velopmental defect” throughout this report, because it includes the full range of kinds and severity of defects and the full range of times of detection—before, at, and after birth.

In recognition of the opportunity to use recent advances in developmental biology and genomics to elucidate further the role of environmental agents in human developmental defects, the NRC approved a project to evaluate the current understanding of the mechanism of action of toxicants that results in developmental defects, and make recommendations for the improvement of toxicant evaluation, ultimately in ways that would improve risk assessment. The specific tasks of the committee were as follows: evaluate the evidence supporting hypothesized mechanisms of developmental toxicity; evaluate the state of the science on testing for mechanisms of developmental effects; evaluate how that information can be used to improve qualitative and quantitative risk assessment for developmental effects; and develop recommendations for future research in developmental toxicology and developmental biology; focusing on those areas most likely to assist in risk assessment for developmental defects.

BACKGROUND

Awareness of developmental toxicants increased greatly in the early 1960s when the detrimental effect of thalidomide (used at that time as a sedative/hypnotic) primarily on human limb development was recognized (thalidomide causes other developmental defects as well). Before that time, various chemicals had been tested on adult animals but only intermittently on pregnant animals, and it was generally accepted that what was then thought of as the placental barrier protected the fetus from foreign agents. Since the recognition of prenatal vulnerability in the early 1960s, much has been done to detect potential developmental toxicants in the environment and to regulate human exposure to them. Adverse developmental effects of toxicants now are recognized to include not only malformations at birth but also growth retardation, death (including embryonic and fetal loss), and functional defects in the newborn. Over 1,200 specific compounds, pathogens, and conditions have been identified in experimental animals as causing adverse developmental effects, and the impact of human exposure to many of these agents is not understood (Shepard 1998).

Since the 1960s, the science of developmental toxicology—that is, the study of the impact of toxicants on critical processes of normal development—has advanced. The science of risk assessment of chemical effects on humans, which depends on the advances in toxicology, has also advanced. To predict risk, assessors rely primarily on two kinds of information: estimates of the level of human exposure to a particular chemical, and estimates of the chemical’s toxicity for humans based on the developmental outcome of offspring from experimental pregnant animals exposed to that chemical. Occasionally, information is avail-



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