Methods to identify and characterize developmental neurotoxicity for humanhealth risk assessment. III: Pharmacokinetic and pharmacodynamic considerations

We review pharmacokinetic and pharmacodynamic factors that should be consid ered in the design and interpretation of developmental neurotoxicity studie s. Toxicologic effects on the developing nervous system depend on the deliv ered dose, exposure duration, and developmental stage at which exposure occ urred. Several pharmacokinetic processes (absorption, distribution, metabol ism, and excretion) govern chemical disposition within the dam and the nerv ous system of the offspring. in addition, unique physical features such as the presence or absence of a placental barrier and the gradual development of the blood-brain barrier influence chemical disposition and thus modulate developmental neurotoxicity. Neonatal exposure may depend on maternal phar macokinetic processes and transfer of the xenobiotic through the milk, alth ough direct exposure may occur through other routes (e.g., inhalation). Mea surement of the xenobiotic in milk and evaluation of biomarkers of exposure or effect following exposure can confirm or characterize neonatal exposure . Physiologically based pharmacokinetic and pharmacodynamic models that inc orporate these and other determinants can estimate tissue dose and biologic response following in utero or neonatal exposure. These models can charact erize dose-response relationships and improve extrapolation of results from animal studies to humans. In addition, pharmacologic data allow an experim enter to determine whether exposure to the lest chemical is adequate, wheth er exposure occurs during critical periods of nervous system development, w hether route and duration of exposure are appropriate, and whether developm ental neurotoxicity can be differentiated from direct actions of the xenobi otic.