Chemical mixtures, assessments

Ultimately a derived no-effect level (DNEL) (in humans) or a predicted no-effect concentration (PNEC)20 (in ecosystems) is calculated for a substance, group of substances or chemical mixture. Assessment factors (AF) - sometimes referred to as uncertainty factors or safety factors - compensate for lack of data and assumptions resulting from dose spacing and other test model parameters (adapted from [124]) ... 

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). 

Thorpe, K.L., Gross-Sorokin, M., and Johnson, 1. et al. (2006). An assessment of the model of concentration addition for predicting the estrogenic activity of chemical mixtures in wastewater treatment works effluents. Environmental Health Perspectives 114, 90-97. 

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

Complexity of allelopathic chemical mixtures and improper assessment of their concentrations ... 

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. 

Stacey NH. 1987b. Assessment of the toxicity of chemical mixtures with isolated rat hepatocytes Cadmium and chloroform. Fundam Appl Toxicol 9 616-622. 

Guidelines for Carcinogen Risk Assessment Guidelines for Chemical Mixtures Risk Assessment... 

The main emphasis is paid to the identification of the basic principles for combined actions and interactions of chemicals (Section 10.2), and to the current knowledge on effects of exposures to mixtures of industrial chemicals, including pesticides and environmental contaminants. Test strategies to assess combined actions and interactions of chemicals in mixtures (Section 10.3) as well as toxicological test methods (Section 10.4) are addressed, approaches used in the assessment of chemical mixtures are presented (Section 10.5), and examples of experimental studies using simple, well-defined mixtures are given (Section 10.6). 

The prediction of the toxicological properties of a chemical mixture requires detailed information on the composition of the mixture and the mechanism of action of each of the individual compounds. In order to perform a risk assessment, proper exposure data are also needed. Most often... 

Testing of the whole mixture as such has been recommended for mixtures that are not well characterized (Mumtaz et al. 1993), and has successfully been applied for assessing the combined toxicity of simple, defined chemical mixtures where the toxicological properties of the individual components were also investigated, see Section 10.6. 

When epidemiological studies form the basis for the risk assessment of a single chemical or even complex mixtures, such as various combustion emissions, it may be stated that in those cases the effects of combined action of chemicals have been incorporated. Examples can, for instance, be found in the updated WHO Air Quality guidelines (WHO 2000). Thus, the guideline value for, e.g., ozone was derived from epidemiological studies of persons exposed to ozone as part of the total mixture of chemicals in polluted ambient air. In addition, the risk estimate for exposure to polycyclic aromatic hydrocarbons was derived from studies on coke-oven workers heavily exposed to benzo[fl]pyrene as a component of a mixture of PAH and possibly many other chemicals at the workplace. Therefore, in some instances the derivation of a tolerable intake for a single compound can be based on studies where the compound was part of a complex chemical mixture. 

APPROACHES USED IN THE HAZARD ASSESSMENT OF CHEMICAL MIXTURES... 

Approaches for Assessment of Joint Toxic Action of Chemical Mixtures Suggested by ATSDR... 

ATSDR. 2004. Guidance manual for the assessment of joint toxic action of chemical mixtures. Atlanta, U.S.A. U.S. Department of Health and Human Services, Public Health Service, Agency of Toxic Substances and Disease Registry, Division of Toxicology, http //www.atsdr.cdc.gov/interactionprofiles/ipga.html... 

Cassee, E.R., J.P. Groten, P.J. van Bladeren, and V.J. Eeron. 1998. Toxicological evaluation and risk assessment of chemical mixtures. Crit. Rev. Toxicol. 28 73-101. 

Feron, V.J., J.P. Groten, and P.J. van Bladeren. 1998. Exposure of humans to complex chemical mixtures Hazard identification and risk assessment. Arch. Toxicol. Suppl. 20 363-373. 

Mumtaz, M.M. and P.R. Durkin. 1992. A weight-of-evidence approach for assessing interactions in chemical mixtures. Toxicol. Ind. Health 8 377M-06. 

Mumtaz, M.M., LG. Sipes, H.J. Clewell, and R.S.H. Yang. 1993. Risk assessment of chemical mixtures Biological and toxicological issues. Fund. Appl. Toxicol. 21 258-269. 

Nesnow S. 1994. Mechanistic linkage between DNA adducts, mutations in oncogenes, and tumorigenicity of carcinogenic aromatic hydrocarbons in strain A/J mice. In Chemical mixtures and quantitative risk assessment. Abstract of the second annual HERL symposium, Nov. 7-10., Raleigh, North Carolina Health Effects Research Laboratory, U.S. Environmental Protection Agency. 

Seed, J., R.P. Brown, S.S. Olin, and J.A. Foran. 1995. Chemical mixtures Current risk assessment methodologies and future directions. Reg. Toxicol. Pharmacol. 22 76-94. 

US-EPA. 1999. Guidance for conducting health risk assessment of chemical mixtures (External scientific peer review draft). April 1999. NCEA-C-0148. Washington, DC Risk assessment Fomm, U.S. Environmental Protection Agency. 

Yang, R.S., H.A. El-Masri, R.S. Thomas, A.A. Constan, and J.D. Tessari. 1995. The apphcation of physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling for exploring risk assessment approaches for chemical mixtures. Toxicol. Lett. 79 193-200. 

This thesis focuses on the applicability of in vitro, in vivo bioassays and bioindicators as tools for evaluating the effects of complex chemical mixtures in the process of deciding whether dredged harbour sediments can be disposed of at sea without serious adverse effects on marine ecosystem and human health. It considers the North Sea delta area in order to determine a comprehensive approach for the application of both in vitro and in vivo bioassays for hazard assessment, advanced risk assessment, and location-specific ecological impact assessment for dredged harbour sediments. To aid in the selection of appropriate, robust and reliable in vitro and in vivo bioassay and bioindication methods for these specific purposes, the uneertainty, predictability and specificity of the bioassays have been explored and the applieability in eombination with other analyses is discussed. The focus of the chosen examples is on bioassays and bioindicators for the relatively well studied dioxin-like contaminants and TBT. 

In the case of some oestrogenic chemicals (that mimic the effects of the female hormone oestrogen) it has been shown that what should be added to predict the combined effect of a mixture is not the effects of the individual chemicals but their concentrations (Silva et al, 2002). This means that a substance present at a concentration at which on its own it has no oestrogenic effect will contribute to the total oestrogenic effect of a mixture containing other oestrogenic chemicals. For such substances there is in practice no real threshold concentration below which they do not have an effect. Such no-effect levels are a crucial part of chemicals risk assessment, as I will explain in Chapter 7. 

Haddad, S., M. Beliveau, R. Tardif, and K. Krishnan. A PBPK modeling-based approach to account for interactions in the health risk assessment of chemical mixtures. Toxicol. Sci. 63 125-131, 2001. 

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. 

The enormous cost of multiple-species, multiple-dose, lifetime evaluations of chronic effects has already made the task of carrying out hazard assessments of all chemicals in commercial use impossible. At the same time, quantitative structure activity relationship (QSAR) studies are not yet predictive enough to indicate which chemicals should be so tested and which chemicals need not be tested. In exposure assessment, continued development of analytical methods will permit ever more sensitive and selective determinations of toxicants in food and the environment, as well as the effects of chemical mixtures and the potential for interactions that affect the ultimate expression of toxicity. Developments in QSARs, in short-term tests based on the expected mechanism of toxic action and simplification of chronic testing procedures, will all be necessary if the chemicals to which the public and the environment are exposed are to be assessed adequately for their potential to cause harm. 

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