whether comparable adverse effects would have been caused had similar human exposure occurred. Summary compilations from published data covering more than 4,000 different entities of exposure conditions indicate that more than 1,200 agents, predominantly chemical agents, have produced adverse developmental outcomes by the end point criteria stated above, often including congenital anomalies, in one or more species of experimental animals (Shepard 1998). Among this large number are about 50 agents (almost exclusively designated as drugs) that are known to cause adverse developmental effects in human beings. For most of the agents that were evaluated for developmental hazard potential in experimental animals, human exposures will never occur. Thus, public health was protected, but ascertainment of concordance of animal and human responses was undetermined for those agents. When exposures occur, rarely have human assessments been sufficient for definitive evaluation and establishment of cause-and-effect associations. Because of the background incidence of human developmental abnormalities (addressed in Chapter 2) and the difficulties in conducting epidemiology studies, such associations are extremely difficult to establish unless the outcome is unusual and striking, as was the case of thalidomide.

Among industrial chemicals and environmental contaminants that have been studied in pregnant animal models, often the estimated maximum tolerated dose (MTD) was repeatedly given in conformance with the testing guidelines. Internationally, regulatory authorities require in many instances that the MTD, even up to maternally toxic concentrations, be administered to ensure that no developmental toxicity occurs. Therefore, the underlying principle is that, if regulatory standards are set to protect against maternal toxicity, no adverse effects will occur in offspring. Unfortunately, all too frequently the focus of developmental toxicity testing has been to study the effects of an agent only at high doses that are most likely irrelevant to environmental and occupational exposures. For industrial and environmental chemicals, the dosing regimens at or even above MTDs, as applied in hazard identification studies, typically contrast sharply with anticipated human exposures that are commonly much lower in extent or magnitude, often uncertain, or even entirely unknown.

Because of the design of developmental hazard identification studies, the overwhelming majority of the more than 1,200 agents found to elicit adverse developmental outcomes in experimental animals were tested at doses many times higher than anticipated human exposures during pregnancy and have often elicited extreme maternal toxicity. Furthermore, exposure of the pregnant animals was sustained throughout all of organogenesis by daily repeated administrations, and minimal or no regard was taken for toxicokinetic considerations (see toxicokinetics section of this chapter for details).

Therefore, there are problems associated with the application of these assays for assessing human developmental toxicity potential. Repeated administration of an MTD might produce adverse results that are not indicative of risk from ambient exposure concentrations or intermittent exposures. It is a continuing



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