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Daniel M. Sheehan,¹ Emily Willingham,² David Gaylor,¹ Judith M. Bergeron,² and David Crews²

¹Division of Genetic and Developmental Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079 USA
²Institute of Reproductive Biology, Department of Zoology, University of Texas at Austin, Austin, TX 78712 USA

Abstract

Risk assessments for nongenotoxic chemicals assume a threshold below which no adverse outcomes are seen. However, when an endogenous chemical, such as 17ß-estradiol (E₂) , occurs at a concentration sufficient to cause an effect, the threshold is already exceeded. Under these circumstances, exogenous estradiol is not expected to provide a threshold dose. This principle is demonstrated for E₂ in the red-eared slider, a turtle with temperature-dependent sex determination. In this species, gonadal sex is determined by egg incubation temperature ; female development requires endogenous estrogen produced by elevated temperature. While normal production of females by endogenous estrogens is not an adverse effect, exogenous estrogens can sex reverse presumptive males, which can be an adverse effect. A large dose-response study was conducted using seven doses and a vehicle control (starting n = 300/group) ; a single E₂ dose was applied to the eggshell of recently laid eggs. Animals were sexed after hatching. The incubation temperature chosen, 28.6°C, generates a minority of females. Thus, the criteria for testing the threshold hypothesis were met, i.e., there is evidence that there is endogenous estrogen and that it generates an irreversible response. The lowest E₂ dose tested, 400 pg/egg (40 ng/kg) , sex reversed 14.4% of the animals, demonstrating very low dose sensitivity. The data were fit with a modified Michaelis-Menten equation, which provided an estimate of 1.7 ng/egg for endogenous estradiol. The median effective dose (ED₅₀) was 5.0 ± 2.0 ng/egg (95% confidence limits) , of which 1.7 ng/egg was endogenous estradiol and 3.3 ng/egg came from the applied estradiol. There was no apparent threshold dose for E₂. A smaller replication confirmed these results. These results provide a simple biologically based dose-response model and suggest that chemicals which act mechanistically like E₂ may also show no threshold dose. If so, even low environmental concentrations of such chemicals may carry risk for sex reversal. Key words: biologically based dose-response model, development, endocrine disruptors, estrogens, risk assessment, safety testing, sex determination, sex reversal, threshold, turtle. Environ Health Perspect 107:155-159 (1999) . [Online 14 January 1999]

http://ehpnet1.niehs.nih.gov/docs/1999/107p155-159sheehan/ abstract.html

Address correspondence to D.M. Sheehan, Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079 USA.

We thank Victor Apanius for helpful discussions.

We gratefully acknowledge financial support for this work from NSF (IBN-9723617) , NIMH (00135 to D.C.) , and the National Center for Toxicological Research.

Received 9 September 1998 ; accepted 6 October 1998.