Methods to Identify and Characterize Developmental Neurotoxicity for Human Health Risk Assessment. III: Pharmacokinetic and Pharmacodynamic Considerations

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 occ...

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Bibliographic Details
Published in:Environmental health perspectives 2001-03, Vol.109 (suppl 1), p.101-111
Main Authors: Dorman, David C., Allen, Sandra L., Byczkowski, Janusz Z., Claudio, Luz, Fisher, J. Edward, Fisher, Jeffrey W., Harry, G. Jean, Li, Abby A., Makris, Susan L., Padilla, Stephanie, Sultatos, Lester G., Mileson, Beth E.
Format: Article
Language:English
Subjects:
Animals
Biomarkers - analysis
Brain
Chemical hazards
development
Developmental Neurotoxicology Methods
Dose-Response Relationship, Drug
Drug design
Fetus
Humans
intrauterine exposure
Models, Biological
neonates
Nervous system
Nervous System - drug effects
Nervous System - growth & development
Neurotoxicity
Pharmacokinetics
Placenta
Rats
Research Design
Risk Assessment
Toxicity Tests - methods
Xenobiotics
Xenobiotics - adverse effects
Xenobiotics - pharmacokinetics
Xenobiotics - pharmacology
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Summary: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. Severial 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.
ISSN:0091-6765
1552-9924
DOI:10.1289/ehp.01109s1101