what receptors are exposed to after transport through the environment, so actual exposures are likely to be to mixtures with congener or other component profiles differing from those tested. There are also situations in which the risk assessments required do not correspond completely to the “typical” assessment described here, such as nationwide evaluations of cumulative and aggregate exposures to pesticides (cumulative refers to the multiple-chemical nature of the assessment and aggregate to the multiple pathways of exposure).

Summary of Current Risk-Assessment Approaches

In summary, the usual approach to EPA-style risk assessments for noncancer end points is initially “dose-additive” for all chemicals, partly to ensure an initial conservative assessment. Later, if such a conservative approach does not suffice, the dose-addition approach is applied independently to subsets of chemicals with the same end point or mechanism, where mechanism is not well defined. For cancer end points, the usual approach of summing risk estimates for all chemicals is both response-additive and dose-additive because the two are equivalent when the standard low-dose linear hypothesis is used.6 In every case, direct information on any particular mixture that contradicts the hypothesis of dose addition will override the default approach.


Table 4-2 summarizes the evolution of EPA guidance (or, for the International Life Sciences Institute document, in cooperation with EPA) on cumulative risk assessment. Undoubtedly, other documents have influenced the practice of cumulative risk assessment, but the committee believes that those cited here have been the primary sources for EPA consideration of cumulative risk assessment. Table 4-2 summarizes the stated purpose of the guidance, the definitions of cumulative adopted in the guidance document, and the default approach taken for evaluation of cumulative risks posed by mixtures of chemicals and other stressors when there is no direct information on the particular (or sufficiently similar) mixtures (so that the effect of the mixture has to be estimated from measured effects of individual components). As far as possible, the committee has quoted the documents or relevant memoranda accompanying the documents on their release for the summaries. At times, that proved difficult because there may be more than one statement or definition, and the default approach may not have been explicitly stated. The “Default approach” column of the table highlights some statements made in the guidance about the conditions required for dose addition or independent action.


For brevity, “threshold” carcinogens were not addressed here.

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