Environmental Health Criteria 167
ACETALDEHYDE
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INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 167
ACETALDEHYDE
This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization.
First draft prepared by Mrs. J. de Fouw, National Institute of Public Health and Enviromental Protection, Bilthoven, Netherlands
Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization
World Health Organization Geneva, 1995
The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. The main objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of epidemiological, experimental laboratory, and risk-assessment methods that could produce internationally comparable results, and the development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination of laboratory testing and epidemiological studies, and promotion of research on the mechanisms of the biological action of chemicals.
WHO Library Cataloguing in Publication Data
Acetaldehyde.
(Environmental health criteria ; 167)
1.Acetadehyde - adverse effects 2.Enviromental exposure I.Series
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ISBN 92 4 157167 5 (NLM Classification: QU 99) ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR ACETALDEHYDE
Preamble
Introduction
1. SUMMARY
1.1 Identity, physical and chemical properties, and analytical methods 1.2 Sources of human and environmental exposure 1.3 Environmental transport, distribution, and transformation 1.4 Environmental levels and human exposure 1.5 Kinetics and metabolism 1.5.1 Absorption, distribution, and elimination 1.5.2 Metabolism 1.5.3 Reaction with other components 1.6 Effects on organisms in the environment 1.6.1 Aquatic organisms 1.6.2 Terrestrial organisms 1.7 Effects on experimental animals and in vitro test systems 1.7.1 Single exposure 1.7.2 Short- and long-term exposures 1.7.3 Reproduction, embryotoxicity, and teratogenicity 1.7.4 Mutagenicity and related end-points 1.7.5 Carcinogenicity 1.7.6 Special studies 1.8 Effects on humans
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1.9 Evaluation of human health risks and effects on the environment
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS
2.1 Identity 2.2 Physical and chemical properties 2.3 Conversion factors 2.4 Analytical methods
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence 3.2 Anthropogenic sources 3.2.1 Production 3.2.1.1 Production levels and processes 3.2.1.2 Emissions 3.2.2 Uses 3.2.3 Waste disposal 3.2.4 Other sources
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
4.1 Transport and distribution between media 4.2 Abiotic degradation 4.3 Biodegradation
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels 5.1.1 Air 5.1.2 Water 5.1.3 Soil 5.1.4 Food 5.1.5 Cigarette smoke 5.2 General population exposure 5.3 Occupational exposure
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1 Absorption 6.2 Distribution 6.2.1 Animal studies 6.2.1.1 Distribution after inhalation exposure 6.2.1.2 Distribution to the embryo and fetus 6.2.1.3 Distribution to the brain 6.2.2 Human studies 6.3 Metabolism 6.3.1 Animal studies 6.3.1.1 Liver 6.3.1.2 Respiratory tract 6.3.1.3 Kidneys 6.3.1.4 Testes and ovaries 6.3.1.5 Embryonic tissue 6.3.1.6 Metabolism during pregnancy 6.3.2 Human studies
6.4 Elimination 6.5 Reaction with cellular macromolecules 6.5.1 Proteins 6.5.2 Nucleic acids
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7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
7.1 Aquatic organisms 7.2 Terrestrial organisms
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
8.1 Single exposure 8.1.1 LD50 and LC50 values 8.2 Short-term exposure 8.2.1 Oral 8.2.2 Inhalation 8.2.3 Dermal 8.2.4 Parenteral 8.3 Skin and eye irritation; sensitization 8.4 Long-term exposure 8.4.1 Oral 8.4.2 Inhalation 8.5 Reproductive and developmental toxicity 8.6 Mutagenicity and related end-points 8.6.1 Bacteria 8.6.2 Non-mammalian eukaryotic systems 8.6.2.1 Gene mutation assays 8.6.2.2 Chromosome alterations 8.6.3 Cultured mammalian cells 8.6.3.1 Gene mutation assays 8.6.3.2 Chromosome alterations and sister chromatid exchange 8.6.4 In vivo assays 8.6.4.1 Somatic cells 8.6.4.2 Germ cells 8.6.5 Other assays 8.6.5.1 DNA single-strand breaks 8.6.5.2 DNA cross-linking 8.6.6 Cell transformation 8.7 Carcinogenicity bioassays 8.7.1 Inhalation exposure 8.7.2 Co-carcinogenicity and promotion studies 8.8 Neurological effects 8.9 Immunological effects 8.9.1 Direct effects on immune cells 8.9.2 Generation of antibodies reacting with acetaldehyde-modified proteins 8.9.3 Related immunological effects 8.10 Biochemical effects
9. EFFECTS ON HUMANS
9.1 General population exposure 9.2 Occupational exposure 9.2.1 General observations 9.2.2 Clinical studies 9.2.3 Epidemiological studies 9.3 Effects of endogenous acetaldehyde 9.3.1 Effects of ethanol possibly attributable to acetaldehyde or acetaldehyde metabolism
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1 Evaluation of human health risks 10.1.1 Exposure 10.1.2 Health effects
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10.1.3 Approaches to risk assessment 10.2 Evaluation of effects on the environment
11. RECOMMENDATIONS FOR RESEARCH
REFERENCES
RESUME
RESUMEN
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
Every effort has been made to present information in the criteria monographs as accurately as possible without unduly delaying their publication. In the interest of all users of the Environmental Health Criteria monographs, readers are kindly requested to communicate any errors that may have occurred to the Director of the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corrigenda.
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A detailed data profile and a legal file can be obtained from the International Register of Potentially Toxic Chemicals, Case postale 356, 1219 Châtelaine, Geneva, Switzerland (Telephone No. 9799111).
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This publication was made possible by grant number 5 U01 ES02617-15 from the National Institute of Environmental Health Sciences, National Institutes of Health, USA, and by financial support from the European Commission.
Environmental Health Criteria
PREAMBLE
Objectives
In 1973 the WHO Environmental Health Criteria Programme was initiated with the following objectives:
(i) to assess information on the relationship between exposure to environmental pollutants and human health, and to provide guidelines for setting exposure limits;
(ii) to identify new or potential pollutants;
(iii) to identify gaps in knowledge concerning the health effects of pollutants;
(iv) to promote the harmonization of toxicological and epidemiological methods in order to have internationally comparable results.
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The first Environmental Health Criteria (EHC) monograph, on mercury, was published in 1976 and since that time an everincreasing number of assessments of chemicals and of physical effects have been produced. In addition, many EHC monographs have been devoted to evaluating toxicological methodology, e.g., for genetic, neurotoxic, teratogenic and nephrotoxic effects. Other publications have been concerned with epidemiological guidelines, evaluation of short-term tests for carcinogens, biomarkers, effects on the elderly and so forth.
Since its inauguration the EHC Programme has widened its scope, and the importance of environmental effects, in addition to health effects, has been increasingly emphasized in the total evaluation of chemicals.
The original impetus for the Programme came from World Health Assembly resolutions and the recommendations of the 1972 UN Conference on the Human Environment. Subsequently the work became an integral part of the International Programme on Chemical Safety (IPCS), a cooperative programme of UNEP, ILO and WHO. In this manner, with the strong support of the new partners, the importance of occupational health and environmental effects was fully recognized. The EHC monographs have become widely established, used and recognized throughout the world.
The recommendations of the 1992 UN Conference on Environment and Development and the subsequent establishment of the Intergovernmental Forum on Chemical Safety with the priorities for action in the six programme areas of Chapter 19, Agenda 21, all lend further weight to the need for EHC assessments of the risks of chemicals.
Scope
The criteria monographs are intended to provide critical reviews on the effect on human health and the environment of chemicals and of combinations of chemicals and physical and biological agents. As such, they include and review studies that are of direct relevance for the evaluation. However, they do not describe every study carried out. Worldwide data are used and are quoted from original studies, not from abstracts or reviews. Both published and unpublished reports are considered and it is incumbent on the authors to assess all the articles cited in the references. Preference is always given to published data. Unpublished data are only used when relevant published data are absent or when they are pivotal to the risk assessment. A detailed policy statement is available that describes the procedures used for unpublished proprietary data so that this information can be used in the evaluation without compromising its confidential nature (WHO (1990) Revised Guidelines for the Preparation of Environmental Health Criteria Monographs. PCS/90.69, Geneva, World Health Organization).
In the evaluation of human health risks, sound human data, whenever available, are preferred to animal data. Animal and in vitro studies provide support and are used mainly to supply evidence missing from human studies. It is mandatory that research on human subjects is conducted in full accord with ethical principles, including the provisions of the Helsinki Declaration.
The EHC monographs are intended to assist national and international authorities in making risk assessments and subsequent risk management decisions. They represent a thorough evaluation of risks and are not, in any sense, recommendations for regulation or standard setting. These latter are the exclusive purview of national and regional governments.
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Content
The layout of EHC monographs for chemicals is outlined below.
* Summary - a review of the salient facts and the risk evaluation of the chemical * Identity - physical and chemical properties, analytical methods * Sources of exposure * Environmental transport, distribution and transformation * Environmental levels and human exposure
* Kinetics and metabolism in laboratory animals and humans * Effects on laboratory mammals and in vitro test systems * Effects on humans * Effects on other organisms in the laboratory and field * Evaluation of human health risks and effects on the environment * Conclusions and recommendations for protection of human health and the environment * Further research * Previous evaluations by international bodies, e.g., IARC, JECFA, JMPR
Selection of chemicals
Since the inception of the EHC Programme, the IPCS has organized meetings of scientists to establish lists of priority chemicals for subsequent evaluation. Such meetings have been held in: Ispra, Italy, 1980; Oxford, United Kingdom, 1984; Berlin, Germany, 1987; and North Carolina, USA, 1995. The selection of chemicals has been based on the following criteria: the existence of scientific evidence that the substance presents a hazard to human health and/or the environment; the possible use, persistence, accumulation or degradation of the substance shows that there may be significant human or environmental exposure; the size and nature of populations at risk (both human and other species) and risks for environment; international concern, i.e. the substance is of major interest to several countries; adequate data on the hazards are available.
If an EHC monograph is proposed for a chemical not on the priority list, the IPCS Secretariat consults with the Cooperating Organizations and all the Participating Institutions before embarking on the preparation of the monograph.
Procedures
The order of procedures that result in the publication of an EHC monograph is shown in the flow chart on page 13. A designated staff member of IPCS, responsible for the scientific quality of the document, serves as Responsible Officer (RO). The IPCS Editor is responsible for layout and language. The first draft, prepared by consultants or, more usually, staff from an IPCS Participating Institution, is based initially on data provided from the International Register of Potentially Toxic Chemicals, and reference data bases such as Medline and Toxline.
The draft document, when received by the RO, may require an initial review by a small panel of experts to determine its scientific quality and objectivity. Once the RO finds the document acceptable as a first draft, it is distributed, in its unedited form, to well over 150 EHC contact points throughout the world who are asked to comment on its completeness and accuracy and, where necessary, provide additional material. The contact points, usually designated by
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governments, may be Participating Institutions, IPCS Focal Points, or individual scientists known for their particular expertise. Generally some four months are allowed before the comments are considered by the RO and author(s). A second draft incorporating comments received and approved by the Director, IPCS, is then distributed to Task Group members, who carry out the peer review, at least six weeks before their meeting.
The Task Group members serve as individual scientists, not as representatives of any organization, government or industry. Their function is to evaluate the accuracy, significance and relevance of the information in the document and to assess the health and environmental risks from exposure to the chemical. A summary and recommendations for further research and improved safety aspects are also required. The composition of the Task Group is dictated by the range of expertise required for the subject of the meeting and by the need for a balanced geographical distribution.
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When the Task Group has completed its review and the RO is satisfied as to the scientific correctness and completeness of the document, it then goes for language editing, reference checking, and preparation of camera-ready copy. After approval by the Director, IPCS, the monograph is submitted to the WHO Office of Publications for printing. At this time a copy of the final draft is sent to the Chairperson and Rapporteur of the Task Group to check for any errors.
It is accepted that the following criteria should initiate the updating of an EHC monograph: new data are available that would substantially change the evaluation; there is public concern for health or environmental effects of the agent because of greater exposure; an appreciable time period has elapsed since the last evaluation.
All Participating Institutions are informed, through the EHC progress report, of the authors and institutions proposed for the drafting of the documents. A comprehensive file of all comments received on drafts of each EHC monograph is maintained and is available on request. The Chairpersons of Task Groups are briefed before each meeting on their role and responsibility in ensuring that these rules are followed.
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WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR ACETALDEHYDE
Members
Mrs I. Arts, Department of Biological Toxicology, TNO Nutrition and Food Research, Zeist, The Netherlands
Dr R.E. Barry, Faculty of Medicine, University of Bristol, Bristol Royal Infirmary, Bristol, United Kingdom
Professor D. Beritic-Stahuljak, Andrija œtampar School of Public Health, Faculty of Medicine, University of Zagreb, Zagreb, Croatia
Dr Sai Mei Hou, Karolinska Institute, Huddinge, Sweden
Dr M.E. Meek, Environmental Health Directorate, Priority Substances Section, Health & Welfare Canada, Tunney's Pasture, Ottawa, Canada (Chairperson)
Professor M.H. Noweir, Industrial Engineering Department, College of
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Engineering, King Abdul Aziz University, Jeddah, Saudi Arabia
Professor G. Obe, University of Essen, Essen, Germany
Professor T.V.N. Persaud, Department of Anatomy, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
Mr D. Renshaw, Department of Health, Elephant & Castle, London, United Kingdom
Dr A. Smith, Health and Safety Executive, Toxicology Unit, Bootle, Merseyside, United Kingdom (Co-rapporteur)
Professor A. Watanabe, Toyama Medical and Pharmaceutical University, Faculty of Medicine, Toyama, Japan
Dr S. Worrall, Department of Biochemistry, University of Queensland, Brisbane, Queensland, Australia
Representatives from other organizations
Dr V. Krutovskikh, Programme of Multistage Carcinogenesis, International Agency for Research on Cancer, Lyon, France
Secretariat
Mrs J. de Fouw, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands (Co-rapporteur)
Professor F. Valic, IPCS Consultant, World Health Organization, Geneva, Switzerland, also Vice-Rector, University of Zagreb, Zagreb, Croatia (Responsible Officer and Secretary)
ENVIRONMENTAL HEALTH CRITERIA FOR ACETALDEHYDE
A WHO Task Group on Environmental Health Criteria for Acetaldehyde met in Geneva from 6 to 10 December 1993. Professor F. Valic opened the meeting on behalf of the three cooperating organizations of the IPCS (UNEP/ILO/WHO). The Task Group reviewed and revised the draft monograph and made an evaluation of the risks for human health and the environment from exposure to acetaldehyde.
The first draft of this monograph was prepared by Mrs J. de Fouw, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands.
Professor F. Valic was responsible for the overall scientific content of the monograph and for the organization of the meeting, and Mrs M.O. Head of Oxford for the technical editing of the monograph.
The efforts of all who helped in the preparation and finalization of this publication are gratefully acknowledged.
INTRODUCTION
This monograph will deal mainly with the effects of direct exposure to acetaldehyde. However, it should be borne in mind that for most people exposure to acetaldehyde will occur through the consumption of alcoholic beverages (IARC, 1988). These beverages contain ethanol, which is metabolized to acetaldehyde by alcohol dehydrogenase (ADH). ADH activity has been detected in nearly every tissue including liver, kidney, muscle, intestine, ovary, and testes (Buehler et al., 1983; Agarwal & Goedde, 1990).
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However, data concerning metabolically formed acetaldehyde will only be considered when no data are available on direct exposure.
The accurate determination of acetaldehyde in body fluid and tissue samples is relatively difficult. Only the most recent techniques take into account artifactual acetaldehyde formation in biological samples, especially those containing ethanol (Eriksson & Fukunaga 1993). As values for concentrations of acetaldehyde given in older references may well have been overestimates, absolute values are only given when necessary.
1. SUMMARY
1.1 Identity, physical and chemical properties, and analytical methods
Acetaldehyde is a colourless, volatile liquid with a pungent suffocating odour. The reported odour threshold is 0.09 mg/m3. Acetaldehyde is a highly flammable and reactive compound that is miscible in water and most common solvents.
Analytical methods are available for the detection of acetaldehyde in air (including breath) and water. The principal method is based on the reaction of acetaldehyde with 2,4-dinitrophenylhydrazine and subsequent analysis of the hydrazone derivatives by high pressure liquid chromatography or gas chromatography.
1.2 Sources of human and environmental exposure
Acetaldehyde is a metabolic intermediate in humans and higher plants and a product of alcohol fermentation. It has been identified in food, beverages, and cigarette smoke. It is also present in vehicle exhaust and in wastes from various industries. Degradation of hydrocarbons, sewage, and solid biological wastes produces acetaldehyde, as well as the open burning and incineration of gas, fuel oil, and coal.
More than 80% of the acetaldehyde used commercially is produced by the liquid-phase oxidation of ethylene with a catalytic solution of palladium and copper chlorides. Production in Japan was 323 thousand tonnes in 1981. In the USA, production was 281 thousand tonnes in 1982 while in Western Europe it was 706 thousand tonnes in 1983. Most acetaldehyde produced commercially is used in the production of acetic acid. It is also used in flavourings and foods.
The annual emission of acetaldehyde from all sources in the USA is estimated to be 12.2 million kg.
1.3 Environmental transport, distribution, and transformation
Because of its high reactivity, intercompartmental transport of acetaldehyde is expected to be limited. Some transfer of acetaldehyde to air from water and soil is expected because of the high vapour pressure and low sorption coefficient.
It is suggested that the photo-induced atmospheric removal of acetaldehyde occurs predominantly via radical formation. Photolysis is expected to contribute another substantial fraction to the removal process. Both processes cause a reported daily loss of about 80% of atmospheric acetaldehyde emissions. Reported half-lives of acetaldehyde in water and air are 1.9 h and 10-60 h, respectively.
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Acetaldehyde is readily biodegradable.
1.4 Environmental levels and human exposure
Levels of acetaldehyde in ambient air generally average 5 µg/m3. Concentrations in water are generally less than 0.1 µg/litre. Analysis of a wide range of foodstuffs in the Netherlands showed that concentrations, generally less than 1 mg/kg, occasionally ranged up to several 100 mg/kg, particularly in some fruit juices and vinegar.
By far, the main source of exposure to acetaldehyde for the majority of the general population is through the metabolism of alcohol. Cigarette smoke is also a significant source of exposure. With respect to other media, the general population is exposed to acetaldehyde principally from food and beverages, and, to a lesser extent, from air. The contribution from drinking-water is negligible.
Available data are inadequate to determine the extent of exposure to acetaldehyde in the workplace. Workers may be exposed in some manufacturing industries and during alcohol fermentation, where the principal route of exposure is most likely inhalation with possible dermal contact.
1.5 Kinetics and metabolism
1.5.1 Absorption, distribution, and elimination
Available studies on toxicity indicate that acetaldehyde is absorbed through the lungs and gastrointestinal tract; however, no adequate quantitative studies have been identified. Absorption through the skin is probable.
Following inhalation by rats, acetaldehyde is distributed to the blood, liver, kidney, spleen, heart, and other muscle tissues. Low levels were detected in embryos after maternal intraperitoneal (ip) injection of acetaldehyde (mouse) and following maternal exposure to ethanol (mouse and rat). Potential production of acetaldehyde has also been observed in rat fetuses and in the human placenta, in vitro.
Distribution of acetaldehyde to brain interstitial fluid, but not to brain cells, has been demonstrated following ip injection of ethanol. A high affinity, low Km ALDHa may be important in maintaining low levels of acetaldehyde in the brain during the metabolism of ethanol.
Acetaldehyde is taken up by red blood cells and, following ethanol consumption in humans and in baboons, in vivo, intracellular levels can be 10 times higher than plasma levels.
Following oral administration, virtually no unchanged acetaldehyde is excreted in the urine.
1.5.2 Metabolism
The major pathway for the metabolism of acetaldehyde is by oxidation to acetate under the influence of NADb-dependent ALDH. Acetate enters the citric acid cycle as acetyl-CoA. There are several isoenzymes of ALDH with different kinetic and binding parameters that influence acetaldehyde oxidation rates.
ALDH activity has been localized in the respiratory tract epithelium (excluding olfactory epithelium) in rats, in the renal
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cortex and tubules in the dog, rat, guinea-pig, and baboon, and, in the testes in the mouse.
Acetaldehyde is metabolized by mouse and rat embryonic tissue in vitro. Acetaldehyde crosses the rat placenta, in spite of placental metabolism.
Though there is some metabolism of acetaldehyde in human renal tubules, the liver is the most important metabolic site.
Several isoenzymic forms of ALDH have been identified in the human liver and other tissues. There is polymorphism for the mitochondrial ALDH. Subjects who are homozygous or heterozygous for a point mutation in the mitochondrial ALDH corresponding gene have low activity of this enzyme, metabolize acetaldehyde slowly, and are intolerant of ethanol.
The metabolism of acetaldehyde can be inhibited by crotonaldehyde, dimethylmaleate, phorone, disulfiram, and calcium carbamide.
a ALDH = acetaldehyde dehydrogenase. b NAD = nicotinamide adenine dinocleotide.
1.5.3 Reaction with other components
Acetaldehyde forms stable and unstable adducts with proteins. This can impair protein function, as evidenced by inhibition of enzyme activity, impaired histone-DNA binding, and inhibition of polymerization of tubulin.
Unstable adducts of acetaldehyde of undetermined significance occur in vitro with nucleic acids.
Acetaldehyde can react with various macromolecules in the body, preferentially those containing lysine residues, which can lead to marked alterations in the biological function of these molecules.
1.6 Effects on organisms in the environment
1.6.1 Aquatic organisms
LC50s in fish ranged from 35 (guppy) to 140 mg/litre (species not specified). An EC5 of 82 mg/litre and an EC50 of 42 mg/litre were reported for algae and Daphnia magna, respectively.
1.6.2 Terrestrial organisms
Acetaldehyde in air appears to be toxic for some microorganisms at relatively low concentrations.
Aphids were killed when exposed to acetaldehyde at a concentration of 0.36 µg/m3 for 3 or 4 h.
Median lethal values were 8.91 mg/litre per h and 7.69 mg/litre per h for the slug species, Arion hortensis and Agriolimax reticulatus, respectively.
Inhibition of seed germination in the onion, carrot, and tomato by acetaldehyde (up to 1.52 mg/litre) was reversible, whereas inhibition of Amaranthus palmeri, similarly exposed, was
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irreversible. Acetaldehyde at 0.54 µg/m3 damaged lettuce.
1.7 Effects on experimental animals and in vitro test systems
1.7.1 Single exposure
LD50s in rats and mice and LC50s in rats and Syrian hamsters showed that the acute toxicity of acetaldehyde is low. Acute dermal studies were not identified.
1.7.2 Short- and long-term exposures
In repeated dose studies, by both the oral and inhalation routes, toxic effects at relatively low concentrations were limited principally to the sites of initial contact. In a 28-day study in which acetaldehyde at 675 mg/kg body weight (no-observedeffect level (NOEL): 125 mg/kg body weight) was administered in the drinking-water to rats, effects were limited to slight focal hyperkeratosis of the forestomach. Following administration of a single dose level (0.05% in the drinking-water) for 6 months (estimated by the Task Group to be approximately 40 mg/kg body weight) in a biochemical study, acetaldehyde induced synthesis of rat liver collagen, an observation that was supported by in vitro data.
Following inhalation, NOELs for respiratory effects were 275 mg/m3 in rats exposed for 4 weeks and 700 mg/m3 in hamsters exposed for 13 weeks. At lowest-observed-effect levels, degenerative changes were observed in the olfactory epithelium in rats (437 mg/m3) and the trachea (2400 mg/m3) in hamsters. Degenerative changes in the respiratory epithelium and larynx were observed at higher concentrations. No repeated dose dermal studies were identified.
1.7.3 Reproduction, embryotoxicity, and teratogenicity
In several studies, parenteral exposure of pregnant rats and mice to acetaldehyde induced fetal malformations. In the majority of these studies, maternal toxicity was not evaluated. No data on reproductive toxicity were identified.
1.7.4 Mutagenicity and related end-points
Acetaldehyde is genotoxic in vitro, inducing gene mutations, clastogenic effects, and sister-chromatid exchanges (SCEs) in mammalian cells in the absence of exogenous metabolic activation. However, negative results were reported in adequate tests on Salmonella. Following intraperitoneal injection, acetaldehyde induced SCEs in the bone marrow of Chinese hamsters and mice. However, acetaldehyde administered intraperitoneally did not increase the frequency of micronuclei in early mouse spermatids. There is indirect evidence from in vitro and in vivo studies to suggest that acetaldehyde can induce protein-DNA and DNA-DNA cross-links.
1.7.5 Carcinogenicity
Increased incidences of tumours have been observed in inhalation studies on rats and hamsters exposed to acetaldehyde. In rats, there were dose-related increases in nasal adenocarcinomas and squamous cell carcinomas (significant at all doses). However, in hamsters, increases in nasal and laryngeal carcinomas were non-significant. All concentrations of acetaldehyde administered in the studies induced chronic tissue damage in the respiratory tract.
1.7.6 Special studies
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Adequate studies on the potential neuro- and immunotoxicity of acetaldehyde were not identified.
1.8 Effects on humans
In limited studies on human volunteers, acetaldehyde was mildly irritating to the eyes and upper respiratory tract following exposure for very short periods to concentrations exceeding approximately 90 and 240 mg/m3, respectively. Cutaneous erythema was observed in patch testing with acetaldehyde, in twelve subjects of "Oriental ancestry".
One limited investigation in which the incidence of cancer was examined in workers exposed to acetaldehyde and other compounds has been reported.
On the basis of indirect evidence, acetaldehyde has been implicated as the putatively toxic metabolite in the induction of alcohol-associated liver damage, facial flushing, and developmental effects.
1.9 Evaluation of human health risks and effects on the environment
The acute toxicity of acetaldehyde by the inhalation or oral route in studies conducted on animals was low. According to studies on humans and animals, acetaldehyde is mildly irritating to the eyes and the upper respiratory tract. In limited studies on human volunteers, acetaldehyde was mildly irritating to the eyes and upper respiratory tract (section 1.8). Cutaneous erythema has also been observed in the patch testing of humans. Although a possible mechanism has been identified, available data are inadequate to assess the potential of acetaldehyde to induce sensitization.
Available data on the effects of acetaldehyde following ingestion are limited. Following oral administration of 675 mg/kg body weight per day to rats, a borderline increase in hyper-keratosis of the forestomach was observed (NOEL: 125 mg/kg body weight). In rats exposed to a dose level of approximately 40 mg acetaldehyde/kg body weight in the drinking-water for 6 months, there was an increase in collagen synthesis in the liver, the significance of which is unclear.
On the basis of studies on rats and hamsters, the target tissue in inhalation studies is the upper respiratory tract. In available studies, the lowest concentration at which effects were observed was 437 mg/m3 following administration for 5 weeks. The NOELs identified for respiratory effects were 275 mg/m3 in rats exposed for 4 weeks and 700 mg/m3 in hamsters exposed for 13 weeks.
At concentrations that induced tissue damage in the respiratory tract, increased incidences were observed of nasal adenocarcinomas and squamous cell carcinomas in the rat and laryngeal and nasal carcinomas in the hamster.
There is evidence to suggest that acetaldehyde causes genetic damage to somatic cells in vivo.
Available data are inadequate for the assessment of the potential reproductive, developmental, neurological, or immunological effects associated with exposure to acetaldehyde in the general, or occupationally exposed, populations.
On the basis of data on irritancy in humans, a tolerable concentration of 2 mg/m3 has been derived. Since the mechanism of
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induction of tumours by acetaldehyde has not been well studied, two approaches were adopted for the provision of guidance with respect to this end-point, i.e., the development of a tolerable concentration based on division of an effect level for irritancy in the respiratory tract of rodents by an uncertainty factor, and, estimation of lifetime cancer risk based on linear extrapolation. The tolerable concentration is 0.3 mg/m3. The concentrations associated with a 10-5 excess lifetime risk are 11-65 µg/m3.
The limited available data preclude definitive conclusions concerning the potential risks of acetaldehyde for environmental biota. However, on the basis of the short half-lives of acetaldehyde in air and water and the fact that it is readily biodegradable, the impact of acetaldehyde on organisms in the aquatic and terrestrial environments is expected to be low, except, possibly, during industrial discharges or spills.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS
2.1 Identity
Chemical formula: C2H4O
Chemical structure: CH3-CHO
Common name: acetaldehyde
Common synonyms: ethanal; acetic aldehyde; acetylaldehyde; ethylaldehyde; diethylacetal; 1,1-diethyoxy ethane
CAS chemical name: acetaldehyde
CAS registry number: 75-07-0
RTECS registry number: AB 1925000
2.2 Physical and chemical properties
The most important physical and chemical properties of acetaldehyde are given in Table 1.
Acetaldehyde is a volatile liquid with a pungent, suffocating odour that is fruity in dilute concentrations. The odour threshold for acetaldehyde is reported to be 0.09 mg/m3 (0.05 ppm). This was a geometric average of all available literature data (Amoore & Hautala, 1983). In the case of carbon dioxide solutions in acetaldehyde, the acetaldehyde odour is weakened by the carbon dioxide (Hagemeyer, 1978).
Acetaldehyde is a highly reactive compound that undergoes numerous condensation, addition, and polymerization reactions. It decomposes at temperatures above 400°C, forming principally methane and carbon monoxide. Acetaldehyde is highly flammable when exposed to heat or flame, and, in air, it can be explosive. Acetaldehyde can react violently with acid anhydrides, alcohols, ketones, phenols, NH3, HCN, H2S, P, halogens, isocyanates, strong alkalies, and amines. It is miscible in all proportions with water and the most common organic solvents. In aqueous solutions, acetaldehyde exists in equilibrium with the hydrate, CH3 CH(OH)2. The enol form, vinyl alcohol (CH2=CHOH) exists in equilibrium with acetaldehyde to the extent of approximately one molecule per 30 000 (Hagemeyer, 1978).
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Table 1. Physical and chemical properties of acetaldehydea
Colour colourless Relative molecular mass 44.1 Boiling point at 101.3 kPa 20.2°C Melting point -123.5°C Octanol/water partition coefficient as 0.63 log Pow Flash point, closed cup -38°C Autoignition temperature 185-193°C Explosion limits of mixtures with air 4.5-60.5 vol % acetaldehyde Vapour pressure at -50°C 2.5 kPa 0°C 44.0 kPa 20.16°C 101.3 kPa Specific gravity (20/4) 0.778 Relative vapour density 1.52 Refractive index 20/D 1.33113 -14 Dissociation constant at 0°C, Ka 0.7 × 10 Solubility miscible in water and most common solvents a From: Hagemeyer (1978); IPCS/CEC (1990).
Commercial acetaldehyde should have the following typical specifications: purity, 99% min; acidity (as acetic acid), 0.1% max, and a specific gravity of 0.804-0.811 (0°/20°C) (US NRC, 1981).
2.3 Conversion factors
1 mg acetaldehyde/m3 air = 0.56 ppm at 25°C and 101.3 kPa (760 mmHg). 1 ppm = 1.8 mg acetaldehyde/m3 air.
2.4 Analytical methods
Several analytical procedures used for the sampling and determination of acetaldehyde in various media are summarized in Table 2.
Table 2. Sampling, preparation, and determination of acetaldehydea
Medium Sampling method Analytical method Detection limit
Air collection in a midget HPLC with 18 µg/m3 impinger containing 2,4-DNPH spectrophotometric in acetonitrile with detection perchloric acid as catalyst
Air collection in a tube containing HPLC with 0.9 µg/m3 a thermal stable organic polymer spectrophotometric based on 2,6-diphenyl-p- detection phenylene oxide
Air adsorption on a silica gel GC-FTD 0.09-0.45 treated with 2,4-DNPH µg/m3 exhaust
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Air collection in a 2,4-DNPH HPLC with < 18 µg/m3 coated Sep-PAK cartridge, spectrophotometric acidified with HCl detection
Table 2 (contd).
Medium Sampling method Analytical method Detection
Air collection in annular denuders HPLC with UV 0.36 µg/m3 coated with 2,4-DNPH absorbance or detection voltametric pollution
Air collection and derivatization HPLC with UV 90 µg/m3 on 2,4-DNPH coated detection Chromosorb P
Air collection on DNPH-coated C18 HPLC with UV 12 ng per cartridge detection cartridge
Air collection and derivatization HPLC with UV 32 mg/m3b in midget bubblers containing detection Girard T solution
Table 2 (contd).
Medium Sampling method Analytical method Detection limit
Air collection in a Chromosorb 104 GC-FID 0.1 µg/lit tube installed in an automated sampler
Air collection on a XAD-2 sorbent GC-FID 1.3 mg/m3c coated with 2-(hydroxymethyl)- piperidine
Water derivatization in a two-phase HPLC with 21 µg system by addition of 2,4-DNPH electrochemical and isooctane detection
Water purging with nitrogen gas and sweeping by rapid 200 µg/ collection on a Tenax GC heating of trap litre sorbent and silica gel trap into GC-MS
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Water derivatization with 2,4-DNPH HPLC; the reaction < 10 µg pe (in acetonitrile) mixture is analysed sample directly, without and mist samples prior separation of the DNPH-derivatives
Table 2 (contd).
Medium Sampling method Analytical method Detecti limit
Water collection in a PTFE-cartridge HPLC with UV 0.3 µg/li packed with sulfonated cation detection exchange resin charged with 2,4-DNPH
Water collection of aqueous solution HS-GC-FID 25 µg/lit in vials, no special treatments released from plastics into aqueous foods
Water collection on cyanogen bromide spectrophotometric 0.6 mg/ activated Sepharose 4B detection litre containing aldehyde dehydrogenase; soluble aldehyde dehydrogenase injected in the sampler flow stream using a double injection technique
Beverage collection of the 2,6- HPLC with 0.01 µg p dimethylpyridine derivative spectrophotometric sample on a 3-aminopropyl- detection triethoxysiloxane or a Nucleosil 5NH2 treated silica gel with propionaldehyde as internal standard
Table 2 (contd).
Medium Sampling method Analytical method Detection limit
Beverage steam distillation followed by HPLC with UV ± 5 µg/ liquid liquid extraction, detection litre derivatization with p-nitrobenzyl- oxyamine-hydrochloride with T-2 undecenal as internal standard
Beverage conversion of acetaldehyde HS-GC-FID ± 1 mg/ acetals and bisulfite addition litre products to free acetaldehyde by a series of 1-min acid, base, and iodine treatments followed by a 10-min equilibration period
Breast collection of volatile compounds thermal -- milk on a Tenax cartridge after desorption
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warming milk and purging with into GC-MS helium
Blood precipitation of protein with GC headspace 4.4 µg per perchloric acid analysis sample artificial formation of acetaldehyde
Blood derivatization with 2,4-DNPH HPLC with UV 4.4 ng per with butyraldehyde as internal detection sample standard and perchloric acid (for protein precipitation)
Table 2 (contd).
Medium Sampling method Analytical method Detection limit
Blood rapid separation plasma: HPLC with > 0.9 ng plasma: deproteinization and spectrophotometric per sample derivatization with 2,4-DNPH detection haemolysate: deproteinization haemolysate: and mixed with semicarbazide HS-GC-FID hydrochloride
Blood separation of plasma and HPLC with 11 µg per haemolysate plasma: fluorescence sample 1,3-cyclo-hexanedione and detection isooctane haemolysate: 1,3-cyclo-hexadione both in presence of ammonium ion
Blood reaction with 1,3-cyclo-hexanone HPLC with 4.4 µg per in the presence of ammonium ion fluorescence sample propionaldehyde used as internal detection standard
Blood collection in an organic solution HPLC with > 0.13 µg of 2-diphenylacetyl- spectrofluometric per sample 1,3-indandione-1-hydrazone, and detection forming fluorescent azine derivative-precipitation of proteins
Table 2 (contd).
Medium Sampling method Analytical method Detection limit
Blood reaction with methanolic solution HPLC; the 4.4 µg/lit and of 2,4-DNPH, with acetaldehyde adduct tissue dinitrophenyl-[14C]-formaldehyde was identified by as internal standard co-chromatography with the authentic derivative and by mass spectrometry
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a 2,4-DNPH = 2,4-dinitrophenylhydrazine; HPLC = high pressure liquid chromat detection; GC-FTD = gas chromatography with flame thermionic detection; GC HS-GC-FID = head space gas chromatography with flame ionization detection. b minimum working range (estimated LOD: 1.6 mg/m3). c minimum working range (estimated LOD: 0.67 mg/m3).
The most specific and sensitive analytical method, widely used to date, is based on the reaction of acetaldehyde with 2,4-dinitro-phenylhydrazine (2,4-DNPH) and the subsequent analysis of the hydrazone derivatives by high pressure liquid chromatography (HPLC) or gas chromatography (GC). Methods mentioned by US NIOSH are based on derivatization with Girard T solution followed by HPLC analysis with UV detection (US NIOSH, 1987), or, on derivatization with 2-(hydroxymethyl)piperidine followed by GC analysis with a flame ionization detector (FID) (US NIOSH, 1989). In the method based on Girard T derivation, other volatile aldehydes compete for the Girard T reagent. Chromatographic conditions may be adjusted to resolve acetaldehyde from other aldehydes.
Spingarn et al. (1982) determined volatile organic compounds in aqueous solutions, including acetaldehyde, using a technique in which the compounds were purged from the solution by bubbling with an inert gas into a trap containing a Tenax sorbent and silica gel. The analytes were separated by GC and detected with either specific ionization detection or MS. An improvement in detection limits, compared with those of the widely used spectrophotometric method of analysing carbonyls in aqueous solution, was obtained by Facchini et al. (1986) by means of an electrochemical detector.
In the determination of acetaldehyde in blood, two main difficulties exist. The first is related to its disappearance from blood prior to measurement and the second is related to the formation of acetaldehyde in blood after collection. According to Pezzoli et al. (1984), the addition of butyraldehyde to blood, as an internal standard, immediately after withdrawal, obviates some of the inconveniences in the determination of acetaldehyde in blood. The addition of butyric acid makes it possible to obtain results both for the interaction of the aldehyde group of the acetaldehyde with amino groups, and for the formation and extraction of the derivative compound. However, Di Padova et al. (1986) stated that the addition of butyraldehyde was not specific for the determination of the acetaldehyde but was related to the aldehyde group reactivity. Therefore, they described an improved procedure for measuring acetaldehyde in plasma, based on rapid separation, 2,4-DNPH derivatization, and HPLC analysis, and a procedure for measuring acetaldehyde in red blood cells, based on the use of a semicarbazide solution and analysis by head space gas chromatography.
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
Acetaldehyde is a metabolic intermediate in humans and higher plants and it is a product of alcohol fermentation (IARC, 1985). It has been identified as a volatile component of mature cotton leaves and cotton blossoms (Berni & Stanley, 1982) and as a component in the essential oil of alfalfa at a concentration of about 0.2% (Kami, 1983). It occurs in food, various fruits, and several spices (see section 5.1.4) and in oak and tobacco leaves (Furia & Bellanca, 1975; US NRC, 1985).
Acetaldehyde is formed in the atmosphere in a variety of ways.
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It is generated by the oxidation of non-methane hydrocarbons both in the background troposphere and in photochemical smog (Grosjean, 1982).
3.2 Anthropogenic sources
3.2.1 Production
3.2.1.1 Production levels and processes
Until 1968, most acetaldehyde produced in the USA was made by the partial oxidation of ethanol over a silver catalyst; however, currently less than 5% of US production is based on this process. The liquid-phase oxidation of ethylene using a catalytic solution of palladium and copper chlorides was first used commercially in the USA in 1960 and more than 80% of the world production of acetaldehyde is made by this process. The remainder is produced by the oxidation of ethanol and the hydration of acetylene. Acetaldehyde is produced by a limited number of companies over the world. The total production of acetaldehyde in the USA in 1982 amounted to 281 thousand tonnes. Total acetaldehyde production in Western Europe in 1982 was 706 thousand tonnes, and the production capacity was estimated to have been nearly 1 million tonnes. In Japan, the estimated production in 1981 was 323 thousand tonnes (Hagemeyer, 1978; IARC, 1985).
3.2.1.2 Emissions
Eimutis et al. (1978) estimated that the annual atmospheric emissions of acetaldehyde in the USA amounted to 12.2 thousand tonnes (Table 3). Emissions of acetaldehyde in the Netherlands in the year 1980 were reported to be 584 tonnes (Guicherit & Schulting, 1985).
Table 3. Emission and sources of acetaldehyde in the USA
Source Emissions (tonnes/year)
Residential external combustion of wood 5056.4 Coffee roasting 4411.4 Acetic acid manufacture 1460.9 Vinyl acetate manufacture from ethylene 1094.6 Ethanol manufacture 57.8 Acrylonitrile manufacture 51.6 Acetic acid manufacture from butane 20.8 Crotonaldehyde manufacture 4.5 Acetone and phenol manufacture from cumene 1.9 Acetaldehyde manufacture by hydration of ethylene 0.5 Polyvinyl chloride manufacture 0.2 Acetaldehyde manufacture by oxidation of ethanol 0.1
3.2.2 Uses
Acetaldehyde is an important intermediate in the production of acetic acid, ethyl acetate, peracetic acid, pentaerythritol, chloral, glyoxal, alkylamines, and pyridines (Hagemeyer, 1978). The use pattern for the estimated 281 thousand tonnes of acetaldehyde produced in the USA in 1982 was as follows: acetic acid 61%, pyridine and pyrine bases 9%, peracetic acid 8%, pentaerythritol 7%, 1,3-butylene glycol 2%, chloral 1%, and other applications (including use as a food additive and exports) 12%. The use pattern for the estimated 706 thousand tonnes of acetaldehyde produced in Western Europe was as follows: acetic acid 62%, ethyl acetate 19%, pentaerythritol 5%,
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synthetic pyridines 3%, and all other uses 11% (IARC, 1985).
Acetaldehyde is used for the flavourings: berry, butter, chocolate, apple, apricot, banana, grape, peach, black walnut, and rum, and it is used in the following foods: beverages, ice cream and ices, candy, baked goods, gelatin desserts, and chewing gum (Furia & Bellanca, 1975; US NRC, 1981, 1985). Acetaldehyde is also used in perfumes, aniline dyes, plastics, in the manufacture of synthetic rubber, in the silvering of mirrors, in the hardening of gelatin fibres, and in the laboratory (Verschueren, 1983).
3.2.3 Waste disposal
Degradation of hydrocarbons, sewage, and solid biological wastes produces acetaldehyde. It has been detected in effluents from sewage-treatment plants and chemical plants (US EPA, 1975; Shackelford & Keith, 1976).
Acetaldehyde has been identified as a constituent in the wastes from petroleum refining, coal processing, the oxidation of alcohols, saturated hydrocarbons, or ethylene, and the hydration of acetylene (IARC, 1985).
3.2.4 Other sources
Acetaldehyde is detected as a combustion product of plastics and polycarbonate and polyurethane foams of western European origin (Hagen, 1967; Boettner et al., 1973).
Acetaldehyde occurs in vehicle exhaust at levels of 1.4-8.8 mg/m3 in gasoline exhaust, about 5.8 mg/m3 in diesel exhaust (Verschueren, 1983), and 51.6% acetaldehyde/ n-hexane GC peak area ratio in exhaust gas oxygenates (Hugues & Hum, 1960). It also occurs in the open burning and incineration of gas, fuel oil, and coal, and evaporation products of perfumes (Verschueren, 1983).
Acetaldehyde has been identified in fresh tobacco leaves and in tobacco smoke (concentrations ranging from 2.1 to 4.6 mg/litre smoke) (Buyske et al., 1956; Osborne et al., 1956; Mold & McRae, 1957).
When Lipari et al. (1984) measured aldehyde emissions from wood-burning fireplaces, they ranged from 0.08 to 0.20 g/kg of wood burned, based on tests with cedar, jack pine, red oak, and green ash.
Acetaldehyde emissions from wood-burning furnaces and stoves were also measured in a Swedish study (Rudling et al., 1981) and in a Norwegian study (Ramdahl et al., 1982). In the Swedish study, the emissions ranged from 1-72 mg/kg wood in prechamber ovens to 9-710 mg/kg wood in fireplace stoves. In the Norwegian study, the reported emissions from stoves were 14.4 mg/kg dry wood under normal burning conditions and up to 992 mg/kg dry wood under low-efficiency combustion.
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
4.1 Transport and distribution between media
Acetaldehyde can enter the atmosphere during production of the compound itself, as a product of incomplete combustion, and also as a by-product of fermentation (Grosjean, 1982).
Photochemical oxidation of acetaldehyde has been shown to be an important process in the chemistry of photochemical smog (Bagnall & Sidebottom, 1984; Leone & Seinfeld, 1984). Present theories ascribe
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the importance of acetaldehyde to its being a precursor of peroxyacetylnitrate (PAN) in polluted atmospheres (Kopczynski et al., 1974; Grosjean et al., 1983; Bagnall & Sidebottom, 1984; Moortgat & McQuigg, 1984). Acetaldehyde is likely to be a precursor of acetic acid, which is a component of natural precipitation and contributes to its acidity (Moortgat & McQuigg, 1984).
Intercompartmental transport of acetaldehyde is expected to be limited, because of its high reactivity. However, because of the high vapour pressure of acetaldehyde, some transfer to air from water and soil can be expected.
The tendency of acetaldehyde to adsorb on soil particles can be expressed in terms of Koc, the ratio of the amount of chemical adsorbed per unit weight of organic carbon to the concentration of the chemical in solution at equilibrium. On the basis of the available empirical relationships derived for estimating Koc, a low soil adsorption potential is expected (Lyman et al., 1982). Koch & Nagel (1988) calculated a soil sorption coefficient of 0.90 for acetaldehyde, and, therefore, acetaldehyde was classified as a compound with a very low sorption tendency.
4.2 Abiotic degradation
It is suggested that photo-induced atmospheric removal of acetaldehyde occurs predominantly via radical formation. Singh et al. (1982) reported that photolysis and reaction with hydroxyl radicals cause a daily loss rate of about 80% of atmospheric acetaldehyde emissions. Grosjean et al. (1983) reported that the reaction with hydroxyl radicals could remove 50-300 tonnes of carbonyls from the Los Angeles air over a 12-h daytime period and, thus, is considered to be a major removal process for all aldehydes. The absolute rate constant for the reaction of the hydroxyl radical with acetaldehyde was determined over a temperature range of 26-153°C by Atkinson & Pitts (1978). At 26°C, they obtained a rate constant of (1.60 ± 0.16) × 10-11 cm3 per molecule per second. This results in a half-life for acetaldehyde of 10 h, using a 12-h daytime average hydroxyl radical concentration of 2 × 10-15 mol/litre (Lyman et al., 1982). Hustert & Parlar (1981) reported that 49.5% acetaldehyde was photochemically degraded (reaction with hydroxyl radicals) after a 2-h radiation (lambda > 230 nm) at 25°C, which, contrary to Atkinson & Pitts (1978), shows a half-life of 2 h. Atkinson et al. (1984) obtained a rate constant of (1.34 ± 0.28) × 10-15 for the gas-phase reaction of nitrate radicals with acetaldehyde at 25°C. This results in a half-life for acetaldehyde of 59.6 h using a 12-h nighttime average nitrate radical concentration of 4.0 × 10-12 mol/litre (Atkinson et al., 1987).
There is a considerable amount of evidence that acetaldehyde in aqueous solution is in equilibrium with its hydrated form CH3CH(OH)2. The degree of hydration decreases with increasing temperature (e.g., at 0°C, the fraction of acetaldehyde hydrated is 0.73; at 25°C, it is 0.59) (Bell & Clunie, 1952).
Von Burg & Stout (1991) reported a half-life of 1.9 h for acetaldehyde in river water; no other details were provided.
4.3 Biodegradation
Several studies have revealed significant degradation of acetaldehyde by mixed cultures obtained from sludges and settled sewage. Hatfield (1957) reported the ability of acclimatized sludge to oxidize acetaldehyde (major portion of the biological and chemical
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oxygen demand (BOD and COD) removed within a 4-h aeration period). Ludzack & Ettinger (1960) determined the BOD for acetaldehyde in activated sludge at 20°C and found that 93% of the acetaldehyde was removed after an observation period of 1/3-5 days and an acclimatization period of 30 days. Thom & Agg (1975) and Speece (1983) also reported that acetaldehyde was easily biodegradable by biological sewage treatment (additional information was not provided). However, Gerhold & Malaney (1966) reported little degradation of acetaldehyde by unacclimatized municipal sludge with a BOD of 27.6% as a percentage of the theoretical oxygen demand in 24 h.
Acetaldehyde is also degraded by anaerobic biological treatment with unacclimatized acetate-enriched cultures. A COD-removal of 97% was obtained at the end of a 90-day acclimatization period in completely mixed reactors with a 20-day hydraulic retention time, no solids recycle, and a final daily feed concentration of 10 000 mg/litre (Chou & Speece, 1978).
Acetaldehyde is reported to be readily biodegradable using the biodegradability MITI test, defined in OECD Guidelines for testing of chemicals (OECD, 1992).
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels
5.1.1 Air
The concentrations of acetaldehyde in uncontaminated Arctic air masses, determined over a 24-h period, ranged from not detected to 0.54 µg/m3 (Cavanagh et al., 1969).
In samples collected during April 1981, the levels of acetaldehyde in the air in Pittsburg (PA) and Chicago (Il) were 0.36-4.68 µg/m3 and 1.62-6.12 µg/m3, respectively (Singh et al., 1982). In samples collected at 7 other locations in the USA between 1975 and 1978, mean concentrations in ambient air were 5-124 µg/m3 (Brodzinsky & Singh, 1982).
Schulam et al.(1985) determined the levels of acetaldehyde in air (June-August 1983) in the urban location of Schenectady (NY) and the rural location of Whiteface Mountain (NY). Concentrations of acetaldehyde were similar in the two locations (the levels of acetaldehyde varied from 0.36 to 1.44 µg/m3, detection limit: 0.29 µg/m3).
The average ambient atmospheric level of acetaldehyde, measured during the four seasons at Brookhaven National Laboratory (Upton, Long Island, NY) from July 1982 to May 1983, was 5.2 µg/m3, with a mean minimum concentration in winter of 1.8 µg/m3 and a mean maximum value in summer of 15.1 µg/m3 (Tanner & Meng, 1984). Concentrations of acetaldehyde in the air in Tulsa, OK (sampled in July 1978), Rio Blanco County, CO (sampled in July 1978), and the Great Smoky Mountains, TN (sampled in September 1978), ranged up to 14.9, 16.9, and 23.9 µg/m3, respectively (Arntz & Meeks, 1981).
Mean concentrations of acetaldehyde in the air in Tokyo during four seasons in 1985-86 ranged from 2.2 to 7.3 µg/m3 (Watanabe, 1987). Seasonal trends were not noted. Concentrations of acetaldehyde in an environmental survey conducted by the Japan Environment Agency in 1987 ranged from 0.9 to 22 µg/m3 (number of sites sampled unspecified) (Japan Environment Agency, 1989).
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The mean concentration of acetaldehyde was 2 µg/m3 at three locations in the Netherlands, namely, the island of Terschelling (one of the least polluted areas of the country), Delft (suburban), and Vlaardingen (heavily industrialized area) (Guicherit & Schulting, 1985).
Grosjean (1991) reported levels of acetaldehyde in ambient air, sampled every sixth day over a one-year period, at six locations in Southern California between September 1988 and September 1989. Concentrations ranged up to 23.3 µg/m3 (13 ppb) with average values at the various locations ranging from 5.2 to 8.6 µg/m3 (2.9-4.8 ppb).
The mean concentration of acetaldehyde in fog samples taken in November, 1985 in the Po Valley (Italy) was 21 µg/litre (Facchini et al., 1986). At urban locations in California (Los Angeles) and Alaska (Fairbanks), concentrations of acetaldehyde ranged from 0.007 to 0.13 µg/ml in ice fog (Alaska), 0 to 0.11 µg/ml in rain (CA), 0 to 0.59 µg/ml in cloud (CA), 0.10 to 0.11 µg/ml in mist (CA), and 0.006 to 0.17 µg/ml in fog (CA) (Grosjean & Wright, 1983).
5.1.2 Water
No quantitative data on concentrations of acetaldehyde in raw water supplies were identified.
Acetaldehyde has been detected in drinking-water from Philadelphia and Seattle at levels of up to 0.1 µg/litre (Keith et al., 1976). No other information was provided.
5.1.3 Soil
Data on concentrations of acetaldehyde in soil were not identified.
5.1.4 Food
Acetaldehyde has been detected in a wide range of foodstuffs (US NRC, 1981, 1985; Horvath et al., 1983; Feron et al., 1991), though few quantitative data are available. In a variety of foodstuffs analysed in the Netherlands including fruits and juices, vegetables, milk products, bread, eggs, fish, meat, and alcoholic beverages, concentrations were generally less than 1 mg/kg, but occasionally ranged up to several hundred mg/kg, particularly in some fruit juices and alcoholic beverages; in vinegar, a maximum value of 1060 mg/kg was reported (Maarse & Visscher, 1992). Acetaldehyde has been identified in alcoholic beverages, such as beer and wine (Okamoto et al., 1981; Piendl et al., 1981; Jones et al., 1986); levels in 18 English beers ranged from 2.6 to 13.5 mg/litre (Delcour et al., 1982). Levels of 0.2 to 1.2 mg/litre were found in wine samples in Japan (Okamato et al., 1981), while Margeri et al. (1984) reported levels of acetaldehyde in wines ranging between about 30 and 80 µg/litre.
Acetaldehyde has been detected, but not quantified, in breast milk in the USA (detection limit not reported) (Pellizari et al., 1982).
5.1.5 Cigarette smoke
Acetaldehyde is present in tobacco leaves and in cigarette smoke (Furia & Bellanca, 1975; US NRC, 1985). Hoffman et al. (1975) detected acetaldehyde in the smoke of tobacco (980 µg per cigarette) and marijuana (1200 µg/cigarette). The concentration in smoke from several cigarettes ranged from 0.87 to 1.22 mg per cigarette or from
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1.14 to 1.37 mg/cigarette, depending on the method of detection. The concentration of acetaldehyde in three types of low-tar cigarettes ranged from 0.09 to 0.27 mg/cigarette (Manning et al., 1983).
5.2 General population exposure
Acetaldehyde is a metabolic product of ethanol. On the basis of the assumptions that a standard drink contains 10 g of ethanol and that about 90% of imbibed alcohol is metabolized to acetaldehyde, alcoholic beverages are generally by far the most significant source of exposure to acetaldehyde for the general population.
On the basis of the content of acetaldehyde in cigarettes reported in section 5.1.5, it is likely that cigarettes contribute significantly to the total intake of acetaldehyde by smokers. Assuming that smoke contains about 1 mg acetaldehyde per cigarette, that 20 cigarettes are smoked per day, and a mean adult body weight of 64 kg (WHO, in press), intake from mainstream smoke would be about 300 µg/kg body weight per day.
On the basis of the average dietary intake of food groups in different regions of the world (WHO, in press) and the contents of acetaldehyde in foodstuffs and non-alcoholic beverages in the Netherlands (Maarse & Visscher, 1992), food (particularly fruit juices) may be one of the principal sources of exposure to acetaldehyde in the general environment. More representative data on mean concentrations in foodstuffs have not been identified, but, on the basis of the ranges of concentrations determined in the Dutch survey, intake in food is estimated to range from just less than 10 to several hundred µg/kg body weight per day.
Data from recent studies in various locations in the world indicate that mean concentrations of acetaldehyde in ambient air range from 2 to 8.6 µg/m3 (Guicheret & Schulting, 1985; Watanabe, 1987; Grosjean, 1991) (section 5.1.1). Data on concentrations of acetaldehyde in indoor air were not identified. On the basis of a daily inhalation volume for adults of 22 m3, a mean body weight for males and females of 64 kg (WHO, in press), and the assumption that mean concentrations are approximately 5 µg/m3, the mean intake of acetaldehyde from ambient air for the general population is estimated to be 1.7 µg/kg body weight per day.
Limited identified data on concentrations of acetaldehyde in drinking-water indicate that they are generally less than 0.1 µg/litre (Keith et al., 1976). Assuming a daily volume of ingestion for adults of 1.4 litres and a mean body weight for males and females of 64 kg (WHO, in press), and that levels are less than 0.1 µg/litre, the estimated intake of acetaldehyde from drinking-water for the general population would not exceed 0.002 µg/kg body weight per day.
5.3 Occupational exposure
Workers are exposed to acetaldehyde in the organic chemicals industry and in the fabricated rubber, plastic, and fermentation industries (US NIOSH, 1980, 1981). Concentrations of acetaldehyde were below the detection limits (1-3.4 mg/m3) in five studies in which the workroom air of plants, such as those in textile finishing, propylene bottle production, and ureaformaldehyde foam-insulation manufacturing, was monitored (Rosensteel & Tanaka, 1976; Ahrenholz & Gorman, 1980; Herrick, 1980; Chrostek & Shoemaker, 1981; Chrostek, 1981). Bittersohl (1975) reported levels of acetaldehyde of 1-7 mg/m3 in the hydrogenation unit of a chemical factory after equipment leakages.
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Concentrations of acetaldehyde to which workers may be exposed near aircraft with low-smoke combustor engines were found to range from 139 to 394 µg/m3 (Miyamoto, 1986).
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1 Absorption
No studies are available on animals or humans concerning the absorption of acetaldehyde. However, the results of toxicity studies indicate that absorption via the lungs and gastrointestinal tract does occur. The physical and chemical properties of acetaldehyde indicate that absorption via the skin is also possible.
6.2 Distribution
6.2.1 Animal studies
6.2.1.1 Distribution after inhalation exposure
Distribution studies were conducted on overnight-starved, male Sprague-Dawley rats exposed (whole-body) to unknown concentrations of acetaldehyde vapour for 1 h. Acetaldehyde was recovered in total blood, liver, kidneys, spleen, heart muscle, and skeletal muscle. No other tissues were studied. The concentration of acetaldehyde in the liver was relatively low (Hobara et al., 1985; Watanabe et al., 1986). This can be attributed to rapid metabolism by hepatocytes.
6.2.1.2 Distribution to the embryo and fetus
No studies are available concerning routes of relevance to humans.
Acetaldehyde was detected in the embryo up to 2 h after maternal ip injection of 200 mg acetaldehyde/kg body weight in CD-1 mice on day 10 of gestation; acetaldehyde was measured within 5 min of injection. Following maternal ip injection of 79 mg ethanol/kg body weight, acetaldehyde was measured up to 12 h after injection; however, levels were low and approached the limit of sensitivity (Blakley & Scott, 1984b).
Several other studies have demonstrated the presence of acetaldehyde in the embryos of rats (Espinet & Argiles, 1984; Gordon et al., 1985; Guerri & Sanchis, 1985; Clarke et al., 1986), guinea-pigs, and ewes (Clarke, 1988) exposed to ethanol. Embryological and cytogenic studies with ethanol and acetaldehyde in preimplantation mouse embryos in vitro showed that acetaldehyde is three times more toxic than ethanol. It has been suggested that the preimplantation mouse embryo is able to convert ethanol to acetaldehyde, and that the enzyme involved is alcohol dehydrogenase (ADH) (Lau et al., 1991)
6.2.1.3 Distribution to the brain
In the only study involving a route of relevance to humans, following a single intragastric administration of 4500 mg ethanol/kg body weight to male and female Wistar rats, acetaldehyde was detected in the blood and in brain interstitial fluid collected from the caudate nucleus and the thalamushypothalamus region. Following administration of disulfiram (an inhibitor of the aldehyde dehydrogenase (ALDH)-catalysed oxidation of acetaldehyde to acetate) 20 h prior to exposure to ethanol, there was a 6-fold increase in the concentration of acetaldehyde in the blood and brain. Although acetaldehyde was found in interstitial fluid, none was detected in whole brain (Westcott et al., 1980).
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In albino rats treated first with pyrazole, an inhibitor of ADH, injected (ip) with a solution of acetaldehyde in saline (200 mg/kg body weight per day) for 10 days, and then sacrificed 30 min after receiving the last injection, acetaldehyde was detected in the brain, liver, and blood (Prasanna & Ramakrishnan, 1984b, 1987).
A study by Pettersson & Kiessling (1977) indicated the importance of ALDH activity, with a low Michaelis constant, in maintaining a low level of brain acetaldehyde during ethanol metabolism. They detected acetaldehyde and ethanol in the cerebrospinal fluid of rats after intraperitoneal administration of ethanol alone or of ethanol followed by acetaldehyde.
6.2.2 Human studies
The percentage of acetaldehyde retained by 8 volunteers inhaling acetaldehyde vapour (100-800 mg/m3) from a recording respirometer ranged from 45 to 70%, at different respiratory rates. Total respiratory tract retention was the same whether the vapour was inhaled through the nose or the mouth. A direct relationship was found between the contact time and uptake, independent of rate. Thus, the critical factor in determining acetaldehyde uptake is the duration of the ventilatory cycle (Egle, 1970).
Baraona et al. (1987) used the blood of 5 healthy individuals, 6 alcoholic patients, and 2 baboons to show that, after alcohol consumption, most of the blood acetaldehyde was found in the red blood cells. In vivo, the acetaldehyde concentration in red cells was about 10 times higher than that in the plasma. No significant variations were seen between the 3 groups.
Studies using the perfused human placental cotyledon indicated that the human placenta has the potential to produce acetaldehyde, which can enter the fetal circulation. Furthermore, partial transfer of acetaldehyde from maternal to fetal blood may occur (Karl et al., 1988).
6.3 Metabolism
6.3.1 Animal studies
The main pathway for the metabolism of acetaldehyde is shown in Fig. 1.
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6.3.1.1 Liver
The main pathway for the metabolism of acetaldehyde is by rapid oxidation to acetate, which enters the citric acid cycle in an activated form as acetyl-CoA and is metabolized to CO2 and H2O.
Although catalase and other oxidases may contribute to metabolism (Brien & Loomis, 1983), because of its high affinity, at least 90% of acetaldehyde is oxidized by mitochondrial ALDH (Hellström-Lindahl & Weiner, 1985) reducing NAD+ to NADH in the process. This step can be blocked by disulfiram.
There are multiple molecular forms of ALDH with different kinetic properties that influence the rate of removal of acetaldehyde (Marjanen, 1973; Parilla et al., 1974; Teschke et al., 1977).
Acetaldehyde is a highly reactive molecule that can react with many other large or small molecules by adduction, condensation, or polymerization. These pathways may have little quantitative significance in acetaldehyde metabolism, but the by-products may have biological significance (Collins et al., 1979; Sorrell & Tuma, 1985).
Acetaldehyde is the primary metabolic product of ethanol oxidation. Since ethanol is oxidized to acetaldehyde mole for mole, and, since the exposure to exogenous acetaldehyde is small, endogenous acetaldehyde resulting from the metabolism of ingested ethanol is likely to be the most important source of exposure for most people. Oxidation of ethanol to acetaldehyde occurs predominantly under the influence of ADH, of which there are many isoenzymic forms. Like ALDH, ADH is also NAD dependent. The inseparable metabolism of ethanol and acetaldehyde results in the reduction of NAD+, thus, affecting the redox state of the liver causing secondary metabolic consequences.
6.3.1.2 Respiratory tract
ALDH localization in the respiratory tract of Fischer-344 rats was studied by Bogdanffy et al. (1986). Histochemical studies indicated activity principally in the nasal respiratory epithelium, especially in the supranuclear cytoplasm of ciliated epithelial cells. Activity was also high in the Clara cells of the lower bronchioles. The tracheal epithelia possessed only low levels of ALDH. The olfactory epithelium was almost devoid of ALDH activity.
Casanova-Schmitz et al. (1984) characterized at least 2 isoenzymes of ALDH in rat nasal mucosa homogenates.
6.3.1.3 Kidneys
In an in vitro study, Michoudet & Baverel (1987a,b) studied the metabolism of acetaldehyde in isolated dog, rat, guinea-pig, and baboon kidney-cortex tubules.
Acetaldehyde was found to be metabolized by the tubules at high rates and in a dose-dependent manner in all four species. It was noted that, at all acetaldehyde concentrations, most of the acetaldehyde removed was recovered as acetate in dog, guinea-pig, and baboon, but not in rat kidney tubules.
6.3.1.4 Testes and ovaries
There are no studies on the capacity of the testes or ovaries to mediate the biotransformation of acetaldehyde. However, ALDH activity has been identified in the testes of Swiss-Webster mice (Anderson et
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al., 1985).
6.3.1.5 Embryonic tissue
In an in vitro study, the ability of CBA/beige mouse (10 days old) and Wistar rat (12 days old) embryos to metabolize acetaldehyde was reported by Priscott & Ford (1985).
6.3.1.6 Metabolism during pregnancy
After intravenous administration of acetaldehyde (10 mg/kg body weight) blood acetaldehyde levels were higher in pregnant rats than in virgin rats. Acetaldehyde at high concentrations was able to cross the placental barrier very rapidly. At low maternal concentrations, it was metabolized by aldehyde dehydrogenase activity in the placenta and fetal liver, and acetaldehyde was not detected in fetal blood. Above the acetaldehyde threshold, the metabolic capacity of the feto-placental unit was surpassed and acetaldehyde was detected in fetal blood (Zorzano & Herrera, 1989).
6.3.2 Human studies
No high quality studies of the in vivo metabolism of acetaldehyde in humans have been identified. Accurate assays for acetaldehyde in blood and tissues have only recently become available (Harade et al., 1978a,b).
Human liver ALDH consists of at least 4 main isoenzymes, which are also present in many other tissues (Koivula, 1975; Goedde et al., 1979). Mitochondrial ALDH is inactive in at least 40% of the Oriental population. The frequently observed intolerance to alcohol (the "flushing" reaction) is linked to this deficiency, which is produced by an inherited positive mutation in the corresponding gene (Yoshida et al., 1984; Goedde & Agarwal, 1986, 1987; Hsu et al., 1988). Subjects with phenotypic deficiency have always shown the presence of at least one mutant gene (heterozygous or homozygous) (Crabb et al., 1989; Goedde et al., 1989; Singh et al., 1989).
In vitro, acetaldehyde (0.04-0.88 g/litre) was metabolized at high rates and in a dose-dependent manner in isolated human kidney-cortex tubules (Michoudet & Baverel, 1987b).
6.4 Elimination
In dogs, urinary excretion of acetaldehyde was essentially non-existent following administration of a single dose of 600 mg acetaldehyde/kg body weight, via a stomach tube (Booze & Oehme, 1986).
6.5 Reaction with cellular macromolecules
6.5.1 Proteins
Acetaldehyde can react with nucleophilic groups, such as amino, hydroxyl, and sulfydryl groups, through nucleophilic attack on the carbonyl carbon atom of acetaldehyde to give both stable and unstable adducts (Tuma et al., 1984). Several adduct structures, formed when acetaldehyde reacts with proteins in vitro, have been identified, but have not yet been described fully.
The best characterized nucleophiles able to form adducts with acetaldehyde are amino groups, notably the alpha-amino terminus of peptides and proteins and the epsilon-amino group on the side-chain of lysine residues. These reactions are shown in Fig. 2.
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The structure of 2-methylimidazolidin-4-one adducts has been confirmed by proton NMR (Gidley et al., 1981) and 13C-NMR spectroscopy (San George & Hoberman, 1986). N-ethylation lysine residues have been demonstrated by Tuma et al. (1984).
In a series of studies on lysine-dependent enzymes, Mauch et al. (1986, 1987) were able to demonstrate that incubation of purified enzymes with acetaldehyde for 1 h at 37°C led to inhibition of their catalytic activity. Lysine non-dependent enzymes were not affected by this treatment. A similar study involving the incubation of rat liver histone H1 with physiological concentrations of acetaldehyde showed that spontaneously stable adducts were formed on lysine residues at the carboxy terminus, a site crucial for its function as a eukaryotic repressor (Niëmela et al., 1990). This acetaldehyde-modified histone H1 showed impaired DNA binding activity.
Tuma et al. (1987) have characterized the interaction of acetaldehyde with a "highly reactive" lysine residue in purified alpha-tubulin, which is only available in the monomeric form. They found that modification of this residue was the critical factor in the inhibition of tubulin polymerization by acetaldehyde, and that modification of 5% of these residues was enough to inhibit tubulin polymerization completely in vitro. Crebelli et al. (1989) found similar effects: 0.075% v/v (13.5 mmol/litre) acetaldehyde partially inhibited the in vitro polymerization of cattle brain tubulin, and 0.15% (27 mmol/litre) caused complete inhibition.
Incubation of calf brain microtubular proteins also resulted in decreased polymerization, in an analogous manner to tubulin (McKinnon et al., 1987a,b). Thus, acetaldehyde modification can impair the molecular function of macromolecules, which can lead to marked alterations in biological function.
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No data are available on the formation of acetaldehydemodified proteins in animals or humans directly exposed to acetaldehyde. However, some data are available on proteins modified by acetaldehyde derived from ethanol metabolism. In these studies, proteins carrying acetaldehyde adducts were shown to be present in the liver cytosol of rats fed ethanol for periods of 3 weeks, 12 months, or 27 months (Worrall et al., 1991a). Acetaldehyde-modified proteins have also been detected in the plasma (Liu et al., 1990) and haemoglobin of alcoholics (Niemela & Israel, 1992). Furthermore, a limited immunohistochemical study has demonstrated the presence of acetaldehyde-modified proteins in the livers of some alcoholics (Niemela et al., 1991). These studies demonstrate that acetaldehyde adducts can form in the body. The possible immunological consequences of adduct formation will be discussed in section 8.9.
6.5.2 Nucleic acids
No data are available from in vivo studies on the generation of DNA adducts.
Acetaldehyde reacts with nucleosides and deoxynucleosides at pH 6.5 and 37°C in vitro to form unstable adducts by binding to the exocyclic amino groups of adenine, cytosine, and guanine (Hemminki & Suni, 1984). Addition of a reducing agent (sodium borohydride) leads to the formation of stable adducts, of which the main one was identified as N2-ethylguanosine using mass spectrometry and NMR. Similar data for the formation of unstable adducts formed by reacting
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acetaldehyde with ribonucleosides and deoxyribonucleosides was reported by Fraenkel-Conrat & Singer (1988). When ethanol was present in the reaction mixture, a different type of adduct was formed, which was identified by fast atom bombardment and proton NMR to be a mixed acetal (-NH-CH(CH3)-OR). These adducts were found to have half-lives varying from 2.5 to 24 h at pH 7.5 and 37°C, depending on the base involved.
7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT
7.1 Aquatic organisms
An LC50 (semi-static study) of 35 mg/litre was found for acetaldehyde in the guppy (Poecilia reticulata; 10 laboratory-reared and acclimatized fish, 2-3 months old) (Deneer et al., 1988). Grahl (1983) reported an LC50 (48-96 h) of 124 mg/litre for acetaldehyde in fish (no additional information was provided). Juhnke & Luedemann (1978) presented the results for fish obtained in the Golden Orfe test, and found an LC50 of 140-124 mg/litre for acetaldehyde (no additional information was provided). An LC50 (static conditions; 96-h) of 53 mg/litre was reported for the bluegill (Lepomis macrochirus) by Von Burg & Stout (1991).
Acetaldehyde had a depressing effect on the aggressive behaviour of the fish cichlid (Cichlasoma nigro fasciatum) at concentrations that did not cause locomotor decrements in this species (Peeke & Figler, 1981).
An EC5 (48-h; population growth) of 82 mg/litre and an EC50 (48-h; static conditions; immobilization) of 42 mg/litre were reported for protozoa (Chilomonas paramecium) and the waterflea (Daphnia magna), respectively (Von Burg & Stout, 1991).
7.2 Terrestrial organisms
Aharoni & Barkai-Golan (1973) studied the effects of acetaldehyde vapours on the germination and colony-forming potential of two fungi species, Alternaria tenuis and Stemphylium botryosum. The rate of growth inhibition increased with both concentration and time of exposure. The exposure of the spores was conducted at room temperature. A. tenuis, the more sensitive species, was inactivated by 0.54 µg acetaldehyde/m3 applied for 5 h, whereas 1.08 µg acetaldehyde/m3 for 2 h, was needed to inactivate S. botryosum spores.
Pittevils et al. (1979) reported the activity of acetaldehyde against the fungi affecting stored apples and pears (Colletotrichum gloeosporioides, Cryptosporiopsis malicorticis, Phlyctaena vagabunda, Botrytis cinerea, and Alternaria tenuis). Acetaldehyde was rapidly lethal at low concentrations: after a 24-h treatment period, the lethal concentration of acetaldehyde ranged from 0.036 µg/m3 (A. tenuis) to 0.09 µg/m3 (C. gloeosporioides). Acetaldehyde remained lethal for the five fungi, even when the treatment lasted only 20 min (0.90 µg/m3 for P. vagabunda, C. malicorticis, and A. tenuis, and 0.36 µg/m3 for C. gloeosporioides and B. cinerea).
The fungi Botrytis cinerea, Penicillium expansum, Rhizopus stolonifer, Monilinia fructicola, Erwinia carotovora, and Pseudomonas fluorescens were killed, when exposed to acetaldehyde vapours at concentrations ranging from 0.045 to 3.6 µg/m3, applied for 0.5 to 120 min at room temperature (Aharoni & Stadelbacher, 1973).
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Aharoni et al. (1979) studied acetaldehyde as a fumigant for control of the green peach aphid (Myzus persicae) on head lettuce (Lactuca sativa). When aphids were placed on the lettuce prior to fumigation, 0.36 µg acetaldehyde/m3 and a 3-4 h exposure were required for 100% mortality. A similar treatment (0.27-0.36 µg/m3 for 4 h) was found to cause 100% mortality of aphids on lettuce by Stewart et al. (1980).
The fumigant effect of acetaldehyde was tested on the garden slug (Arion hortensis; weight range, 0.2-0.5 g) and the grey field slug (Agriolimax reticulatus; weight range, 0.3-0.6 g). It caused both species to close the pulmonary aperture and to secrete excess 'irritation' mucus. Medial lethal values of 7.69 ± 0.21 mg/litre per h for A. reticulatus and of 8.91 ± 0.81 mg/litre per h for A. hortensis were found (Henderson, 1970).
The seed germination of the onion (Allium cepa L.), carrot (Daucus carota L.), Palmer Amaranth (Amaranthus palmeri S Wats.), and tomato (Lycopersicon esculentum Mill.) after exposure to acetaldehyde (up to 1.52 mg/litre), was examined by Bradow & Connick (1988). After a 3-day exposure, acetaldehyde inhibited the seed germination of all four plants by more than 50%. Seeds inhibited by a 3-day exposure to acetaldehyde followed by a 4-day recovery period germinated to the same extent as the controls after seven days, except for the Palmer Amaranth, which remained inhibited.
Acetaldehyde at concentrations of 0.54-1.08 µg/m3 affected head lettuce (Lactuca sativa), as evidenced by dark-green, water-soaked, necrotic areas on the outer leaves of the lettuce. Concentrations of up to 0.36 µg/m3 did not affect the lettuce (Aharoni et al., 1979; Stewart et al., 1980).
8. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
8.1 Single exposure
8.1.1 LD50 and LC50 values
Relevant data are summarized in Table 4.
Oral LD50s for acetaldehyde in rats and mice ranged from 660 to 1930 mg/kg body weight. LC50s (0.5-4 h) in rats and Syrian hamsters ranged from 24 to 37 g/m3. It is, therefore, concluded that the acute toxicity of acetaldehyde is low. LD50 values by the dermal route were not available.
LD50s for intratracheal, subcutaneous, intraperitoneal, and intravenous administration are also presented in Table 4.
Table 4. LD50/LC50 values for acetaldehyde
Species Route of LD50/LC50 Reference administration
Rat oral 1930 mg/kg body weight Smyth et a Rat oral 660 mg/kg body weight Sprince et Mouse oral 1230 mg/kg body weight US NRC (19 Dog oral > 600 mg/kg body weight Booze & Oe Rat inhalation 24 g/m3; 4 h Appelman e Rat inhalation 37 g/m3; 0.5 h Skog (1950
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Syrian hamster inhalation 31 g/m3; 4 h Kruysse (1 Syrian hamster intratracheal 96.1 mg/kg body weight Feron & De Rat subcutaneous 640 mg/kg body weight Skog (1950 Mouse subcutaneous 560 mg/kg body weight Skog (1950 Mouse intraperitoneal 500 mg/kg body weight Truitt & W Mouse intravenous 165 mg/kg body weight O'Shea & K (pregnant) (1979)
8.2 Short-term exposure
8.2.1 Oral
Oral administration in the drinking-water of 675 mg acetaldehyde/kg body weight to Wistar rats, daily for 4 weeks, resulted in slight to moderate focal hyperkeratosis of the forestomach in 8/10 males and 8/10 females. No effects were observed at lower dose levels of 25 and 125 mg/kg body weight. In the control group, very slight focal hyperkeratosis of the forestomach was noted in 6/20 females and 3/20 males (1/20 slight). At the top dose (675 mg/kg), relative kidney weights were slightly increased in males, urinary production was decreased, and there were variations in serum biochemistry, most of which were attributable to reduced water intake. There were no effects in the liver. The no-observed-effect level (NOEL) was 125 mg/kg, the lowest-observed-effect level (LOEL) was 675 mg/kg (Til et al., 1988).
8.2.2 Inhalation
Male Sprague-Dawley rats were continuously exposed to acetaldehyde vapour for 22 days at levels gradually increasing from 750 mg/m3 for a few days up to 2500 mg/m3 for the last few days. By gradually increasing the concentrations, mortality in the early period following exposure to 2000-2500 mg/m3 was prevented, presumably because of metabolic adaptation; sudden, high, blood acetaldehyde levels inducing vagal reflex reactions may result in respiratory inhibition, and, as a consequence, death (Lamboeuf et al., 1987; Latge et al., 1987).
Groups of 10 male and 10 female Wistar rats were exposed to acetaldehyde at 0, 720, 1800, 3950, or 9000 mg/m3 (0, 400, 1000, 2200, or 5000 ppm) for 6 h/day, 5 days/week, for 4 weeks. Mortality was slightly increased at 3950 and 9000 mg/m3, whereas growth was retarded at 1800 mg/m3 and above in males, and at 9000 mg/m3 in females. At 9000 mg/m3, relative liver weight decreased, and relative lung weight in males increased. No treatment-related histopathological changes were observed in the liver. Degenerative changes of the nose were observed after exposure to all concentrations (720 mg/m3-9000 mg/m3), with hyperplasia and metaplasia occurring at concentrations of 3950 mg/m3 or more. A NOEL was not identified (LOEL: 720 mg/m3) (Appelman et al., 1982).
Groups of 10 male Wistar rats were exposed to acetaldehyde, for 6 h/day, 5 days/week, for 4 weeks, in three different patterns: (a) as a continuous daily exposure of 6 h to 0, 270, or 900 mg/m3 (0, 150, or 500 ppm), (b) as two daily exposures of 3 h to similar concentrations with an intervening 1.5-h period with no exposure, or (c) as two daily 3-h periods of exposure to similar concentrations with an intervening 1.5-h period with eight short (5-min) peaks of 6 times the basic concentration, resulting in time-weighted average
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concentrations of 0, 255, or 1050 mg/m3, respectively. Though there were no indications of toxicity following continuous or interrupted exposures to 270 and 900 mg/m3 and intermittent high/low exposure to 255 mg/m3, intermittent high/low exposure to 1050 mg/m3 induced growth retardation (Appelman et al., 1986).
At 900 mg/m3, the observed effects were very similar to the ones reported earlier by Appelman et al. (1982) at 720 mg/m3. Variation of the pattern of exposure, by including a 1.5-h break, or by additionally including eight 5-min, 6-fold higher peak exposures, did not alter the observed degenerative effects. No effects were observed in Wistar rats exposed to a lower concentration, 5 days/week for 4 weeks, either as a "continuous" (6 h/day) exposure of 270 mg/m3, or as a time-weighted average of 255 mg/m3 after the described intermittent low-high exposure. The NOEL was 255 mg/m3, 6-h TWA (LOEL = 1050 mg/m3, 6-h time weighted average) (Appelman et al., 1986).
In another study, groups of 12 male Wistar rats were exposed to 0 or 437 mg acetaldehyde/m3 (0 or 243 ppm), 8 h/day, 5 days per week, for 5 weeks. Hyperplasia of the olfactory epithelium and nasal inflammation were observed in exposed animals, and on the basis of lung function tests, residual volume and functional residual capacity were increased, indicating some (unspecified) damage of the distal airways (Saldiva et al., 1985).
8.2.3 Dermal
No relevant studies were identified.
8.2.4 Parenteral
Effects in the liver have been reported in several studies, but only at very high doses. Intraperitoneal injection of male albino rats with 200 mg acetaldehyde/kg body weight, daily, for 10 days, with additional pyrazole treatment to inhibit the conversion of acetaldehyde to ethanol, caused fatty accumulation in the liver, as indicated by accumulation of total lipids, triacyl glycerols, and total cholesterol, increased glycogenolysis, and a shift in metabolism from the citric acid cycle towards the pentose phosphate pathway in the liver. Serum triacyl glycerol, total cholesterol, and free fatty acid levels were also increased. Changes were similar in rats not receiving pyrazole pretreatment (Prasanna & Ramakrishnan, 1984a, 1987). The same treatment altered thyroid function, as indicated by lower serum T4 and decreased iodine uptake in male albino rats, though these effects may have been secondary to the observed hepatic changes (Prasanna et al., 1986) and histopathological changes of the pancreas, with resulting changes in trypsinogen levels and amylase secretion and activity in female Sprague-Dawley rats (Majumdar et al., 1986).
8.3 Skin and eye irritation; sensitization
No relevant data were identified.
8.4 Long-term exposure
8.4.1 Oral
In rats exposed to 0.05% acetaldehyde in drinking-water (estimated by the Task Group to be approximately 40 mg/kg body weight) for 6 months, there was an increase in collagen synthesis in the liver (Bankowski et al., 1993). The toxicological significance of this observation is not known; no other effects were examined.
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8.4.2 Inhalation
Non-neoplastic effects observed in carcinogenicity studies are discussed in section 8.7.1.
Groups of 20 Syrian hamsters were exposed to acetaldehyde vapour at 0, 700, 2400, or 8200 mg/m3 (0, 390, 1340, or 4560 ppm) for 6 h/day, 5 days/week, for 13 weeks. Increased relative lung and heart weights as well as growth retardation were reported after exposure to 8200 mg/m3, though there were no increases in mortality in any of the exposed groups (Kruysse et al., 1975). At the highest concentration, there were severe degenerative, hyperplastic, and metaplastic changes in the epithelium as well as subepithelial glands and turbinate bones. Rhinitis was observed, with abundant nasal discharge and salivation. The epithelium of the larynx, trachea, and lungs was damaged, with some focal hyperplasia and metaplasia, accompanied by tracheitis and focal bronchopneumonia. Changes in the tracheal epithelium were also observed at 2400 mg/m3. At 700 mg/m3, no significant effects were observed (NOEL: 700 mg/m3; LOEL: 2400 mg/m3).
8.5 Reproductive and developmental toxicity
Studies on reproductive effects have not been identified. A number of studies on developmental effects have been conducted, primarily to investigate the role of acetaldehyde in ethanol-induced teratogenicity. However, in all of these studies, acetaldehyde was administered by injection rather than by the principal routes of exposure in the occupational and general environments (i.e., ingestion and inhalation). Results of identified studies in which acetaldehyde was administered during gestation to rats and mice by intraperitoneal, intravenous, or amniotic injection are presented in Table 5. Though dose-related embryotoxic, fetotoxic, and teratogenic effects were observed in most of these studies, particularly those on rats, maternal toxicity was not adequately assessed or reported in any of these investigations. Dose-related embryotoxic effects were also observed in in vitro studies on rat embryos exposed to acetaldehyde (Popov et al., 1981; Campbell & Fantel, 1983).
Effects on the placenta have been observed following intraperitoneal injection of acetaldehyde into pregnant rats (Sreenathan et al., 1984a). In an in vitro study on human placental membrane vesicles, very high concentrations (approximately 100 times higher than the highest reported levels in blood), inhibited L-alanine transport (Asai et al., 1985).
8.6 Mutagenicity and related end-points
Relevant data are summarized in Table 6.
8.6.1 Bacteria
Acetaldehyde was not mutagenic when tested adequately in standard preincubation assays with S. typhimurium.
Statistically significant mutagenic responses were induced in E. coli WP2uvrA in preincubation assays without metabolic activation at 37°C (Veghelyi et al., 1978) and 0°C (Igali & Gazso, 1980). In contrast, in another study on the same strain, results were negative (Hemminki et al., 1980).
8.6.2 Non-mammalian eukaryotic systems
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8.6.2.1 Gene mutation assays
Acetaldehyde (0.1% or 1.0% for 2 h) induced mutations in genes that affect the egg-laying system of Caenorhabditis elegans (Greenwald & Horvitz, 1980).
Acetaldehyde induced sex-linked recessive lethal mutations in Drosophila melanogaster (Woodruff et al., 1985).
8.6.2.2 Chromosome alterations
Acetaldehyde induced chromosome malsegregation and mitotic cross-over (yA2 marker) in Aspergillus nidulans diploid strain P1 during early conidial germination (Crebelli et al., 1989).
There was a dose-related increase in chromosomal aberrations in Vicia faba root tips exposed to acetaldehyde (Rieger & Michaelis, 1960). Acetaldehyde also induced chromosome aberrations, micronuclei, and sister chromatid exchanges (SCEs) in the root meristem cells of Allium cepa (Cortes et al., 1986).
Table 5. Developmental toxicity
Species Exposure Dose Effects
Rat day 10, 11, or 12; 0, 50, 75, 100 mg/kg fetal resorption, ma days 10-12 of body weight, ip micrognathia, microm pregnancy; days retardation; reduced 8-15 (50 mg/kg days 8-15: delays in body weight per such as wavy ribs; n day)
Rat days 8-15 of 50, 75, 100 or 150 increase in resorpti pregnancy mg/kg body weight, dependent); malforma ip micromelia, syndacty haemorrhage in the f placental weight and fluid weight maternal toxicity: r reduced body weight
Rat day 13 of pregnancy 1% or 10% solution 10%: 100% mortality; embryo amniotic injections controls
Rat days 9-12 of pregancy 1% (100 mg/kg body reduction in head le weight), ip scores or crown rump
Table 5 (contd).
Species Exposure Dose Effects
Rat days 8-13 of 10 or 50 mg/kg body reduced performance pregnancy weight, ip discrimination, and in an auditory start addressed; age of te
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Rat day 5 of gestation 0.03-0.04 µg/kg body retarded blastulatio weight examination on day 5 of gestation
Mouse day 7 or 8 of 0.32 g/kg, iv exencephaly, mandibu pregnancy; day 9 polydactyly club foo or 10 of pregnancy
Mouse day 10 of pregnancy 1000 mg/kg, ip no increase in resor in fetal weight; no
Mouse day 7, 8 or 9 of 31 or 62 mg/kg body dose-dependent embry pregnancy weight, iv; posterior neuropore; examination on day maternal effects 10 or 19 of gestation
Mouse day 9 of pregnancy 2, 4, 6% (8 ml/kg no intermediate cell body weight), ip
Mouse day 6, 7 or 8 of 62 mg/kg body weight, neural tube effects; pregnancy; and days iv; examination on of maternal effects 6-8, 7-8 or 7-9 of day 10 or 12 of pregnancy gestation
Table 6. Tests for gene mutation, chromosomal damage, and sister chromatid e
Test system Measured end-point Test conditions
Prokaryotic systems
Escherichia coli WP2uvrA reverse mutations 40 µg/ml; preincubated
Escherichia coli WP2uvrA reverse mutations 0.88-441 µg/ml; incuba tubes at 37°C
Escherichia coli Wp2uvrA reverse mutations 0.8 µg/ml; incubated i at 0°C
Salmonella typhimurium TA102 reverse mutations 1014 µg/plate; liquid TA104
Salmonella typhimurium reverse mutations 33-10 000 µg/plate; li TA1535 TA1537
TA97
TA98
TA100
Table 6 (contd).
Test system Measured end-point Test conditions
Salmonella typhimurium concentration not given;
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TA100 liquid preincubation
Non-mammalian eukaryotic systems
Allium cepa root chromosomal aberration 7.5-7500 µg/ml meristem cells and SCE
Vicia faba root tips chromosomal aberration 220-2205 µg/ml for 24
Caenorhabditis elegans gene mutation 794-7940 µg/ml for 2 h
Drosophila melanogaster sex-linked recessive 22 500 mg/litre in 10% injection Canton-S wild-type lethal mutations 25 000 mg/litre in 10% feeding
Aspergilus nodulans chromosomal 198-2381 µg/ml Diploid P1 malsegregation
In vitro mammalian systems
Mouse lymphoma L5178Y forward mutation (tk 176-353 µg/ml for 4 h cells locus)
Chinese hamster ovary chromosomal aberration 88-5000 µg/ml cells
Table 6 (contd).
Test system Measured end-point Test conditions
Chinese hamster ovary SCE 1.3-13 µg/ml cells
Chinese hamster ovary SCE 8-80 µg/ml for 1 h cells
Chinese hamster ovary SCE 2-12 µg/ml for 24 h cells
Chinese hamster ovary SCE 4-8 µg/ml for 8 days cells
Chinese hamster ovary hyperploidy 0.35-1.05 mmol/litre cells hypoploidy
Human lymphocytes forward mutations 26.5-106 µg/ml for 24 (hprt locus) 8.8-26.5 µg/ml for 48
Human lymphocytes chromosomal aberration 0.1-20 mmol/litre adde every 12 h for 5 days
Human lymphocytes chromosomal aberration 8-15 µg/ml (normal Franconis anaemia)
Table 6 (contd).
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Test system Measured end-point Test conditions
Human lymphocytes chromosomal aberration 0.8 µg/ml 2x/day, 4 da
Human lymphocytes chromosomal aberration 4-48 µg/ml for 72 h SCE
Human (whole blood, chromosomal aberration 20-40 µg/ml alcoholics)
Human lymphocytes SCE 4.4-106 µg/ml for 1-70
Human lymphocytes SCE 4.4-13 µg/ml for 70 h
Human lymphocytes SCE 4.4-18 µg/ml for 72 h
Human lymphocytes SCE 4.4-22 µg/ml for 48 h
Human lymphocytes SCE 4-8 µg/ml for 90 h
Human lymphocytes SCE 0.04-4.4 µg/ml for 55
Human lymphocytes SCE 5.5-88 µg/ml for 48 h
Human lymphocytes SCE reaction mixture added samples in dialysis tu concentration not give
Human lymphocytes SCE 4-16 µg/ml for 24 h
Table 6 (contd).
Test system Measured end-point Test conditions
Human lymphocytes chromosomal aberration 1.8-35 µg/ml for 72 h
Human lymphocytes SCE 1.8-35 µg/ml for 72 h
Wistar rat (skin chromosomal aberration 4.4-44 µg/ml for 12, 2 fibroblast) (micronuclei)
Mouse embryo cell transformation 10-100 µg acetaldehyde C3H/10T1/2 cells 10-100 µg/ml followed TPA/ml 2x/week
Rat (HRRT kidney cells) cell transformation acetaldehyde acetaldehyde followed
MA = Metabolic activation; RES = Result.
8.6.3 Cultured mammalian cells
8.6.3.1 Gene mutation assays
Acetaldehyde induced gene mutations at the hypoxanthineguanine
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phosphoribosyl transferase (hprt) locus in human lymphocytes in vitro; there was a statistically significant and dose-related increase in the frequency of mutants (He & Lambert, 1990). Acetaldehyde produced a significant dose-related increase in forward mutations in a mouse lymphoma L5178Y thimidine kinase locus assay, without exogenous metabolic activation (Wangenheim & Bolcsfoldi, 1986, 1988).
8.6.3.2 Chromosome alterations and sister chromatid exchange
Dose-dependent increased frequencies of chromosome aberrations have been observed in human lymphocytes following incubation with acetaldehyde (Badr & Hussain, 1977; Obe et al., 1978, 1979, 1985; Veghelyi & Ostovics, 1978; Boehlke et al., 1983).
Acetaldehyde induced a dose-dependent increase in chromosomal damage in Chinese hamster ovary cells, though it was reported that the activity was reduced (not quantified) in the presence of liver homogenate fraction (Au & Badr, 1979). Dose-related increases in micronuclei and chromosome aberrations were observed in cultured rat skin fibroblasts in the absence of metabolic activation (Bird et al., 1982).
SCE was induced by acetaldehyde (1.3-106 µg/ml) in the absence of exogenous metabolic activation in Chinese hamster ovary cells and human lymphocyte cultures (Obe & Ristow, 1977; Ristow & Obe, 1978; Veghelyi et al., 1978; Veghelyi & Osztovics, 1978; Obe & Beek, 1979; Jansson, 1982; Boehlke et al., 1983; De Raat et al., 1983; He & Lambert, 1985; Knadle, 1985; Norppa et al., 1985; Brambilla et al., 1986; Obe et al., 1986; Lambert & He, 1988; Helander & Lindahl-Kiessling, 1991; Sipi et al., 1992). The increase in SCEs in Chinese hamster ovary cells was less pronounced after addition of an exogenous metabolic activating system (De Raat et al., 1983). Similarly, addition of NAD+ and ALDH to human lymphocyte cultures exposed to acetaldehyde decreased SCE induction (Obe et al., 1986). Addition of 1-amino-cyclopropanol, an inhibitor of ALDH, to human lymphocytes enhanced SCE induction by acetaldehyde (Helander & Lindahl-Kiessling, 1991). These observations suggest that ALDH may reduce the genotoxic potential of acetaldehyde.
Acetaldehyde induced aneuploidy has been reported in Chinese hamster ovary cells (Dulout & Furnus, 1988). However, mainly hypoploid cells were increased and, therefore, no firm conclusion can be drawn from these studies. Acetaldehyde induced SCE in pre-implantation mouse embryos in vitro (Lau et al., 1991).
8.6.4 In vivo assays
Only limited data are available on the genotoxicity of acetaldehyde in vivo.
8.6.4.1 Somatic cells
C57BL/6J mice (only 2 animals of unspecified sex at each dose level) received daily intraperitoneal doses of 0, 6, or 12 mg acetaldehyde/kg body weight per day, for 5 days, and blood samples were collected on days 3-6. The frequencies of micronuclei in mature peripheral erythrocytes on days 5 and 6 (combined) were significantly increased at the low dose, but not at the high dose (Ma et al., 1985). No information on the frequency in polychromatic erythrocytes was provided, so the possibility that this result was due to increased erythropoiesis instead of mutagenesis cannot be discounted. This study was reported only in the form of an abstract.
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Groups of 6-7 Chinese hamsters (male and female) received 0.01, 0.1, or 0.5 mg acetaldehyde/kg body weight in saline by single intraperitoneal injection and were killed 24 h later. Doses of 0.6 mg/kg body weight were lethal in preliminary tests. The frequencies of SCEs in bone-marrow metaphases were elevated at 0.5 mg acetaldehyde/kg body weight, but not at the lower doses (Korte & Obe, 1981). These observations support earlier findings in a more limited study at an embryotoxic dose in mice and indicate in vivo formation of SCEs (Obe et al., 1979).
Female Wistar rats were injected with 0.02 ml of 1% acetaldehyde intra-amniotically on day 13 of pregnancy. Embryonic cells were obtained 24 h later for cytogenetic analysis. Exposed rat embryos had a higher frequency of chromosomal aberrations (mostly chromatid gaps and breaks) than controls (Barilyak & Kozachuk, 1983). There was no increase in the frequency of aneuploid cells.
8.6.4.2 Germ cells
Hybrid male mice ((C57B1/6J × C3H/He)F1), 4/dose group, were injected intraperitoneally with a single dose of 0, 125, 250, 375, or 500 mg acetaldehyde/kg body weight in saline. Thirteen days after exposure, the frequency of micronuclei in early spermatids was not increased, though there were adequate positive controls (Lahdetie, 1988).
8.6.5 Other assays
Relevant data are summarized in Table 7.
8.6.5.1 DNA single-strand breaks
No single-strand breaks were detected with the alkaline elution assay in DNA from various sources, after exposure in vitro to acetaldehyde (Sina et al., 1983; Marinari et al., 1984; Harris et al., 1985; Lambert et al., 1985; Saladino et al., 1985).
8.6.5.2 DNA cross-linking
There is some indirect evidence suggesting DNA cross-linking by acetaldehyde.
Ristow & Obe (1978) observed enhanced reannealing of heat denatured, isolated, calf thymus DNA following incubation with acetaldehyde. It was suggested that this may have been due to DNA-DNA cross-linking, because thermally denatured DNA will not reanneal in this assay, unless complimentary DNA strands are held together by cross-linkings.
Altered alkaline elution patterns indicative of DNA-DNA cross-links were observed with DNA isolated from cultured human leukocytes and exposed initially to acetaldehyde and then to X-rays (Lambert et al., 1985; Lambert & He, 1988). DNA-protein cross-linking was not observed by Harris et al. (1985) or by Saladino et al. (1985) after exposure of human bronchial epithelial cells in vitro, but it was observed by Lam et al. (1986) after incubation of either calf thymus nucleohistones or fresh homogenates of the nasal mucosa of rats with acetaldehyde. The possibility that acetaldehyde induces DNA-protein cross-links in male Fischer-344 rat nasal mucosa has been indirectly studied by measuring the extractability of DNA from insoluble proteins following in vitro and in vivo exposures. Decreased extractability of DNA was observed in preparations from tissue homogenates exposed to acetaldehyde at concentrations of 100 and 500 mmol per litre but not 10 mmol/litre. Similarly, decreased
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extractability was observed in nasal mucosal preparations from rats exposed for 6 h to 1000 or 3000 mg/litre (ppm) but not 100 or 300 mg/litre (ppm) (Lam et al., 1986).
Table 7. Other tests indicative of genetic damage induced by acetaldehyd
Test system Measured end-point Test conditions
Calf thymus DNA DNA-DNA cross-links 44 100 µg/ml for
Calf thymus nucleohistones DNA-protein cross-links 4410-44 100 µg/m
Chinese hamster ovary DNA single-strand breaks no details K1-cells DNA-DNA cross-links
Rat hepatocytes DNA single-strand breaks 1.3 µg/ml for 3
Human bronchial epithelial DNA single-strand breaks unknown concentr cells DNA-protein cross-links 6 h
Human bronchial epithelial DNA single-strand breaks up to 44 µg/ml f cells DNA-protein cross-links
Human leukocytes DNA single-strand breaks 441-882 µg/ml fo DNA-DNA cross-links
Human lymphocytes DNA-DNA cross-links 441 µg/ml
8.6.6 Cell transformation
Acetaldehyde did not initiate cell transformation in cultured C3H/10T1/2 cells in the presence of the tumour promotor 12- O-tetradecanoylphorbol-13-acetate (TPA) (Abernethy et al., 1982).
Acetaldehyde initiated cell transformation in a rat kidney cell line (HRRT) after pretreatment with tumour promotors (Eker & Sanner, 1986).
8.7 Carcinogenicity bioassays
8.7.1 Inhalation exposure
Only one carcinogenicity study in which animals were exposed by inhalation to acetaldehyde over a lifetime has been performed. In other carcinogenicity bioassays, animals were exposed for shorter periods.
Wistar rats (55/sex per dose) were exposed for life (6 h/day, 5 days/week, for 28 months) to acetaldehyde concentrations of 1350, 2700, or 1800-5400 mg/m3 (the last concentration was gradually reduced from 5400 mg/m3 in week 20 to 1800 mg/m3 in week 52). Satellite groups of 5-10 additional rats of each sex were killed at 13, 26, and 52 weeks. Growth retardation occurred throughout the study at all dose levels. Mortality was greater than in controls in all dose groups and all of the animals in the high-dose group had died by week 102. At week 52, there were degenerative changes in the
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olfactory nasal epithelium at all dose levels including slight to severe hyperplasia and keratinized stratified metaplasia of the larynx (high dose only) and degenerative changes of the upper respiratory epithelium (including papillomatous hyperplasia at the top dose only). In the trachea, there was focal flattening and irregular arrangement of the epithelium in 3/10 top-dose males at 52 weeks. In satellite groups of 30 rats per sex, for which there was a 26-week recovery period after 52 weeks of exposure, there was evidence of partial regeneration of the olfactory epithelium in the low- and mid-dose groups; there was also progression from hyperplasia and metaplasia to neoplasia in some animals. At 28 months, carcinomas of the nose developed in all exposed groups (Table 8). Although tumour incidence was dose-related, the latency period appeared to be independent of concentration. First tumours in all groups appeared during the 12th month of exposure. The incidence of tumours was not increased in the lungs, larynx, and trachea.
In simultaneously exposed groups of 30 Wistar rats/sex per dose, exposure was terminated after 52 weeks and the animals killed following a recovery period of 26 weeks. After the recovery period, both mortality and nasal tumour incidence were very similar to those in the groups in which exposure had been continued for 26 more weeks (Woutersen et al., 1984, 1986; Woutersen & Feron, 1987).
Groups of Syrian golden hamsters (36/sex per dose) were exposed for 52 weeks (7 h/day, 5 days/week) to a concentration gradually reduced from 4500 mg/m3 in week 9 to 2970 mg/m3 in week 52. At week 52, six animals/sex per dose were killed; the remaining animals (30/sex per dose) were killed after a recovery period of 29 weeks. At the end of the recovery period, nasal carcinomas were observed in 1/26 males and 1/27 females versus 0/24 and 0/23 in controls, and the incidence of laryngeal carcinomas was increased (5/23 in males, 3/20 in females, against 0/20 and 0/22 in controls). No tumours were observed in bronchi or lungs (Feron et al., 1982).
Table 8. Incidence of nasal tumours in Wistar rats after 28 months of exposurea,b
Types of tumour 0 1350 2700 2760c mg/m3 mg/m3 mg/m3 mg/m3
Males
Squamous cell carcinoma 1/49 1/52 10/53* 16/49*** Adenocarcinoma 0/49 16/52*** 31/53*** 21/49*** Carcinoma in situ 0/49 0/52 0/53 1/49
Females
Squamous cell carcinoma 0/50 0/48 5/53 17/53*** Adenocarcinoma 0/50 6/48* 28/53*** 23/53*** Carcinoma in situ 0/50 0/48 3/53 5/53 a From: Woutersen et al. (1986). b Total number of tumour-bearing animals not specified. Significance: Fisher Exact Test *P < 0.05, **P < 0.01, ***P < 0.001. c The highest concentration was gradually reduced from 5400 mg/m3 during the first 20 weeks to 1800 mg/m3 in week 52; the time-weighted average concentration for 28 months of
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exposure was calculated by the Task Group to be 2760 mg/m3.
Groups of 35 male Syrian hamsters were exposed by inhalation to 0 or 2700 mg acetaldehyde/m3 (0 or 1500 ppm) for 7 h/day, 5 days/week for 52 weeks. At 52 weeks, 5 animals were killed for pathological examination. The remainder of the animals were maintained for a further 26-week recovery period. Body weight gain was less in the exposed animals and mortality was increased from week 52 onwards.
There was a slight, but significant, decrease in rbc, haemoglobin, and haematocrit in exposed animals. Relative kidney weights were increased and urinary levels of protein and GOT were elevated. There were marked lesions in the nasal cavity of animals killed at 52 weeks: flattened epithelial cells with bizarre nuclei, fewer subepithelial glands, submucosal thickening, and keratinizing stratified squamous metaplasia of olfactory and respiratory epithelium. There was also slight focal hyperplasia and metaplasia of the epithelium of the trachea. There was partial or complete recovery from these lesions in the animals killed at the end of the recovery period. There were no tumours of the respiratory tract in any of the animals exposed to acetaldehyde (Feron, 1979).
Weekly intratracheal administration of 0.2 ml of 2 or 4% acetaldehyde in saline during a period of 52 weeks, followed by a recovery period of another 52 weeks, did not induce any tumours in the respiratory tract of male and female Syrian golden hamsters (Feron, 1979).
8.7.2 Co-carcinogenicity and promotion studies
In a mid-term test (Ito Model), groups of 19-20 male F344 rats received a single intraperitoneal injection of diethylnitrosamine and then various concentrations of acetaldehyde (2.5% and 5%, associated with a recorded daily intake of 1.66 and 2.75 mg/kg body weight) in their drinking-water, from week 2 until termination in week 6. All rats had a two-thirds partial hepatectomy in week 3, in order to stimulate cell proliferation. At 6 weeks, there was a significant decrease in liver and body weight in all exposed animals, but acetaldehyde had no effect on the development of glutathione S-transferase (placental type)-positive liver cell foci (Ikawa et al., 1986).
There were laryngeal tumours in 7/31 male and 6/32 female Syrian golden hamsters exposed to a mixture of isoprene (approximately 2.09 mg/m3 or 750 ppm), methyl chloride (approximately 1.94 mg/m3 or 950 ppm) methyl nitrite (approximately 0.49 mg/m3 or 195 ppm) and acetaldehyde (approximately 2340 mg/m3 or 1300 ppm) for 6 h/day, 5 days/week, over 23 months. There were no tumours of the respiratory tract in controls (Feron et al., 1985). The authors suggested that the laryngeal effects observed in hamsters exposed to the vapour mixture were most probably caused by acetaldehyde alone (presumably based on comparison with results in studies on hamsters exposed to acetaldehyde alone).
There was no evidence of co-carcinogenicity in Syrian golden hamsters exposed either by simultaneous inhalation exposure to acetaldehyde and intratracheal instillation of benzo(a)pyrene (Feron, 1979; Feron et al., 1982) or by intratracheal instillation of diethylnitrosamine (Feron et al., 1982) for 52 weeks followed by recovery periods of 26-28 weeks. Nor was there any evidence of the co-carcinogenicity of acetaldehyde following simultaneous intratracheal instillations of acetaldehyde and either benzo (a)pyrene or diethylnitrosamine for 52 weeks, followed by a recovery period of
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52 weeks (Feron et al., 1982).
8.8 Neurological effects
Secondary effects of acetaldehyde on the respiratory and cardiovascular systems, attributed to its influence on the autonomic nervous system, have been observed following acute exposure of experimental animals to acetaldehyde, principally by infusion or intravenous administration. In two identified studies in which animals were exposed by a route more relevant to environmental or occupational exposure (i.e., inhalation), a 50% decrease in respiratory rate was observed in two strains of mice and in rats during inhalation of 5000 mg/m3 for 10 min (Steinhagen & Barrow, 1984; Babiuk et al., 1985; Takahashi et al., 1986).
Neurological effects following exposure by routes most relevant to environmental and occupational exposure (i.e., inhalation and ingestion) were limited to biochemical changes in the brain in short-term studies on rats and mice exposed to relatively high concentrations of acetaldehyde (750-13 230 mg/m3). Reported effects included changes in the phospholipid fractions and increases in the concentrations of monoamines and Na+/K+ATPase (Ortiz et al., 1974; Shiohara et al., 1985; Latge et al., 1987; Roumec et al., 1988). Manifestations of neurotoxicity were not examined in any of these studies.
In the only identified study in which histopathological effects on the nervous system were reported, degeneration was observable using both light and electron microscopy in the cerebral cortex of rats receiving a single intraperitoneal injection of 5 mg acetaldehyde/kg body weight (Phillips, 1987).
In a short-term study involving intravenous exposure (24-26 mg/kg body weight per day, for 20 days), the level of salsolinol in the brain of rats was increased (Myers et al., 1985). Biochemical effects of acetaldehyde on the brain have also been observed in vitro in cerebral cortical neurons and brain microsomal preparations (Lahti & Majchrowicz, 1969; Cederbaum & Rubin, 1977; Kuriyama et al., 1987).
8.9 Immunological effects
8.9.1 Direct effects on immune cells
Only one study has been carried out on whole animals. In a study on CD1 mice exposed to 324 mg/m3, 3 h/day for 5 days, the bacteriocidal activity of alveolar macrophages was reduced by 15%. However, acetaldehyde did not affect mortality following streptococcal infection (Aranyi et al., 1986).
In in vitro studies, 0.01% acetaldehyde caused a significant inhibition of human granulocyte chemotaxis (Schopf et al., 1985). At 0.03%, acetaldehyde inhibited the release of lysozyme from monocytes, but granulocytes were unaffected. The generation of oxygen radicals by zymosan particle-stimulated monocytes and granulocytes was inhibited by acetaldehyde in a dose-dependent manner. In a similar study in which peripheral mononuclear cells were incubated with acetaldehyde, decreased lytic activity against K562 cells was observed at concentrations higher than 12 µmol per litre (Fink & Dancygier, 1988). In another study, acetaldehyde decreased 3H thymidine incorporation into phytohaemagglutinin or Concanavalin A - stimulated human lymphocytes (Levallois et al., 1987).
8.9.2 Generation of antibodies reacting with acetaldehyde-modified proteins
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The modification of proteins has been described in section 6.5.1. In several studies, these modified proteins induced an immune response when injected into rabbits and mice (Israel et al., 1986; Worrall et al., 1989). The reactivity of the resulting antibodies towards proteins, modified by acetaldehyde in vitro, is independent of the carrier protein. These studies demonstrate (a) that acetaldehyde-modified proteins are immunogenic; and (b) that antibodies raised against a single modified protein will cross-react with any other protein modified in the same manner.
Passive immunization of rats with a monoclonal IgE antiacetaldehyde adduct antibody, derived from mice immunized with acetaldehyde-modified proteins, rendered these animals hypersensitive to acetaldehyde-modified proteins (Israel et al., 1992).
No immunization studies analogous to those described above have been carried out on humans. In several studies, the presence of antibodies, reactive with proteins modified by acetaldehyde in vitro, has been reported in the plasma of alcoholics (Niemela et al., 1987; Hoerner et al., 1988; Worrall et al., 1990, 1991a,b). The results of these studies suggest that acetaldehyde-modified proteins are generated in humans.
8.9.3 Related immunological effects
In rat liver membrane vesicles, exposed to acetaldehyde in vitro, superoxide anion production by neutrophils was significantly enhanced (Williams & Barry, 1986). In a further study, human liver plasma membranes, modified by acetaldehyde, activated complement protein C3 components (Barry & McGivan, 1985).
8.10 Biochemical effects
Biochemical effects have been observed in cultured hepatocytes, liver homogenates and mitochondrial fractions, purified enzymes, isolated hepatic lipid membranes and whole liver preparations, including: metabolic effects on lipid peroxidation (Stege, 1982; Mueller & Sies, 1987; Shaw & Jayatilleke, 1987), phospholipid metabolism (Snyder, 1988), transaminase activity (Solomon, 1987; Snyder, 1988), carbohydrate and lipid metabolism (Matsuzaki & Lieber, 1977; Cederbaum & Dicker, 1981), and mitochondrial respiration (Cederbaum et al., 1974). Increased hepatic collagen synthesis has also been observed (Savolainen et al., 1984; Brenner & Chojkier, 1987).
Metabolic effects have been observed in other in vitro systems including: renal cortex tubules (Michoudet & Baverel, 1985: altered pyruvate/lactate metabolism), kidney, and muscle microsomal preparations (Cederbaum & Rubin, 1977: inhibition of pyruvate dehydrogenase), perfused hearts and cardiac whole homogenates (Schreiber et al., 1972, 1974: myocardial protein synthesis and inhibition of cardiac microsomal protein synthesis; Rawat, 1979: reduced protein synthesis; Segel, 1984: no effect on mitochondrial respiration), myocardial cells (McCall & Ryan, 1987: no effect on Na+/K+-ATPase), leukocytes (Green & Baron, 1986: inhibition of Na+/K+-ATPase), erythrocytes (Helander & Tottmar, 1987: inhibition of the disappearance rate of biogenic aldehydes; Ninfali et al., 1987: induction of intracellular reduced state; Solomon, 1988: inhibition of aldolase-mediated by acetaldehyde oxidation- and inhibition of the aminotransferases-mediated by non-oxidative acetaldehyde metabolization; Atukorala et al., 1988: inhibition of transketolase), and leukocytes and platelets (Helander & Tottmar, 1987: inhibition of the disappearance rate of biogenic aldehydes).
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9. EFFECTS ON HUMANS
9.1 General population exposure
No specific studies were available.
9.2 Occupational exposure
9.2.1 General observations
Acute exposure to acetaldehyde vapours has resulted in irritation of the eyes and mucous membranes, reddening of the skin, pulmonary oedema, headache, and sore throat. Repeated exposure causes dermatitis and conjunctivitis. Ingestion causes nausea, vomiting, diarrhoea, narcosis, and respiratory failure. Liquid acetaldehyde was reported to cause superficial injury of the cornea. These effects were reported in reviews and not in documented studies (Grant, 1974; Hagemeyer, 1978; Dreisbach, 1987). In addition, a statement was found in a textbook stating that prolonged exposure to acetaldehyde caused a decrease in red and white blood cells plus a sustained rise in blood pressure; however, no further information was available (Hagemeyer, 1978).
9.2.2 Clinical studies
A group of 12 volunteers were exposed in a chamber to various nominal concentrations of acetaldehyde vapour on 15 different occasions. No atmospheric sampling was performed. At 90 mg/m3 (50 ppm), the majority of the group experienced some degree of eye irritation. Several subjects were discomforted at a lower concentration of 45 mg/m3 (25 ppm), but no details were provided (Silverman et al., 1946).
A group of 14 "healthy male" volunteers, aged 18-45 years, were exposed in a 100 m3 chamber to a measured concentration of acetaldehyde vapour of 240 mg/m3 (134 ppm) for 30 min. This concentration was said to be mildly irritating to the upper respiratory tract. No other clinical signs were reported (Sim & Pattle, 1957).
Twelve volunteers of Oriental ancestry were patch-tested with acetaldehyde (75%), ethanol (75%), and ethyl acetate (25%). With acetaldehyde treatment, cutaneous erythema was seen in all 12 subjects, whereas ethanol was positive in 5 subjects. No vascular response was detected for the acetaldehyde metabolite, ethyl acetate (Wilkin & Fortner, 1985).
In an additional study, increased heart rate, ventilation, and calculated respiratory dead space, and a decrease in alveolar CO2 levels were reported, following intravenous infusion of acetaldehyde (5% v/v) in young male volunteers (Asmussen et al., 1948).
9.2.3 Epidemiological studies
A very limited investigation was performed on an unspecified number of people, selected from 150 workers who had been employed for 20 years or more in a chemical factory. Nine cases of cancer were identified (all in male smokers) 5 of which were in the respiratory tract, 2 in the oral cavity, 1 in the stomach, and 1 in the caecum. The number of respiratory cancers was higher than expected compared with the prevalence in the national population (not corrected for smoking). In parts of the factory, there was exposure to a variety of chemicals. In one area, 1-7 mg acetaldehyde/m3 had been measured,
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together with 5-70 mg butyraldehyde/m3, 1-7 mg crotonaldehyde/m3, 2-6 mg n-butanol per m3, and about 15 mg ethylhexanol/m3. Other areas of the factory were known to have higher concentrations of vapours of aldehydes and aldol, which caused irritation of the eyes and upper respiratory tract (Bittersohl, 1974, 1975).
9.3 Effects of endogenous acetaldehyde
9.3.1 Effects of ethanol possibly attributable to acetaldehyde or acetaldehyde metabolism
There is no direct evidence to link acetaldehyde with liver injury. However, data obtained from animal models and human subjects suggest that acetaldehyde may play a role in liver damage, especially that associated with ethanol (sections 3.1.1 and 8.10).
An increased sensitivity to ethanol with respect to facial flushing was observed in certain human populations (especially of Oriental origin), which was ascribed to genetic differences in acetaldehyde elimination, due to aldehyde dehydrogenase polymorphism (Goedde & Agarwal, 1986, 1987; Eriksson, 1987; see also section 6.2.2).
The fetal alcohol syndrome is a specific pattern of congenital abnormalities found in children of mothers who drink heavily. The abnormalities most typically associated with alcohol-induced developmental effects can be grouped into four categories: central nervous system dysfunction (mental retardation, microcephaly, hyperactivity); growth deficiencies (reduced prenatal length and especially weight, with no catch-up postnatal growth; reduced adipose tissue, normal growth hormone, cortisol, and gonadotropins); a characteristic cluster of facial abnormalities (short palpebral fissures, short upturned nose, hypoplastic philtrum, thinned upper-lip vermillion, flattened midface); and variable major and minor malformations (such as, heart failure, anomalies of the genitalia, joints, and palmar creases) (Clarren & Smith, 1978).
The mechanisms by which ethanol produces its developmental effects are not completely understood, and no data are available with respect to ethanol doses and/or blood levels needed for such effects. It is generally assumed that acetaldehyde, as the primary metabolite, may contribute to the developmental effects of ethanol. Several animal studies have demonstrated the direct teratogenic effect of acetaldehyde (Ali & Persaud, 1988; see also section 8.5); however, no reports are available with respect to the direct teratogenicity of acetaldehyde in humans.
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1 Evaluation of human health risks
10.1.1 Exposure
By far, the principal source of exposure to acetaldehyde for the majority of the general population is through the metabolism of alcohol. Cigarette smoke is also a significant source of exposure for smokers. With respect to other media, the general population is exposed to acetaldehyde principally from food, and to a lesser extent from air. Intake from drinking-water is negligible compared with that from other media.
Available data are inadequate to determine the extent of exposure to acetaldehyde in the workplace. Workers may be exposed in some manufacturing industries and during alcohol fermentation, where the
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principal route is most likely inhalation and, possibly, dermal contact.
10.1.2 Health effects
Acetaldehyde is a reactive molecule that adducts to macromolecules and can also condense or polymerise with small molecules. Although quantitatively unimportant in acetaldehyde metabolism, these by-products may have important biological effects.
In studies conducted on animals, the acute toxicity of acetaldehyde by the oral or inhalation routes was low. Oral LD50s ranged from 660 to 1930 mg/kg body weight and LC50s (0.5-4 h) from 3 24 to 37 g/m . RD50s in rats and mice are slightly greater than 5000 mg/m3.
Data on the irritant effects of acetaldehyde on the skin and eye are restricted to those from limited studies on human volunteers. It was mildly irritating to the eyes and upper respiratory tract following acute exposure for very short periods, in limited studies on human volunteers at concentrations exceeding approximately 90 and 240 mg/m3, respectively (Silverman et al., 1946; Sim & Pattle, 1957). Cutaneous erythema was observed in the patch testing of twelve subjects of "Oriental ancestry" with acetaldehyde (Wilkin & Fortner, 1985). Although a possible mechanism has been identified, available data are inadequate to assess the potential of acetaldehyde to induce sensitization.
Available data relevant to the assessment of the potential adverse effects in humans of exposure to acetaldehyde in the occupational and general environments are limited to those on irritation mentioned above. The remainder of this evaluation is, therefore, based on studies on animals.
Effects of acetaldehyde following oral administration to animals have been much less well studied than those following inhalation. In one of the two available studies by the oral route, the no-observed-effect level (NOEL) following four weeks of administration of acetaldehyde to rats was 125 mg/kg body weight per day (Til et al., 1988). At the next higher concentration (675 mg/kg body weight per day), a borderline increase in hyperkeratosis of the forestomach was observed. In rats exposed to 0.05% acetaldehyde (estimated by the Task Group to be approximately 40 mg/kg body weight) in the drinking-water for 6 months, there was an increase in collagen synthesis in the liver (Bankowski et al., 1993). No other effects were examined and the toxicological significance of this observation is unknown.
Acetaldehyde has induced gene mutations, clastogenic effects, and sister chromatid exchanges (SCE) in mammalian cells in vitro. Though available data on genotoxicity in vivo are limited, increases in SCE have been observed in hamsters and mice exposed intraperitoneally to acetaldehyde (Obe et al., 1979; Korte & Obe, 1981). This suggests genetic damage to somatic cells in vivo. Available data are inadequate to assess the potential of acetaldehyde to induce genetic damage in mammalian germ cells in vivo.
On the basis of studies on rats and hamsters, the target tissue in inhalation studies is the upper respiratory tract. In the respiratory tract, degenerative changes of the olfactory epithelium in rats and trachea in hamsters have been observed at the lowest concentrations. Degenerative changes in the respiratory epithelium and larynx have been observed at higher concentrations. In available studies, the lowest concentration at which effects were observed
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(degenerative changes in the olfactory epithelium of rats) was 437 mg/m3 following administration for 5 weeks (Saldiva et al., 1985). The NOELs identified for respiratory effects were 275 mg/m3 in rats exposed for 4 weeks (Appelman et al., 1986) and 700 mg/m3 in hamsters exposed for 13 weeks (Kruysse et al., 1975).
Increased incidences of tumours have been observed in inhalation studies on rats and hamsters exposed to acetaldehyde. In rats, there were dose-related increases in nasal adenocarcinomas and squamous cell carcinomas (significant at all doses of 1350 mg/m3 and greater) (Woutersen et al., 1986) and non significant increases in laryngeal and nasal carcinomas in hamsters (Feron et al., 1982). All concentrations of acetaldehyde administered in these studies induced tissue damage in the respiratory tract. On the basis of limited available data, no conclusions can be drawn concerning the potential of acetaldehyde to promote tumours.
The distribution of nasal lesions induced in rats exposed to acetaldehyde in inhalation studies correlates with regional deficiencies in ALDH, observed in a different strain of rats, prompting the authors to suggest that regional susceptibility to the toxic effects may be due, at least in part, to a lack of ALDH in the susceptible regions (Bogdanffy et al., 1986).
Available data are inadequate for assessment of the potential reproductive, developmental, neurological, or immunological effects associated with exposure to acetaldehyde in occupationally exposed or general populations.
10.1.3 Approaches to risk assessment
The following guidance is provided as a potential basis for derivation of limits of exposure by relevant authorities. Though the principal sources of exposure to acetaldehyde in the general population are through the metabolism of alcohol, in cigarette smoke, and food, air is believed to be the main route of exposure in the occupational environment. In addition, available data are inadequate to provide guidance concerning the potential risks associated with oral exposure to acetaldehyde. On this basis, only air is addressed here.
On the basis of data on irritancy in humans, a tolerable concentration can be derived as follows:
45 mg/m3 Tolerable concentration = = 2 mg/m3 (2000 µg/m3) 20 where: no effects were observed in a limited study on human volunteers at 45 mg/m3 (Silverman et al., 1946) and 20 is the uncertainty factor (×10 for intraspecies variation and × 2 for the poor quality of the data).
Data suggest that acetaldehyde causes genetic damage to somatic cells in vivo. The irritancy of acetaldehyde may also play an important role in the development of tumours in the nose and larynx of rats and hamsters, respectively, exposed by inhalation, though all concentrations of acetaldehyde administered in carcinogenesis bioassays induced both irritancy and nasal tumours. Therefore, two approaches were adopted for the provision of guidance with respect to the potential carcinogenicity of acetaldehyde.
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In the first, a tolerable concentration (TC) was derived on the basis of division of an effect level for irritancy in the respiratory tract of rodents by an uncertainty factor, based on the principles outlined in WHO (in press) and the assumption that there is a threshold for acetaldehyde-induced cancer of the respiratory tract in rodents exposed via inhalation. There is some support for this approach on the basis of relevant data on the analogues of acetaldehyde, i.e., formaldehyde and glutaraldehyde, which have similar spectra of in vitro mutagenic effects, but are clearly not mutagenic in vivo (IARC, 1985; WHO, 1989). Thus,
275 mg/m3 Tolerable concentration = = 0.3 mg/m3 (300 µg/m3) 1000 where:
275 mg/m3 was the NOEL for irritation in rats in a 4-week study (Appelman et al., 1986) and 1000 is the uncertainty factor (×10 for interspecies variation, ×10 for intraspecies variation and ×10 for a less than long-term study and severity of effect, i.e., carcinogenicity associated with irritation).
Since the mechanism of induction of tumours by acetaldehyde has not been well studied, lifetime cancer risk has also been estimated on the basis of a default model (i.e., linearized multistage) (WHO, in press). However, it is very likely that, since estimated risk is based on tumour incidence at concentrations that induce irritancy in the respiratory tract and no-observed-effect levels for irritancy are well below these concentrations, the true cancer risk is most likely much lower at concentrations generally present in the environment and may, indeed, be zero.
Concentrations associated with a 10-5 excess lifetime risk (lower 95% confidence limits) for nasal tumours (adenocarcinomas, squamous cell carcinomas, and carcinomas in situ) in male and female rats, in the only carcinogenicity study in which animals were exposed via inhalation to acetaldehyde over the lifetime (Woutersen et al., 1986), calculated on the basis of the linearized multistage model (Global 82), are 11-65 µg/m3. The high-dose animal groups were excluded in the derivation of these estimates because of early mortality. A body surface area correction was not incorporated.
10.2 Evaluation of effects on the environment
Acetaldehyde enters the environment during industrial production, as a product of incomplete combustion (e.g., in vehicle exhausts) and as a product of alcohol fermentation. Once released, intercompartmental transport of acetaldehyde is expected to be limited, because of its reactivity. However, because of its high vapour pressure and low tendency for sorption onto soil, it is most likely to be present in air. Acetaldehyde is readily biodegradable; approximate half-lives are 10-60 h and 1.9 h in air and water, respectively.
No quantitative data on levels in ambient water were identified. However, on the basis of concentrations measured in drinking-water, levels in the aquatic environment are expected to be low (i.e., less than 0.1 µg/litre). Concentrations in ambient air average about 5 µg/m3.
Acetaldehyde is slightly toxic for fish. The lowest reported LC50 was 35 µg/litre (Poecilia reticulata). No long-term toxicity
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tests have been performed. Acetaldehyde is toxic for micro-organisms at relatively low concentrations. Seed germination of several plants was inhibited by more than 50% after exposure to 1.52 mg/litre (3 h). There were no effects on lettuce exposed to 0.36 µg/m3 acetaldehyde.
The limited available data preclude definitive conclusions concerning the potential risks of acetaldehyde for environmental biota. However, on the basis of the short half-lives of acetaldehyde in air and water and the fact that it is readily biodegradable, the impact of acetaldehyde on organisms in the aquatic and terrestrial environments is expected to be low, except, possibly, during industrial discharges or spills.
11. RECOMMENDATIONS FOR RESEARCH
1. Additional studies on the fate in the environment and impact of acetaldehyde on biota.
2. Additional information on exposure of workers in the occupational environment and levels in the vicinity of industrial facilities.
3. Carcinogenesis bioassays by the inhalation route including doses that do not induce cytotoxicity (e.g., 275 mg/m3).
4. Studies on the biological significance of byproducts of acetaldehyde, such as acetaldehyde-modified proteins.
5. Studies on pathogenicity, reproductive and developmental toxicity, and genotoxicity in vivo by relevant routes of exposure.
6. Additional studies on toxicity following ingestion in experimental animals.
7. Studies of irritation in workers exposed to acetaldehyde.
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Watanabe A, Hobara N, & Nagashima H (1986) Blood and liver acetaldehyde concentration in rats following acetaldehyde inhalation and intravenous and intragastric ethanol administration. Bull Environ Contam Toxicol, 37: 513-516.
Webster WS, Walsh DA, McEwen SE, & Lipson AH (1983) Some teratogenic properties of ethanol and acetaldehyde in C57BL/6J mice: implications
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Westcott JY, Weiner H, Schultz J, & Myers RD (1980) In vivo acetaldehyde in the brain of the rat treated with ethanol. Biochem Pharmacol, 29: 411-417.
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Résumé
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1. Identité, propriétés physiques et chimiques et méthodes d'analyse
L'acétaldéhyde est un liquide incolore et volatil à l'odeur acre et suffocante. D'après la littérature, son seuil olfactif est de 0,09 mg/m3. L'acétaldéhyde est un composé très inflammable et réactif qui est miscible à l'eau et à la plupart des solvants ordinaires.
Il existe un certain nombre de méthodes d'analyse pour la recherche de l'acétaldéhyde dans l'air (y compris dans l'haleine) et dans l'eau. La principale méthode repose sur la réaction de l'acétaldéhyde avec la 2,4-dinitrophénylhydrazine, puis analyse de l'hydrazone obtenue par chromatographie liquide à haute pression ou chromatographie en phase gazeuse.
2. Sources d'exposition humaine et environnementale
L'acétaldéhyde est un intermédiaire métabolique chez l'homme et les plantes supérieures; c'est également un produit de la fermentation alcoolique. On a décelé sa présence dans certaines denrées alimentaires et boissons ainsi que dans la fumée de cigarette. Il est également présent dans les gaz d'échappement des véhicules à moteur ainsi que dans divers déchets industriels. La décomposition des hydrocarbures, des effluents d'égouts et des déchets biologiques solides produit de l'acétaldéhyde, de même que la combustion à l'air libre ou, selon le cas, l'incinération du gaz, du mazout et de la houille.
Plus de 80% de l'acétaldéhyde utilisé à des fins commerciales est produit par l'oxydation en phase liquide de l'éthylène en présence d'une solution catalytique de chlorures de palladium et de cuivre. Au Japon, la production était de 323.000 tonnes en 1981. Aux Etats-Unis d'Amérique elle a été de 281.000 tonnes en 1982 et en Europe occidentale de 706.000 tonnes en 1983. La majeure partie de l'acétaldéhyde produit commercialement est utilisé pour la préparation de l'acide acétique. On l'utilise également pour la préparation de certains arômes et denrées alimentaires.
On estime qu'aux Etats-Unis d'Amérique, les émissions annuelles d'acétaldéhyde de toutes origines atteignent 12,2 millions de kg.
3. Transport, distribution et transformation dans l'environnement
En raison de la forte réactivité de l'acétaldéhyde, le transport intercompartimental de ce composé devrait être limité. On peut s'attendre à un certain transfert d'acétaldéhyde de l'air vers l'eau et le sol en raison de sa forte tension de vapeur et de son faible coefficient de sorption.
On pense que l'élimination photo-induite de l'acétaldéhyde atmosphérique passe essentiellement par la formation de radicaux. La photolyse devrait jouer également un rôle important dans le processus d'élimination. Environ 80% des émissions d'acétaldéhyde dans l'atmosphère sont éliminés chaque jour par ces deux processus. D'après la littérature, la demi-vie de l'acétaldéhyde dans l'eau et l'air est respectivement égale à 1,9 heure et 10-60 heures.
L'acétaldéhyde est facilement biodégradable.
4. Concentrations dans l'environnement et exposition humaine
Les concentrations moyennes d'acétaldéhyde dans l'environnement sont généralement égales à 5 µg/m3. Dans l'eau, elles sont généralement inférieures à 0,1 µg/litre. L'analyse de denrées
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alimentaires très diverses effectuées aux Pays-Bas a montré que leur teneur en acétaldéhyde est généralement inférieure à 1 mg/kg, mais peut atteindre occasionnellement jusqu'à plusieurs centaines de mg/kg, en particulier dans certains jus de fruit et dans le vinaigre.
Pour la population générale, la principale source d'exposition à l'acétaldéhyde est de loin le métabolisme de l'alcool. La fumée de cigarette constitue également une importante source d'exposition. En ce qui concerne les autres véhicules, la population générale est exposée à l'acétaldéhyde essentiellement par l'intermédiaire de la nourriture et des boissons et, dans une moindre mesure, de l'air. L'eau de boisson est négligeable à cet égard.
Les données disponibles sont insuffisantes pour qu'on puisse évaluer l'ampleur de l'exposition à l'acétaldéhyde sur les lieux de travail. Les travailleurs peuvent y être exposés dans certaines industries ainsi que lors de la fermentation de l'alcool; dans ces conditions la principale voie d'exposition est très probablement l'inhalation avec possibilité également de contacts cutanés.
5. Cinétique et métabolisme
5.1 Absorption, distribution et élimination
Les données toxicologiques dont on dispose indiquent que l'acétaldéhyde est résorbé au niveau des poumons et des voies digestives; toutefois on ne connaît pas d'études quantitatives appropriées qui aient été consacrées à ce problème. Il est probable qu'il y a également une résorption cutanée.
Après avoir fait inhaler de l'acétaldéhyde à des rats, on a constaté qu'il se répartissait dans le sang, le foie, les reins, la rate, le coeur et le tissu musculaire. De faibles quantités en ont été décelées dans des embryons après injection intrapéritonéale à la mère (souris) ainsi qu'après exposition de la mère à de l'éthanol (souris et rat). Il pourrait également y avoir production d'acétaldé-hyde in vitro chez les foetus de rat et dans le placenta humain.
Après injection intrapéritonéale d'éthanol, on a pu mettre en évidence la distribution de l'acétaldéhyde dans le liquide interstitiel de l'encéphale, à l'exclusion des cellules cérébrales. Il est possible qu'une acétaldéhyde-déshydrogénase de forte affinité et de faible Km joue un rôle important dans le maintien de faibles concentrations d'acétaldéhyde dans le cerveau au cours de la métabolisation de l'éthanol.
On a constaté que chez l'homme et les babouins, l'acétaldéhyde pouvait être fixé par les globules rouges in vivo, la concentration intraglobulaire pouvant atteindre dix fois la concentration plasmatique.
Après administration par voie orale, il n'y a pratiquement pas d'acétaldéhyde qui soit excrété tel quel dans les urines.
5.2 Métabolisme
La principale voie métabolique de l'acétaldéhyde consiste dans une oxydation en acétate sous l'action de l'ALDHa NADb-dépendante. L'acétate entre dans le cycle de l'acide citrique sous forme d'acétyl-CoA. Il existe plusieurs isoenzymes de l'ALDH présentant divers paramètres cinétiques et paramètres de liaison qui influent sur la vitesse d'oxydation de l'acétaldéhyde.
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Chez le rat, on a pu localiser une activité ALDH dans l'épithélium respiratoire (à l'exclusion de l'épithélium olfactif), alors que cette localisation se situe au niveau du rein chez la souris et au niveau du cortex et des tubules rénaux chez le chien, le rat, le cobaye et le babouin.
Les tissus embryonnaires de souris et de rat métabolisent l'acétaldéhyde in vitro. L'acétaldéhyde traverse le placenta du rat malgré l'existence d'un métabolisme placentaire.
a acétaldéhyde-déshydrogénase b nicotinamide-adénine-dinucléotide
Il y a un certaine métabolisation de l'acétaldéhyde au niveau des tubules rénaux chez l'homme mais c'est le foie qui est le principal site du métabolisme.
Chez l'homme, on a décelé la présence de plusieurs formes isoenzymatiques d'ALDH, au niveau du foie et d'autres tissus. Il y a également un polymorphisme de l'ALDH michocondrial. Les sujets qui sont homozygotes ou hétérozygotes pour une mutation ponctuelle du gène correspondant à l'ALDH mitrochondriale, présentent une faible activité ALDH, métabolisent lentement l'acétaldéhyde et ne supportent pas l'alcool éthylique.
Le crotonadéhyde, la maléate de diméthyle, la phorone, le disulfirame et le carbamide calcique inhibent le métabolisme de l'acétaldéhyde.
5.3 Réactions avec d'autres constituants
L'acétaldéhyde forme des adduits stables ou instables avec les protéines. Ces adduits peuvent perturber la fonction de ces protéines comme le montre d'ailleurs l'inhibition des enzymes, les difficultés de liaison entre histones et ADN et l'inhibition de la polymérisation de la tubuline.
Des adduits instables de l'acétaldéhyde dont on connaît mal l'importance se forment in vitro avec les acides nucléiques.
L'acétaldéhyde peut réagir sur diverses macromolécules de l'organisme, de préférence avec celles qui sont porteuses de résidus de lysine; cette réaction peut conduire à des altérations importantes de la fonction biologique de ces molécules.
6. Effets sur les êtres vivants dans leur milieu naturel
6.1 Organismes aquatiques
Chez les poissons la CL50 peut varier de 35 mg/litre (guppy) à 140 mg/litre (espèces non précisées). Une CE5 de 82 mg/litre et une CE50 de 42 mg/litre ont été observées respectivement chez des algues et chez Daphnia magna.
6.2 Organismes terrestres
La présence d'acétaldéhyde dans l'air se révèle toxique pour certains microorganismes, à des concentrations relativement faibles.
Des aphidiens ont été tués par exposition de 3 à 4 heures à de l'acétaldéhyde à une concentration de 0,36 µg/m3.
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Chez deux espèces de limaces, Arion hortensis et Agriolimax reticulatus, on a observé des concentrations létales médianes respectivement égales à 8,91 mg/litre et par heure et 7,69 mg/litre et par heure.
L'acétaldéhyde provoque une inhibition réversible de la germination des oignons, des carottes et des tomates à des concentrations allant jusqu'à 1,52 mg/litre; par contre cette inhibition est irréversible pour Amaranthus palmeri, dans les mêmes conditions d'exposition. A la concentration de 0.54 µg/m3, l'acétaldéhyde a détérioré des laitues.
7. Effets sur les animaux de laboratoire et les systèmes d'épreuve in vitro
7.1 Exposition unique
Les valeurs de la DL50 pour le rat et la souris et de la CL50 pour le rat et le hamster doré montrent que la toxicité aiguë de l'acétaldéhyde est faible. On n'a pas connaissance d'études relatives à la toxicité cutanée aiguë de l'acétaldéhyde.
7.2 Exposition à court et à long terme
Lors d'études au cours desquelles des doses ont été administrées à plusieurs reprises, tant par la voie orale que par la voie respiratoire, les effets toxiques observés à des concentrations relativement faibles se limitaient essentiellement aux points de contact initiaux. Lors d'une étude de 28 jours au cours de laquelle de l'acétaldéhyde a été administré à des rats, mélangé à leur eau de boisson, à la dose de 675 mg/kg de poids corporel (dose sans effets observables 125 mg/kg de poids corporel), on a constaté que les effets se limitaient à une légère hyperkératose focale au niveau de la portion cardiaque de l'estomac. Après administration d'acétaldéhyde à concentration constante de 0,05% dans l'eau de boisson pendant une durée de 6 mois (le Groupe de travail estime que cela correspond à peu près à 40 mg/kg de poids corporel) au cours d'une étude biochimique, on a constaté que l'acétaldéhyde provoquait la synthèse de collagène au niveau du foie chez le rat, observation d'ailleurs corroborée par les résultats obtenus in vitro.
Lors d'une étude d'inhalation de 4 semaines chez le rat et de 13 semaines chez le hamster, on a obtenu, pour la concentration sans effets respiratoires observables, des valeurs respectivement égales à 275 mg/m3 et 700 mg/m3. Aux concentrations les plus faibles produisant un effet, on a observé des altérations dégénératives au niveau de l'épithélium olfactif chez le rat (437 mg/m3) et de la trachée (2400 mg/m3) chez le hamster. Des altérations dégénératives de l'épithélium respiratoire et du larynx ont été observées à des concentrations plus élevées. On n'a pas connaissance d'études relatives à l'administration répétée d'acétaldéhyde au niveau cutané.
7.3 Reproduction, embryotoxicité et tératogénicité
Plusieurs études montrent que des malformations foetales peuvent survenir par suite de l'exposition parentérale de rattes et de souris gravides à l'acétaldéhyde. Dans la plupart de ces études, on n'a pas étudié la toxicité pour la mère. On n'a pas pu trouver de données relatives à la toxicité de l'acétaldéhyde pour la fonction de reproduction.
7.4 Mutagénicité et points d'aboutissement des effets correspondants
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In vitro, l'acétaldéhyde est génotoxique et produit des mutations géniques, des effets clastogènes ainsi que des échanges entre chromatides soeurs dans des cultures de cellules mammaliennes en l'absence d'activation métabolique exogène. Toutefois, des épreuves effectuées dans les règles sur des salmonelles ont donné des résultats négatifs. Après avoir injecté de l'acétaldéhyde par voie intrapéritonéale à des hamsters chinois et à des souris, on a constaté que ce composé produisait des échanges entre chromatides soeurs au niveau de la moelle osseuse. Cependant, de l'acétaldéhyde administré par la même voie n'a pas eu pour conséquence un accroissement de la fréquence des micronoyaux dans les spermatides de souris récemment formés. On peut déduire indirectement de certaines études in vitro et in vivo que l'acétaldéhyde est susceptible de produire des pontages protéines-ADN et ADN-ADN.
7.5 Cancérogénicité
Des études d'inhalation effectuées sur des rats et des hamsters ont permis de constater un accroissement de l'incidence des tumeurs. Chez le rat, il s'agissait d'une augmentation, liée à la dose, de la fréquence des adénocarcinomes au niveau de la muqueuse nasale ainsi que des carcinomes spino-cellulaires (accroissement significatif à toutes les doses). Toutefois chez le hamster, l'accroissement constaté de la fréquence des carcinomes du nez et du larynx n'était pas significatif. A toutes les concentrations d'acétaldéhyde, on a constaté l'apparition de lésions tissulaires chroniques au niveau des voies respiratoires.
7.6 Etudes spéciales
On n'a pas connaissance d'études appropriées portant sur la neuro- et l'immunotoxicité potentielle de l'acétaldéhyde.
8. Effets sur l'homme
Lors d'études limitées portant sur des volontaires humains, on a constaté que l'acétaldéhyde avait un effet légèrement irritant sur les yeux et les voies respiratoires supérieures, après exposition de très brève durée à des concentrations respectivement supérieures à environ 90 et 240 mg/m3. Après l'application d'un timbre inbibé d'acétaldéhyde, on a constaté la présence d'un érythème cutané chez 12 sujets "d'ascendance orientale".
On a signalé l'existence d'une enquête limitée au cours de laquelle on a étudié l'incidence des cancers chez des travailleurs exposés à de l'acétaldéhyde.
On possède des preuves indirectes que le métabolite toxique supposé être à l'origine des lésions hépatiques imputables à l'alcool, de bouffées de chaleur et d'effets sur la développement, est en fait l'acétaldéhyde.
9. Evaluation des risques pour la santé humaine et des effets sur l'environnement
Les études effectuées sur l'animal montrent que, par voie respiratoire ou par voie orale, l'acétaldéhyde n'est que faiblement toxique. D'après les études effectuées sur l'animal mais également sur l'homme, on a constaté que ce composé était légèrement irritant pour l'oeil et les voies respiratoires supérieures. Chez l'homme, l'application d'un timbre cutané inbibé d'acétaldéhyde peut provoquer l'apparition d'un érythème cutané. On pense avoir découvert le mécanisme à l'origine de cet effet mais les données disponibles sont encore insuffisantes pour qu'on puisse évaluer le pouvoir
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sensibilisateur de l'acétaldéhyde.
On ne dispose que de données limitées sur les effets d'une ingestion d'acétaldéhyde. Après administration d'acétaldéhyde par voie orale à des rats à la dose quotidienne de 675 mg/kg de poids corporel, on a constaté un accroissement limite de l'hyperkératose au niveau de la portion cardiaque de l'estomac (dose sans effets nocifs observables: 125 mg/kg de poids corporel). Après avoir fait boire à des rats six mois durant de l'eau contenant environ 40 mg d'acétaldéhyde/kg de poids corporel, on a constaté un accroissement de la synthèse du collagène hépatique, effet dont la signification reste obscure.
D'après des études effectuées sur des rats et des hamsters, ce sont les voies respiratoires supérieures qui constituent l'organe cible de l'acétaldéhyde lorsque ce composé est inhalé. D'après les résultats obtenus, la concentration la plus faible à laquelle on a commencé à observer des effets était de 437 mg/m3, après une période d'administration de 5 semaines. Chez des rats exposés pendant 4 semaines, la dose sans effets respiratoires observables était de 275 mg/m3; elle était de 700 mg/m3 chez des hamsters exposés pendant 13 semaines.
Aux concentrations qui produisaient des lésions tissulaires des voies respiratoires, on a observé un accroissement de l'incidence des adénocarcinomes du nez et des carcinomes spino-cellulaires chez le rat; il y a également eu accroissement des carcinomes du larynx et du nez chez le hamster.
On est fondé à penser qu' in vivo, l'acétaldéhyde provoque des lésions génétiques dans les cellules somatiques.
les données disponibles sont insuffisantes pour qu'on puisse apprécier les effets qu'une exposition à l'acétaldéhyde pourrait avoir sur la reproduction, le développement ainsi que les fonctions neurologiques et immunologiques de la population générale ou de la population professionnellement exposées.
Pour ce qui est du pouvoir irritant de ce composé chez l'homme, on estime que la concentration tolérable est de 2 mg/m3. Etant donné que le mécanisme d'induction de tumeurs par l'acétaldéhyde n'a pas été bien étudié, on a adopté deux approches concernant ce point d'aboutissement de son action toxique, à savoir la fixation d'une concentration tolérable qui serait obtenue en divisant la dose irritante pour les voies respiratoires chez les rongeurs, par un certain facteur d'incertitude et l'estimation d'un risque de cancer sur toute la durée de l'existence, en procédant par extrapolation linéaire. La concentration tolérable est de 0,3 mg/m3. La concentration produisant un excès de risque de 10-5 sur toute la durée de la vie se situe entre 11-65 µg/m3.
Les données limitées dont on dispose ne permettent pas de tirer des conclusions définitives quant au risque que l'acétaldéhyde pourrait représenter pour l'ensemble de la faune et de la flore. Toutefois, si l'on considère la courte durée de vie de l'acétaldéhyde dans l'air et dans l'eau et le fait qu'il est facilement biodégradable, on est amené à penser que ce composé n'est guère menaçant pour les organismes aquatiques ou terrestres, sauf peut-être en cas de décharge ou de déversement de produits industriels.
RESUMEN
1. Identidad, propiedades físicas y químicas y métodos analíticos
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El acetaldehído es un líquido incoloro, volátil y de olor acre y sofocante. El umbral señalado para el olor es de 0,09 mg/m3. El acetaldehído es un compuesto muy inflamable y reactivo, soluble en agua y en la mayoría de los disolventes comunes.
Existen métodos de análisis para la detección del acetaldehído en el aire (incluso en el aliento) y en el agua. El principal de ellos se basa en la reacción del producto con 2,4-dinitrofenilhidracina y ulterior análisis de los derivados de la hidrazona por cromatografía de líquidos a alta presión o cromatografía de gases.
2. Fuentes de exposición humana y ambiental
El acetaldehído es un producto intermedio del metabolismo en los hombres y en las plantas superiores, y también proviene de la fermentación alcohólica. Ha sido identificado en los alimentos, las bebidas y el humo de los cigarrillos. También se encuentra en los gases de escape de los vehículos y en ciertos desechos industriales. La degradación de los hidrocarburos, las aguas residuales y los desechos biológicos sólidos produce acetaldehído, como también lo hacen la combustión al aire libre y la incineración de gas, fuel oil y carbón.
Más del 80% del acetaldehído usado comercialmente proviene de la oxidación en fase líquida de etileno con una solución catalítica de paladio y cloruros de cobre. En 1981, la producción japonesa fue de 323 000 toneladas. En los Estados Unidos de América fue de 281 000 toneladas en 1982 y en Europa occidental de 706 000 toneladas en 1983. La mayoría del acetaldehído producido comercialmente se destina a la fabricación de ácido acético. También se utiliza en sustancias aromáticas y en alimentos.
En los Estados Unidos, la emisión anual de acetaldehído de todo origen se calcula en 12,2 millones de kilogramos.
3. Transporte, distribución y transformación en el medio ambiente
Debido a su alta reactividad, el transporte intercompartimental de acetaldehído debe ser limitado. Es de suponer que hay cierta transferencia de la sustancia al aire desde el agua y el suelo, como consecuencia de la fuerte presión del vapor y el bajo coeficiente de sorción.
Es posible que la eliminación fotoinducida del acetaldehído en la atmósfera tenga lugar principalmente por formación de un radical. La fotosíntesis puede también contribuir bastante al proceso de eliminación. La pérdida resultante de acetaldehído proveniente de emisiones en la atmósfera es de alrededor del 80%. La vida media de la sustancia en el agua y en el aire es de 1,9 h y 10-60 h, respectivamente.
El acetaldehído es muy biodegradable.
4. Niveles medioambientales y exposición humana
Los niveles de acetaldehído en el aire ambiente suelen ser por término medio de 5 µg/m3. Las concentraciones en el agua no llegan en general a 0,1 µg/litro. El análisis de diversos alimentos en los Países Bajos demostró que las concentraciones, normalmente inferiores a 1 mg/kg, a veces llegaban a 100 mg/kg, particularmente en algunos zumos de frutas y en el vinagre.
La principal fuente, con mucho, de exposición al acetaldehído
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para la mayoría de la población es el metabolismo del alcohol. El humo del cigarrillo es también una fuente significativa. Aparte de eso pueden mencionarse en segundo lugar los alimentos y bebidas y, en menor grado, el aire. La contribución del agua de beber es insignificante.
No existen datos suficientes para determinar la importancia de la exposición al acetaldehído en el lugar de trabajo. El personal puede estar expuesto en algunas industrias manufactureras y donde hay fermentación con producción de alcohol, siendo la principal vía la inhalación y posiblemente el contacto con la piel.
5. Cinética y metabolismo
5.1 Absorción, distribución y eliminación
Los estudios existentes sobre toxicidad indican que el acetaldehído se absorbe por los pulmones y el conducto gastrointestinal; sin embargo, no parecen existir análisis cuantitativos adecuados. Es probable la absorción por la piel.
En las ratas, el acetaldehído inhalado se distribuye por la sangre, pasando al hígado, el riñón, el bazo, el corazón y otros tejidos musculares. Se han detectado bajos niveles en embriones de ratón tras inyectar la sustancia a la madre por vía intraperitoneal o tras exposición de ratas o ratones hembra a etanol. La producción potencial de acetaldehído in vitro se ha observado en fetos de rata y en la placenta humana.
Tras inyección intraperitoneal de etanol se ha demostrado la distribución de acetaldehído en el líquido intersticial pero no en las células del cerebro. Una alta afinidad y escaso Km ALDHa pueden ser importantes para mantener bajos niveles de acetaldehído en el cerebro durante el metabolismo del etanol.
El acetaldehído es absorbido por los eritrocitos y, tras consumo de etanol, los niveles intracelulares en hombres y babuinos pueden ser in vivo 10 veces más altos que los del plasma.
Después de la administración por vía oral, la excreción de acetaldehído por la orina prácticamente no cambia.
5.2 Metabolismo
Un medio importante en el metabolismo del acetaldehído es la oxidación para pasar a acetato bajo la influencia de una ALDH dependiente de NADb. El acetato pasa al ciclo de ácido cítrico como acetil-CoA. Hay varios isoenzimas de ALDH con distintos parámetros cinéticos y de ligazón que influyen en la rapidez de la oxidación del acetaldehído.
Se ha detectado actividad de la ALDH en el epitelio del tracto respiratorio (excluido el de las vías olfativas) de ratas, en el cortex renal y los túbulos del perro, la rata, el cobayo y el babuino, y también en los testículos del ratón.
El acetaldehído es metabolizado in vitro por el tejido embrionario del ratón y la rata. La sustancia atraviesa la placenta del ratón, pese al metabolismo placentario.
Aunque hay algún metabolismo en los túbulos renales humanos, el principal órgano metabolizador es el hígado.
En el hígado y otros tejidos humanos se han detectado varias
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formas isoenzimáticas de ALDH. En las mitocondrias la ALDH presenta polimorfismo. Los sujetos que son homozigóticos o heterozigóticos por una mutación singular del gen correspondiente a la ALDH de las mitocondrias presentan poca actividad de esta enzima, metabolizan el acetaldehído lentamente y no toleran el etanol.
El metabolismo del acetaldehído puede ser inhibido por el crotonaldehído, el dimetilmaleato, el forón, el disulfiram y la carbamida de calcio.
5.3 Reacción con otros compuestos
El acetaldehído puede formar aductores estables e inestables con las proteínas. Eso menoscaba la función proteínica, como lo demuestra la inhibición de la actividad enzimática, la menor ligazón histona-ADN y la polimerización inhibida de la tubulina.
Los aductores inestables, de importancia indeterminada, se producen in vitro con ácidos nucleicos.
El acetaldehído puede reaccionar con diversas macromoléculas en el organismo humano, de preferencia las que contienen residuos de lisina, lo que puede conducir a notables alteraciones de la función biológica de dichas moléculas.
6. Efectos sobre los organismos presentes en el medioambiente
6.1 Organismos acuáticos
La CL50 para los peces va de 35 (Lebistes reticulatus) a 140 mg/litro (especies no especificadas). Se ha señalado una CE5 de 82 mg/litro y una CE50 de 42 mg/litro para las algas y para Daphnia magna, respectivamente.
6.2 Organismos terrestres
El acetaldehído atmosférico a concentraciones relativamente bajas parece ser tóxico para algunos microorganismos.
Los afidios mueren cuando son expuestos a concentraciones de 0,36 µg/m3 durante tres o cuatro horas.
Para las especies de babosa Arion hortensis y Agriolimax reticulatus se han registrado valores letales medios de 8,91 mg/litro y 7,69 mg/litro por hora, respectivamente.
La inhibición de la germinación para la semilla de cebolla, zanahoria y tomate tratada con acetaldehído (hasta 1,52 mg/litro) es reversible, mientras que la de Amaranthus palmeri expuesta del mismo modo es irreversible. El acetaldehído a 0,54 µg/m3 es perjudicial para la lechuga.
7. Efectos en animales experimentales y sistemas de prueba in vitro
7.1 Exposición única
El acetaldehído tiene una toxicidad aguda baja, con una DL50 en ratas y ratones y una CL50 en ratas y hámsters sirios. No se han encontrado estudios de toxicidad dérmica aguda.
7.2 Exposición a corto y a largo plazo
En estudios reiterados del efecto tóxico de dosis por vía oral y por inhalación, los efectos tóxicos de concentraciones relativamente
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bajas se limitaron más bien a los puntos de contacto inicial. En un estudio de 28 días en el que se administró a ratas con el agua de beber acetaldehído a razón de 675 mg/kg de peso corporal (nivel sin efecto observado (NOEL) = 125 mg/kg de peso corporal) los efectos se limitaron a una ligera hiperqueratosis focal en la parte anterior del estómago. En un estudio bioquímico, tras la administración a ratas de dosis singulares (0,05% en el agua de beber) durante seis meses (equivalente según el Grupo Especial a alrededor de un 40 mg/kg de peso corporal), el acetaldehído indujo la síntesis de colágeno hepático, observación corroborada mediante pruebas in vitro.
El nivel sin efecto respiratorio observado (NOEL) fue de 275 mg/m3 para ratas expuestas a acetaldehído por inhalación durante cuatro semanas y 700 mg/m3 en hámsters expuestos durante 13 semanas. A los niveles más bajos de efecto observado se produjeron cambios degenerativos del epitelio olfativo en ratas (437 mg/m3) y de la tráquea (2400 mg/m3) en hámsters. A concentraciones superiores se produjeron cambios degenerativos del epitelio respiratorio y de la laringe. No se han identificado estudios dérmicos con dosis repetidas.
7.3 Reproducción, embriotoxicidad y teratogenicidad
En varios estudios, la exposición parenteral de ratas y ratones gestantes a acetaldehído produjo malformaciones fetales. En la mayoría de esos estudios no se evaluó la toxicidad materna. Tampoco se dispone de datos sobre la toxicidad reproductiva.
7.4 Mutagenicidad y otros efectos finales afines
El acetaldehído es genotóxico in vitro e induce mutación de los genes, con efectos clastogénicos e intercambios de cromatidios hermanos (SCE) en las células de mamíferos, en ausencia de activación metabólica exógena. Sin embargo se han registrado resultados negativos en pruebas adecuadas con Salmonella. Tras inyección intraperitoneal, el acetaldehído indujo SCE en la médula ósea de hámsters chinos y ratones pero, en cambio, no hizo aumentar la frecuencia de los micronúcleos en las espermátides precoces de ratón. Indirectamente, ciertos estudios in vitro e in vivo parecen indicar que el acetaldehído puede inducir enlaces cruzados proteína-ADN y ADN-ADN.
7.5 Carcinogenicidad
Se ha observado una mayor incidencia de tumores en ratas y hámsters expuestos a acetaldehído por inhalación. En las ratas, los adenocarcinomas nasales aumentaron según la dosis pero los carcinomas de células escamosas fueron significativos independientemente de la dosis. Por el contrario, en los hámsters, el aumento de los carcinomas nasales y laríngeos fue insignificante. A todas las concentraciones, el acetaldehído administrado en los estudios produjo daños irreversibles del tejido respiratorio.
7.6 Estudios especiales
No se conocen estudios adecuados sobre la neurotoxicidad y la inmunotoxicidad potencial del acetaldehído.
8. Efectos en el ser humano
En estudios limitados con voluntarios, el acetaldehído produjo irritación moderada de los ojos y de las vías respiratorias superiores tras exposición por muy breves periodos a concentraciones que excedían
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algo de 90 y 240 mg/m3, respectivamente. Las pruebas de parche efectuadas con acetaldehído produjeron eritema cutáneo en 12 sujetos de «ascendencia oriental».
Se ha tenido conocimiento de una investigación limitada sobre la incidencia del cáncer entre trabajadores expuestos a acetaldehído y otras sustancias.
Según pruebas indirectas, el acetaldehído participa como metabolito potencialmente tóxico en la inducción de las afecciones hepáticas, la congestión facial y las alteraciones del desarrollo asociadas con el alcohol.
9. Evaluación de los riesgos para la salud humana y los efectos en el medio ambiente
Los estudios efectuados con animales indican que la toxicidad aguda del acetaldehído por inhalación o por vía oral es baja. Según las investigaciones con sujetos humanos y con animales, esa sustancia es algo irritante para los ojos y las vías respiratorias superiores. Esos mismos efectos se han apreciado en voluntarios a los que se administró acetaldehído (sección 1.8). Se ha observado eritema cutáneo consiguiente a las pruebas de parche en sujetos humanos. Aunque se ha identificado un posible mecanismo, los datos de que se dispone son insuficientes para calcular el potencial del acetaldehído como inductor de sensibilización.
Existe poca información sobre los efectos del acetaldehído ingerido. Tras administrar diariamente a ratas por vía oral 675 mg/kg de peso corporal (NOEL = 125 mg/kg de peso corporal) se observó un aumento liminar de la hiperqueratosis en la parte anterior del estómago. En las ratas que ingirieron durante seis meses con el agua de beber dosis aproximadas de 40 mg/kg de peso corporal hubo un aumento de la síntesis de colágeno en el hígado, cuya significación está por dilucidar.
Los estudios de inhalación con ratas y hámsters permiten afirmar que el tejido sensible es el de las vías respiratorias superiores. La concentración más baja a la que se observaron efectos fue 437 mg/m3 durante cinco semanas. El NOEL identificado del tracto respiratorio fue 275 mg/m3 en ratas expuestas durante cuatro semanas y 700 mg/m3 en hámsters expuestos durante 13 semanas.
A las concentraciones que producen daños en los tejidos del tracto respiratorio se observaron aumentos de la incidencia del adenocarcinoma nasal y del carcinoma de células escamosas en la rata, y de los carcinomas laríngeos y nasales en el hámster.
Hay indicios de que el acetaldehído produce in vivo alteraciones genéticas en las células somáticas.
No se dispone de datos suficientes para determinar si el acetaldehído tiene efectos en la reproducción y el desarrollo o en el estado neurológico o inmunológico de la población general o de la que está particularmente expuesta por razón de su trabajo.
A partir de datos sobre la acción irritante en sujetos humanos se ha considerado que la concentración tolerable es de 2 mg/m3. El mecanismo de inducción de tumores por el acetaldehído no está bien estudiado. En consecuencia, se han adoptado dos criterios orientativos a ese respecto; a saber, la determinación de una concentración tolerable obtenida dividiendo un nivel de efecto irritante en el tracto respiratorio de los roedores por un factor de incertidumbre, y la estimación del riesgo de cáncer mediante
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extrapolación linear. La concentración tolerable resulta ser de 0,3 mg/m3. Las concentraciones asociadas con un aumento del riesgo permanente de 10-5 son de 11-65 µg/m3.
La escasez de datos impide llegar a conclusiones definitivas sobre los riesgos potenciales del acetaldehído para la biota en el medio ambiente. Sin embargo, basándose en la breve vida media del acetaldehído en el aire y en el agua, asi como en el hecho de que es fácilmente biodegradable, cabe afirmar que los efectos de esa sustancia en los organismos terrestres y acuáticos son escasos, excepto posiblemente con ocasión de descargas industriales o vertidos.
See Also: Toxicological Abbreviations Acetaldehyde (HSG 90, 1995) Acetaldehyde (ICSC) ACETALDEHYDE (JECFA Evaluation) Acetaldehyde (IARC Summary & Evaluation, Volume 71, 1999)
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