tration effects are predictive of all effects at low exposure doses and concentrations unless they are proved to be secondary to maternal toxicity. Some research has been conducted to demonstrate the existence of maternally mediated mechanisms of adverse development (Daston et al. 1991a, 1994). Examples are the induction of transitory zinc deficiencies in the dam by metallothionein inducers (Daston and Lehman-McKeeman 1996) and the overwhelming of acid-base buffering by acidic metabolites of ethylene glycol (Carney et al. 1996). Understanding the molecular processes that lead to specific developmental abnormalities will be useful in determining the low-dose relevance of high-dose effects. In those instances in which the high-dose effects are predictive of low-dose responses, the relevant molecular processes would be expected to increase with dose (i.e., to involve higher levels of gene expression or cellular response and involve more cells). For those instances in which the high-dose effects are the result of a secondary mechanism, the dose-response curve for the adverse effect and the underlying molecular perturbation would be expected to be steep, with an inflection at the dose where the maternal homeostasis was overwhelmed.

SUMMARY

This chapter has defined developmental toxicity risk assessment and outlined issues that regulators face as they strive to protect the human population from chemically induced birth defects. Each section also identified limitations in the current knowledge and methodologies. Biomarkers for developmental toxicity are also discussed. They hold great potential for epidemiological analysis of developmental defects, especially those defects due to complex gene-environment interactions. The information presented in this chapter, and in the next chapter on mechanisms of developmental toxicants (Chapter 4), will be used to define the current state of developmental toxicology and will provide a context for how advances in developmental biology and genomics can improve the approaches for protecting public health.



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