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David C. Dorman,¹ Sandra L. Allen,² Janusz Z. Byczkowski,³ Luz Claudio,⁴ J. Edward Fisher Jr.,⁵ Jeffrey W. Fisher,⁶ G. Jean Harry,⁷ Abby A. Li,⁸ Susan L. Makris,⁹ Stephanie Padilla,¹⁰ Lester G. Sultatos,¹¹ and Beth E. Mileson¹²

¹Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina, USA; ²Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, United Kingdom; ³Consultant, Fairborn, Ohio, USA; ⁴Mount Sinai School of Medicine, Division of Environmental and Occupational Medicine, New York, New York, USA; ⁵Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, MD, USA; ⁶Department of Environmental Health Science, University of Georgia, Athens, Georgia, USA; ⁷Neurotoxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; ⁸Metabolism and Safety Evaluation-Newstead Laboratory, Monsanto Company, St. Louis, Missouri, USA; ⁹Office of Prevention, Pesticides and Toxic Substances, U.S. Environmental Protection Agency, Washington, DC, USA; ¹⁰Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA; ¹¹Department of Pharmacology and Toxicology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA; ¹²ARCADIS Geraghty & Miller, Millersville, MD, USA

Abstract

We review pharmacokinetic and pharmacodynamic factors that should be considered in the design and interpretation of developmental neurotoxicity studies. Toxicologic effects on the developing nervous system depend on the delivered dose, exposure duration, and developmental stage at which exposure occurred. Several pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern chemical disposition within the dam and the nervous 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 pharmacokinetic processes and transfer of the xenobiotic through the milk, although direct exposure may occur through other routes (e.g., inhalation) . Measurement 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 incorporate these and other determinants can estimate tissue dose and biologic response following in utero or neonatal exposure. These models can characterize dose-response relationships and improve extrapolation of results from animal studies to humans. In addition, pharmacologic data allow an experimenter to determine whether exposure to the test chemical is adequate, whether exposure occurs during critical periods of nervous system development, whether route and duration of exposure are appropriate, and whether developmental neurotoxicity can be differentiated from direct actions of the xenobiotic. Key words: developmental neurotoxicity, pharmacodynamics, pharmacokinetics, physiologically based pharmacokinetic modeling, rat. -- Environ Health Perspect 109(suppl 1) :101-111 (2001) .

http://ehpnet1.niehs.nih.gov/docs/2001/suppl-1/101-111dorman/abstract.html