values of 10 and have been used to decrease the 10-fold factor used for interspecies extrapolation when there is sufficient knowledge about the similarities in toxicant kinetics in both rodents and humans (Moore et al. 1995).
Pharmaceutical agents almost always have a smaller difference between therapeutic and toxic dosages than is considered safe for environmental agents. A narrow therapeutic index is considered acceptable because pharmaceutical agents are given under the guidance of a health professional and because the therapeutic benefit has been determined to outweigh the risk. That is not the situation for agents such as environmental contaminants and food additives; hence, RfDs and ADIs are more conservative. It is worth stressing that the default uncertainty factors can be superceded when relevant exposure data are available to address key uncertainties. For example, the residual amounts of ethanol present in fruit juices, yeast breads, or vanilla ice cream are within a factor of 100-1,000 of the amount of alcohol (taken in alcoholic beverages) that results in fetal alcohol syndrome but do not constitute a risk to the fetus.
Renwick (1998) has discussed the concept of viewing uncertainty as being composed of kinetic and dynamic components and has proposed the concept of reducing the uncertainty associated with either or both of those components with additional mechanistic information. This structure has provided an initial framework by which mechanistic information can be used in the current risk assessment approaches. Chapters that follow will show how important new information on species differences and data on human variability can replace our reliance on such default approaches for developmental toxicity risk assessment.
Exposure assessments are a critical component of the risk characterization process. Ideally, for developmental toxicity, one would like to have information about how much of the critical reactive species of the test chemical is present at the biological target throughout gestation. At the molecular level, that would mean knowing how much of and how long the toxic compound is bound to a specific target receptor. At the organism level, that would mean knowing how exposure occurred, when it occurred, how much of a compound was absorbed, what type of metabolism of the compound took place within the maternal compartment, and how that metabolism affected the exposure of the conceptus compartment. Information on how the conceptus metabolized and eliminated the compounds would also be important to know. Thus, an understanding of both time of exposure and dose is particularly important for characterizing the potential impacts of developmental toxicants. Numerous studies have shown dramatically different dose-response relationships when exposures occur even 8-12 hr apart due to the significant temporal differences in tissue susceptibility. Temporal differences make exposure assessments for developmental toxicants one of the most challenging of all exposure assessments. Although general toxicokinetic