tions (relative risks in the range of 25 and 300-400, respectively) (Lenz and Knapp 1962; Lammer et al. 1985). Although conventional epidemiological studies have been useful in quantifying the magnitude of risk produced by those potent agents, they were first identified as human developmental toxicants through case reports. Conventional epidemiological studies can be influenced sufficiently with biases, uncertainties, and methodological weaknesses that they may not be useful to detect accurately and assign significance to weak associations—those with relative risks in the range of 1 to 3, the range in which many environmental toxicants can be expected to act (Taubes 1995). In the context of risk assessment, such methodological limits mean that a 2- or 3-fold increase of risk, which amounts to a major health problem, would go undetected.

Another concern with conventional epidemiological studies on chemicals is that studies frequently rely on occupationally exposed cohorts under conditions in which exposure patterns are higher and potentially more consistent than environmental exposures of the general public.

Another potential complication in interpreting data from conventional epidemiological studies is that the complexities and variabilities of human activities, such as life-style factors and diet, cannot be controlled in human studies in the same manner as animal studies. Thus, interpretation of epidemiological study results requires sophisticated experimental designs and analyses to ascertain true relationships.

The ability of an epidemiological study to identify chemically related effects is dependent on the size of the study population, the variability of population effects, the study design, and the background incidence of the adverse health effect being studied. Such information is especially important for risk assessors when they are evaluating epidemiological studies with widely varying results. Understanding how much power a study with negative results has to detect an adverse outcome strengthens the utility of these studies for risk assessments.

Dose-Response Assessment

As part of the evaluation of dose-response relationships, a quantitative evaluation is conducted (EPA 1991; Moore et al. 1995). Doses or concentrations are identified that have no or minimal associated adverse developmental effects. A NOAEL or a lowest-observed-adverse-effect level (LOAEL) is chosen from one of the experimental doses or concentrations tested. These levels are identified for each human and experimental animal study and manifestation of developmental toxicity (i.e., death, structural abnormalities, growth alterations, and functional deficits). Using the NOAEL or other most sensitive effect levels (i.e., end points adversely affected at the lowest doses tested), the reference dose (RfD) or reference concentration (RfC) is determined. These values are an estimate of a daily exposure to the human population that is assumed to be without appreciable risk of adverse developmental effects (EPA 1991).



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