models exist for pregnancy, a refined exposure-modeling tool is not available for most chemicals. The lack of that tool is probably a key factor behind efforts to use exposure biomarkers and direct tissue measurements to improve estimates of conceptus exposures. Biomarkers of exposure have proved to be especially useful in addressing the limitations of exposure data in epidemiological assessments. Such biomarkers allow for a more accurate and representative exposure assessment and, when linked temporarily with biomarkers of effect, can frequently enhance the ability of a human epidemiological study to estimate human risk. New advances in biomarkers of susceptibility are allowing investigators to understand more fully variability in human response and have been proposed as improvements for human risk characterization.

One approach for using exposure information is to calculate a margin of exposure (MOE). The MOE is a ratio of the dose judged to be without effect to the anticipated levels of human exposure (Moore et al. 1995). However, because the calculation does not include the use of any default values to account for sources of uncertainty, it can only give a general indication of different levels of effects versus exposures levels for a quick exposure-scenario comparison.

The challenge for human health risk assessment is to convert exposure assessment information into relevant information for humans. The subsequent section on toxicokinetics will expand upon these concepts and will explain what information is needed to conduct relevant human exposure assessments.

Toxicokinetics

Toxicokinetics is the description of the absorption, distribution, metabolism, and excretion of a toxic chemical into and from the body (commonly referred to as ADME). The importance of chemical toxicokinetics for risk assessment is demonstrated by several example documents (California Environmental Protection Agency 1991; Moore et al. 1995; EPA 1996a; O’Flaherty 1997). These combined documents show a consensus that toxicokinetic data provide key elements to understanding species differences in response to developmental toxicants. Figure 3-2 shows an illustration of how exposure to a compound is then evaluated by using ADME. ADME controls how much of, when, and in what form a toxicant comes in contact with target organs. For developmental toxicants, these key questions are related to the amount and form of the toxicant that reaches tissues of the conceptus. Such knowledge can reduce the uncertainty in the extrapolation of results collected from experimental animals for the prediction of hazard associated with exposure of pregnant women. This section provides a brief discussion of a number of issues that require further investigation, as work continues to improve the scientific basis for risk assessment.

Decisions about toxicity hazard and risk to human development based on toxicokinetics from pregnant animals can rarely provide an unequivocal answer



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