons took part in the examinations performed during the period of 2000-03.

Data protection and availability 33 Privacy legislation The full names of participants were available only for the leader of program. Each of participants was coded with an identification number and during all steps of samples analysis, only these numbers were recognized. Confidence procedure was agreement with the Polish low on the protection of personnel data. (Dz. U Nr 133 poz. 883 z 1997r.). The local Biomedical Ethics Committee approved the study protocol. 34 Intellectual property rights There are no patents. The obtained data will be published in Environmental Research. The manuscript entitled “The effects of environmental cadmium exposure on kidney function: the possible influence of age” by Trzcinka-Ochocka M., Jakubowski M., Razniewska G., Halatek T., Gazewski A. is in the press. 35 Banking of biological samples Always samples that had been taken for participants were

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Poland 06 stored in the Laboratory of Biomonitoring at NIOM, during 5 years

Communication (individual level, group level, level (sub) population)

36 Reporting results to public The findings imply that children who were born and grew up authority, to general public, to in the cadmium-contaminated areas are potentially more participant susceptible to kidney dysfunction, particularly in the form of decreased tubular resorption, than adults As in environmental lead exposure, children may constitute the critical population also in the case of cadmium exposure. The participants received individual biomonitoring results.

37 Professional involved, contacts During the meeting the discuses with participants about between professionals and results, problems and purposes was realized. participant 38 Role of media The study was given attention in local media: radio, newspaper. 39 Public debate In the end of study, meeting was organized for the inhabitants participated in this research. At that time the results of investigations were presented and the participants were informed in details about all aspects of exploration. Results of the individual measurements and of the entire study were offered to the participants. 40 Consequences of external communication

41 Problems No major problems. The minor problem was with the children selection, obtaining agreement from children’s parents and encourages them for the examination.

42 Experiences Close collaboration with the local policlinic helped persuade participants to take part in the study.

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Poland 07 N° General Data 1 type Regional biomonitoring study (and individual follow-up services) Biomonitoring of lead exposure in children aged 24 – 84 months 2 country Poland 3 title Prevention of childhood lead poisoning in urban children, Silesia 4 aim To identify children excessively exposed to lead, living in urban center of the heavily industrialized region of Poland – Upper Sielsia. To provide individual follow-up services to lead exposed children in the Environmental Medicine Unit at the Institute of Occupational Medicine and Environmental Health To assess the magnitude of the problem of lead exposure in urban children population in Silesia 5 beginning date 1993 6 ending date 1998 7 contact person Dorota Jarosińska, MD PhD Institute of Occupational Medicine and Environmental Health 13 Koscielna 41-200 Sosnowiec, POLAND [email protected] +48 32 2660885 8 initiator Institute of Occupational Medicine and Environmental Health (IOMEH) 9 involved/responsible IOMEH, Provincial Sanitary Epidemiological Station, organisations Katowice 10 budget available Several separately funded projects 11 who is financing Regional and National Funds of Environmental Protection and Water Management Ministry of Health IOMEH

Description of the population 12 total number of children Apr 14 000 children 13 age groups and number of persons in Children aged 24 – 84 months each group 14 inclusion criteria, exclusion criteria Inclusion criteria: Written informed consent Living in the selected urban area in the center of the Upper Silesia. Age 24-84 months (as the primary goal of the project was identification of lead exposed individuals, children exceeding this age range, eg. siblings, neighbours, were also accepted) 15 sampling strategy In principle population based programme. Due to resource limitations, focus on children living in the

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Poland 07 city centres. Complete lists of eligible children were obtained from the local paediatrician outpatient clinics. 16 time schedule of biomonitoring Biomonitoring took place between 1993 and 1998, both in the “heating” season (mid_October to mid- April) and “non-heating” season (mid-April to mid- October). 17 consent procedures Before blood sampling parents or legal guardians had to sign written consent. All parents received letter of invitation together with the information on the type and objective of the program, as well as educational material on lead poisoning prevention. 18 how is participation encouraged? We provided information on the program and on the issue (lead poisoning in children) to encourage participati in the program. Children who were tested received a set of the vitamins (available on Polish market, recommended by paediatricians).

Data collection 19 biomarkers of exposure lead in venous blood 20 biomarkers of effect 21 biomarkers of susceptibility

Other data 22 environmental sampling Not performed; data on airborne lead concentrations and lead fallout for each city available from the regional ambient air monitoring system lifestyle data average time spent by a child outdoors (hours per day), consumption of home grown vegetables; smoking habits not included 24 health data no 25 parental exposure One question on occupational exposure to lead 26 medication no 27 socio-economic factors Housing standard, carpet in the apt, recreational habits (trips outside the region), vicinity of busy road

Analysis and quality control procedures 28 intra/interlaboratory testing Department of Chemical Hazards of IOMEH participates in the internal and external QC systems. 29 external laboratory control 30 accuracy, limit of Detection limit - 0.6 ug/dl. detection/quantification, reproducibility Other data available on request 31 data analysis (statistics, power llti) 331

Poland 07 calculations) 32 representativity Overall response rate was 80%. Children participating in the program represented from 10 to 90% of children population of the specified age group in the participating cities.

Data protection and availability 33 privacy legislation Questionnaires are maintained by the IOMEH team. Individual records are stred anonymously in the database. Measures are taken to ensure confidentiality and security of the data. 34 intellectual property rights No patents. Data are published. 35 banking of biological samples No Communication (individual level, group level, level (sub)population )

36 reporting results to public authority, to Parents of each participating child received general public, to participant individual results of the blood lead test. Children with elevated blood lead level received invitation to IOMEH for further diagnostic tests and consultation. On the group level - report from the biomonitoring activities in given location was presented to the local authorities. Findings have been presented in several papers. 37 professionals involved , contacts On individual level contact between professionals between professionals and participants and participants was at IOMEH – during paediatrician consultations of lead exposed children. On the group level there were meetings organised, when doctors from IOMEH presented the program and invited parents to participate, e.g. in the day care centres. At the end of the program, in each participating city we organised seminars with the local authorities, medical doctors, teachers, etc. To present the results. 38 role of media During the realisation of the program, information appeared few times in the local newspapers. In our opinion, this way of communication and education could have been used much more extensively. However, the communication with media was not always satisfactory – with our attempts to present rational information and a need for "the news" - spectacular, sometimes exagerrated statemets (expected by the media).

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Poland 07 39 public debate To some extend - by presenting the program results to the local authorities. 40 consequences of external communication 41 Problems There was a big interest in this program. Most parents agreed to have the child tested for lead. Every child with elevated blood lead level was invited to IOMEH for further diagnostic tests and paediatrician consultation. However, many of those children never appeared, despite numerous invitations and no additional costs for the follow-up services. As for the whole program, assurance and continuity of resources was the major problem. The whole program comprised of few separately funded projects. This made the planning of the activities more difficult. Limited resources did not allow to repeat blood tests in the monitored population, following the first test, and to evaluate effectiveness of information and education activities performed. 42 Experiences Experiences from this program helped to develop a working algorithm of the individual follow- up services for lead exposed children. Based on the experiences from biomonitoring activities and contacts with parents of lead exposed child, we we elaborated a set of educational material on childhood lead poisoning and revention, addressed to different receipeints: children, parents (including those occupationally exposed to lead), nurses, medical doctors, teachers, local authorities. These materials are distributed during the meetings, during educational campaignes and handed to the parents of lead exposed children.

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Poland 08 N° General Data 1. Type Regional study. Health survey of the health status in population living close to the big municipal waste landfill “Lubna”. 2 Country Poland 3 title Biological monitoing of exposure to environmental hazards in population living close to the municipal waste landfill 4. aim The overall goal of the study was to assess the health status and exposure to environmental factors in population living close to big municipal waste landfill “Lubna”. 5. beginning date 1998 6. ending date 1999 7. contact person Prof. Jan E Zejda – project leader; Dr Dorota Jarosinska – coordinator of the health assessment group [email protected]; + 48 32 2660885; Dr Danuta Mielżyńska, [email protected] +48 32 266 08 85, ext. 271 (for mutagenic substances) Institute of Occupational Medicine and Environmental Health, 41- 200 Sosnowiec, 13 Koscielna St., Poland 8. initiator Local community of the villages located close to the big municipal waste landfill “Lubna” Management of the Municipal Clean Up Services, Warsaw

9. involved/responsible Institute of Occupational Medicine and Environmental Health, organisations Sosnowiec Local Health care Unit, Piaseczno 10 budget available 11. who is financing Municipal Clean Up Services, Warsaw Description of the population 12. total number of children 33 children 13. age groups and number of Total number of participants in the questionnaire survey: 393 persons in each group adults and 188 children. Biological monitoring group 140 adults; 33 children 4-14 years old 14. inclusion criteria, Living in the villages close to the big municipal waste landfill “Lubna” Participation in the questionnaire part of the project 15. Sampling strategy Participation on the voluntary basis 16. time schedule of One blood and urine sampling in summer 1998 biomonitoring 17. consent procedures Parents of participating children signed written consent 18. how is participation Voluntary participation. Information and promotion of the program encouraged? done by the representatives of the group of concerned citizens Data collection 19. biomarkers of exposure Lead in venous blood, cadmium, mercury in urine Acetylcholinesterase activity Phenol, hippuric acid, trichloroacetic acid in urine Mutagenic substances in urine (Ames plate incorporation test,

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Poland 08 TA98±S9,YG1021, 24, 41+S9), 1-hydroxypyrene in urine 20 biomarkers of effect Methemoglobin, B2-microglobuline, NAG, total Ig E 21 biomarkers of susceptibility Other data 22. environmental sampling Not performed 23 lifestyle data Smoking, smoking on the day of sampling (for adults) 24 heath data Chronic diseases of kidneys, liver; urinary infections last month 25 parental exposure Occupational exposure to chemicals (metals, solvents), pesticides 26. medication Antibiotics (a week before sampling), antihistaminic drugs; any drugs taken regularly 27 socio-economic factors Analysis and quality control procedures 28 intra/interlaboratory testing Diagnostic Laboratory and Dept of Chemical Hazards of IOMEH participate in the internal and external QC systems (details available at request). Reliability of 1-HpU and creatinine concentration measurements was confirmed by the intralaboratory control. 29. external laboratory control Reliability of 1-HpU and creatinine concentration measurements was confirmed also by the participation in the intercomparison programme 18/1996 for occupational/environmental medical- toxicological analyses organised by the German Society for Occupational and Environmental Medicine in Erlangen which resulted in receiving the certificate for 1-HpU analysis in occupational and medical applications. 30 accuracy, limit of Data are available on request detection/quantification, reproducibility 31 data analysis (statistics, Participation in the study was on voluntary basis. power calculations) Range, mean values, univariate analysis 32 representativity The study was developed in response to the community concerns. Participation in the study was on voluntary basis, thus can’t claim to be representative for the population concerned. Data protection and availability 33 privacy legislation Samples and questionnaires are maintained by the responsible person in IOMEH. Data are stored anonymously in the database. 34 intellectual property rights No patents. 35. banking of biological No samples Communication (individual level, group level, level (sub)population) 36 reporting results to public The study was developed and performed in response to the authority, to general public, community concerns about potential adverse health effects of to participant living close to the big municipal waste site. Bothe in the preparatiry phase and at the end of the project, IOMEH group participated in the meetings with local community representatives. The report was presented to the representatives of the concerned citizens, to the local authorities, local medical community, as well as to the Municipal Clean Up Services, Warsaw, which financed

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Poland 08 the project. Some findings were published: Zejda, JE, Jarosinska D, Bisaiada M, Laczynski J, Jazwiec- Kanyion B, Zlotkowska R, Muszynska M: Results of the health survey of population living in the vicinity of a large waste site (Warsaw, Poland). CEJPH 2000; 8:238-244. Jarosinska D, Zejda JE, Biesiada M, Laczynski J.: Biological monitoring of exposure to enviornemntal hazards in population living in the vicinity of municipal waste dumping site. Umweltmedizin in Forschumg und Praxis 1999;4:233-234 (S 052). Miel żyńska D. et al.: Exposure to mutagenic substances in the population living in the vicinity of solid waste landfill “Łubna”, Environmental Medicine, Vol 2, 1, 1999 (in Polish) 37 professionals involved, As mentioned above, there were extensive contacts between the contacts between research team and the concerned community. Besides the IOMEH professionals and team, local medical doctors and nurses were involved, as they participants conducted questionnaire survey and medical examination of the participants. They also collected biological samples, which were then transported to IOMEH and analysed. 38 role of media No media involved 39 public debate There was a debate both at the beginning and after completion of the study. 40 consequences of external communication 41 Problems The study was developed in response to concerns expressed by the local community. However, there appeared to be two fractions in the community – one strongly concerned and determined to “prove” advers effects of living close to the waste site, leading to the closure of the site; the other interested rather in maintaing and development of the site. In fact, reasons for this concern were not only of medical nature (although expressed mainly as such), but to a big extend of social and economic ones. This aspect, and exisitence of two, almost “opposite” groups affected both the design and performance of the study. There was no social permission to conduct epidemiological study, using any defined sampling strategy. The study was intended as population based, but participation rate was not satisfactory. 42 Experiences This community driven study was a very interesting, though challenging experience. With all the methodological limitations we collected information which could be a subject of analysis, and some findings could have been a starting point for further, more research oriented studies. Working with the community with highly polarised attitudes to the problem revealed the whole complexity of the driving forces which triggered the project. This experience was very useful for us in designing and implementing other community based projects.

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Poland 09 N° General data 1 type Regional biomonitoring study and research study 2 country Poland 3 title Effects of environmental lead level exposure on children’s hearing and posture. 4 aim Assessment of environmental low-lead exposure effects on hearing, balance, central nervous system and behavioural outcomes in children To identify 5 beginning date 1999 6 ending date 2002 7 contact person Krystyna Pawlas D.Sc. Laboratory of Audiology and Noise Institute of Occupational Medicine &Environmental Health (IOMEH) Koscielna 13 41-200 Sosnowiec [email protected] +4832 2660885 8 initiator IOMEH 9 involved/responsible IOMEH (in recent similar study carried out in 1994-1997 organisations Karolinska Institute of Stockholm was involved) 10 budget available Euros 80000 ( approximately) 11 who is financing Polish Ministry of Science

Description of the population 12 total number of children 327 children 13 age groups and number of Age groups: persons in each group 3-5 years old- 48 6-7 years old – 244 8-12 - 45 14 inclusion criteria, exclusion Inclusion criteria: criteria age children should be living in the are of Upper Silesia should be healthy 15 sampling strategy Children were recruited via kindergardens 16 time schedule of biomonitoring October 2000 – June 2001 October 2001 – June 2002 17 consent procedures Child and 1 parent : written informed consent 18 how is participation 1. Results of individual measurements and entire study to encouraged? the children’s parents 2. 2. Individual diagnosis and treatment to the children’s parents if necessary

Data collection 19 biomarkers of exposure Lead in blood

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Poland 09 20 biomarkers of effect Hearing threshold levels Brain Stem Response Audiometry Otoacoustic emmissions Stapedius reflex Assessment of balance organ ( posturography) Psychological tests EEG with brain mapping and neurological assessment 21 biomarkers of susceptibility none

Other data 22 environmental sampling Questionnaires on environmental tobacco smoking and environmental noise exposure, lead level in blood sample 23 lifestyle data Passive smoking, 24 health data Duration of pregnancy, apgar score, medication after delivery, BMI, medical ( health) history focused on neurodevelopment and hearing problems, ORL status, 25 parental exposure Smoking during pregnancy , medication during pregnancy, hearing problems in the family, 26 medication medication -use( frequency, type) after delivery, antibiotics and other medication history 27 socio-economic factors Structure of the family, educational levels of parents, incomes of the family

Analysis and quality control procedures 28 intra/interlaboratory testing Calibrations according to Polish regulation and according to manufacturers instructions

29 external laboratory control Interlaboratory control system for BPb ( domestic as well as international 30 accuracy, limit of Data for all parameters are available on request detection/quantification, reproducibility 31 data analysis (statistics, power Statistical analysis was made using simple correlation( calculations) numeric and parametric) tests, multivariable analysis 32 representativity Recruitment efficiency was monitored

Data protection and availability 33 privacy legislation questionnaires are maintained by medical doctors and psychologists and under secure conditions in accordance to Polish data protection legislation Acceptance of local ethical commission was obtained according to the Declaration of Helsinki 34 intellectual property rights No patents. Data was published on workshops and symposia and will be published in pre review journals. 35 banking of biological samples No long term storage is used

Communication (individual level, group level, level (sub)population ) 36 reporting results to public Each year the Polish Ministry of Science was informed about

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Poland 09 authority, to general public, to the progress of the study and after finishing the study was participant given the final report. Pre reviewers reviewed the final report. Recent study The participants were given individual results with further recommendations Ethical commission was informed about the progress of the study and final outcomes 37 professionals involved, contacts Pre reviewers assessed progress in the study as well as between professionals and entire study participants 38 role of media Not involved 39 public debate Participation in symposia focused on the filed of survey 40 consequences of external communication

41 Problems The study was focused on 6-7 years old children but sometimes it was necessary to accept participation of siblings of recruited children. Parents were mostly interested in blood lead level of their children. In case of low lead levels parents refused further health examination of their children. So called poor social family were not interested in participation in the study. During Summer time holidays children were not reachable and during Autumn and Spring time there were ORL health problem

42 Experiences A lot of energy was spent in communication with parents for organising participation in the medical examination. Participation level was higher when siblings of selected children were accepted for the study. (kind of gift) and reimbursement of travel cost were offered. The study has showed that lead exposure, even at low levels influences on peripheral as well as central nervous system. Children’s health parameters to lead seems to be not the same sensitive at different age, and shows great inter-subject variability. Further study is needed to clarify this problem.

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Poland 10 N° General Data

1 Type Cross-sectional

2 Country Poland

3 Title 1. Evaluation of psychological functions impairment in children environmentally exposed to lead 2. School abilities and social functioning in children environmentally exposed to lead 4 Aim The aim of projects was to evaluate possible effect of present lead exposure in contaminated area in Poland on development of psychological function, school performance and social functioning in children inhabiting ther regions in the vicinity of copper mill 5 Beginning date 01. 10. 1991

6 Ending date 30. 09. 1994

7 Contact person Dr. Dorota Merecz Nofer Institute of Occupational Medicine Work Psychology Department 8 Sw. Teresy St., 90-950 Lodz e-mail [email protected] tel: (+48) 42 63 14 598 fax: (+48) 42 63 14 813

8 Initiator Institute of Occupational Medicine, Lodz, Poland together with Foundation for Children form Copper Mills Region

9 Involved/responsible Nofer Institute of Occupational Medicine (NIOM) organizations Work Psychology Department 8 Sw Teresy St., 90-950 Lodz

10 Budget available 1. 50,000.00 Euro 2. 20,000.00 Euro

11 Who is financing The Polish Committee for Scientific Research supported this study (grant 4 S404 107 04, ).

Description of the population 12 Total number of children 400 children selected from medical records of 4,548 children. 200 with the highest blood lead levels ( above 120µg/l) and 200 randomly selected from the remaining children to obtain a wide spectrum of exposure levels in the

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Poland 10 region 13 Age groups and number of The age of the children varied between 6 and 11 years person in each group 14 Inclusion criteria, exclusion Inclusion criteria – children living in the vicinity of a copper criteria mill

Exclusion criteria – no mental retardation diagnosed before the study, children living without biological parents

15 Sampling strategy Children were recruited via schools and kindergartens located in the contaminated (choice for examination) areas. The samples from investigated persons were taken in schools or public health clinics. Blood samples were collected by venipuncture using vacutainers Becton-Dickinson (Li- Heparine).

16 Time schedule of biomonitoring The samples were collected within May-June as well as October –November. The subjects were sampled once in this period.

17 Consent procedures The parents: written informed consent.

18 How is participation The inhabitants living in the vicinity of zinc smelter are encouraged? interested in a medical survey and different forms of biomonitoring. The subjects were encouraged on short meetings organized by the leaders of program with the peoples who would be going to take part in the study. At that time the people were informed about the aim of the investigation and advantages connected with its realization.

Data collection 19 Biomarkers of exposure Lead blood concentration in the examined group ranged from 12µg/l to 272µg/l, mean equaled 101.8µg/l, and the standard deviation was 4.7 20 Biomarkers of effects The effect of exposure was evaluated by psychological testing. The set of questionnaires was used to evaluate the possible effects of lead on CNS functions and school performance of children. The methods used were the same or compatible to those ones recommended by WHO to this type of studies 21 Biomarkers of susceptibility

Other data 22 Environmental sampling 23 Lifestyle data Where living, how long in the same place, distance from smelter, active/passive smoking (starting age, amount, frequency), alcohol use (frequency, amount) hobbies, time

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Poland 10 spent outdoor/indoor, economic situation of the family, housing, family state, parental education level. 24 Health data The course of pregnancy to evaluate the confounding effects of prenatal condition on CNS functioning, diseases in early childhood, and actual state of health 25 Parental exposure Occupational exposure to lead (yes/no) assessed indirectly by the place where parents work 26 Medication 27 Socio-economic factors Occupational status of parents

Analysis and quality control procedures

28 Intra/interlaboratory testing The using methods have been always tested by internal and external quality assurance scheme. For internal quality control Seronorm – Nycomed, BCR, lyophilized blood samples were used. The determination of the references materials was carried out every 20 samples; Shewhart Charts were constructed. The following references materials were used • Pb-B, B1=413 µg/l; B2=745 µg/l; BCR 194=124 µg/l; 195=416 µg/l; 196=772 µg/l; N1=42 µg/l; N2=380 µg/l; N3=671 µg/l

29 External laboratory control The laboratory has been taking part in the U.K. National External Quality Assessment Schemes for lead and cadmium in blood since 1983. In addition, for 49 blood samples collected in 1993 parallel determination of lead were performed by the Institute of Occupational Medicine in Lodz and Danish National Institute of Occupational Health in Copenhagen. The regression equation for Pb-B concentrations within range from 30.0 to 190.0 µg/l was y = 0.84x + 0.39, where y = NIOM. 30 Accuracy, limit of detection/ lead concentration (Pb-B) in blood, concentration was quantification, reproducibility determined by graphite furnace atomic absorption spectrometry (GF-AAS) Perkin Elmer 4100 ZL. • Lead in blood was established with Stoeppler, Brandt, Rains method (1978) where blood samples were deproteinized by the addition of 5% HNO3. Linearity = 50-500 µg/l; limit of detection = 2.7 µg/l; limit of quantification = 5.5 µg/l; BIAS=1.1% (for N1 = 42 µg/l); repeatability (as a precision) = 8.1% (for N1 = 42 µg/l); precision in the working range=4.4% 31 Data analysis (statistics, power The differences between geometric means were tested by the calculations) analysis of variance and multiple comparison tests. The parameters with a skew distortion were transformed logarithmically. Relationship between continuous variables was examined by linear regression. In each regression model confounders were taken into account 32 Representativity The recruitment was very efficient - about 95% of children

342

Poland 10 chosen for this study, took part in this program.

Data protection and availability 33 Privacy legislation The full names of participants were available only for the leader of program. Each of participants was coded with an identification number and during all steps of samples analysis, only these numbers were recognized. Confidence procedure was agreement with the Polish low on the protection of personnel data. The local Biomedical Ethics Committee approved the study protocol. 34 Intellectual property rights There are no patents. The obtained data was published in 1) European Journal of Oncology,6, 1999, 2) International Journal of Occupational Medicine and Environmental health, 10,17,1997 35 Banking of biological samples Always samples that had been taken for participants were stored in the Laboratory of Biomonitoring at NIOM, during 5 years.

Communication (individual level, group level, level (sub) population) 36 Reporting results to public The results were passed to the medical service in schools and authority, to general public, to policlinic cooperated with the organizers. The information participant about the study results was disseminated among health professionals during semminars 37 Professional involved, contacts During the meeting the discuses with participants about between professionals and results, problems and purposes was realized. participant 38 Role of media The study was given attention in local media: radio, newspaper. 39 Public debate In the end of study, meeting was organized for the inhabitants participated in this research. At that time the results of investigations were presented and the participants were informed in details about all aspects of exploration. Results of the individual measurements and of the entire study were offered to the participants. 40 Consequences of external communication

41 Problems The problem was with the children selection and encourages them for the examination as well as with obtaining agreement from children’s parents on the partaking in this study.

42 Experiences

Close collaboration with the local authorities, personnel of polyclinic as well as managers and medical workers of schools, helped persuade participants to take part in the study.

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Poland 11 N° General Data 1. type Regional biomonitoring study Study population: 150 children, 8 years old chosen by random selection to cover to cover the whole area of Bytom city in the industrial region of Upper Silesia, Poland 2 country Poland 3 title Analysis of Children’s Risk in the Town of Bytom with respect to Environmental Pollution 4. aim The project was aimed at investigation of the spatial distribution of some parameters commonly used in the biological monitoring, as well as at analyzing the co-occurrence of the changes in these parameters and environmental quality indicators 5. beginning date 1991 6. ending date 1993 7. contact person Dr Danuta Mielżyńska, Institute of Occupational Medicine and Environmental Health, 41-200 Sosnowiec, 13 Koscielna St., Poland [email protected] +48 32 266 08 85, ext. 271 8. initiator Municipal Council of Bytom Town 9. involved/responsible Institute of Ecology of Industrialized Areas, Katowice, Poland organisations Institute of Occupational Medicine and Environmental Health, Sosnowiec, Poland Silesian Medical Academy, Zabrze, Poland Karolinska Institutet, Stockholm, Sweden Catholic University of Nijmegen, The Netherlands 10 budget available (?) 500 ml zlotych 11. who is financing Municipal Council of Bytom, Karolinska Institutet, Stockholm, Catholic University of Nijmegen Description of the population 12. total number of children 150 children 13. age groups and number 8 years old of persons in each group 14. inclusion criteria, age, inhabitants of Bytom, students of public primary schools 15. Sampling strategy The address data base for all children (see inclusion criteria) = 3167 children, was established. 150 children were selected on random basis by the use of the special computer program to cover the whole area of the city. 16. time schedule of February – May 1992, every week 7-10 children biomonitoring 17. consent procedures Informed consent was written by children’s parents 18. how is participation Results of individual measurements were offered to the parents and encouraged? school physicians and vitamins were handed during sampling Data collection 19. biomarkers of exposure presence of the mutagenic and toxic substances in urine (Ames spot test, TA98±S9, ±β-gluc., TA100±S9, ±β-gluc.), 1-hydroxypyrene in urine, lead, cadmium, selenium in blood, Mg, Ca, Cu, Zn in serum blood

344

Poland 11 20 biomarkers of effect cytological changes in expectoration from the upper respiratory system hematological blood indicators, activity of glutathione peroxidase, general parameters of urine, 21 biomarkers of susceptibility Other data 22. environmental sampling Outdoor pollution: ; sulphur oxides, nitrogen oxides; dustfall, including metals; suspended particular matter, including metals, BaP, tar substances, soil contamination with metals from the period 1980- 1990. The data were obtained from the Sanitary Epidemiological Station in Katowice. 23 lifestyle data Questionnaire: nutrition of children (kind of food, way of food preparation), intake of home-grown vegetables; frequency of staying outside the industrial area, e.g. on holidays; exposure to ETS. 24 heath data 1.Birth height, weight, Apgar score, current height, weight, medical history. 2. Illnesses in the past one week. 25 parental exposure Current smoking (frequency, amount duration of smoking), smoking in pregnancy. children exposure Localization of the flat, heating system. 26. medication 1. Intake of medication during last 6 months. 2. Current intake of vitamins and preparations for immunity. 27 socio-economic factors Structure of the family, educational level of parents, economical conditions Analysis and quality control procedures 28 intra/interlaboratory Heavy metals concentrations were determined in Karolinska testing Institutet in Stockholm, 1-hydroxypyrene concentration in the Catholic University in Nijmegen, the Netherlands. 29. external laboratory control 30 accuracy, limit of Data for all parameters are available on request. detection/quantification, reproducibility 31 data analysis (statistics, Data analysis included spatial stratification of environmental and power calculations) biomonitoring data. 32 representatively Recruitment efficiency was about 90%. Data protection and availability 33 privacy legislation Samples and questionnaires were maintained by the responsible person (author of the project). Data are anonymous. 34 intellectual property No patents. rights 35. banking of biological No samples Communication (individual level, group level, level (sub)population) 36 reporting results to public 1.Report on results was prepared for the Municipal Council of authority, to general Bytom. public, to participant 2. Some results were given to children’s parents and school physicians.

345

Poland 11 3. Paper: Osman K. et al. (1994), Blood levels of lead, cadmium and selenium in children from Bytom, Poland, I J Environ Health Research, 4 Jongeneelen F., (1994) Biological monitoring of environmental exposure to polycyclic aromatic hydrocarbons: 1- hydroxypyrene in urine of people. Toxicol Letters, 72 37 professionals involved, contacts between professionals and participants 38 role of media The project was briefly presented on regional TV, radio and newspapers. 39 public debate At the end of the project a public debate was organised by the Municipal Council of Bytom. The main researchers were present. 40 consequences of external communication 41 Problems There were some problems but it was a long time ago 42 Experiences The cooperation with the Municipal Council (Department of Health and Ecology) was very helpful.

346

Poland 12 N° General Data 1. type Regional biomonitoring study Study population: children, 7-8 year old living in three different places of the industrial region of Upper Silesia, Poland; the old urbanized town of Bytom (136 children), relatively modern industrial town of Dąbrowa Górnicza (128 children) and a rural area Pilica (148 children). 2 country Poland 3 title Urinary 1-hydroxypyrene as a biomarker of environmental exposure to polycyclic aromatic hydrocarbons. 4. aim The project was aimed at the assessment of environmental exposure to PAHs and the influence of indoor pollution. 5. beginning date 1992 6. ending date 1993 7. contact person Dr Danuta Miel żyńska, Institute of Occupational Medicine and Environmental Health, 41-200 Sosnowiec, 13 Koscielna St., Poland [email protected] +48 32 266 08 85, ext. 271 8. initiator Institute of Occupational Medicine and Environmental Health, Sosnowiec, Poland 9. involved/responsible Institute of Occupational Medicine and Environmental Health, organisations Sosnowiec, Poland Regional Sanitary-Epidemiological Station, Katowice, Poland Catholic University of Nijmegen, The Netherlands 10 budget available ? 11. who is financing Institute of Occupational Medicine and Environmental Health, Sosnowiec, Poland Description of the population 12. total number of children 412 children 13. age groups and number of 8-9 year old persons in each group 14. inclusion criteria, Age, inhabitants of Bytom, Dąbrowa Górnicza and Pilica, students of public primary schools 15. Sampling strategy Random selection. 16. time schedule of 1991/1992 – 1992/3: samples collected in winter. biomonitoring 17. consent procedures No consent was written by children’s parents (only urine collection). The parents got the information about the study. 18. how is participation Results of individual general parameters of urine were given to encouraged? children’s parents Data collection 19. biomarkers of exposure 1-hydroxypyrene in urine 20 biomarkers of effect general parameters of urine 21 biomarkers of susceptibility Other data 22. environmental sampling Outdoor pollution: suspended particular matter and B(a)P from

347

Poland 12 the 12 months period prior to urine sampling. The environmental samples were collected in the air quality network of the Regional Sanitary-Epidemiological Station in Katowice. 23 lifestyle data Questionnaire: nutrition of children (kind of food, way of food preparation, intake of home-grown vegetables); frequency of staying outside the industrial area, eg on holidays; exposure to ETS 24 heath data 1.Birth height, weight, Apgar score, current height, weight, medical history. 2. Illnesses in the past one week. 25 parental exposure Current smoking (frequency, amount duration of smoking), smoking in pregnancy. children exposure Localization of the flat, heating system. 26. medication 1. Intake of medication during last 6 months. 2. Current intake of vitamins and preparations for immunity. 27 socio-economic factors Structure of the family, educational level of parents, economical conditions. Analysis and quality control procedures 28 intra/interlaboratory testing Reliability of 1-HpU and creatinine concentration measurements was confirmed by the intralaboratory control 29. external laboratory control Reliability of 1-HpU and creatinine concentration measurements was confirmed also by the participation in the intercomparison programme for occupational/environmental medical-toxicological analyses organised by the German Society for Occupational and Environmental Medicine in Erlangen which resulted in receiving the certificate for 1-HpU analysis in occupational and medical applications. 30 accuracy, limit of Data for all parameters are available on request. detection/quantification, reproducibility 31 data analysis (statistics, power calculations) 32 representatively Recruitment efficiency was about 90%. Data protection and availability 33 privacy legislation Samples and questionnaires were maintained by the responsible person (author of the project). Data are anonymous. 34 intellectual property rights No patents. 35. banking of biological No samples Communication (individual level, group level, level (sub)population) 36 reporting results to public 1.Report on results. authority, to general public, 2. Some results were given to children’s parents to participant 3. Presentations on several conferences and paper: Siwińska E et al. (1999) The effect of coal stoves and environmental tobacco smoke on the level of urinary 1-hydroxypyrene, Mutation Res, 445

348

Poland 12 37 professionals involved, contacts between professionals and participants 38 role of media . 39 public debate 40 consequences of external communication 41 Problems

42 Experiences The cooperation with schools where the samples were collected was very helpful

349

Poland 13 N° General Data 1. type Regional biomonitoring study Study population: children, 8 year old living in the industrial region of Upper Silesia, Poland in the town of Sosnowiec (30 children) 2 country Poland 3 title Evaluation of intra-and interindividual variation of urinary 1- hydroxypyrene, a biomarker of exposure to polycyclic aromatic hydrocarbons 4. aim The aim of the study was to estimate the appropriate sample size for reliable assessment of the environmental exposure to PAH 5. beginning date 1995 6. ending date 1995 7. contact person Dr Ewa Siwińska, Institute of Occupational Medicine and Environmental Health, 41-200 Sosnowiec, 13 Koscielna St., Poland [email protected] +48 32 266 08 85, ext. 181 8. initiator Institute of Occupational Medicine and Environmental Health, Sosnowiec, Poland 9. involved/responsible Institute of Occupational Medicine and Environmental Health, organisations Sosnowiec, Poland 10 budget available 11. who is financing Polish Committee of Scientific Research (grant no. PB- 554/P05/96/10) Description of the population 12. total number of children 30 children 13. age groups and number 8 year old of persons in each group 14. inclusion criteria, Age, children living at the same housing estate and attending the same primary school in Sosnowiec 15. sampling strategy Selection according to inclusion criteria 16. time schedule of Samples were collected in July to avoid the influence of heating biomonitoring with coal. Urine samples were collected directly after waking up on 6 consecutive days 17. consent procedures No consent was written by children’s parents (only urine collection). The parents got the information about the study 18. how is participation Results of individual general parameters of urine were given to encouraged? children’s parents Data collection 19. biomarkers of exposure 1-hydroxypyrene 20 biomarkers of effect General parameters of urine 21 biomarkers of susceptibility Other data 22. environmental sampling 23 lifestyle data Questionnaire: nutrition of children (kind of food, way of food preparation, intake of home-grown vegetables); exposure to ETS. 24 heath data Medical history, illnesses in the past one week. 25 parental exposure Current smoking (frequency, amount duration of smoking). 26. medication Intake of medication during last 6 months 27 socio-economic factors Structure of the family, living conditions,

350

Poland 13 Analysis and quality control procedures 28 intra/interlaboratory Reliability of 1-HpU and creatinine concentration measurements testing was confirmed by the intralaboratory control, 29. external laboratory Reliability of 1-HpU and creatinine concentration measurements control was confirmed also by the participation in the intercomparison programme for occupational/environmental medical-toxicological analyses organised by the German Society for Occupational and Environmental Medicine in Erlangen which resulted in receiving the certificate for 1-HpU analysis in occupational and medical applications. 30 accuracy, limit of Data are available on request. detection/quantification, reproducibility 31 data analysis (statistics, power calculations) 32 representatively Very good Data protection and availability 33 privacy legislation Samples and questionnaires were maintained by the responsible person (author of the project). Data are anonymous. 34 intellectual property No patents. rights 35. banking of biological no samples Communication (individual level, group level, level (sub)population) 36 reporting results to 1.Report on results (for Polish Committee of Scientific Research). public authority, to 2. The project was a part of doctor thesis. general public, to 2. Results of general parameters of urine were given to children’s participant parents. 3. Paper: Siwińska E et al. (1998) Evaluation of intra-and interindividual variation of urinary 1-hydroxypyrene, a biomarker of exposure to polycyclic aromatic hydrocarbons 37 professionals involved, contacts between professionals and participants 38 role of media . 39 public debate 40 consequences of external communication 41 Problems 42 Experiences The cooperation with a school where the samples were collected was very helpful

351

Poland 14 N° General Data 1. type Regional biomonitoring study. Study population: 74 children, 5-14 year old living in the industrial region of Upper Silesia, Poland. 2 country Poland 3 title Assessment of early cytogenetic effects in children population exposed to lead and PAHs. 4. aim The aim of the project was to assess cytogenetic effects in PBL of children in relation to their exposure to polycyclic aromatic hydrocarbons and lead. 5. beginning date 1998 6. ending date 2000 7. contact person Dr Danuta Mielżyńska, Institute of Occupational Medicine and Environmental Health, 41-200 Sosnowiec, 13 Koscielna St., Poland [email protected] +48 32 266 08 85, ext. 271 8. initiator Institute of Occupational Medicine and Environmental Health, Sosnowiec, Poland 9. involved/responsible Institute of Occupational Medicine and Environmental Health, organisations Sosnowiec, Poland Silesian Medical Academy, Katowice, Poland Institute of Genetics of Polish Academy of Sciences, Poznań, Poland 10 budget available 160 000 PLZ 11. who is financing Polish Committee of Scientific Research (grant no. 4 P05D 088 14) Description of the population 12. total number of children 74 children 13. age groups and number of 5-14 year old persons in each group 14. inclusion criteria, Children living in two cities: Katowice and Sosnowiec, which are placed in the most polluted centre of the Silesia province. These children were participants of the previous project based on the examination of lead in blood level. Invitations send to 870 children, which were selected on the BPb level (high and low). 15. Sampling strategy According to inclusion criteria 16. time schedule of 1999 – 2000 in October to April; about 8 children/week biomonitoring 17. consent procedures Informed consent was written by children’s parents. The study was accepted by the Ethic Committee of Silesian Medical Academy 18. how is participation Results of individual measurements were offered to the parents. encouraged? The possibility of medical examination by paediatrician, laryngologist, neurologist was offered. Each participant was given money. Data collection 19. biomarkers of exposure Presence of the mutagenic substances in urine (Ames plate incorporation test, TA98+S9,YG1021+S9,YG1024+S9, YG1041+S9), 1-hydroxypyrene and cotinine in urine, Pb, Cd and Fe in blood,

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Poland 14 Mg, Ca, Cu, Zn and Fe in serum blood, aromatic DNA adducts. 20 biomarkers of effect Chromosomal aberrations (CA),sister chromatid exchange (SCE), micronuclei (MN), hematological blood indicators, general parameters of urine. 21 biomarkers of susceptibility Genes polymorphism: GSTM1, GSTM3, GSTT1, GSTP1, NAT2, EPHX Other data 22. environmental sampling Outdoor pollution: PM10 including heavy metals and B(a)P – month average for every month and place of sampling. The data were obtained from the Sanitary Epidemiological Station in Katowice. 23 lifestyle data Questionnaire: intake of home-grown vegetables; frequency of staying outside the industrial area, e.g. on holidays; frequency of playing outdoor 24 heath data Medical history, present health status; incidents of cancer diseases in family, results of medical examination 25 parental exposure Current smoking (frequency, amount and duration of smoking)

children exposure Localization of flat, additional sources of exposure at the dwelling site (i.e. industrial plants, heavy traffic); heating system; x-ray exposition during past 3 months. 26. medication 1. Intake of medication during last 6 months. 2. Current intake of drugs. 27 socio-economic factors Structure of the family, occupational exposure of parents, living conditions. Analysis and quality control procedures 28 intra/interlaboratory testing 29. external laboratory control Heavy metal laboratory is involved in external quality control. IOMEH has got the certificate for 1-HpU analysis in occupational and medical applications. 30 accuracy, limit of Data for all parameters are available on request. detection/quantification, reproducibility 31 data analysis (statistics, power calculations) 32 representativity Recruitment efficiency was about 8% (very poor). Data protection and availability 33 privacy legislation Samples and questionnaires were maintained by the responsible person (author of the project). Data are anonymous. 34 intellectual property rights No patents. 35. banking of biological Frozen DNA samples. samples Communication (individual level, group level, level (sub)population) 36 reporting results to public 1.Report on results was prepared for the Polish Committee of authority, to general public, Scientific Research. to participant 2. Some results were given to children’s parents. 3. Results were presented at several international and Polish conferences. 37 professionals involved, contacts between

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Poland 14 professionals and participants 38 role of media 39 public debate 40 consequences of external communication 41 Problems Bad requirement. 42 Experiences

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Poland 15 N° General Data 1. type Regional biomonitoring study. Study population: 120 children, 9 year old living in the industrial region of Upper Silesia, Poland, 30 children – control group 2 country Poland 3 title DNA damage in children environmentally exposed to lead with the assessment of individual susceptibility for toxic effect of lead, and genetic polymorphism of lead biotransformation and mechanism of DNA repair.. 4. aim The purpose of the project is to confirm lead's contribution in the development of cytogenetic damage and its impact on the efficacy of the DNA damage repair in children environmentally exposed to lead, taking into account genetic polymorphism of lead biotransformation and DNA damage repair mechanisms. 5. beginning date 2003 6. ending date 2006 7. contact person Dr Danuta Mielżyńska, Institute of Occupational Medicine and Environmental Health, 41-200 Sosnowiec, 13 Koscielna St., Poland [email protected] +48 32 266 08 85, ext. 271 8. initiator Institute of Occupational Medicine and Environmental Health, Sosnowiec, Poland 9. involved/responsible Institute of Occupational Medicine and Environmental Health, organisations Sosnowiec, Poland Institute of Oncology in Gliwice, Poland Medical Academy in Poznań, Poland 10 budget available 200 000 PLZ 11. who is financing Polish Committee of Scientific Research (grant no. 3 P05D 052 24) Description of the population 12. total number of children 120 exposed children , 30 control children 13. age groups and number of 9 year old persons in each group 14. inclusion criteria, Children living in the area with lead exposure. 15. Sampling strategy All 9 year old children living in this area. 16. time schedule of Winter period: 2003 - 2004 biomonitoring 17. consent procedures Informed consent will be written by children’s parents. The study was accepted by the Ethic Committee of IOMEH, Sosnowiec. 18. how is participation Results of individual measurements will be offered to the parents. encouraged? Children with higher level of BPb (>10 µg/dl) will be examined by physicians. Each participant will obtain some money and small gift. Data collection 19. biomarkers of exposure Presence of mutagenic substances in urine (Ames plate incorporation test, TA98+S9,YG1024+S9), 1-hydroxypyrene, cotinine and cadmium in urine, lead in blood, selenium in serum, aromatic DNA adducts. 20 biomarkers of effect Sister chromatid exchange (SCE), micronuclei, (MNBN), FISH (centromere probe), level of DNA damage and repair (SSB by

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Poland 15 comet assay), hematological blood indicators, general parameters of urine. 21 biomarkers of susceptibility Genes polymorphism: GSTM1, GSTT1, XRCC1, XRCC3, XPD, XPA, TDG, ALAD Other data 22. environmental sampling 8 hour PM10 samples will be collected at every day of blood and urine sampling, Pb, Cd and 9 PAHs will be determined. 23 lifestyle data Questionnaire: intake of home-grown vegetables; frequency of staying outside the industrial area, e.g. on holidays; frequency of playing outdoor 24 heath data Medical history, present health status; incidents of cancer diseases in family , results of medical examination. 25 parental exposure Current smoking (frequency, amount and duration of smoking).

42 Experiences

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Poland 16 N° General Data 1 type Regional biomonitoring study + survey The biomonitoring study involves 2 groups - Kindergarten children - Primary school children 2 country Poland 3 title Study on children exposure to lead 4 aim Biomonitoring of children living in the area of Miasteczko Śląskie in Poland has been conducted for 5 years from 1992- 1996. The aim of this study was to confirm the strong relationship between levels of emitted pollutants from zinc smelting works and the level of lead concentration in children's blood. The results of examinations were analyzed in the context of wide information on lifestyle, conditions of life, living standard of family and so on. 5 beginning date 1992 6 ending date 1996 7 contact person Mr. Mieczys ław Dumienski, Director of Foundation for Children “Miasteczko Śląskie” 8 initiator The foundation 9 involved/responsible Silesian Pediatric Center of Medical Academy organisations Institute of Occupational medicine in Łód ź 10 budget available 11 who is financing National and Regional Fund of Environment Protection and Water Management

Description of the population

12 total number of children (and parents) 6 000 children 13 age groups and number of persons in each Age groups: group - 6 years - 7-10 years 14 inclusion criteria, exclusion criteria Inclusion criteria are: Age children should be living in the area of Miasteczko Śląskie 15 sampling strategy A random stratified sampling scheme is followed. - Children are recruited via schools and kindergartens 16 time schedule of biomonitoring - Children were sampled in the period from 1992 – 1996 17 consent procedures 18 how is participation encouraged? - Schools were offered an educational package on environment and health. Data collection

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Poland 16 19 biomarkers of exposure - Lead in cord blood. 20 biomarkers of effect - Biometry, analysis of data in relation to location, sex, age. 21 biomarkers of susceptibility - Other data 22 environmental sampling Analysis of study results in the context of emission from zinc smelting works in Miasteczko Śląskie 23 lifestyle data Hygiene, smoking by parents, type of food (meat, milk, vegetables grown in the area), tested food, fruits, fruits grown in the own gardens, juices, water (through filter or not) 24 health data 25 parental exposure Contact with metals by parents work at present and in the past, metals processing in the house – private enterprise 26 medication 27 socio-economic factors Location of house, level of education of parents, material condition of the family, child’s vacation – out of the area or not, way of spending leisure time, use of the child for cleaning work at home, Analysis and quality control procedures 28 intra/interlaboratory testing Samples were analysed in The Central Laboratory in Miasteczko Śląskie by the spectrophotometer AAS (SOLAAR 939 QZ from Great Britain) with graphite cuvette by so-called micro- method – WHO standard. The laboratory has the national accreditation

29 external laboratory control CDC in Atlanta, Georgia 30 accuracy, limit of detection/quantification, Data for all parameters are available on reproducibility request 31 data analysis (statistics, power Statistical analysis was performed according to calculations) a stratified plan 32 representativity Recruitment efficiency was monitored. Non- responder analysis is ongoing. Data protection and availability 33 privacy legislation Samples and questionnaires are maintained by the responsible medical doctor and subsequently anonymised in order to maintain confidentiality. Measures are taken to ensure confidentiality and security of the data. Ethical advice has been taken to determine the

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Poland 16 maximum volume of blood samples that may be taken in order to minimise distress to the participant. 34 intellectual property rights No patents. Data were published upon approval of the steering group. The results of statistical analysis and conclusions were presented in publications by the Foundation. 35 banking of biological samples No long term storage is foreseen

Communication (individual level, group level, level (sub)population )

36 reporting results to public authority, to Each year the Foundation is publishing the general public, to participant report of its activities in the area of children biomonitoring. Results of the studies are communicated to the scientific community and also to the public

37 professionals involved , contacts between A steering group including scientists for the professionals and participants entire program includes professors from the Silesian Medical Academy

38 role of media Media are occasionally invited for the presentation of the results of study. 39 public debate Conferences organized in the subject are the occasion for discussion between stakeholders. 40 consequences of external communication Pollution in surroundings of industries are hot- topics, therefore communication needs to be prepared carefully. A communication program is developed by professionals in the field of communication and sociology. 41 Problems

The results of analysis show, that the levels of lead concentration in blood are higher in boys than in girls as well as higher is percentage of exceeded admissible levels of lead concentration in blood. There is a tendency of falling down of the lead concentration level on blood over the period of the study. 42 Experiences

Lead toxicity is deceitful for children, because it causes damage of cognitive capacity already at low concentrations treated as safe and not giving any symptoms of disease. While examining single cases they cannot be noticed. In some areas children are equally exposed to lead impact and to other environmental factors. The toxicity effect does not to be noticed or it can be considered as normal, typical for a given group – putting our vigilance to sleep.

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Poland 17 N° General Data 1 type Regional biomonitoring study + survey The biomonitoring study involves 2 groups - Kindergarten children - Primary school children 2 country Poland

3 title Study on children exposure to lead 4 aim Biomonitoring of children living in the area of Legnica- G łogów Copper Basin in Poland has been conducted for 10 years from 1991-1999. The aim of this study was to confirm the strong relationship between levels of emitted pollutants from the copper industry and the level of lead concentration in children's blood. The results of examinations were the basis for organization of prophylactic-rehabilitation program including: - tours in ecologically clean places for these groups of children in whom lead level in blood was exceeding admissible value. - supplying mineral water rich in calcium, magnesium and iron - intensive rehabilitation

5 beginning date 1991 6 ending date 1999 7 contact person Prof. Dr. Halina Struga ła-S ławik Fundation for Children form Legnica Copper Basin 8 initiator 9 involved/responsible organisations 10 budget available 11 who is financing

Description of the population

12 total number of children (and parents) 77 000 children

13 age groups and number of persons in each Age groups: group - 4-6 years old children - 7-12 old children

14 inclusion criteria, exclusion criteria Inclusion criteria are: Age children should be living in the area of G łogów and Legnica 15 sampling strategy A random stratified sampling scheme is followed. - Children are recruited via schools and

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Poland 17 kindergartens 16 time schedule of biomonitoring - Children were sampled in the period from 1991 – 1999 17 consent procedures 18 how is participation encouraged? - Results of individual measurements and of the entire study were the basis of sending children for prophylactic- rehabilitation tours - Schools were offered an educational package on environment and health. Data collection 19 biomarkers of exposure - Lead in cord blood. 20 biomarkers of effect - Biometry, analysis of data in relation to location, sex, age. 21 biomarkers of susceptibility - Other data

22 environmental sampling Analysis of study results in the context of emission from Copper Smelter of Legnica and G łogów 23 lifestyle data 24 health data 25 parental exposure 26 medication 27 socio-economic factors Analysis and quality control procedures 28 intra/interlaboratory testing Samples were analysed in The Foundation Laboratory by the absorption atomic spectroscopy method on the equipment Hitachi Z 8200. 29 external laboratory control 30 accuracy, limit of detection/quantification, Data for all parameters are available on reproducibility request

31 data analysis (statistics, power Statistical analysis was performed according to calculations) a stratified plan

32 representativity Recruitment efficiency was monitored. Non- responder analysis is ongoing. Data protection and availability 33 privacy legislation Samples and questionnaires are maintained by the responsible medical doctor and subsequently anonymised in order to maintain confidentiality under secure conditions in accordance with the 1995 EC Data Protection Directive and data protection legislation. Measures are taken to ensure confidentiality and security of the data. Ethical advice has been taken to determine the maximum volume of blood samples that may

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Poland 17 be taken in order to minimise distress to the participant. 34 intellectual property rights No patents. Data were published upon approval of the steering group. The results of statistical analysis and conclusions were presented at the yearly conference organized by the Foundation. 35 banking of biological samples No long term storage is foreseen Communication (individual level, group level, level (sub)population ) 36 reporting results to public authority, to Each year the Foundation is organizing general public, to participant conference on the problems of children health and environment. Various cases are presented at the conference concerning i.a. biomonitoring studies conducted in various regions of the country. Results of the studies are communicated to the scientific community and also to the public

37 professionals involved , contacts between A steering group including scientists for the professionals and participants entire program GP’s and teachers are the in-between professionals. 38 role of media Media are invited for the conference each year.

39 public debate The yearly conference is the occasion for discussion between stakeholders. 40 consequences of external communication Pollution in surroundings of industries are hot- topics, therefore communication needs to be prepared carefully. A communication program is developed by professionals in the field of communication and sociology. 41 Problems

A lot of energy has to be spent in communication for organizing participation of different stakeholders. Collaboration with existing initiatives such as the blood bank and educational centres is highly recommended. The educational package was very helpful to involve schools in the encouragement of their students.

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Poland 18

General data type Regional biomonitoring study, involves children, both sexes, age 7-12 country Poland title Biomonitoring of the damage of genetic matierial in the inhabitants of Silesia aim Upper Silesia, a region located on the South of Poland is inhabited by 5 mln persons and the core of the region - big urban agglomeration is also saturated with thousands industrial installations including coal mines, chemical and coke factories, steel mills, smelters and also the biggest steel plant are located there. Altogether the industry, very densely inhabited area which emites to the ambient air products of incomplete combustion containing carcinogenic compounds. Among other pollutants, the group of polycyclic aromatic hydrocarbons is widespread in the ambient air. Many compounds belonging to this group are known carcinogens in animal studies, many can also bind covalently to DNA. We studied the level of PAH-DNA adducts in the inhabitants of Silesia, mainly adults, but we included also the group of children inhabiting this region. The analyses were done from WBCs from peripheral blood. beginning date 1990 ending date 1993 contact person Dr Ewa Grzybowska, Dept. Of Tumour Biology, Centre of Oncology-Maria Sklodowska memorial Institute, PL44-101 Gliwice, Poland initiator Centre of Oncology involved/responsible Centre of Oncology in Gliwice, Poland, Institute of Occupational Medicine, organisations Helsinki, Finland budget available who is financing Institute of Occupational Medicine, Helsinki, Finland

Description of the population total number of children 35 age groups and number one group, 7-12 years old, both sexes of persons in each group inclusion criteria, Inclusion Criteria Are: Written informed consent, Age, Parents and children exclusion criteria should be living in the area for 5 years. Exclusion criteria are: cancer, chronic disease lasting more than three months, X-ray examination within the last three months, constant medication

sampling strategy Children were recruited via pediatric outpatient clinic time schedule of Sampling was done between 1990-1993 biomonitoring consent procedures Parents: written informed consent how is participation Results of the measurements should improve the quality of environment. encouraged? In Silesia it has always been important issue and parents are usually conrned about that.

Data collection biomarkers of exposure aromatic DNA adducts measured in peripheral white blood cells

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Poland 18 biomarkers of effect biomarkers of susceptibility Other data environmental sampling Measurement of PAHs levels in the ambient air in the region lifestyle data Questionnaires on the smoking status of parents health data Information about chronic diseases, cancer parental exposure medication socio-economic factors

Analysis and quality control procedures intra/interlaboratory The analyses were done on coded samples together with samples from testing other volunteers to avoid bias external laboratory The laboratory participated in the international control system control accuracy, limit of The analyses were done twice for each child in condition there was detection/quantification, enough DNA for that. Data are available on request reproducibility data analysis (statistics, The goup studied was rather small, so that only basic statistical analysis power calculations) was done representativity The recruitment was efficient

Data protection and availability privacy legislation Samples and questionnaires are maintained by the responsible doctor and subsequently anonymised in order to maintain confidentiality intellectual property No patents, Data were published rights banking of biological All samples were used for analyses samples Communication (individual level, group level, level (sub)population ) reporting results to The results were not reported to general public public authority, to general public, to participant professionals involved, Medical doctors, biologists doing the analyses contacts between professionals and participants role of media public debate Occasional symposia were organized consequences of external communication

Problems We collected only 2 ml of blood from each child and sometimes it was not enough to do two measurements of DNA adducts for each volunteer

Experiences We learned that aromatic DNA adducts connected with the environmental pollution are present as well in children as in adultd

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Portugal

Short summary to the questionnaires:

1. VALORSUL Environmental Health Survey Program.

The program evaluates exposure and health effects in the area in the vicinity of municipal solid waste incinerator north of Lisbon. The program started in 1999 and is ongoing. Several age groups are studied, including an annual sample of 280 children, newborns and children 12-72 months. Exposure is assessed measuring lead in maternal ands cord blood, dioxins, furans and PCB’s and endocrine modulator activity (CALUX screen) in breast milk. Questionnaires are used to collect information on many relevant aspects. Descriptive information on pregna\ncy and the child’s biometry and illnesses are recorded as health indicators. A 6 month study update and an annual ‘Global Report’ are issued.

2. MEIA SERRA Environmental Health Survey Program.

The program evaluates exposure and health effects in the area in the vicinity of municipal slaughterhouse and hospital solid waste incinerator at Madeira. The program started in 2002 and is ongoing. Several age groups are studied, including a bi-annual sample of 280 children, newborns and children 12-72 months. Exposure is assessed measuring lead in maternal and cord blood, dioxins, furans and PCB’s and endocrine modulator activity (CALUX screen) in breast milk. Questionnaires are used to collect information on many relevant aspects. Descriptive information on pregnancy and the child’s biometry and illnesses are recorded as health indicators. A 6 month study update is communiucated and an annual ‘Global Report’ will be issued.

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Portugal 01 General Data 1. Type − Regional (Metropolitan Area of North Lisbon - PORTUGAL) − Environmental Health Survey Program − Relatively to children, the Program involves: 1. Biomonitoring of 2 risk groups: a. Newborns and their mothers b. Children 12-72 months 2. Analyzing of epidemiological data of specific public health indicators (for children or different age groups including children): a. Cancer incidence and cancer mortality b. Infant and perinatal mortality c. Congenital malformation incidence d. Low birthweight incidence e. Spontaneous abortion incidence 3. Obtaining data on asthma incidence and smoking habits from young students (12-18 years) 2. Country PORTUGAL 3. Title Environmental Health Survey Program relative to the VALORSUL Municipal Solid Waste (MSW) Incinerator Facility

Acronym ProVEpA (from Portuguese title: Programa de Vigilância Epidemiológica Ambiental) 4. Aim 1. To contribute to the safeguard of the Public Health by monitoring and surveying human health in the area of influence of the incineration facility. Ultimately, a. to determine whether living/working in the vicinity of the MSW incinerator increase both human exposure to the most critical pollutants potentially emitted during incineration process and the risk of the most relevant health problems related with those pollutants; b. to evaluate trends, following the evolution of human exposure and relevant potential adverse health effects during lifetime incinerator operation, starting before the beginning of operation of the incineration plant; c. whenever justified, to provide conclusions and to elaborate recommendations aiming the implementation and adoption of corrective measures (preventive, legislative, educational) intended to be needed. 2. To contribute for the development of scientifically based methodologies for the risk evaluation and monitoring relatively to the environmental impact of MSW facilities on the health of the population residing and/or working in their vicinity. 5. Beginning date Ongoing activities started at 1999/2000 6. Ending date Ongoing activities 7. Contact person Prof. Dr. M. Fátima Reis Institute of Preventive Medicine – Faculty of Medicine of Lisbon Av. Prof. Egas Moniz 1649-028 LISBOA PORTUGAL [email protected] or [email protected] +351 21 795 7409 or +351 21 797 2037 8. Initiator VALORSUL – Valorização e Tratamento de Resíduos Sólidos Urbanos da

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Portugal 01 Área Metropolitana de Lisboa Norte, responsible, by contract, of the Environmental Health Survey Program to be developed under the scientific and thecnological responsability of the Institute of Preventive Medicine, Faculty of Medicine of Lisbon 9. • Maternidade Dr. Alfredo da Costa (Lisboa) Involved/responsible • Clínica Universitária de Pediatria – Hospital de Santa Maria (Lisboa) organisations • Hospital Dona Estefânia (Lisboa) • Centro Regional de Saúde Pública de Lisboa e Vale do Tejo • Serviço de Obstetrícia e Ginecologia – Hospital de Santa Maria (Lisboa) 10. Budget available 11. Who is financing Multi-Municipal Company: VALORSUL – Valorização e Tratamento de Resíduos Sólidos Urbanos da Área Metropolitana de Lisboa Norte Description of the population 12. Total number of Every year, ≈ 280 children are involved in biomonitoring programs; in the children asthma and smoking habits studies, usually more than 1000 young students are included 13. Age groups and 1. Children included in biomonitoring programs: ≈ number of persons a. Newborns and their mothers: 80x2 (*) newborn/mother pairs every year in each group b. Children 12-72 months: ≈ 60x2 every year 2. In the asthma and smoking habits study, ≥2x600 young students (12-18 years old) are monitored every year. 3. In the analysis of epidemiological data of specific public health indicators, the whole population from the study areas (*) is included.

(*) – The development of the Environmental Health Survey Program considers two study areas: a potentially exposed area (inside the circle of 5 km around MSW incineration facility) and an outside area. Thus, the number of persons included in the monitoring groups is multiplied by two, since they come from both areas. 14. Inclusion criteria, General inclusion criteria are (irrespective of the study type): exclusion criteria − Distance between residence/working place and MSW incinerator − Written informed consent − Age − Primiparae women (or last child for more than three years). 15. Sampling strategy Convenience samples are recruited as follows: − Mother-newborn pairs are recruited in the Central Maternity of the study areas − Children are recruited via schools and/or during hospitalization for compatible pathology. − Young students are recruited via schools. 16. Time schedule of − Mothers-newborns are sampled every year, along the year, until the biomonitoring minimum required number of pairs is obtained − Children are sampled every year, along the year, until the minimum required number of children is obtained − Young students are sampled every year in the period April – June. 17. Consent − Mothers: written informed consent − procedures Child and 1 parent: written informed consent 18. How is − Results of individual clinical measurements are offered to the participation participants 367

Portugal 01 participation − Children are offered a very (very) small present. Results of individual encouraged? clinical measurements are offered to the participant’s legal representing. − Results of the entire study are made available through local and national media and other ways accessible to the participants Data collection 19. Biomarkers of − Lead in maternal and cord blood. − exposure Dioxins and furans (and PCBs, for a few samples) in breast milk collected 1 month after delivery (GC-MS). − Dioxin-activity (CALUX) in breast milk collected 1 month after delivery. 20. Biomarkers of − Biometry, Apgar score, physical examination. − effect Follow-up studies with children: neurological and neuropsychological development tests for the children with blood lead levels outside pre- defined limits − Questionnaire on asthma 21. Biomarkers of − Iron-status in blood susceptibility Other data 22. Environmental Questionnaires on contaminant intake via alternative sources (mother- newborn pairs and children) are administered. sampling In a small subset of local food samples (eggs, cow-milk and sheep-milk), dioxin-activity has been monitored. In a small subset of mother-newborn pairs, indoor dust samples have been analyzed and dioxin-activity has been monitored. 23. Lifestyle data − Mother: a. Dietary information on recent fat intake. b. Active/passive smoking habits (starting age, amount, frequency, exposure) c. Contact with chemicals d. Drug-use (frequency, type) e. Professional activity f. Hobbies g. Alcohol use (frequency, amount)

3. Newborn: Nutrition of the breastfed baby 24. Health data − Duration of the pregnancy, biometry, Apgar score, medical history, breastfeeding, parity − Biometry, respiratory problems, illnesses in the past 2 months, use of medicines 25. Parental exposure − Smoking during pregnancy, medication during pregnancy. − Asthma or allergy in the family of young students. − Children home environment: traffic ‘pressure’, construction works, decoration works, heating, use of pesticides in house/garden. 26. Medication Use of medication during pregnancy. 27. Socio-economic Structure of the family, educational level of parents, home-owning, factors educational level of child Analysis and quality control procedures 28. Intra/interlaboratory − Inspection has been made of not yet accredited laboratories for testing analytical performance checking relative to the specific analyses used for monitoring. − Written descriptions of quality assurance programs used in the contracting analytical laboratories are available. Documented routine internal quality control procedures are available for the contracting analytical laboratories. − Critical phases in sampling procedures have been identified (collection,

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Portugal 01 identification, transport, storage and preparation of the samples) and written protocols as well as commented video-clips have been prepared and made available for the staff involved. 29. External laboratory − Documented national and international interlaboratory quality control control studies are available for the contracting analytical laboratories. − Interlaboratory assessment for dioxin-activity (CALUX) − Specific analytical strategies have been adopted (concerning dioxin and dioxin-like compounds) in order to promote interlaboratory and/or intertechnique (CALUX vs GC-MS) testing. 30. Accuracy, limit of detection/quantifica Data for all parameters are available on request tion, reproducibility 31. Data analysis − Power calculations were based on previous biomonitoring studies. − (statistics, power Adequate statistical analysis is performed according to the specific variables involved. calculations) 32. Representativity − Convenience samples are used in all biomonitoring programs. − Whenever justified, recruitment efficiency is monitored. − Non-responder analysis is made. Data protection and availability

33. Privacy legislation − Individuals are coded and data from individual sample analysis and questionnaires are integrated in specific databases, maintained by the responsible of the Program, where closed tables are only accessed by password, in order to maintain confidentiality under secure conditions in accordance with data protection legislation. − To ensure confidentiality and security of the data, only the codes are used to identify individuals, except for the situations where follow-up is required. − In the analysis of time series of health data, variables such as names and addresses are not known. − Data from rare cases and/or individuals from areas with reduced population and/or dimension are grouped in order to avoid individual identification. 34. Intellectual − No patents. − property rights Data will be published after being communicated to VALORSUL (in order to be previously informed). 35. Banking of A few blood and milk samples will be kept frozen biological samples Communication [individual level, group level, level (sub) population] 36. Reporting results − Every six-month period, VALORSUL is informed on the to public authority, progress/problems of the Program. − After the final recruitment and analyses, the results of to general public, biomonitoring are reported and communicated to VALORSUL, to participant scientific community (preferentially by publication in peer-reviewed journals), local health authorities, and the general public, namely the volunteer participants. − The participants are given individual results from all the clinical parameters measured to evaluate their health status. Individual results from the main study variables (e.g., blood lead levels or breast milk levels of dioxins) are given to the participants only if those results are susceptible of concern from a public health perspective. In any case, participants are always asked to present (to communicate) all their analytical results to the respective

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Portugal 01 medical doctor. − A VALORSUL global Report is prepared every year and supplied to several groups and individuals. It is also available under request (Portuguese language). 37. Professionals − A group including health and environment professionals involved (physicians, pediatricians, chemists, epidemiologists, statisticians, psychologists, teachers, nurses and technicians) is involved in the entire program. Contacts between − Depending on the characteristics of their activities, pediatricians, professionals and teachers, nurses and/or technicians are the in-between participants professionals relatively to participants. 38. Role of media − Because of the characteristics and scale of the Program and of public concern on pollution problems, media attention is significant. − Whenever results were made available, the Program has been given attention in all media (TV, local and national Newspapers and Radio). 39. Public debate National and local symposia or technical meetings have been organized by VALORSUL initiative, which included debates between different stakeholders. 40. Consequences of − Greater incentive to participation among individuals external residing/working in the surroundings of the incineration plant. − Higher interest, from the general public, towards the problems communication under investigation in the Program. 41. Problems − Collection of blood samples (either for children measurements or adult determinations, mainly of blood levels of dioxins) is a significant disincentive to participation. International development of less- or non-invasive sampling techniques would be crucial for the succeeding of future large-scale biomonitoring studies. Breast milk monitoring for evaluation of prenatal (in-uterus) and perinatal chemical exposure mainly to dioxin and related compounds (using mixed analytical strategies, including bioassay for screening and instrumental methodologies for confirmation), as well as cord blood monitoring for prenatal heavy metals exposure evaluation, which use less- or non-invasive sampling techniques, would allow for more consistent data on trends over time and would provide useful information for guiding exposure reduction efforts. − Including participants living in the area of study (surroundings of the incinerator) for less than 5 years may introduce some bias. Excluding those participants may lead to insufficient number of volunteers for these areas. − Recruitment of a pre-defined number of mother-newborn pairs in a pre-defined period is risky. Health professionals complain because of the needed involvement at the delivery and it is not rare that women satisfying inclusion criteria are “lost”. − Offering a gift is not allowed, due to ethical reasons (non-volunteer, induced participation!). That implies lower participation level. 42. Experiences − It is mandatory creating a net of focal points among local health, environment and education professionals to motivate self- involvement and individual volunteer’s participation from each local community. Local sessions, in different communities, conducted by the respective focal point (previously motivated) seem to be the best strategy to organize participation of different stakeholders. − Collaboration with blood bank is highly recommended and is now being used. − Feedback information has been proved to be very helpful to involve Professionals from the health, environment and education

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Portugal 01 fields in the development of their specific activities needed for the development of the Program. − An introductory letter, from the Institute of Preventive Medicine – Faculty of Medicine of Lisbon, helped persuade schools, Maternity and other health institutions to collaborate.

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Portugal 02 General Data 1. Type − Regional (Meia Serra – MADEIRA ISLAND – PORTUGAL) − Environmental Health Survey Program − Relatively to children, the Program involves: 1 Biomonitoring of 2 risk groups: a. Newborns and their mothers b. Children 12-72 months 2 Analyzing of epidemiological data of specific public health indicators (for children or different age groups including children): c. Cancer incidence and cancer mortality d. Infant and perinatal mortality e. Congenital malformation incidence f. Low birthweight incidence g. Spontaneous abortion incidence 3 Obtaining data on asthma incidence and smoking habits from young students (12-18 years) 2. Country PORTUGAL 3. Title Environmental Health Survey Program relative to the Meia Serra Municipal, Slaughterhouse and Hospital Solid Waste (MSHSW) Incinerator Facility

Acronym ProVEpA-MS (from Portuguese title: Programa de Vigilância Epidemiológica Ambiental da Meia Serra) 4. Aim 1 To contribute to the safeguard of the Public Health by monitoring and surveying human health in the area of influence of the incineration facility. Ultimately, a. to determine whether living/working in the vicinity of the MSHSW incinerator increase both human exposure to the most critical pollutants potentially emitted during incineration process and the risk of the most relevant health problems related with those pollutants; b. to evaluate trends, following the evolution of human exposure and relevant potential adverse health effects during lifetime incinerator operation, starting before the beginning of operation of the incineration plant; c. whenever justified, to provide conclusions and to elaborate recommendations aiming the implementation and adoption of corrective measures (preventive, legislative, educational) intended to be needed. 2 To contribute for the development of scientifically based methodologies for the risk evaluation and monitoring relatively to the environmental impact of MSW facilities on the health of the population residing and/or working in their vicinity. 5. Beginning date Ongoing activities started at 2002 6. Ending date Ongoing activities 7. Contact person Prof. Dr. M. Fátima Reis Institute of Preventive Medicine – Faculty of Medicine of Lisbon Av. Prof. Egas Moniz 1649-028 LISBOA PORTUGAL [email protected] or [email protected] +351 21 795 7409 or +351 21 797 2037

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Portugal 02 8. Initiator Regional Department of Environment and Natural Resources – Autonomous Region of Madeira (SRARN – RAM), responsible, by contract, of the Environmental Health Survey Program to be developed under the scientific and thecnological responsability of the Institute of Preventive Medicine, Faculty of Medicine of Lisbon 9. Involved/responsible − Direcção Regional de Saúde Pública organisations − Centro Hospitalar do Funchal − Universidade da Madeira − Centros de Saúde de Camacha e Estreito de Câmara de Lobos − Laboratório de Saúde Pública 10. Budget available 11. Who is financing Regional Department of Environment and Natural Resources – Autonomous Region of Madeira and EU Cohesion Fund (?) Description of the population 12. Total number of Every two years, ≈ 280 children are involved in biomonitoring programs; in children the asthma and smoking habits studies, usually around 1400 young students are included every year 13. Age groups and 1 Children included in biomonitoring programs: number of persons a. Newborns and their mothers: ≈ 80x2 (*) newborn/mother pairs every in each group two years b. Children 12-72 months: ≈ 60x2 every two years 2 In the asthma and smoking habits study, ≥2x600 young students (12- 18 years old) are monitored every year. 3 In the analysis of epidemiological data of specific public health indicators, the whole population from the study areas (*) is included.

(*) – The development of the Environmental Health Survey Program considers two study areas: a potentially exposed area (inside the circle of 3 km around MSHSW incineration facility) and an outside area. Thus, the number of persons included in the monitoring groups is multiplied by two, since they come from both areas. 14. Inclusion criteria, General inclusion criteria are (irrespective of the study type): exclusion criteria − Distance between residence/working place and MSHSW incinerator − Written informed consent − Age − Primiparae women (or last child for more than three years). 15. Sampling strategy Convenience samples are recruited as follows: 1 Mother-newborn pairs are recruited in the Central Maternity of the study areas 2 Children are recruited via schools, local communities and/or during hospitalization for compatible pathology. 3 Young students are recruited via schools. 16. Time schedule of 1 Mothers-newborns are sampled every two years, along this period, biomonitoring until the minimum required number of pairs is obtained 2 Children are sampled every two years, along this period, until the minimum required number of children is obtained 3 Young students are sampled every year in the period February – March. 17. Consent 1 Mothers: written informed consent

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Portugal 02 procedures 2 Child and 1 parent: written informed consent 18. How is 1 Results of individual clinical measurements are offered to the participation participants encouraged? 2 Results of individual clinical measurements are offered to the participant’s legal representing. 3 Results of the entire study are made available through local and national media and other ways accessible to the participants Data collection 19. Biomarkers of 1 Lead in maternal and cord blood. exposure 2 Dioxins and furans (and PCBs, for a few samples) in breast milk collected 1 month after delivery (GC-MS). 3 Dioxin-activity (CALUX) in breast milk collected 1 month after delivery. 20. Biomarkers of 1. Biometry, Apgar score, physical examination. effect 2. Follow-up studies with children: neurological and neuropsychological development tests for the children with blood lead levels outside pre- defined limits 3. Questionnaire on asthma 21. Biomarkers of 1. Iron-status in blood susceptibility Other data 22. Environmental Questionnaires on contaminant intake via alternative sources (mother- sampling newborn pairs and children) are administered. m. In a small subset of local food samples (eggs, cow-milk and sheep-milk), dioxin-activity has been monitored. In a small subset of mother-newborn pairs, indoor dust samples will be analyzed and dioxin-activity will be monitored. 23. Lifestyle data 1 Mother: a. Dietary information on recent fat intake. b. Active/passive smoking habits (starting age, amount, frequency, exposure) c. Contact with chemicals d. Drug-use (frequency, type) e. Professional activity f. Hobbies g. Alcohol use (frequency, amount)

2 Newborn: Nutrition of the breastfed baby 24. Health data 1 Duration of the pregnancy, biometry, Apgar score, medical history, breastfeeding, parity 2 Biometry, respiratory problems, illnesses in the past 2 months, use of medicines 25. Parental exposure 1 Smoking during pregnancy, medication during pregnancy. 2 Asthma or allergy in the family of young students. 3 Children home environment: traffic ‘pressure’, construction works, decoration works, heating, use of pesticides in house/garden. 26. Medication Use of medication during pregnancy. 27. Socio-economic Structure of the family, educational level of parents, home-owning, factors educational level of child Analysis and quality control procedures 28. Intra/interlaboratory − Inspection has been made of not yet accredited laboratories for testing analytical performance checking relative to the specific analyses df it i 374

Portugal 02 used for monitoring. − Written descriptions of quality assurance programs used in the contracting analytical laboratories are available. Documented routine internal quality control procedures are available for the contracting analytical laboratories. − Critical phases in sampling procedures have been identified (collection, identification, transport, storage and preparation of the samples) and written protocols as well as commented video-clips have been prepared and made available for the staff involved. 29. External laboratory − Documented national and international interlaboratory quality control control studies are available for the contracting analytical laboratories. − Interlaboratory assessment for dioxin-activity (CALUX) − Specific analytical strategies have been adopted (concerning dioxin and dioxin-like compounds) in order to promote interlaboratory and/or intertechnique (CALUX vs GC-MS) testing. 30. Accuracy, limit of detection/quantifica Data for all parameters are available on request tion, reproducibility 31. Data analysis − Power calculations were based on previous biomonitoring studies. (statistics, power − Adequate statistical analysis is performed according to the specific calculations) variables involved. 32. Representativity − Convenience samples are used in all biomonitoring programs. − Whenever justified, recruitment efficiency is monitored. − Non-responder analysis is made. Data protection and availability

33. Privacy legislation − Individuals are coded and data from individual sample analysis and questionnaires are integrated in specific databases, maintained by the responsible of the Program, where closed tables are only accessed by password, in order to maintain confidentiality under secure conditions in accordance with data protection legislation. − To ensure confidentiality and security of the data, only the codes are used to identify individuals, except for the situations where follow-up is required. − In the analysis of time series of health data, variables such as names and addresses are not known. − Data from rare cases and/or individuals from areas with reduced population and/or dimension are grouped in order to avoid individual identification. 34. Intellectual − No patents. property rights − Data will be published after being communicated to (SRARN – RAM) (in order to be previously informed). 35. Banking of A few blood and milk samples will be kept frozen biological samples Communication [individual level, group level, level (sub) population] 36. Reporting results − Every six-month period, SRARN – RAM is informed on the to public authority, progress/problems of the Program. − to general public, After the final recruitment and analyses, the results of biomonitoring are reported and communicated to SRARN – RAM, scientific to participant community (preferentially by publication in peer-reviewed journals), local health authorities, general public, and volunteer participants. − The participants are given individual results from all the clinical parameters measured to evaluate their health status. Individual

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Portugal 02 results from the main study variables (e.g., blood lead levels or breast milk levels of dioxins) are given to the participants only if those results are susceptible of concern from a public health perspective. In any case, participants are always asked to present (to communicate) all their analytical results to the respective medical doctor. − A SRARN – RAM global Report will be prepared every year and supplied to several groups and individuals. It will also be available under request (Portuguese language). 37. Professionals − A group including health and environment professionals (physicians, involved pediatricians, chemists, epidemiologists, statisticians, psychologists, teachers, nurses and technicians) is involved in the entire program. − Depending on the characteristics of their activities, pediatricians, Contacts between teachers, nurses and/or technicians are the in-between professionals professionals and relatively to participants. participants 38. Role of media Because of the characteristics and scale of the Program and of public concern on pollution problems, media attention is significant. 39. Public debate Local symposia or technical meetings have been organized by SRARN – RAM initiative, which included debates between different stakeholders. 40. Consequences of − Greater incentive to participation among individuals residing/working external in the surroundings of the incineration plant. − communication Higher interest, from the general public, towards the problems under investigation in the Program. 41. Problems − Collection of blood samples (either for children measurements or adult determinations, mainly of blood levels of dioxins) is a significant disincentive to participation. International development of less- or non-invasive sampling techniques would be crucial for the succeeding of future large-scale biomonitoring studies. Breast milk monitoring for evaluation of prenatal (in-uterus) and perinatal chemical exposure mainly to dioxin and related compounds (using mixed analytical strategies, including bioassay for screening and instrumental methodologies for confirmation), as well as cord blood monitoring for prenatal heavy metals exposure evaluation, which use less- or non-invasive sampling techniques, would allow for more consistent data on trends over time and would provide useful information for guiding exposure reduction efforts. − Including participants living in the area of study (surroundings of the incinerator) for less than 5 years may introduce some bias. Excluding those participants may lead to insufficient number of volunteers for these areas. − Recruitment of a pre-defined number of mother-newborn pairs in a pre-defined period is risky, having in mind the specific characteristics of age for the population in the area of study. Yet, health professionals complain because of the needed involvement at the delivery and it is not rare that women satisfying inclusion criteria can be “lost”. − Offering a gift is not allowed, due to ethical reasons (non-volunteer, induced participation!). That eventually will imply lower participation level. 42. Experiences − It is mandatory creating a net of focal points among local health, environment and education professionals to motivate self- involvement and individual volunteer’s participation from each local community. Local sessions, in different communities, conducted by the respective focal point (previously motivated) seem to be the best strategy to organize participation of different stakeholders. − Feedback information has been proved to be very helpful to involve Professionals from the health, environment and education fields in the development of their specific activities needed for the

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Portugal 02 development of the Program. − An introductory letter, from the Institute of Preventive Medicine – Faculty of Medicine of Lisbon together with Regional Department of Health, helped persuade schools, Maternity and other health centers to collaborate.

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Slovakia

Slovakia 01 General information 1 type International prospective longitudinal survey. This was the first geographically-based population multicentre study commercing in pregnancy and continuing until age of 15 2 country United Kingdom, Isle of Mann, Czech Republik, Slovak Republik, Ukraine, Russia 3 title The European Longitudinal Study of Pregnancy & Childhood /ELSPAC/ 4 aims l. To determine wether certain biological, enviromental, social, psychological and social factors are associated with survival, health and development of the fetus, infant and child and to asses wether the same factors appear to be influential to a similar degree in each participating countries 2. The study was originally designed to identify strategies wich may improve health of children and their mothers and to test them using appropriate research methods. 5 beginning 1993 6 ending The study is continuing 7 contact persons Slovak Republic office Central survey office PhMr Ida Válkyová prof. Jean Golding National Public Health Institute of Child Health of the University of Institute,831 01 Bratislava Bristol, 24 Tyndall Avenue, Brustol BS8 1 TQ Trnavská 24 Fax: 44 117 928 5010, Tel: 44 117 928 5099

Dr Lubomír Kukla Medical Faculty of Masaryk University Department of Preventive an Social Pediatrics 631 00 Brno, Bieblova 16. Czech Republic 8 initiator WHO Regional Office for Europe

9 involved Czech Rep.- Medical Faculty of Masaryk University Department of organisations Preventive and Social Pediatrics 613 00 Brno, Bieblova 16

Isle of Man - Isle of Man Postgraduate Medical Centre, Nobles Hospital, Westmoreland Road, Douglas IMI 4QA

Slovak Rep. National Public Health Institute, 831 01 Bratislava, Trnavska cesta 24.

Russia - Russian Academy of Medical Sciences, Vorontzovo pole St. 12 103 064 Moscow

United Kingdom /Avon/ - Institute of Child Health, 24 Tyndall Avenue, Bristolí

Ukraine - Kiev Institute of Paediatrics, Obstetrics & Gynaecology, Ukrainian

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Slovakia 01 Academy of Medical Science, Manuilslsky str 8 252050, Kiev 50

10 budget available 30 000 Eur /y 11 who is financing MoH Description of the population 12 total number 30 000 of children 13 age groups The group is followed up longitudinally from the beginnig of pregnancy 14 inclusion The population is comming from the defined geographical region. criteria Written informed consent 15 sampling The mothers were contacted as early in pregnancy as possible strategy Both livebirths and fetal deaths occurring after 20 weeks gestation to residents of the area are included Mother resident in the area at time of delivery were followed up as far as it was possible The children are followed up until the age of 15 years Data collection use self-completion questionnaires filled in by the mother and her partner and linked to information obtainable from health records All informations are confidential All study centres asked the same questions in the same way Comparative analyses were done by Bristol - results are available for all centres 16 time schedule project is continuig - some results were published in periodicals and some parts are in books 17 consent Both parents are giving written informed consent procedures 18 How is Small presents for children, participation Medical advise and help at medical problems of children encourged Media support for participating families and specially for "ELSPAC" children etc.

Data collection 19 biomarkers Cadmium and Lead in Czech and Bristol center of exposure Pesticides in milk and placenta in center of Ukraina 20 biomarkers of Apgar score, Biometry, Follow up studies of children - neurological and effect neuropsychological development, Psychologic examinations,Hearing test, Vision test, Morbidity, Health reports, Investigations and results, Treatment and medications - pediatric exam. at 8 y. Questionnaire - prenatal, natal, at 6 weeks, 1,5 y., 3y., at 5., at 7. and at 8 year after delivery - 32 types of questionnares. 21 biomarkersof - susceptibility Other data 22 environmental Air quality data were collected and analysed from each participating centers sampling

23 lifestyle data This part is prepared very in detail regarding nutrition, active and passive smoking, contact with chemicals, alcohol use etc. 24 health data Before and during pregnancy, During and after delivery 25 parental Alcohol use and smoking during pregnancy, medication during pregnancy and

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Slovakia 01 exposure delivery, complications of pregnancy and delivery 26 medication use of medicines is completely recorded 27 socio- all socio-economic factors are recorded economic factors Analysis and quality control procedures

28 international Rules for translation and back- translation of questionnaires. testing Coding and keying of questions. 29 - - 30 quantification of Principal self-completion psyhosocial measures employed in the study : data 1. The Edinburgh postnatal depressionscale, 2.Crown - Crisp experiential index, 3. Personality : Interpersonal sensitivity measure Boyce and Parker /1989/, 4. Life events inventory, 5. Social network and social support, 6. Marital relationship, 7. Life circumstances 31 data analysis Analysis of the international database of the main study was done in Bristol. The analyses of the national data are the responsibility of each project centre. 32 representativity Recruitment efficiency is regularly monitored Data protection and availability 33 privacy Confidentiality and ethics have the highest priority in the study. legislation Questionnaires are anonymised in order to maintain confidentiality under secure conditions. 34 intellectual International comparisons are published upon approval of the Central Survey property rights Office. 35 banking of biol. - sampl. Communication 36 informations The international component of the study is governed by regular meetings of the principle investigators from national ELSPAC centres. Results of the study is communicated to the scientific community by publication in peer reviewed journals and books. 37 professionals Pediatricians, ophtalmologists, neurologists, psychologists, involved othorhinolaryngologists and psychiatrists are cooperating on study in national Centres. 38 role of media To keep media attention is important for succes of study 39 public debate The investigators of national ELSPAC centres taking part on conferences 40 conseq. of - external communication Problems - experiences The most serious problem is big volume of information. We need more intensive cooperation with evaluation of results. These international studies a very needy. The most interesting ideas of our study are e.g. - high level of morbidity of pregnant women in countries participating on study - quality of life of young women after delivery in consequences of intrapartal maternal injury -consequences of delivery complications and medications.

It would be interresting to use results and experiences from this study in preparing of more precise

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Slovakia 01 project using more laboratory examinations.

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Sweden

Sweden 01 N° General data 1 type national research study 2 country Sweden 3 title Lead exposure in children in contaminated areas of Sweden 4 aim To investigate the impact of Pb in soil and dust on blood lead levels in children 5 beginning date 1992 6 ending date 1994 7 contact person Dr Marika Berglund, Institute of Environmental Medicine, Box 210, S-17177 Stockholm, Sweden; [email protected] 8 initiator Institue of Environmental Medicine (IMM) 9 involved/responsible IMM/regional health authorities organisations 10 budget available 11 who is financing Swedish Environmental protection agency, Karolinska Institute

Description of the population 12 total number of children about 200 13 age groups and number of 13-59 month persons in each group 14 inclusion criteria, exclusion Informed consent criteria 15 sampling strategy children were recruited via mailed letter and via day care centers 16 time schedule of from Oct 1992 to Nov 1994 biomonitoring 17 consent procedures parent informed consent 18 how is participation Results of individual measurements were offered encouraged? Data collection 19 biomarkers of exposure Pb in blood, hemoglobin 20 biomarkers of effect 21 biomarkers of susceptibility

Other data 22 environmental data Pb in soil and dust 23 lifestyle data exposure factors for Pb 24 health data 25 parental exposure exposure factors for Pb 26 medication 27 socio-economic factors exposure factors for Pb

Analysis and quality control procedures

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Sweden 01 28 intra/interlaboratory testing analysis of reference materials 29 external laboratory control analysis of external quality control samples for Pb in blood 30 accuracy, limit of det limit of PB in blood was 5 µg/L detection/quantification, reproducibility 31 data analysis (statistics, power calculations) 32 representativity partly random and partly recruted via day care centers

Data protection and availability 33 privacy legislation data is anonymous 34 intellectual property rights no, data is published 35 banking of biological no samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to public information to participating parents and personel was given authority, to general public, prior to study start and results were reported afterwords to participant 37 professionals involved, project leader and nurses had contact with children and contacts between parents professionals and participants 38 role of media results were in the daily papers 39 public debate some 40 consequences of external Exposure was rather low, and the Swedish EPA was communication planning on clean-up actions in contaminated areas

41 Problems

42 Experiences

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United Kingdom

Short summary to the questionnaires

Owing to scheduling constraints, only one UK questionnaire was received in time to be included in this report. This described a study in Scotland investigating diet as a risk further for asthma and eczema, with the aim of assessing whether maternal or childhood antioxidant or fatty acid intake influences the development of childhood asthma and allergy.

It is known, however, that there are a number of other ongoing research activities, for example on endocrine disruption, air pollution and asthma that may be relevant for inclusion in this survey.

In addition, there are specific studies on cohorts of children; of particular importance is the 'Avon Longitudinal Study of Parents and Children' (ALSPAC) based in the Bristol area of England, which involved the recruitment of around 14,000 pregnant women and subsequent study of their offspring. The project collected vast amounts of environmental, dietary, personal and socio-economic data, as well as clinical data and biological samples. Data collection and analysis is ongoing, including the annual examination and further study of the children who are currently aged 10-11.

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United Kingdom 01 N° General data 1 type Cohort study of diet as a risk factor for asthma and eczema in children 2 country Scotland (UK) 3 title Study of eczema and asthma to observe the effect of nutrition (SEATON) 4 aim To assess whether maternal or childhood antioxidant or fatty acid intake influences the development of childhood asthma and allergy 5 beginning date 1998 6 ending date 5 year follow up to be completed in 2004 7 contact person Dr Graham Devereux / Prof Peter Helms 8 initiator Prof Anthony Seaton 9 involved/responsible University of Aberdeen organisations 10 budget available £ 170,000 for 5 year follow up 11 who is financing UK National Asthma Campaign

Description of the population 12 total number of children 1.924 13 age groups and number of All born between persons in each group 14 inclusion criteria, exclusion Singleton live births in Aberdeen Maternity Hospital criteria 15 sampling strategy Recruitment in antenatal clinic according to research staff availability time schedule of 6, 12 and 24 months; 5y and others to be decided biomonitoring 17 consent procedures Written consent obtained at recruitment and for clinical measurements at 5y 18 how is participation Regular newsletters to participants; child and family friendly encouraged? clinical investigation unit Data collection 19 biomarkers of exposure Nutrient intake (particulary vitamins C, E, betacarotene and n-3 and n-6 poltyunsaturated fatty acids) from diet and supplements; maternal and cord blood selenium, antioxidant vitamins 20 biomarkers of effect Parent-reported asthma and eczema; skin prick and lung function tests at 5 years 21 biomarkers of susceptibility Parental atopic disease (in mothers assessed by skin prick tests); breast feeding

Other data 22 environmental data Housing, use of gas cookers in early life 23 lifestyle data Parental smoking, 24 health data Use of antibiotics in first 2 years 25 parental exposure (see 21)

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United Kingdom 01 26 medication Use of antibiotics in first 2 years 27 socio-economic factors Parental occupation; postcode deprivation category

Analysis and quality control procedures 28 intra/interlaboratory testing 29 external laboratory control 30 accuracy, limit of detection/quantification, reproducibility 31 data analysis (statistics, Logistic regression with adjustment for confounding power calculations) variables. With 475 subjects in each of three equal groups of nutrient intake (low, medium and high) we will have 90% power to detect a linear trend in proportions of children with asthma or eczema ranging from 15% in the lowest rick intake group to 25% in the highest risk intake group at 1% significance level. 32 representativity Initial sample of 1,924 very similar to total obstetric population. Response is higher in mothers with higher educational levels

Data protection and availability 33 privacy legislation UK Data Protection Act 1998 34 intellectual property rights None foreseen 35 banking of biological None samples

Communication (individual level, group level, level (sub)population ) 36 reporting results to public Yearly progress reports to funding body; bi-annual authority, to general public, newsletters to participants to participant 37 professionals involved, Adult and paediatric chest physicians, epidemiologists, contacts between research nurses professionals and participants 38 role of media Press releases for major results 39 public debate Results presented to public at World Asthma Day, May 2003 40 consequences of external communication

41 Problems

42 Experiences Response rate of approx 70% to postal questionnaire at 5y. Of these 95% complete a children's diet questionnaire and 75% have lung function and skin prick tests

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12 Annex VI: Written Comments on the baseline report

Overview • Inclusion of prenatal and postnatal exposure is welcomed by "Women in Europe for a Common Future" (WECF, Mrs. Marie Kranendonk, annex VI-A)

• Biomonitoring of children should also include the earlier phase before conception. The so-called “body burden” (levels of contaminants that may pose a risk to fertility or to the development of the fetus) of young adults who will be future parents, is extremely important to monitor. For policy and monitoring measures in the action plan, aimed at prevention, the parents- to- be, young adults, should be included. (WECF).

• To get better knowledge about the effects of in-utero exposure biomonitoring of cohorts of children from birth up to adulthood is a good instrument. However it is expensive. Therefore it is a pity that such research that has been performed e.g. in the Netherlands, in an internationally acclaimed way, had to be stopped after 6 or ten years because funding was not available. It would be cost-effective to use the valuable material already collected for follow-up research. WECF recommends the Commission to enable follow up of such research and to follow if possible these cohorts of children into adulthood, so as to use all data already collected and look at possible effects in puberty, on sexual development etc. (WECF).

• Breast milk samples and cord blood samples at birth should be collected, because this gives a good picture of the type and levels of substances that were present in the womb. (WECF)

• In an integrated monitoring system participation of people, particularly parents and local communities is essential: positive examples of community monitoring systems have and are being developed in which involvement of parents and local communities helps to develop an understanding of complex factors and to create a good communication with the public, necessary for successful control/management activities, to apply the approaches developed by research (WECF)

• A monitoring programme on heavy metals should focus on lead, cadmium, mercury, arsenic and nickel in the first place. Other metals could be studied in limited pilot projects by countries with specific interests (high exposures?), good analytical capacity etc. (Sweden, Ann Thuvander, annex VI-B).

• There should be a focus on monitoring of human exposure as well as on disease monitoring instead of a collection of analytical data from all various matrices. Sweden just started a monitoring programme on cadmium and protein in human urine as a biomarker for cadmium-induced kidney lesions, which is assumed to generate interesting results and will serve as a good basis for desicion-makers. It has recently been reported in Sweden that the intake of cadmium in infants may be close to the PTWI (based on kidney lesions in adults) due to fairly high levels in certain infant formulas. Further studies of infant exposure (as well as on the neurotoxic effects on cadmium during early life) seems thus important (Sweden, Ann Thuvander, annex VI-B).

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• A clear definition and guidelines on what biomonitoring will be used for and what it will deliver and what it will not deliver is necessary. A cause-effect framework can not be developed by simply linking biomonitoring data with health tracking data. Clearly, biomonitoring is useful for many things but a cause-effect framework would require specifically planned cohort studies that (unfortunately) fall outside the priorities of the current SCALE process (CEFIC, Madeleine Laffont, annex VI-C).

• Whenever biomonitoring is used, it should be used in conjunction with clear and simple pre-defined normative values (which in this case, should be child-specific) - for example what the exposure is, how it is measured, what the health outcomes are, how they are measured... Biomonitoring in and of itself, is of limited use. Clearly, in addition to a link with normative values, its use in conjunction with prospective studies would be useful. The defining of normative values might come under the remit of the biomonitoring group, or the research needs group (CEFIC).

• The biomonitoring group should develop links with the indicators group. Biomonitoring and indicators, although different, clearly have similarities. Used in conjunction with indicators, biomonitoring could perhaps provide the base for health impact analysis which can control for confounders, and monitor the effectiveness of public health interventions - this too might be an avenue for future research (CEFIC). • A preface should be added to the report of integrated monitoring to indicate that the pilot projects were chosen due to the great amount of data and experience available. They should serve as a basis to identify the elements of an improved integrated biomonitoring system. This purpose should be clearly communicated to the working groups and the public by adding a preface to the report on integrated monitoring. Otherwise the publication of the baseline reports on the internet webside of the commission will raise the perception that the areas of dioxins&PCBs, ED and heavy metals are the major cause of adverse effects on children´s health, which they definitely are not. (CEFIC, Mr. Klotz, annex VI-D).

• The overall impression of the presentations was that data sharing is the key issue. We would like to stress that quality check of data must have the same priority as the simple sharing of data of largely different quality can lead to wrong focus and priority setting (CEFIC).

• The work of the TWG on the action plan must include proposals for methodology, clear targets as well as focus of work, research needs and more information on the cost side of implementing such an approach (CEFIC).

• CEFIC understands that SCALE is still run under the position of the EU Commission laid down in its communication 2000 on the Precautionary Principle. In the future work and debate of the action plan the consultants and representatives of the EU should focus the work on the specific task set for the working groups to develop methods for integrated biomonitoring in order to make best use of existing resources (CEFIC).

• It is unclear, if integrated monitoring would provide new insight to causal inference, especially when no elaborate details of how integrated monitoring would differ from epidemiological research are written out. The key to guarantee high quality causal

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inference is to develop analytical study protocols. Surveillance programs, where you simultaneously collect health and exposure data without much attention to study design, do not render themselves easily to analytic studies. (Finland, Mikko Paunio, annex VI-E).

• Difficult problems arise in developing guidelines on how to use the precautionary principle. Reasonably good working EC guidelines exist on how to use the precautionary principle in a risk analysis framework. A paper by Gary Marchant on the precautionary principle has been published in the Environmental Health Perspectives Journal’s November issue (Finland).

Remark: These comments and suggestions will be discussed within step 2 of the biomonitoring group.

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Annex VI-A

Women in Europe for a Common Future. Regulierenring 9, 3781 LA Bunnik. Netherlands.

29 December 2004 re: comments first report TWG

Dear Professor Casteleyn,

As agreed during the Consultative Forum two weeks ago, we are sending you our remarks on the TWG report in writing. Our international network has welcomed your report on the first phase of your activities and was pleased with the results. Particularly we have a positive reaction on the fact that your working group has been looking at monitoring effects of prenatal and postnatal exposure . Our additional recommendation is that monitoring should also include the earlier phase before conception: The so-called “body burden “ (levels of contaminants that may pose a risk to fertility or to the development of the fetus) of young adults who will be future parents, is extremely important to monitor. If in a certain percentage of a population levels of e.g. dioxins are still too high, this will have effect on their offspring. So for policy and monitoring measures in the action plan, aimed at prevention, the parents- to- be, young adults , should be included.

The TWG recognises that diseases and disorders in several cases may be linked to exposures (for instance to Endocrine Disruptors) that may have occurred many years earlier during in-utero development. Our second suggestion is related to this. To get better knowledge about the effects of in- utero exposure biomonitoring of cohorts of children from birth up to adulthood is a good instrument. However as you stated in your presentation, it is expensive. Therefore it is a pity that such research that has been performed e.g. in the Netherlands, in an internationally acclaimed way, had to be stopped after 6 or ten years because funding is not available. It would be cost-effective to use the valuable material already collected for follow-up research. At the Consultative Forum we have already mentioned to you the importance of longitudinal monitoring of cohorts of children as has for instance been undertaken by research teams of the Universities of Groningen, Rotterdam and Amsterdam , (research on health effects of Dioxins and PCB exposure) where children were monitored for 6 or ten to twelve years ; negative effects on their development and health were shown in the group of children with the highest levels of exposure (still 5-10 % of these children). Our recommendation to the Commission would be to enable follow up of such research and to follow if possible these cohorts of children into adulthood, so as to use all data already

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collected and look at possible effects in puberty, on sexual development etc. As PCB’s and dioxins have effects that are endocrine disrupting, such research may help to understand the potential role of ED’s as a risk factor in specific diseases and developmental disorders of children. We particularly draw attention to the increasing concern about behavioural and attention deficits of children and learning problems, that could be linked to exposure in the womb to chemical substances. [I have mentioned to you that Dr.Gavin ten Tusscher can give you more information on the Dutch research].

In this respect we like to point at your remark under ‘Requirements’ of the executive summary : where you mention that you are looking for non-invasive techniques and cost efficiency.. We would like to suggest to think also of collecting breastmilk samples and cord blood samples at birth to be kept in data specimen banks, because they give a good picture of the type and levels of substances that were present in the womb. This would for instance help the tracking of later disease incidence and the identification of possible associations with in –utero exposures.

Our last remark is related to requirement 7 mentioned on the last page of the executive summary. In an integrated monitoring system , that looks also at other risk factors, that aims to provide positive, operational models, participation of people, particularly parents and local communities, is essential : positive examples of community monitoring systems have and are being developed in which involvement of parents and local communities helps to develop an understanding of complex factors and to create a good communication with the public, necessary for successful control/management activities, to apply the approaches developed by research.

We wish you and the TWG a fruitful second phase of your activities,

Sincerely Marie

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Annex VI-B

Ann Thuvander, Sweden:

As one of the Swedish representative in the Consultative Group I'd like to take the opportunity to send you a few comments on the baseline report on heavy metals.

In the report you discuss which metals that should be included in a monitoring programme. In our opinion it is important to focus on lead, cadmium, mercury, arsenic and nickel in the first place. Other metals could be studied in limited pilot projects by countries with specific interests (high exposures?), good analytical capacity etc.

As we mentioned at the meeting with the Consultative group we feel slightly worried about collection of analytical data from all various matrices (air, soil, water, food...) and would instead like to focus on monitoring of human exposure (in children when relevant) as well as on 'disease monitoring' - where possible. Perhaps this will be part of the actions suggested by the 'Biomonitoring in children group. For example, we have just started a monitoring programme on cadmium and protein in human urine as a biomarker for cadmium-induced kidney lesions, which we think will generate very interesting results and will serve as a good basis for desicion-makers.

We are also uncertain about the need for monitoring in the "residential environment". Since the sources of human exposure to the main toxic metals are fairly well known, is this really necessary?

Finally, it has recently been reported in Sweden that the intake of cadmium in infants may be close to the PTWI (based on kidney lesions in adults) due to fairly high levels in certain infant formulas. Further studies of infant exposure (as well as on the neurotoxic effects on cadmium during early life) seems thus important.

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Annex VI-C

Madeleine Laffont, CEFIC:

Dear Ludwine,

I very much enjoyed your presentation at the consultative forum yesturday. I would like to submit these comments below for consideration for the finalisation of the Biomonitoring Baseline Report:

- The need for clear definitions and guidelines on what biomonitoring will be used for and what it will deliver and what it won't deliver. This is very important, in order to clarify what seems to be a fundamental misconception within the SCALE strategy. A clear objective of the SCALE strategy is to establish a cause-effect framework.From the terminology of the SCALE Communication and at all the presentations I have heard from the Commission, there seems to be an assumption that a cause-effect framework can be developed simply by linking biomonitoring data with health tracking data. Clearly, biomonitoring is useful for many things but a cause-effect framework would require specifically planned cohort studies that (unfortunately) fall outside the priorities of the current SCALE process.

- Whenever biomonitoring is used, it should be used in conjunction with clear and simple pre-defined normative values (which in this case, should be child-specific) - for example what the exposure is, how it is measured, what the health outcomes are, how they are measured... Biomonitoring in and of itself, is of limited use. Clearly, in addition to a link with normative values, its use in conjunction with prospective studies would be useful. The defining of normative values might come under the remit of the biomonitoring group, or the research needs group.

- I would recommend that the biomonitoring TWG develop links with the Indicators TWG. I do not believe that under the current meeting schedule, facilitates this, but perhaps both groups could have parallel discussions. Biomonitoring and indicators, although different, clearly have similarities and working in closer association may benefit both groups in finding the focus that is so badly needed in SCALE. Used in conjunction with indicators, biomonitoring could perhaps provide the base for health impact analysis which can control for confounders, and monitor the effectiveness of public health interventions - this too might be an avenue for future research...

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Annex VI-D

Comments from CEFIC member of the Consultative Forum on meeting December 18/19th 2003 Gernot Klotz (CEFIC/BAYER)

On behalve of CEFIC the following comments on some issues:

Pilotproject: Integrated biomonitoring

As presented by Mr.Perera the pilotprojects are set up to develop an improved system for integrated biomonitoring not to duplicate ongoing work within the various strategies already inplace (e.g. EU strategy on dioxins, EU strategy on endocrine disruption). The pilotprojects where chosen because of the great amount of data and experience available and should serve as a basis to identify the elements of an improved integrated biomonitoring system. This purpose should be clearly communicated to the working groups and the public by adding a preface to the report on integrated biomonitoiring. Otherwise the publication of the baseline reports on the internet webside of the commission will raise the perception that the areas of dioxins&PCBs, ED and heavy metals are the major cause of adverse effects on children´s health, which they definitely are not.

The overall impression of the presentations was that data sharing is the key issue. We would like to stress that quality check of data must have the same priority as the simple sharing of data of largely different quality can lead to wrong focus and priority setting.

CEFIC supports the view of several member states (e.g. France, Germany) that the work of the TWG on the action plan must include proposals for methodology, clear targets as well as focus of work, research needs and more information on the cost side of implementing such an approach.

In addition the work of the TWGs sometimes includes discussions regarded outside the scope of the group. An example is the discussion to develop a new, children health specific approach to the Precautionary Principle within the pilotprojects. CEFIC understands that SCALE is still run under the position of the EU Commision laid down in its communication 2000 on the PP. In the future work and debate of the action plan the consultants and representatives of the EU should focus the work on the specific task set for the working groups to develop methods for integrated biomonitoring in order to make best use of existing ressources.

Presentation of TWG Endocrine disruption

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This difficult debate has been constructive and the report gives a balanced reflection of the debate. However we still request that the technical term BKH list is substituted by the term “list of substances for further evaluation regarding their endocrine potential”, which is the official title of the list under the EU Strategy. The EU has committed to work within the OECD process to establish a testing and assessment scheme and using the “Weybridge definition” for endocrine disruptors. As the OECD work is still ongoing, it is at the moment not feasable to define substances as endocrine disruptors. Instead the term “candidate substances” should be used throughout the baseline report. Many substances labelled by the BKH as being of high priority have been shown to have no relevant endocrine induced adverse effects in the recently published WRc report of the EU Commission. Therefore care must be taken to label substances as endocrine disruptors in the public by publishing the baseline report.

We would point to the fact that endocrine disruptors is not a homogeneous structural group as is eg. Dioxins and would support the presentation of the EU Commission at the consultative forum which called TWG “Endocrine disruption “ instead of “endocrine disruptors”. This would enable the group to cover a wider range of potential effects focussed on health implications as requested by the SCALE strategy. Many of the potential health effects are still under considerable scientific debate.

As mentioned several times by the EU Commission SCALE should support the already established EU Strategy on endocrine disruption. Relevant decisions for the action plan within SCALE must take into account the already established structures and positions discussed in the EU stakeholder forum, the many positions developed within this strategy including important statements made by various scientific committees (e.g. CSTEE, SCP, SCNFCP) and in consultation.

General comments

• Presentation of Prof: Helms; all relevant baseline reports)

The recent publication of EEA Background paper No. 5 on how to deal with multicausality in complex systems and the request to remove on risk factor from the multifactoral causal chain got attention by various TWGs and was especially mentioned by Prof.Helms in his presentation on childhood respiratory diseases, asthma and allergies. The conclusions of the EEA paper need further debate as they significantly contradict a statement by the WHO on the same issue laid down in WHO Guidelines (2000) on “Evaluation and use of epidemiological evidence for environmental health risk assessment” (page 11). In order to be scientifically sound this conflict should be mentioned in all baseline report which refer and make citation of the EEA paper. As this conflict was discussed in TWG ED and formulated in the report we propose to use the text laid down in the baseline report on ED

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(point 2.2.7, page 5, starting from line 13 “ As underlined by the EEA...”) in the relevant baseline reports.

Dr. Gernot Klotz December 31th 2003 CEFIC/BAYER e-mail [email protected]

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Annex VI-E

Finland’s written comments in the “European Environment & Health Strategy” Consultative Forum, Brussels, 18-19 December

Mikko Paunio, MD, PhD, MHS, Doc, Senior Medical Officer, Ministry of Social Affairs and Health of Finland, P.O. Box 33 (00023 Government) Finland, e-mail: [email protected]

Biomonitoring of Children

As being an epidemiologist – in addition to present governmental duties, it was - at first - difficult to understand some of the words that are written out in the European Environment and Health Strategy. Integrated monitoring was one of those words. Finally I realized that it means something what we epidemiologists have been doing since John Snow who worked in the mid 19th century. Even now, after extensive theory building and extensive accumulated experience, especially we epidemiologists know, how difficult it is to make sound causal inference, which lays the foundations to good governance.

It is unclear, if integrated monitoring, what more or less means making epidemiological research of environmental exposures would provide new insight to causal inference, especially when no elaborate details of how integrated monitoring would differ from epidemiological research is written out. Furthermore integrated monitoring now appears to be a kind of a surveillance system. This potentially creates problems, as the key to guarantee high quality causal inference, is to develop analytical study protocols, not on going surveillance system where you simultaneously collect health and exposure data without much attention to study design. Surveillance programs do not render themselves easily to analytic studies. There is plenty of discussion in advanced textbooks about this.

Another thing, which is of great interest to me, is the notion in the executive summary about precautionary principle. I, along with a few colleagues, have tried hard - since March - in the WHO Budapest ministerial process to develop guidelines of how to use PP. Unfortunately our work has not been very successful, as the problems related to developing guidelines in order to properly use this principle are truly difficult.

I would like to remind you that we already have reasonably good working EC guidelines of how to use precautionary principle in risk analysis framework.

At last I would also like to take the opportunity to mention that Gary Marchant’s probably influential paper, or a mini monograph, on the precautionary principle discussing fully the

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unwanted consequences, i.e. adverse health effects, and legal side effects, has been published in the Environmental Health Perspectives Journal’s November issue.

Integrated Monitoring of dioxins & PCBs in the Baltic Region

This has really been a remarkable exercise, that you have been able to put together under severe time constraints. It must be applauded. The subject matter to Finland is of great importance. I must remind you that at least to Finns, Baltic herring is not just a dietary or a health matter, but a cultural and economic matter as well. To have herring in a Christmas table is a must, something like Christmas carp to certain regions in Central Europe or il porcini in general to Italians. It is thus important that risk assessment and further risk management actions are based on sound science and good governance.

We have just heard, that the problem seems to be taking care of itself, i.e. the trends are not alarming. Furthermore, there was a child cohort, which is now around their 20’s and who have been heavily exposed even ten times more than today. There is evidence that some of these children might have suffered developmental effects as molar disruption in tooth number 5. There is practically little evidence from epidemiological literature that dioxin would increase cancer rates. As a matter of fact the extensive work of the working group quotes an upcoming Finnish study, which shows contrary to original findings – which have been subject critique and public scrutiny recently – dioxin is inversely associated with soft tissue sarcomas, not positively as was reported in a historically important, but now questionable study. Acute health effects such in the form of chloracne are indisputable.

Finland as well as other Scandinavian countries have been champions in the area of child health for the past 80 years or so. We have long traditions in antenatal and childcare in general. We have highest vaccination rates and lowest morbidity rates in Europe.

We live in north and right now as of speaking sun barely seen above horizon even in Helsinki, and is not seen at all in Lapland. We have to protect our children under these harsh conditions. It went almost unnoticed to the Finnish public that several food items are now more fortified with D-vitamin because of alarming population data about lowered population D-vitamin levels. In this context, the question of eating or not eating fish, is not only a trade-off of theoretical cancer risks versus fish being good to the heart, but it is also a question of micronutrients to growing children and perhaps even preventing cancer by eating fish. Fish is a good source of D-vitamin. Thus the question whether, our children, eat Baltic herring is of great importance to us.

The question got a dramatic twist last week when Finnish researchers published in a respected Journal Faseb. In this study they reported a new D-vitamin, which unlike traditional D-vitamin, has health effects to multiple, if not all organs. This vitamin might – according to the report – yield substantial protection against the most common cancer

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among males, i.e. prostate cancer. The finding might ultimately explain why young boys, who have experienced sunburns in early life have five times lower prostate cancer rates than those who have not experienced sunburns in early life. Thus the issue comes even more complex for health protection officials as the current cancer dogma in UV-light policies stresses the need to avoid sunburns.

At the end we would like to remind you that US government has decided instead of setting reference levels for dioxin in food their policy is to limit sources. Unfortunately, as can be read from the report, it is possible, that airborne fraction from Central Europe is a significant source for Baltic herring. This is something we cannot control ourselves.

Finally the state-of-the art literature – as we have heard - does not warrant tighter reference values for dioxin, but instead calls clearly for multidimensional approach. This - in essence - also calls for common sense to be used in formulating risk management policies around this important hygienic problem.

We hope multidimensionality will clearly be reflected in the Recommendations for actions and in the Action Plan itself, which is to be passed to Budapest environment and health minister’s conference.

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