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ToxSci Advance Access published online on March 31, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh109
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received June 23, 2003; accepted February 12, 2004
© 2004 Toxicological Sciences © Society of Toxicology 2004; all rights reserved.

Risk Assessment

Evaluation of the Potential Impact of Age- and Gender-Specific Pharmacokinetic Differences on Tissue Dosimetry

Harvey J. Clewell 1*, P. Robinan Gentry 1, Tammie R. Covington 1, Ramesh Sarangapani 2, and Justin G. Teeguarden 1

1 ENVIRON Health Sciences Institute, Ruston, LA
2 The K.S. Crump Group, Inc., ICF Consulting, RTP, NC

* To whom correspondence should be addressed. E-mail: HClewell{at}ENVIRONCorp.com.


  Abstract

The physiological and biochemical processes that determine the tissue concentration time courses (pharmacokinetics) of xenobiotics vary, in some cases significantly, with age and gender. While it is known that age- and gender-specific differences have the potential to affect tissue concentrations, and hence individual risk, the relative importance of the contributing processes and the quantitative impact of these differences for various life-stages are not well characterized. The objective of this study was to identify age- and gender-specific differences in physiological and biochemical processes that affect tissue dosimetry and integrate them into a predictive physiologically based pharmacokinetic (PBPK) life-stage model. The life-stage model was exercised for several environmental chemicals with a variety of physicochemical, biochemical and mode-of-action properties. In general, predictions of average pharmacokinetic dose metrics for a chemical across life-stages were within a factor of two; although larger transient variations were predicted, particularly during the neonatal period. The most important age-dependent pharmacokinetic factor appears to be the potential for decreased clearance of a toxic chemical in the perinatal period due to the immaturity of many metabolic enzyme systems, although this same factor may also reduce the production of a reactive metabolite. Given the potential for age-dependent pharmacodynamic factors during early life, there may be chemicals and health outcomes for which decreased clearance over a relatively brief period could have a substantial impact on risk.

Key Words: pharmacokinetics, PBPK, children, age, gender, dosimetry .


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