A simple data transformation for estimating benchmark doses in developmental toxicity experiments.
Developmental anomalies induced by toxic chemicals may be identified using laboratory experiments with rats, mice or rabbits. Multinomial responses of fetuses from the same mother are often positively correlated, resulting in overdispersion relative to multinomial variation. In this article, a simple data transformation based on the concept of generalized design effects due to Rao-Scott is proposed for dose-response modeling of developmental toxicity. After scaling the original multinomial data using the average design effect, standard methods for analysis of uncorrelated multinomial data can be applied. Benchmark doses derived using this approach are comparable to those obtained using generalized estimating equations with an extended Dirichlet-trinomial covariance function to describe the dispersion of the original data. This empirical agreement, coupled with a large sample theoretical justification of the Rao-Scott transformation, confirms the applicability of the statistical methods proposed in this article for developmental toxicity risk assessment.
Krewski
D
D
Health Protection Branch, Health Canada, Ottawa, Ontario.
Zhu
Y
Y
D000014:Abnormalities, Drug-Induced; D000818:Animals; D016009:Chi-Square Distribution; D016000:Cluster Analysis; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D005260:Female; D005313:Fetal Death; D005333:Fetus / Q000002:abnormalities / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D015233:Models, Statistical; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D012044:Regression Analysis; D012107:Research Design; D018570:Risk Assessment; D018675:Toxicity Tests / Q000706:statistics & numerical data*