tube defects and others are not. The particular genotype of individual offspring in the same mouse uterus was shown to be associated with benzo[a]pyrene-induced birth defects (Shum et al. 1979; Nebert 1989). A more recent example is the finding that oral clefting is more common in the offspring of mothers who smoke and who have a variant allele of the transforming growth factor (TGF) gene. The correlation implicates direct or indirect interactions between constituents in tobacco smoke and TGF, a secreted protein that binds to the epidermal-growth-factor receptor and is known to be expressed in palatal epithelium before and during palatal closure (Hwang et al. 1995; see Chapter 5). Examples such as these, together with a wealth of data indicating that many developmental defects of unknown etiology exhibit a multifactorial pattern of inheritance, have led to the conclusion that gene-gene and gene-environment interactions play a significant role in the etiology of many developmental defects.

MECHANISMS OF TOXICITY

An understanding of how exposure to a toxicant can result in an adverse developmental outcome is needed to develop intervention and preventive public health practices. Risk assessors seek to obtain mechanism-based toxicity results from animal tests in order to make justifiable extrapolations to humans. The process by which a toxicant can produce dysmorphogenesis, growth retardation, lethality, and functional alterations commonly is referred to as the “mechanism” by which developmental toxicity is produced. In general, it has been difficult to analyze mechanisms in sufficient detail and depth for risk assessment purposes. There are four reasons.

1. Normal development is extremely complex, and it is possible that there is a myriad of points at which a toxicant might interact with an important molecular component and cause developmental toxicity. Information about molecular components and processes of development has only been available in the past few years, largely through the study of developmental mutants of invertebrate model organisms, such as Drosophila and Caenorhabditis elegans. As highlighted by Wilson’s principles, an understanding of mechanisms would be greatly enhanced by identifying critical key events altered by toxicants. Recent advances in research on signaling pathways and genetic regulatory circuits in development might have identified especially critical processes, ones that, if studied for their alteration by developmental toxicants, might provide exciting new clues for mechanistic investigations (see discussion in Chapters 6 and 7). For now, such insights are available in only a few cases, such as toxicant interactions with components of the nuclear hormone-receptor family of signal receptors and gene regulators.

2. Environmental toxicants include a wide range of chemical, physical, and biological agents that initiate a wide variety of mechanisms. Some agents are



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