INTARESE Project No. 018385 INTARESE Integrated Assessment of Health Risks of Environmental Stressors in Europe Integrated Project Thematic Priority Deliverable 20: Biomarker review and development strategy (WP 2.2) Due date of deliverable: 05/2007 Actual submission date: 06/2007 Start Date of Project: 1 November 2005 Duration: 60 Months Organisation name of lead contractor for this deliverable: VITO Revision: Final version Project co-funded by the European Commission with the Sixth Framework Programme (2002- 2006) Dissemination Level PU Public PP Restricted to other programme participants (including the Commission Services) RE Restricted to a group specified by the consortium (including the Commission Services) CO Confidential, only for members of the consortium (including the Commission Services Table of content 1 A brief introduction to human biomonitoring ............................................................... 2 2 Alkylphenols ............................................................................................................... 7 3 Alpha1-microglobulin (α1-m) ..................................................................................... 20 4 Arsenic ...................................................................................................................... 23 5 β2-microglobulin (β2-m) ............................................................................................ 34 6 Bisphenol A .............................................................................................................. 37 7 Brominated flame retardants ...................................................................................... 51 8 Cadmium (Cd) ........................................................................................................... 61 9 Chiral POPs/EDCs .................................................................................................... 65 10 Dioxins ...................................................................................................................... 85 11 Disinfection By-Products (Trihalomethanes & Trichloroacetic acid)........................ 101 12 Fluorinated surfactants ............................................................................................ 124 13 Lead (Pb) ................................................................................................................. 138 14 Parabens .................................................................................................................. 141 15 Pesticides ................................................................................................................ 152 16 Phthalates ................................................................................................................ 247 17 Polycyclic aromatic hydrocarbons (PAHs) ............................................................... 269 18 Polychlorinated biphenyls ........................................................................................ 280 19 Retinol binding protein (RBP) ................................................................................. 308 20 Further Strategy to integrate biomonitoring in the risk assessment paradigm (months 10 - 18) ........................................................................................................................... 311 21 References ............................................................................................................... 315 1 1 A BRIEF INTRODUCTION TO HUMAN BIOMONITORING Human biomonitoring makes pollution get personal Environmental health sciences focus on the link between the presence of contaminants in the environment, and their relation with possible adverse health effects. The traditional way of describing these relationships is by estimating the concentration of chemicals in different environmental compartments using empirical or modeling efforts, taking into account human exposure estimates to quantify the dose. Recently, due to both an increase in analytical capacity and a change in social awareness towards pollution exposure, there has been a rapid increase in the development and application of human biomonitoring (HBM) as a tool to evaluate exposure (i.e. the use of human tissue or fluid samples to estimate exposure). In many cases, HBM data have been proven to be a valuable completion, or have even surpassed, estimates of exposure based on environmental measures (Bates et al 2005). HBM directly measures the amount of a chemical substance in a person‘s body, taking into account often poorly understood processes such as bioaccumulation, excretion, metabolism and the integrative uptake variability through different exposure pathways, rather than each individual exposure source (Hoppin et al 2000). Hence, these data are much more relevant for risk assessment than extrapolations from chemical concentrations in soil, air, and water. As was phrased by Stokstad (2004), ―pollution gets personal‖ when HBM data are being collected. Not only does this pertain a change of philosophy in the general public, it also integrates environmental exposure in a way that is more likely to be consistent with health effects, as the causative compounds have actually entered the body and are still detectable (Hoppin et al 2000). Types of HBM Biological indicators, or biomarkers, generally are biochemical, molecular, genetic, immunologic, or physiologic observations in biological systems. Traditionally, biomarkers have been classified as biomarkers of exposure, effects and susceptibility. Though this classification suggests the existence of clearly defined subgroups, biomarkers actually form a continuum between the external exposure to a chemical and 2 the internal clinical effect (Figure 1) (NRC 2006). According to the WHO (2001), biomarkers of exposure, effect, and susceptibility are defined as follows: o Biomarkers of exposure: The chemical or its metabolite or the product of an interaction between a chemical and some target molecule or cell that is measured in a compartment in an organism o Biomarker of effect: A measurable biochemical, physiological, behavioral, or other alteration in an organism that, depending on the magnitude, can be recognized as associated with an established or possible health impairment or disease. o Biomarker of susceptibility: An indicator of an inherent or acquired ability of an organism to respond to the challenge of exposure to a specific chemical substance. Figure 1.1: Simplified flow chart of classes of biomarkers (NRC 1987, 2006) This report mainly focuses on biomarkers of exposure, and aims at providing an overview of the major classes of biomarkers that are currently available, describes their use, indicates (if available) standardized methods and reference values, and tries to identify confounding factors. However, before going into detail, it is desirable to first briefly sketch the policy framework for the implementation of HBM in the European Environment and Health Action plan, and to provide the reader with a framework to integrate HBM in the current risk assessment paradigm. HBM and the European Environment & Health Action Plan 2004-2010 The ―European Environment & Health Action Plan 2004-2010‖ originates from the concern of EU citizens on the well-being of individuals and the general population. Together with improving general public health, there are also indirect yet large benefits in terms of long-term economic growth and sustainable development, since the indirect 3 costs in productivity losses due to illness or premature death may be substantially larger than the cost for direct health care (EC, 2004a). The Action Plan has three main themes: 1. Improving the information chain to understand the links between sources of pollution and health effects (Action 1-4); 2. Filling the knowledge gap by strengthening research and addressing the emerging issues on environment and health (Action 5-8); 3. Reviewing policies and improving communication (Action 9-13). For each of these three themes, a number of actions were identified. The need for human biomonitoring is presented specifically under Action 3: Develop a coherent approach to biomonitoring in Europe. Within this Action 3, the need for integration with environmental and health data is specifically foreseen: Biomonitoring is not an automatic instrument, which can be considered in isolation, but has to be integrated with environmental monitoring, toxicological and eco-toxicological data and especially with considerations related to analytical epidemiology. (EC, 2004b) From this, it can be postulated that human biomonitoring (HBM) is not an island on itself, but should be considered a stepstone between environmental and health data. The final aim of this view should be an integrated and holistic systematic risk assessment paradigm where HBM serves as a pivotal point between environment and health, on the one hand leaning on environmental data to provide detailed information on the sources and pathways of pollutants that enter the human body, and on the other hand clarifying new and existing hypotheses on the relationship between environmental pollutants and the prevalence of diseases or the occurrence and identification of disease clusters (Hoppin et al 2000). Also, since most health responses are the result of long-term, chronic exposure to environmental pollutants, linking historical exposure to current response without looking at the integrating dose will overlook the history of individuals. A need for