TERATOLOGY 60:365–375 (1999) Teratology Society Public Affairs Committee Position Paper: Developmental Toxicity of Endocrine Disruptors to Humans† SUSAN BARLOW,1 ROBERT J. KAVLOCK,2 JOHN A. MOORE,3 SUSAN L. SCHANTZ,4 DANIEL M. SHEEHAN,5 DANA L. SHUEY,6 AND JOSEPH M. LARY7* 1Consultant Toxicologist, Brighton, East Sussex, BN1 6RE United Kingdom 2Reproductive Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711 3Institute for Evaluating Health Risks, Washington, DC 20006 4Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, Illinois 61802 5Genetic and Reproductive Toxicology Division, National Center for Toxicological Research, Jefferson, Arkansas 72079 6DuPont Pharmaceuticals Company, Stine-Haskell Research Center, Newark, Delaware 19714 7Division of Birth Defects and Pediatric Genetics, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia 30341 In recent years there has been a growing concern that ing the prenatal or neonatal period include the develop- exposure to chemicals in the environment poses a serious ment of structure and function of the male and female threat to human reproduction and development via disrupt- reproductive tracts, neurological development, onset of ing effects on endocrine function (Colborn and Clement, puberty, gender identity, sexual behavior, oocyte num- ’92; Colborn et al., ’93; Sharpe and Skakkebaek, ’93, ber, gonadotrophic and sex hormone levels, semen Toppari, et al., ’96). An ‘‘endocrine disruptor’’ has been quality, fertility, pregnancy outcome, sex ratios, neoplas- broadly defined as ‘‘an exogenous agent that interferes tic and non-neoplastic changes in the gonads and second- with the production, release, transport, metabolism, bind- ary sex organs and tissues, and onset of menopause. ing, action, or elimination of natural hormones responsible The most prominent endpoints of potential developmen- for the maintenance of homeostasis and the regulation of tal origin include congenital abnormalities (e.g., hypo- developmental processes (Kavlock et al., ’96). Due to the spadias and cryptorchidism), testicular cancer, reduced critical role of hormones in directing differentiation in semen quality, and neurobehavioral alterations. Infor- many tissues, the developing organism is particularly mation gaps and research needs to address controver- vulnerable to fluctuations in the timing or intensity of sial issues and to better assess the magnitude of exposure to chemicals with hormonal (or anti-hormonal) exposure and risk of adverse effects are also identified. activity. Concerns have reached such a level that legislative requirements for identifying chemicals with endocrine SUPPORTING EVIDENCE OF THE disrupting potential were included in the Food Quality DEVELOPMENTAL TOXICITY Protection Act and the Safe Drinking Water Act, which OF ENDOCRINE DISRUPTORS were passed by the U.S. Congress in 1996. The regulatory Wildlife studies requirements emerging from these Acts will shortly begin Considerable evidence for adverse effects of endocrine- to generate a considerable amount of information regard- disrupting chemicals has come from studies of wildlife ing the potential of a wide variety of chemicals to interact with various components of the endocrine system (US EPA, This position paper was prepared by the authors at the request of the ’98). More recently, the European Parliament voted to Public Affairs Committee of the Teratology Society. Drafts of this recommend the use of the precautionary principle in deal- document were reviewed by more than 25 scientists with expertise in a ing with the regulation of chemicals with endocrine- wide variety of basic, clinical, and regulatory disciplines. The final disrupting actions (European Parliament, ’98). version published here has been approved by the Public Affairs Committee and the Council of the Teratology Society. The opinions This position paper explores the relevant evidence expressed in this document are those of the authors and do not imply from wildlife and laboratory animal studies on the endorsement by the authors’ respective institutions. effects of endocrine-disrupting chemicals and provides This paper has been subjected to US EPA technical review; however, a critical examination of the evidence for the occurrence the views expressed are those of the authors and do not reflect US EPA and magnitude of human health effects, particularly policy, or that of any other organizations mentioned herein. those mediated during development by the effects of *Correspondence to: Dr. Joseph M. Lary, Division of Birth Defects and environmental estrogens, anti-estrogens, androgens, Pediatric Genetics, Centers for Disease Control and Prevention, MS anti-androgens, and chemicals affecting thyroid gland F-45, 4770 Buford Highway, Atlanta, GA 30341-3724. function. Endpoints relevant to the assessment of pos- E-mail: [email protected] sible risks from exposure to endocrine disruptors dur- Received 19 August 1999; Accepted 23 August 1999 Published 1999 WILEY-LISS, INC. †This article was prepared by a group of US government employees and non-US government employees and, as such, is subject to 17 U.S.C. sec. 105. 366 BARLOW ET AL. populations exposed to environmental contaminants. principal modes of action, effective dose ranges and Effects have been observed at all levels of biological critical periods (to the extent currently understood), organization, from elevated biomarkers of exposure to and characteristic phenotypes are summarized in Table behavioral disturbances, overt malformations, and, ul- 1. Pertinent aspects of these findings are discussed timately, population declines. Such effects have been below. observed in a variety of phyla and classes, including Chemicals with estrogenic activity are a well- invertebrates, fish, reptiles, birds, and mammals. Due described class of developmental toxicants based on to the focus on human health, only selected examples standard criteria of causing specific malformations are briefly mentioned here; readers are directed to during critical developmental periods of relatively short recent reviews for more information (e.g., Umweltbun- duration (Schardein, ’93). The malformations increase des Amt, ’95; US EPA, ’97; Daston et al., ’97; Ankley et both in severity and incidence with dose, although as al., ’98; Olsson et al., ’98). noted below non-monotonic dose-response relation- In the case of imposex (formation of a penis and vas ships have been noted for a few endpoints. Estrogens deferens) in female molluscs, exposure to the anti- induce pleiotropic effects, acting on many types of cells fouling agent tributyltin (a former constituent of ma- with estrogen receptors, and can display cell and organ- rine paints) has been demonstrated to alter the activity specific agonist and antagonist actions. The pattern of of enzymes involved in the synthesis of estradiol (Ellis outcomes is generally similar across different estro- and Pattisina, ’90). In populations of fish from several gens, although not all possible outcomes have been geographical regions, vitellogenin (an estrogen-induc- described for each. Diethylstilbestrol (DES) provides ible egg yolk protein) has been detected in the serum of one of the most well-characterized examples of the male fish. The source of the estrogenic exposure ap- effects of an estrogen on development. Manifestations pears to be both anthropogenic (ethynyl estradiol from of DES exposure include malformations and adverse birth control pills as well as natural estrogens that are functional alterations of the male and female reproduc- excreted by women and eventually released into rivers tive tract and brain. In the CD-1 mouse, effective from sewage treatment plants), and industrial (surfac- exposures are in the range of 0.01–100 µg/kg on GD tants including alkyl phenol ethoxylates in effluents) 9–16 (Newbold, ’95). At the higher end of the exposure and other as yet unidentified chemicals depending on range (10–100 µg/kg), total sterility of female offspring the location (Mattheissen et al., ’98). Reproductive is noted, due in part to structural abnormalities of the failure, genital abnormalities, and decreased survival oviduct, uterus, cervix, and vagina and to depletion and have been observed in alligators in Lake Apopka, abnormalities of ovarian follicles. In adulthood, off- Florida. These effects have been associated with a large spring show excessive vaginal keratinization, hypospa- spill of pesticides, including dicofol and DDT (Guillette dias, and epidermoid tumors of the vagina. Vaginal et al., ’94). The biological outcomes may be related to adenocarcinoma is seen at doses as low as 2.5 µg/kg. the anti-androgenic effects of p,pЈ-DDE, a persistent Benign uterine tumors (leiomyomas) are seen as low as metabolite of DDT. Injections of 3–10 µg/kg egg mass of 0.1 µg/kg. In male offspring, sterility is observed at high p,pЈ-DDE induced female phenotypes at otherwise male doses, the result of retained rete testes and Mullerian producing temperatures in the alligator (Matters et al., duct remnants, abnormal sperm morphology and motil- ’98). Observations of early life stage mortality in Lake ity, lesions in the reproductive tract (including cryptor- Trout from Lake Ontario (Ankley and Giesy, ’98) and chidism and rete testis adenocarcinoma), abnormal malformations such as cross-beaks in Lake Michigan reproductive tract secretions, and inflammation (New- cormorants (Giesy