Toxicology at the Food and Drug Administration: new century, new challenges.

Dr. Schwetz is the Acting Deputy Commissioner of the Food and Drug Administration (FDA). He was Director of FDA National Center for Toxicological Research in Jefferson, AR, from 1993 to 1999. A diplomate of the American Board of Toxicology, Dr. Schwetz was acting Director of the Environmental Toxicology Program at the National Institutes of Health National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, NC, before coming to the FDA in 1993. He was also Associate Director of the National Toxicology program there. He had been Chief of the Institute Systems Toxicity Branch since 1982. Dr. Schwetz currently serves as Adjunct Professor, Department of Pharmacology and Toxicology/Division of Interdisciplinary Toxicology, at the University of Arkansas for Medical Sciences. He was editor of Fundamental and Applied Toxicology from 1986 to 1992, and serves on the Editorial Advisory Board of Environmental Health Perspectives and Critical Reviews in Toxicology. Dr. Schwetz is an invited member of the Canada Health Protection Branch Science Advisory Board, and an elected member of the National Academy of Sciences Institute of Medicine. He is a member of the Society of Toxicology (SOT) and the National Capitol Area Chapter, SOT; the American Veterinary Medical Association; National Society of Phi Zeta, Honor Society of Veterinary Medicine; Teratology Society; Behavioral Teratology Society; and the Reproductive Toxicology Specialty Section of the SOT. He is past president of the Reproductive Toxicology Specialty Section of the SOT and of the North Carolina and the South Central Chapters of the SOT. In addition to numerous other professional awards during his career, Dr. Schwetz received the U.S. Government 1998 Meritorious Executive Presidential Rank Award.

Thoughts on carcinogenesis testing: the FDA today.

Prevention of human cancer in the future will depend on using the results of epidemiologic and animal studies and strategies to minimize exposure. Changes are occurring in the area of animal testing and research that potentially represent significant steps toward reducing our dependence on the traditional 2-year bioassay as our primary tool for identification of chemical carcinogens and management of risk. Efforts to prevent cancer would be enhanced by more attention to describing modes of action so that the development of tumors would not be the only basis for predicting carcinogenic potential. These markers might also serve for early detection of cancer at a stage more amenable to treatment. What carcinogens do we want to detect through animal tests in the future? Whether the goal is to identify weak or potent carcinogens, or both, there will still be a need for 2-year bioassays, but hopefully for confirmatory rather than screening purposes.

Developmental neurotoxicity of endocrine disrupters: focus on estrogens.

A number of different environmental compounds are proposed to interact with the endocrine system (i.e., endocrine disrupters). Many of these have estrogenic effects in vitro and/or in vivo. Recent reviews have focused attention on the need for assessing the neurotoxicity of these compounds following developmental exposure. This attention comes in part from the literature on the effects of developmental exposure to exogenous estrogen on later behavioral and neuropathological alterations. A review of the ongoing neurobehavioral and neuropathological studies at the National Center for Toxicological Research on four such estrogen mimics (genistein, methoxychlor, nonylphenol, and ethinyl estradiol) is presented with results indicating that intake of a sodium solution is sensitive to these estrogen mimics. Developmental dietary exposure in male and female rats resulted in increased consumption of the sodium solution. Volume of the sexually dimorphic nucleus of the medial preoptic area was reduced by genistein, nonylphenol, and ethinyl estradiol exposure in males. The regulatory impact of these data and the directions for future research are discussed.

An FDA review of sulfamethazine toxicity.

Recently, changes have been proposed in the criteria historically used in the evaluation of the applicability to humans of some of the results obtained from the rodent carcinogenicity bioassay data. These questions center on the suitability of the rodent model for agents that exert their toxic effects via specific enzyme interactions and endocrine mechanisms which appear to be inoperative within humans. Within the U.S. Food and Drug Administration (FDA), this issue has been brought to the forefront of concern with the recent application for a New Animal Drug Application for sulfamethazine (SMZ). A panel of FDA experts from the National Center for Toxicological Research (NCTR), the Center for Veterinary Medicine (CVM), and the Center for Food Safety and Applied Nutrition has reviewed the sum of the scientific evidence available on the toxicology of SMZ. They noted that, in previous feeding studies at NCTR, high doses of SMZ were associated with significant incidences of thyroid tumors in mice and rats. The panel also notes that the tumorigenic activity of SMZ in rodents was due to its goitrogenic activity, resulting in constant stimulation of the thyroid by TSH. Humans, on the other hand, were found to be insensitive to the SMZ-like inhibition of thyroid function. Further, apart from X-irradiation and radioactive iodine, there are no other physical or chemical agents known to cause thyroid tumors in humans. Thus, the expert panel concludes that the best scientific information available indicates that elevated levels of TSH and the consequent thyroid tumors would not be produced under approved use conditions of SMZ. This conclusion is in agreement with recommendations made by three other panels, viz. the World Health Organization, the U.S. Environmental Protection Agency, and CVM, which also evaluated the public health risk of SMZ.