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Ronald Melnick,¹ George Lucier,¹ Mary Wolfe,¹ Roxanne Hall,¹ George Stancel,² Gail Prins,³ Michael Gallo,⁴ Kenneth Reuhl,⁵ Shuk-Mei Ho,⁶ Terry Brown,⁷ John Moore,⁸ Julian Leakey,⁹ Joseph Haseman,¹ and Michael Kohn¹

¹National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; ²University of Texas Health Science Center, Houston, Texas, USA; ³College of Medicine, University of Illinois, Chicago, Illinois, USA; ⁴University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA; ⁵College of Pharmacy, Rutgers University, Piscataway, New Jersey, USA; ⁶University of Massachusetts Medical School, Worcester, Massachusetts, USA; ⁷Johns Hopkins University School of Public Health, Baltimore, Maryland, USA; ⁸Sciences International, Inc., Alexandria, Virginia, USA; ⁹National Center for Toxicological Research, Jefferson, Arkansas, USA

Abstract

At the request of the U.S. Environmental Protection Agency (U.S. EPA) , the National Toxicology Program organized an independent and open peer review to evaluate the scientific evidence on low-dose effects and nonmonotonic dose-response relationships for endocrine-disrupting chemicals in mammalian species. For this peer review, "low-dose effects" referred to biologic changes that occur in the range of human exposures or at doses lower than those typically used in the standard testing paradigm of the U.S. EPA for evaluating reproductive and developmental toxicity. The demonstration that an effect is adverse was not required because in many cases the long-term health consequences of altered endocrine function during development have not been fully characterized. A unique aspect of this peer review was the willing submission of individual animal data by principal investigators of primary research groups active in this field and the independent statistical reanalyses of selected parameters prior to the peer review meeting by a subpanel of statisticians. The expert peer-review panel (the panel) also considered mechanistic data that might influence the plausibility of low-dose effects and identified study design issues or other biologic factors that might account for differences in reported outcomes among studies. The panel found that low-dose effects, as defined for this review, have been demonstrated in laboratory animals exposed to certain endocrine-active agents. In some cases where low-dose effects have been reported, the findings have not been replicated. The shape of the dose-response curves for reported effects varied with the end point and dosing regimen and were low-dose linear, threshold-appearing, or nonmonotonic. The findings of the panel indicate that the current testing paradigm used for assessments of reproductive and developmental toxicity should be revisited to see whether changes are needed regarding dose selection, animal-model selection, age when animals are evaluated, and the end points being measured following exposure to endocrine-active agents. Key words: androgen, antiandrogen, bisphenol A, developmental toxicity, endocrine disruptors, estrogen, in utero exposure, low-dose effects, multigeneration study, neonatal exposure, reproductive toxicity. Environ Health Perspect 110:427-431 (2002) . [Online 12 March 2002]

http://ehpnet1.niehs.nih.gov/docs/2002/110p427-431melnick/ abstract.html

Address correspondence to R. Melnick, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, North Carolina 27709 USA. Telephone: (919) 541-4142. Fax: (919) 541-3647. E-mail: melnickr@niehs.nih.gov

The Peer Review Organizing Committee included W. Allaben, National Center For Toxicological Research, Food and Drug Administration ; C. De Rosa, Agency for Toxic Substances and Disease Registry ; P. Fenner-Crisp, U.S. Environmental Protection Agency (currently at International Life Sciences Institute) ; L. Goldman, Johns Hopkins University ; S. Inkster, U.S. Consumer Products Safety Commission ; J. Kariya, U.S. Environmental Protection Agency ; R. Kavlock, U.S. Environmental Protection Agency ; G. Lucier, NIEHS (retired) ; R. Melnick, NIEHS (Chair) ; E. Murono, Centers for Disease Control and Prevention ; M. Wolfe, NIEHS ; and R. Hall, NIEHS.

Received 28 June 2001 ; accepted 16 October 2001.