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ToxSci Advance Access published online on April 19, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj202
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received February 22, 2006
Accepted April 13, 2006

Risk Assessment

A Regression Spline Model for Developmental Toxicity Data

Daniel L. Hunt 1 * and Chin-Shang Li 1

1 Department of Biostatistics, St. Jude Children's Research Hospital, 332 N. Lauderdale Street, Memphis, TN 38105

* To whom correspondence should be addressed.
Daniel L. Hunt, E-mail: daniel.hunt{at}stjude.org


  Abstract

Observed dose-response pattern of data from several developmental toxicity experiments appears to be nonlinear and should be characterized by an appropriate model to adequately fit this observed pattern. Information from these animal studies of ambient substances that are non-carcinogenic, yet potentially toxic, to humans is used by federal protection agencies (EPA, OSHA, FDA) to determine safe exposure levels, such as no-observed-adverse-effects level (NOAEL) and benchmark dose. We have developed a flexible regression linear B-spline model for application to developmental toxicity dose-response data from animal studies of these non-carcinogens. We apply our model to data from two CD-1 mice studies of the National Toxicology Program (NTP); observed dose-response pattern from both appears nonlinear: (1) experiment of 131 pregnant mice allocated over five exposure levels (0, 0.025, 0.05, 0.10, and 0.15% diet) of diethylhexyl phthalate (DEHP); and (2) experiment of 111 pregnant mice exposed to five levels (0, 62.5, 125, 250, and 500 mg/kg/day) of diethylene glycol dimethyl ether (DYME). In each study, we measure litter response as proportion of adversely affected fetuses. Upon applying our B-spline model to the data from both studies, we predict nonlinear dose-response, with improvement over the more typical logistic dose-response model in each of the two studies.

Keywords: developmental toxicity; dose-response; interior knot; linear B-spline; threshold.
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