Mixtures risk assessment

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

FIGURE 5.1 Mixed-model mixture risk assessment approach. Note This illustrates the calculation of steps for combined effects of mixtures with similarly (e.g., Substances 1 to 3) and dissimilarly (e.g., Substances 1 to 3 versus Substances 6 to 8) acting components. 

For addressing multispecies risk of mixture toxicity, we propose the following same procedure that is followed in general mixture studies in single-species ecotoxi-cology. That is, one must consider exposure, look at exposed species groups when necessary in view of the assessment endpoints, consider the mode of action of the components, and apply either of the sets of models based on this information. The practical protocols for mixture risk assessment that stem from this choice are worked out and discussed in the section below. 

Andersen ME, Dennison JE. 2004. Mechanistic approaches for mixture risk assessments present capabilities with simple mixtures and future directions. Environ Toxicol Pharmacol 16 1-11. 

Haddad S, Krishnan K. 1998. Physiological modeling of toxicokinetic interactions implications for mixture risk assessment. Environ Hlth Perspect 106 1377-1384. 

Krishnan K, Paterson J, Williams DT. 1997. Health risk assessment of drinking water contaminants in Canada the applicability of mixture risk assessment methods. Reg Toxicol Pharmacol 26 179-187. http //www.ncbi.nlm.nih.gov/entrez/query.fcgi7cm d=Retrieve db=PubMed dopt=Citation list uids=9356281 (accessed December 28, 2007). 

The mere presence of any single chemical or chemical mixture in the environment does not indicate that a health threat exists. An important step of mixture risk assessment is the evaluation of completed exposure pathways. Completed exposure pathways link together the source of contamination, environmental medium, point of exposure, route of exposure, and a receptor population. It means that without the potential for chemicals actually entering (or contacting) the human body, no threat is present. 

The general goal of this chapter is to outline a consistent approach for conducting mixture risk assessments that is in line with the IRA approach and builds upon the best of the science and current practices in the respective fields of human and ecological risk assessment. It starts by comparing risk assessment of single substances with mixtures in order to identify the key features of mixture assessments. Subsequently, the current scientific state of the art in human mixture assessment is described, followed by the scientific state of the art in ecological mixture assessment. Both... 

Figure 5.11 implies that the certainty of a whole mixture risk assessment generally increases as the characterization improves from a complete lack of characterization to partial characterization to a similar mixture to a well-characterized mixture (i.e., mixture of concern). In other words, based on available mixture insights, it is considered likely that refinement of information on the mixture can be reached by characterization of the mixture. 

Another typical source of uncertainty in mixture assessment is the potential interaction between substances. Interactions may occur in the environment (e.g., precipitation after emission in water), during absorption, transportation, and transformation in the organism, or at the site of toxic action. Interactions can be either direct, for example, a chemical reaction between 2 or more mixture components, or indirect, for example, if 1 mixture component blocks an enzyme that metabolizes another mixture component (see Chapters 1 and 2). Direct interactions between mixture components are relatively easy to predict based on physical-chemical data, but prediction of indirect interactions is much more difficult because it requires detailed information about the processes involved in the toxic mechanisms of action. One of the main challenges in mixture risk assessment is the development of a method to predict mixture interactions. A first step toward such a method could be the setup of a database, which contains the results of mixture toxicity tests. Provided such a database would contain sufficient data, it could be used to predict the likelihood and magnitude of potential interaction effects, that is, deviations for CA and RA. This information could subsequently be used to decide whether application of an extra safety factor for potential interaction effects is warranted, and to determine the size of such a factor. The mixture toxicity database could also support the search for predictive parameters of interaction effects, for example, determine which modes of action are involved in typical interactions. 

There is a clear need for mixture risk assessment, since most environments are characterized by mixture exposure situations. This means that risk assessments should pay specific attention to all aspects of mixture exposures and effects in order to make accurate risk predictions. 

Aim 3 Toward a conceptual framework for mixture risk assessment... 

Sterner TR, Robinson PJ, Mattie DR, Burton GA. 2005. The toxicology of chemical mixtures risk assessment for human and ecological receptors. AFRL-HE-WP-TR-2005-0173. Wright-Patterson AFB (OH) Air Force Research Laboratory, Human Effectiveness Directorate, Biosciences and Protection Division, Applied Biotechnology Branch. 

Teuschler LK. 2007. Deciding which chemical mixtures risk assessment methods work best for what mixtures. Toxicol Appl Pharmacol 223 139-147. 

The in-depth way the book covers the state of the art for mixture toxicology and ecotoxicology principles means it serves well as a textbook on the subject. At the same time, the inclusion of the considerations on application of novel developments in these principles, and their integration across human and environmental mixture risk assessment, makes it an ideal tool for researchers, regulators, and other risk assessment practitioners as mixture considerations start to enter regulatory forums over the next years. 

Multichemical exposures are ubiquitous. A number of uncertainties exist from the mode of action, type of interaction to toxic outcome in the mixture risk assessment. Computer-based technologies have huge potential to elucidate the mechanisms and predict the outcome for real-world mixtures rather than the defined mixtures at high-dose concentration. 

Svensgaard DJ and Hertzberg RC (1994) Statistical methods for toxicological evaluation of the additivity assumption as used in the EPA Chemical Mixture Risk Assessment Guidelines. In Yang R (ed.) Toxicology of Chemical Mixtures Case Studies, Mechanisms, and Novel Approaches, pp. 599-642. New York Academic Press. 

Teuschler LK, Groten J, Hertzberg RC, Mumtaz M, and Rice G (2001) Environmental chemical mixtures risk assessment Current approaches and emerging issues. Communications in Toxicology 7 453—493. 

Mixtures Risk Assessment The mere occurrence of chemicals and contaminants in the environment does not increase the potential of risk to human or environment, but their exposure does. A five-step process is used to determine the extent, route, and duration of exposure and includes its environmental fate and transport. This process allows identification of likely site-specific exposure to chemicals and chemical mixtures, the extent of exposure, and the conditions under which the exposure occurred. This way contaminants of concern can be identified in a systematic manner by combining the chemical hazard and exposure data [7],... 

Hazard Index Approach A chemical mixtures risk assessment method where hazard quotients for component chemicals are only developed using the critical effect. Hazard quotient values are grouped by critical effect and summed. Multiple hazard indexes are developed, one for each affected target organ or system. 

Haddad, S., and Krishnan, K. (1998). Physiolr cal modeling of toxicokinetic interactions Implications for mixture risk assessment. Environ Health Perspec 106, 1377-1384. 

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