ToxSci Advance Access published online on November 4, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfh008
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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1 Gaylor and Associates, Little Rock, AR 72212
* To whom correspondence should be addressed. E-mail: DavidWGaylor{at}aol.com.
Statistical analyses of non-monotonic dose response curves are proposed, experimental designs to detect low dose effects of J-shaped curves are suggested, and sample sizes are provided. For quantal data such as cancer incidence rates, much larger numbers of animals are required than for continuous data such as biomarker measurements. For example, 155 animals per dose group are required to have at least an 80% chance of detecting a decrease from a 20% incidence in controls to an incidence of 10% at a low dose. For a continuous measurement, only 14 animals per group are required to have at least an 80% chance of detecting a change of the mean by one standard deviation of the control group. Experimental designs based on three dose groups plus controls are discussed to detect non-monotonicity or to estimate the zero equivalent dose (ZED), i.e., the dose that produces a response equal to the average response in the controls. Cell proliferation data in the nasal respiratory epithelium of rats exposed to formaldehyde by inhalation are used to illustrate the statistical procedures. Statistically significant departures from a monotonic dose response were obtained for time-weighted average labeling indices with an estimated ZED at a formaldehyde dose of 5.4 ppm with a lower 95% confidence limit of 2.7 ppm. It is concluded that demonstration of a statistically significant bi-phasic dose response curve, together with estimation of the resulting ZED, could serve as a point-of departure in establishing a reference dose for low-dose risk assessment.
© 2003 Society of Toxicology
Risk Assessment
Statistical Analysis of Non-Monotonic Dose Response Relationships: Research Design and Analysis of Nasal Cell Proliferation in Rats Exposed to Formaldehyde
2 Department of Toxicology, University of Würzburg, 97078 Würzburg, Germany
3 CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709
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