very tiny fraction—of the exposures for which it has been possible to collect hazard and dose–response information. Studies of occupational cohorts, for example, typically involve exposures well in excess of general population exposures, and animal studies similarly involve high-dose effects. For the risks to the target population to be described, a method or model must be used to extrapolate from the high-dose scientific findings to infer the risks at much lower doses. That extrapolation can create large uncertainties in risk assessment. The biological bases for selecting among different models for extrapolation are not well established, and different models can yield different estimates of low-dose risk.

In other cases very little might be known about the actual exposures in the target population, adding additional uncertainty. Individuals within a population also vary with respect to both their exposures and their responses to hazardous substances. Reliable, quantitative information that allows an understanding of the magnitudes of that variability can be difficult, if not impossible, to acquire (Samoli et al., 2005). Risk assessments need to account for possible differences in response between the populations that were studied to understand hazards and dose response in the target population, which typically is more diverse than the population studied (Pope, 2000). Studies of human exposure in limited populations cannot be used to apply to other, more diverse populations without considering the uncertainties from the different populations.

Those uncertainties are part of almost all risk assessments conducted by EPA (EPA, 2004). Additional uncertainties related to the effects of chemicals at different life stages and different comorbidities, the effects of exposures to complex mixtures, and the effects of chemicals that have received very little toxicological study are also introduced in many assessments (EPA, 2004). In many cases the analyst or scientist who is conducting the risk assessment is able only to describe those uncertainties in largely qualitative terms, and formulating scientifically rigorous statements about the effects of these uncertainties on a risk result is beset with difficulties (EPA, 2004).

THE HISTORY OF UNCERTAINTY ANALYSIS

The 1983 NAS Report, Uncertainties and the Use of Defaults

Given the EPA’s mandate to protect human health, the agency has had to find a way to make decisions taking into account the scientific uncertainty discussed above. The Red Book emphasized that the uncertainties inherent in risk assessment were so pervasive that virtually no risk assessment could be completed without the use of assumptions or some types of models for extrapolations (NRC, 1983). Moreover, it recognized that



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