Risk assessment chemical mixtures

At the end of the project, a set of research gaps to be taken into consideration for the future have been identified such as the lack of data about chemicals in products as well as their emission to the environmental compartments, the need to assess the risk of chemical mixtures and not the chemicals by themselves, or the necessity of optimizing the current legislation on chemicals. 

Considering additionally that the risk assessment of mixtures is presently an urgent issue, and that usually mixtures of exclusively organic chemicals or exclusively metals are investigated, in future more emphasis should be placed on the interactions of xenobiotic HIOCs with metals. Major research questions will include how these interactions influence bioavailability of both metals and HIOCs, interactions with biological membranes, uptake, and common toxic effects. 

The immediate future in risk assessment will focus on the difficult but necessary task of integrating experimental data from all levels into the risk assessment process. A continuing challenge to toxicologists engaged in hazard or risk assessment is that of risk from chemical mixtures. Neither human beings nor ecosystems are exposed to chemicals one at a time, yet logic dictates that the initial assessment of toxicity start with individual chemicals. The resolution of this problem will require considerable work at all levels, in vivo and in vitro, into the implications of chemical interactions for the expression to toxicity, particularly chronic toxicity. 

Recently, some models have been derived to analyze the occurrence of interactive joint action in binary single-species toxicity experiments (Jonker 2003). Such detailed analysis models are well equipped to serve as null models for a precision analysis of experimental data, next to the generalized use of concentration addition and response addition as alternative null models. However, in our opinion these models are not applicable to quantitatively predict the combined toxicity of mixtures with a complexity that is prevalent in a contaminated environment, because the parameters of such models are typically not known. Recently a hazard index (Hertzberg and Teus-chler 2002) was developed for human risk assessment for exposure to multiple chemicals. Based on a weight-of-evidence approach, this index can be equipped with an option to adjust the index value for possible interactions between toxicants. It seems plausible that a comparable kind of technique could be applied in ecotoxicological risk assessments of mixtures for single species. However, at present, the widespread application of this approach is prevented by lack of available information. 

This section outlines the current scientific state of the art in the assessment of human health risks for chemical mixtures. It focuses on the gathering, assessment, and evaluation of effect data. The reader is referred to Chapter 1 for detailed information on exposure assessment of chemical mixtures. The section starts with an overview of methods commonly used to obtain effect data on chemical mixtures. This is followed by an overview of the current mixture approaches in human health assessments, that is, the whole mixture approach for common mixtures and the component-based approach. The section concludes with a paragraph on uncertainties in human health assessments of chemical mixtures. 

Ecological risk assessment of chemical mixtures may be conducted using the same types of data sources and approaches as in human risk assessment of mixtures. Available data and approaches are, however, different in kind and numbers. The vast majority of data are from laboratory toxicity tests with mostly binary mixtures... 

The review presented in the previous sections shows an enormous diversity in risk assessment methods and procedures for chemical mixtures. This diversity is characteristic for the current state of the art. The awareness that mixtures may cause risks that are not fully covered by single compound evaluations is growing, but the knowledge required to accurately assess the risks of chemical mixtures is still limited. The scientific community is attempting to unravel the mechanisms involved in mixture exposure and toxicity, and over recent decades, a multitude of new techniques to assess mixture risks have been developed. However, a comprehensive and solid conceptual framework to evaluate the risks of chemical mixtures is still lacking. The framework outlined in Section 5.4 can be considered a first step toward such a conceptual framework. The framework recognizes that the problem definitions vary greatly (between protective and retrospective assessments, for humans and ecosystems), and that each question has resulted in a different type of approach. 

Based on the review and discussion of human and ecological assessment techniques for chemical mixtures, several conclusions can be drawn. These conclusions are listed below and related to the aims of this chapter, outlined in Section 5.1. The recommendations to improve human and ecological risk assessment of mixtures (Aim 5) are provided in the next section. 

The multitude of different mixture assessment techniques is typical for the current state of the art in mixture assessment. There is a clear need for a comprehensive and solid conceptual framework to evaluate the risks of chemical mixtures. 

This book presents an overview of developments in both fields, comparing and contrasting their current state of the art to identify where one field can learn from the other. In terms of subject matter, the book progresses from exposure through to risk assessment, at each step identifying the special complications that are typically raised by mixtures (compared to single chemicals). Five chapters are included, each addressing a specific step from exposure to risk assessment for mixtures ... 

Committee on toxicity of chemicals in food, C.P.A.T.E. (2002) Risk assessment of mixtures of pesticides and similar substances. London Food Standards Agency. 

C.J. van Leeuwen, H.J.M. Verhaar and J.L.M. Hermens, Quality Criteria and Risk Assessment for Mixtures of Chemicals in the Aquatic Environment, Human and Ecological Risk Management, 1996, 2, 419. 

Chemical Mixtures, Toxicology and Risk Assessment see Mixtures, Toxicology and Risk Assessment. 

EPA recommends three approaches (1) if the toxicity data on mixture of concern are available, the quantitative risk assessment is done directly form these preferred data (2) when toxicity data are not available for the mixture of concern, data of a sufficiently similar mixture can be used to derive quantitative risk assessment for mixture of concern and (3) if the data are not available for both mixture of concern and the similar mixture, mixture effects can be evaluated from the toxicity data of components. According to EPA, the dose-additive models reasonably predict the systemic toxicity of mixtures composed of similar (dose addition) and dissimilar (response addition) compounds. Therefore, the potential health risk of a mixture can be estimated using a hazard index (HI) derived by summation of the ratios of the actual human exposure level to estimated maximum acceptable level of each toxicant. A HI near to unity is suggestive of concern for public health. This approach will hold true for the mixtures that do not deviate from additivity and do not consider the mode of action of chemicals. Modifications of the standard HI approach are being developed to take account of the data on interactions. 

As can be expected, some chemicals are data-rich while others are data-poor. Often they are data-poor, especially for chemical mixtures where the data may be adequate, barely adequate or nonexistent for a specific mixture. Thus limited methods are available for the toxicity assessment of chemical mixtures [1,9]. Even though there are various uncertainties and assumptions embedded in these methods, the following three approaches have gained acceptance by the regulatory agencies and the regulated community for risk assessment of mixtures of industrial, occupational, and environmental chemicals. The method employed is on a case-by-case basis, it depends on the exposure scenario and the quality of available data on exposure and toxicity. 

Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment, Risk Assessment of Mixtures of Pesticides and Similar Substances, Document FSA/0691/0902, Food Standards Agency, London, 2002. 

To assess tlie overall potential for noncarcinogenic effects posed by more dian one chemical, a liazard index (HI) approach has been developed based on EPA s Guidelines for Healdi Risk Assessment of Chemical Mixtures. This approach assumes that simultaneous subtlu eshold exposures to several chemicals could result in an adverse healtli effect. It also assumes tliat tlie magnitude of the adverse effect will be proportional to tlie sum of the ratios of the subtlireshold exposures to acceptable exposures. The non cancer hazard index is equal to tlie sum of the hazard quotients, as described below, where E and tlie RfD represent the same exposure period (e.g., subclironic, clironic, or shorter-term). 

The sheer complexity of environmental mixtnres of EDCs, possible interactive effects, and capacity of some EDCs to bioaccumulate (e.g., in fish, steroidal estrogens and alkylphenolic chemicals have been shown to be concentrated up to 40,000-fold in the bile [Larsson et al. 1999 Gibson et al. 2005]) raises questions about the adequacy of the risk assessment process and safety margins established for EDCs. There is little question that considerable further work is needed to generate a realistic pictnre of the mixture effects and exposure threats of EDCs to wildlife populations than has been derived from studies on individual EDCs. Further discussion of the toxicity of mixtures will be found in Chapter 2, Section 2.6. 

Safe, S. (1998) Hazard and Risk Assessment of Chemical Mixtures Using the Toxic Equivalency Factor Approach. Environmental Health Perspectives, 106(Suppl. 4), 1051-1058. 

On July 18, 2000, the Agency released HWIR-waste exemption levels for 36 chemicals that were developed using a risk model known as the Multimedia, Multi-pathway and Multi-receptor Risk Assessment (3MRA) Model.17 The May 16, 2001, HWIR-waste rule revised and retained the hazardous waste mixture and derived-from rules as previously discussed in this module. In addition, the rule finalized provisions that conditionally exempt mixed waste (waste that is both radioactive and hazardous), if the mixed waste meets certain conditions in the rule.5... 

Most of the provisions of the Toxic Substances Control Act (TSCA) of 1976 (PL 94-469) rely in some way on risk assessment of chemicals. Under the reporting requirements of the statute, any manufacturer, processor, or distributor of a chemical for commercial purposes must inform the EPA immediately after discovering any information which "reasonably supports the conclusion" that a chemical substance or mixture "presents a substantial risk of injury to health or to the environment" unless the EPA Administrator has been adequately informed already. EPA is mandated to establish regulations for testing new or existing substances when it is determined that there is not enough health or environmental information, that testing is necessary to develop such information and that the chemical or mixture "may present an unreasonable risk of injury to health or the environment."... 

Risk assessment of landfill leachate, which is traditionally based on chemical analyses of specific compounds, is not sufficiently developed to take into account interactions among chemicals in the complex mixtures ... 

Due to the fact that JP-8 contains hundreds of aliphatic and aromatic hydrocarbons, in addition to various performance additives, this complex mixture poses a serious challenge for risk assessment. Exposure assessment is complicated by the fact that JP-8 may be encountered as a vapor, aerosol, or liquid, and possibly as combustible products, and each physical state may contain different chemical entities. However, progress has been made in the identification of JP-8 components that may serve as reliable and predictable biomarkers of exposure, particularly for dermal exposures [12,35,81,82,83,84],... 

The methodology for conducting aquatic model ecosystem studies was well established by the late 1990s. However, the use of the data in risk assessments raised a number of uncertainties regarding their interpretation and implementation [32]. Four of the uncertainties that were identified were the extent to which aquatic model ecosystem data generated in one location could be applied to another situation, the potential influence of mixtures of chemicals or stressors, whether the timing (season) of application would influence the outcome of the study, and whether differences in ecosystem properties (e.g., trophic status) might influence the results. 

Defining the risk assessment problem to be evaluated should precede entering the four-step process set out in Figure 7.1, Chapter 7. This means identifying the population that is to be the subject of the assessment, and specifying the conditions under which it is or may come to be exposed to a chemical or mixture of chemicals. Formulations of the problem might be similar to any of the five examples offered at the beginning of Chapter 7. 

In summary, our data provide evidence for the suitability of zebrafish eleuther-oembryos as a predictive vertebrate model for evaluating the effect of individual chemicals and mixtures on thyroid gland function. TIQDT performed on zebrafish eleutheroembryos is an alternative whole-organism screening assay that provides relevant information for environmental and human risk assessments. 

At present the risk assessment of contaminated objects is mainly based on the chemical analyses of a priority list of toxic substances. This analytical approach does not allow for mixture toxicity, nor does it take into account the bioavailability of the pollutants present. In this respect, bioassays provide an alternative because they constitute a measure for environmentally relevant toxicity, that is, the effects of a bioavailable fraction of an interacting set of pollutants in a complex environmental matrix [9-12]. 

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