and other regulatory and public health agencies to establish levels of lifetime daily intake of chemical substances that are likely to be without adverse effects in the general human population. EPA describes such levels (or doses) as risk Reference Doses (RfDs) for oral exposure and as risk Reference Concentrations (RfCs) for inhalation exposures (Faustmann and Omenn, 2001). EPA and other agencies also may establish levels to protect humans against short-term exposures or to protect specific subpopulations, such as individuals in occupational settings. In addition, EPA develops risk values for carcinogens, often based on animal data.

The use of animal data rests on substantial evidence that a relatively high degree of concordance exists between experimental animal findings and expected outcomes in humans. Their use also is necessitated by the fact that it is not possible to evaluate most forms of toxicity through intentional dosing studies in humans. The predictive value of animal studies for humans is, however, far from exact. Therefore, decisions to use results from animal studies rest, at least in part, on a “science policy” choice in which results from animal studies are generally assumed to hold for humans unless there is highly convincing evidence to the contrary (NRC, 1983; NRC, 1994).Taking into account the extensive batteries of animal studies conducted at high doses that are normally required for human risk assessment and the safety factors and conservative assumptions built into the risk-assessment process, this science policy choice generally reflects a cautious stance; but the possibility that animal studies, no matter how complete, may sometimes fail to reveal adverse health effects that are significant for humans cannot be ignored.

Data from some types of human studies have played a significant role in the establishment of RfDs, RfCs, and other measures of protection (Dourson et al., 1996; EPA, 1999). Data from both intentional dosing studies in humans and epidemiological studies have been used, with the former generally limited to effects resulting from single or very short-term exposures. In a significant number of important cases, EPA has elected to derive risk values for carcinogens from epidemiological data (e.g., benzene, arsenic, chromium [VI], and several others), given the strength of the databases for these compounds. EPA guidelines for risk assessment express a preference for human over animal data, although they clearly note the difficulties in developing human data adequate for such quantitative assessments (EPA, 2003).

Generally, knowledge of the quantitative differences between doses causing adverse effects in animals and those causing adverse effects in humans is not precise. Beginning in the 1950s, scientists in regulatory agencies began applying “safety factors” to data from animal studies to establish “acceptable daily intakes” (Lehmann and Fitzhugh, 1954). Those factors (100-fold when the animal data were derived from chronic stud-

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