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Toxicological Sciences 69, 391-399 (2002)
Copyright © 2002 by the Society of Toxicology

REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY

Response-Surface Analysis of Exposure-Duration Relationships: The Effects of Hyperthermia on Embryonic Development of the Rat in Vitro

G. L. Kimmel*,1, P. L. Williams{dagger}, T. W. Claggett{ddagger} and C. A. Kimmel*

* National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, D.C. 20460; {dagger} Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115; and {ddagger} Pathology Associates, International, Frederick, Maryland 21701

In developing exposure standards, an assumption is often made in the case of less-than-lifetime exposures that the probability of response depends on the cumulative exposure, i.e., the product of exposure concentration and duration. Over the last two decades, the general applicability of this assumption, referred to as Haber’s Law, has begun to be questioned. This study examined the interaction of exposure concentration and duration on embryonic development during a portion of organogenesis. Embryos were exposed in whole embryo culture to various temperature-duration combinations and evaluated for alterations in development 24 h later. The specific purpose of the study was to assess whether the developmental responses followed Haber’s Law, or whether an additional component of exposure was needed to model the relationship. The current study demonstrated that the response of the developing embryo to hyperthermia, with rare exception, was dependent on an additional component of exposure beyond the cumulative exposure. For the vast majority of the parameters measured in this study, the probability of an effect was greater at higher temperatures for short durations than at lower temperatures for long durations, given the same cumulative exposure. Thus, Haber’s Law did not adequately describe the results of our study.

Key Words: Haber’s Law; hyperthermia; whole embryo culture; developmental toxicity; risk assessment; rat; dose-rate; dose-duration; heat shock.


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