Student Research: Kelly Marie Schumacher

MS, , 2004
Faculty Advisor: Elaine M. Faustman

Toxicokinetic and Toxicodynamic Factors Affecting Chlorpyrifos Development Toxicity


An underlying challenge in children's health risk assessment is understanding how to compare and extrapolate results from controlled animal studies in order to assess adverse developmental effects in humans, given that these results are affected by toxicokinetics and dynamic factors such as does and time of exposure. Because researchers may not agree upon which types of molecular, pathological, and/or behavioral endpoints are most important to humans, only a fraction of the available animal studies concerning a compound of interest may include measurements of a particular adverse developmental effect. Measurements of effect levels, such as IC50s, may vary greatly across studies depending on the dose, starting time, and duration of exposure. This is partly because specific brain regions have critical windows of susceptibility that differ according to time-dependent neurodevelopmental processes such as proliferation or differentiation. Another difficulty when using results from animal studies to identify adverse developmental effects in humans is that the exposure scenarios used in these studies are not always directly comparable to human or other animal exposures. For example, animals may be exposed to very high doses by injection or gavage, while humans are more often exposed to low doses in their food or drinking water. In addition, animals in most studies are exposed to a single parent compound, such as chlorpyrifos, but humans are typically exposed to a mixture of parent compounds and metabolites that may share some mechanism(s) of action.

Toxicokinetic models may help researchers evaluate the effects of kinetic and dynamic factors on the developmental toxicity of various xenobiotics. Such models are constructed using time-dependent dosimetric data and, depending on the complexity of the available data, are used to calculate the bioavailable dose of a compound and/or its metabolites in either the tissue(s) or the compartment(s) of interest at a given time following exposure. Because the internal doses calculated using toxicokinetics models account for the external dose as well as the route and duration of exposure, these models improve comparison of the developmental toxicity of a compound across animal studies. One limitation in the use of toxicokinetics models in children's health risk assessment is that most of the reported models have been developed using data from adult subjects rather than age-appropriate data for the developing fetus or neonate. The specific focus of this paper is on how toxicokinetics and dynamic factors affect the neurodevelopmental toxicity of chlorpyrifos, one of the few compounds for which adequate toxicokinetic data in the pregnant animal have been reported.

Taken from the beginning of thesis.