not account for differences among humans in cancer susceptibility other than from possible early-life susceptibility (see Chapter 4).

For noncancer end points, it is assumed that homeostatic and defense mechanisms lead to a dose threshold1 (that is, there is low-dose nonlinearity), below which effects do not occur or are extremely unlikely. For these agents, risk assessments have focused on defining the reference dose (RfD) or reference concentration (RfC), a putative quantity that is “likely to be without an appreciable risk of deleterious effects” (EPA 2002a, p. 4-4). The “hazard quotient” (the ratio of the environmental exposure to the RfD or RfC) and the “hazard index” (HI, the sum of hazard quotients of chemicals to which a person is exposed that affect the same target organ or operate by the same mechanism of action) (EPA 2000b) are sometimes used as indicators of the likelihood of harm. An HI less than unity is generally understood as being indicative of lack of appreciable risk, and a value over unity indicates some increased risk. The larger the HI, the greater the risk, but the index is not related to the likelihood of adverse effect except in qualitative terms: “the HI cannot be translated to a probability that adverse effects will occur, and is not likely to be proportional to risk” (EPA 2006a). Thus, current RfD-based risk characterizations do not provide information on the fraction of the population adversely affected by a given dose or on any other direct measure of risk (EPA 2000a). That deficiency is present whether the dose is above the RfD (in which case the risk may be treated as nonzero but is not quantified) or below the RfD (in which case the risk can be treated as “unappreciable” or zero even though with some unquantified probability it is not zero).

As in cancer dose-response assessment, the RfD is also derived from a POD, which could be a no-observed-adverse-effect level (NOAEL) or a benchmark dose (BMD). However, instead of extrapolating to a low-dose risk, the POD is divided by “uncertainty factors” to adjust for animal-human differences, human-human differences in susceptibility, and other factors (for example, data gaps or study duration). In a variant of the RfD approach to noncancer or low-dose nonlinear cancer risk assessment, the agency calculates a “margin of exposure” (MOE), the ratio of a NOAEL or POD to a projected environmental exposure (EPA 2000a, 2005b). The MOE is compared with the product of uncertainty factors; an MOE greater than the product is considered to be without appreciable risk or “of low concern,” and an MOE smaller than the product reflects a potential health concern (EPA 2000b). MOEs and RfDs are defined for durations of exposure (for example, acute, sub-chronic, and chronic) and may be defined for specific life stages (for example, developmental) (EPA 2002a).

Recent refinements in risk-assessment methods in EPA have used mode-of-action (MOA)2 evaluations in dose-response assessment. EPA’s Guidelines for Carcinogen Risk Assessment (2005b) state that if a compound is determined to be “DNA reactive and [to] have direct mutagenic activity” or to have high human exposures or body burdens “near doses associated with key precursor events” (EPA 2005b, p. 3-21), a no-threshold approach is applied; risk below the POD is assumed to decrease linearly with dose. For carcinogens with sufficient MOA data to conclude nonlinearity at low doses, such as those acting through a cytotoxic MOA, the RfD approach outlined above for noncancer end points is applied (EPA 2005b),


More recent noncancer guidelines have abandoned the term threshold, noting the difficulty of empirically distinguishing dose-response relationships with true biologic thresholds from ones that are nonlinear at low doses (EPA 2005b, p. 3-24).


Following EPA 2005b (p. 1-10), the MOA is defined as “a sequence of key events and processes, starting with interaction of an agent with a cell, proceeding through operational and anatomical changes, and resulting” in the adverse effect. “A ‘key event’ is an empirically observable precursor step that is itself a necessary element of the mode of action or is a biologically based marker for such an element.”

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