ment is manifest by both temporal- and tissue-specific sensitivities; thus, assessing a toxicant’s potential effects for development requires a dynamic and multilevel assessment strategy.

  • Environmental toxicants represent a broad spectrum of agents, probably working by a variety of mechanisms. Some toxicants probably have one or a few targets in the conceptus (the embryo or fetus, plus the embryo-derived extraembryonic tissues). Others probably have numerous targets (“broad specificity”) in the mother and conceptus, and others probably affect the mother, whose altered health secondarily affects the conceptus.

  • Without a thorough understanding of basic mechanisms of development and knowledge about variability in responses across species to toxicants, insights from animal studies have largely been only of assumed validity for human mechanisms.

The analysis of mechanisms of toxicity requires advanced interdisciplinary information and approaches of the kind that have only recently become available.

In considering hypothesized mechanisms, the committee discussed the different scopes and levels of understanding implied by the term “mechanism,” as used by different researchers in biochemistry, molecular biology, genetics, developmental biology, toxicology, and epidemiology. If the emphasis on toxicant action is exclusively molecular, some members felt that the mechanism misses the scope of potential linked impacts of a toxicant on overall development and morphogenesis. Additionally, most felt that a mechanism lacking molecular detail is inadequate for explaining the action of toxicants. Realizing this complexity, the U.S. Environmental Protection Agency (EPA 1996b) and International Programme on Chemical Safety (IPCS Workshop on Developing a Conceptual Framework for Cancer Risk Assessment, 16-18 February 1999, Lyon, France) have defined chemical “modes of action” in addition to “mechanisms of action.” In these definitions, “mechanism of toxicant action” is taken to refer to a detailed understanding of the overall toxic response. In contrast, “mode of action” usually refers to a more limited description of the overall process of toxicity that focuses on defining possible cascades of biological events that can occur following exposure to a toxic agent. To preserve the full range of causes and effects relevant to risk assessment of human developmental toxicity, the committee sought to designate “levels of information” obtainable from various model systems (including in vitro assays and mammalian and nonmammalian assays) to illuminate mechanisms of action (see Chapter 8). Hypotheses about toxicant action in humans, based on the information from animal models, can then be strengthened or dismissed by using information obtained from various types of human data. Chapter 8 provides suggestions on how these different types of data can specifically improve our ability to predict potential developmental toxicity in humans.

The committee believes that it is impossible to provide the most scientifically defensible risk assessments without understanding mechanisms of action.



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