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Androstenedione NTP TECHNICAL REPORT ON THE TOXICOLOGY ANd CARCINOGENESIS STUdIES OF ANdROSTENEdIONE (CAS NO. 63-05-8) IN F344/N RATS ANd B6C3F1 MICE (GAVAGE STUdIES) NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709 September 2010 NTP TR 560 NIH Publication No. 10-5901 National Institutes of Health Public Health Service U.S. dEPARTMENT OF HEALTH ANd HUMAN SERVICES FOREWORd The National Toxicology Program (NTP) is an interagency program within the Public Health Service (PHS) of the Department of Health and Human Services (HHS) and is headquartered at the National Institute of Environmental Health Sciences of the National Institutes of Health (NIEHS/NIH). Three agencies contribute resources to the program: NIEHS/NIH, the National Institute for Occupational Safety and Health of the Centers for Disease Control and Prevention (NIOSH/CDC), and the National Center for Toxicological Research of the Food and Drug Administration (NCTR/FDA). Established in 1978, the NTP is charged with coordinating toxicological testing activities, strengthening the science base in toxicology, developing and validating improved testing methods, and providing information about potentially toxic substances to health regulatory and research agencies, scientific and medical communities, and the public. The Technical Report series began in 1976 with carcinogenesis studies conducted by the National Cancer Institute. In 1981, this bioassay program was transferred to the NTP. The studies described in the Technical Report series are designed and conducted to characterize and evaluate the toxicologic potential, including carcinogenic activity, of selected substances in laboratory animals (usually two species, rats and mice). Substances selected for NTP toxicity and carcinogenicity studies are chosen primarily on the basis of human exposure, level of production, and chemical structure. The interpretive conclusions presented in NTP Technical Reports are based only on the results of these NTP studies. Extrapolation of these results to other species, including characterization of hazards and risks to humans, requires analyses beyond the intent of these reports. Selection per se is not an indicator of a substance’s carcinogenic potential. The NTP conducts its studies in compliance with its laboratory health and safety guidelines and FDA Good Laboratory Practice Regulations and must meet or exceed all applicable federal, state, and local health and safety regulations. Animal care and use are in accordance with the Public Health Service Policy on Humane Care and Use of Animals. Studies are subjected to retrospective quality assurance audits before being presented for public review. NTP Technical Reports are indexed in the NIH/NLM PubMed database and are available free of charge electronically on the NTP website (http://ntp.niehs.nih.gov) or in hardcopy upon request from the NTP Central Data Management group at [email protected] or (919) 541-3419. NTP TECHNICAL REPORT ON THE TOXICOLOGY ANd CARCINOGENESIS STUdIES OF ANdROSTENEdIONE (CAS NO. 63-05-8) IN F344/N RATS ANd B6C3F1 MICE (GAVAGE STUdIES) NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 Research Triangle Park, NC 27709 September 2010 NTP TR 560 NIH Publication No. 10-5901 National Institutes of Health Public Health Service U.S. dEPARTMENT OF HEALTH ANd HUMAN SERVICES 2 CONTRIBUTORS National Toxicology Program TherImmune Research Corporation Evaluated and interpreted results and reported findings Provided SMVCE analysis C.R. Blystone, Ph.D., Study Scientist G.W. Wolfe, Ph.D., Principal Investigator S.A. Elmore, D.V.M., M.S., Study Pathologist H.S. Seung, M.S. J.B. Bishop, Ph.D. D.W. Bristol, Ph.D. dynamac Corporation J.R. Bucher, Ph.D. Prepared quality assessment audits R.S. Chhabra, Ph.D. P.M. Foster, Ph.D. S. Brecher, Ph.D., Principal Investigator R.A. Herbert, D.V.M., Ph.D. S. Iyer, B.S. M.J. Hooth, Ph.D. V.S. Tharakan, D.V.M. A.P. King-Herbert, D.V.M. G.E. Kissling, Ph.D. NTP Pathology Working Group D.E. Malarkey, D.V.M., Ph.D. Evaluated slides and contributed to pathology report on rats (October 23, 2007) J.H. Roycroft, Ph.D. J.M. Sanders, Ph.D. L.H. Kooistra, D.V.M., Ph.D., Coordinator C.S. Smith, Ph.D. Pathology Associates International, A Charles River Company G.S. Travlos, D.V.M. M.F. Cesta, D.V.M. N.J. Walker, Ph.D. National Toxicology Program K.L. Witt, M.S. D. Dixon, D.V.M., Ph.D. National Toxicology Program S.A. Elmore, D.V.M., M.S. Battelle Columbus Operations National Toxicology Program Conducted 2-week studies and evaluated pathology findings G.P. Flake, M.D. National Toxicology Program M.R. Hejtmancik, Ph.D., Principal Investigator R.A. Herbert, D.V.M., Ph.D. D.K. Gerken, D.V.M., Ph.D. National Toxicology Program H.M. Kolenda-Roberts, D.V.M., Ph.D. Southern Research Institute Experimental Pathology Laboratories, Inc. Conducted 3-month and 2-year studies and evaluated pathology R.R. Maronpot, D.V.M. findings Consultant J.B. Nold, D.V.M. C.D. Hébert, Ph.D., Principal Investigator GlaxoSmithKline J.E. Heath, D.V.M. B.P. Singh, D.V.M., M.S. R.B. Thompson, D.V.M., Ph.D. National Toxicology Program Experimental Pathology Laboratories, Inc. Provided pathology review M.H. Hamlin, II, D.V.M., Principal Investigator E.T. Adams, D.V.M., Ph.D. H.M. Kolenda-Roberts, D.V.M., Ph.D. Androstenedione, NTP TR 560 3 NTP Pathology Working Group SRA International, Inc. Evaluated slides and contributed to pathology report on mice Provided statistical analyses (July 26 and September 18, 2007) P.W. Crockett, Ph.D., Principal Investigator L.H. Kooistra, D.V.M., Ph.D., Coordinator L.J. Betz, M.S. Pathology Associates International, A Charles River Company K.P. McGowan, M.B.A. E.T. Adams, D.V.M., Ph.D. Experimental Pathology Laboratories, Inc. M.F. Cesta, D.V.M. Biotechnical Services, Inc. National Toxicology Program Prepared Technical Report J.M. Cullen, V.M.D., Ph.D. North Carolina State University S.R. Gunnels, M.A., Principal Investigator S.A. Elmore, D.V.M., M.S. L.M. Harper, B.S. National Toxicology Program P.C. Rathman, B.S.E. G.P. Flake, M.D. D.C. Serbus, Ph.D. National Toxicology Program R.A. Herbert, D.V.M., Ph.D. National Toxicology Program T. Koujitani, D.V.M., Ph.D. National Toxicology Program D.E. Malarkey, D.V.M., Ph.D. National Toxicology Program J.B. Nold, D.V.M. GlaxoSmithKline 4 CONTENTS ABSTRACT . 7 EXPLANATION OF LEVELS OF EVIdENCE OF CARCINOGENIC ACTIVITY . 12 TECHNICAL REPORTS REVIEW SUBCOMMITTEE . 13 SUMMARY OF TECHNICAL REPORTS REVIEW SUBCOMMITTEE COMMENTS . 14 INTROdUCTION . 15 MATERIALS ANd METHOdS . 21 RESULTS . 33 dISCUSSION ANd CONCLUSIONS . 61 REFERENCES . 65 APPENdIX A Summary of Lesions in Male Rats in the 2-Year Gavage Study of Androstenedione . 73 APPENdIX B Summary of Lesions in Female Rats in the 2-Year Gavage Study of Androstenedione . 93 APPENdIX C Summary of Lesions in Male Mice in the 2-Year Gavage Study of Androstenedione . 107 APPENdIX d Summary of Lesions in Female Mice in the 2-Year Gavage Study of Androstenedione . 123 APPENdIX E Genetic Toxicology . 139 APPENdIX F Clinical Pathology Results . 147 APPENdIX G Hepatic Biomarkers . 155 APPENdIX H Organ Weights and Organ-Weight-to-Body-Weight Ratios . 159 APPENdIX I Reproductive Tissue Evaluations and Estrous Cycle Characterization . 165 APPENdIX J Chemical Characterization and dose Formulation Studies . 169 APPENdIX K Ingredients, Nutrient Composition, and Contaminant Levels in NTP-2000 Rat and Mouse Ration . 185 APPENdIX L Sentinel Animal Program . 189 Androstenedione, NTP TR 560 5 SUMMARY Background Androstenedione is a natural androgen steroid hormone that is synthesized in men and women. Commercially it is used as an intermediate in the production of other steroids including oral contraceptives and anti-inflammatory products. Until its over-the-counter sales were banned in 2004, androstenedione was marketed as a supplement to aid athletes in gaining muscle mass. We studied the effects of androstenedione on male and female rats and mice to identify potential toxic or cancer-related hazards. Methods We deposited androstenedione dissolved in methylcellulose solutions through a tube directly into the stomach to groups of 50 male and female rats and mice for two years. Male and female rats and male mice received 10, 20, or 50 milligrams of androstenedione per kilogram of body weight each day; female mice received 2,10, or 50 mg/kg. Control animals received methylcellulose solutions with no chemical added by the same method. At the end of the study tissues from more than 40 sites were examined for every animal. Results A few adenomas and one carcinoma of the lung were seen in male rats receiving androstenedione and there was a slight increase in the rate of mononuclear cell leukemia in exposed female rats. Male and female mice given androstenedione had marked increases in a variety of liver tumors, including adenomas, carcinomas and hepato- blastomas. There were also increases in the rates of pancreatic islet adenomas in male and female mice. Female rats also had increased rates of hyperplasia of the pancreatic islets and atrophy of the exocrine pancreas. Female mice had very marked increases in the rates of hyperplasia of the clitoral gland, metaplasia in the kidney, and cyto- plasmic alteration of the salivary gland. Conclusions We conclude that androstenedione caused liver cancer and pancreatic islet cancer in male and female mice. The occurrence of lung tumors in male rats and mononuclear cell leukemia in female rats may have been related to androstendione exposure. Increases in nonneoplastic lesions of the pancreas in female rats and of the clitoral gland, kidney, and salivary gland in female mice were attributed to androstenedione exposure. 6 Androstenedione, NTP TR 560 7 ABSTRACT ANdROSTENEdIONE CAS No.
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