Weight of the Evidence Evaluation of Low-Dose Reproductive and Developmental Effects of Bisphenol A

REFERENCES

• Andrews , GS . 1951 . The histology of the human foetal and prepubertal prostates . J Anat , 85 : 44 – 54 .
   PubMed Web of Science ®Google Scholar
• Ashby , J . 1999 . The dose levels of 0.01–0.2 ug/kg/day diethylstilbestrol are not suitable for use as a positive control in endocrine toxicity studies . Regul Toxicol Pharmacol , 29 : 235 – 7 .
   PubMed Web of Science ®Google Scholar
• Ashby , J . 2000 . Getting the problem of endocrine disruption into focus: The need for pause for thought . APMIS , 108 : 805 – 13 .
   PubMed Web of Science ®Google Scholar
• Ashby , J and Lefevre , PA . 2000 . The peripubertal male rat assay as an alternative to the Hershberger castrated male rat assay for the detection of anti-androgens, oestrogens and metabolic modulators . J Appl Toxicol , 20 ( 1 ) : 35 – 47 .
   PubMed Web of Science ®Google Scholar
• Ashby , J and Tinwell , H . 1998 . Uterotrophic activity of bisphenol A in the immature rat . Environ Health Perspect , 106 ( 11 ) : 719 – 20 .
   PubMed Web of Science ®Google Scholar
• Ashby , J , Tinwell , H and Haseman , J . 1999 . Lack of effects for low dose levels of bisphenol A and diethylstilbestrol on the prostate gland of CF1 mice exposed in utero . Regul Toxicol Pharmacol , 30 ( 2 ) : 156 – 66 .
   PubMed Web of Science ®Google Scholar
• Barnes , DG and Dourson , M . 1988 . Reference dose (RfD): Description and use in health risk assessments . Regul Toxicol Pharmacol , 8 : 471 – 86 .
   PubMed Web of Science ®Google Scholar
• Bartos , L and Brain , PF . 1993 . Physiological responses to social status and housing conditions in male mice subject to food competition tests . B Zool , 60 : 293 – 6 .
   Google Scholar
• Bibbo , M , Gill , WB Azizi , F . 1977 . Follow-up study of male and female offspring of DES-exposed mothers . Obstet Gynecol , 49 ( 1 ) : 1 – 8 .
   PubMed Web of Science ®Google Scholar
• Brody , H and Goldman , S . 1940 . Metaplasia of the epithelium of the prostate glands, utricle and urethra of the fetus and newborn infant . Arch Pathol , 29 : 494 – 504 .
   Google Scholar
• Cagen , SZ , Waechter , JM Jr Dimond , SS . 1999a . Normal reproductive organ development in Wistar rats exposed to bisphenol A in the drinking water . Regul Toxicol Pharmacol , 30 ( 2 ) : 130 – 9 .
   PubMed Web of Science ®Google Scholar
• Cagen , SZ , Waechter , JM Jr Dimond , SS . 1999b . Normal reproductive organ development in CF-1 mice following prenatal exposure to bisphenol A . Toxicol Sci , 50 ( 1 ) : 36 – 44 .
   PubMed Web of Science ®Google Scholar
• Coldham , NG , Dave , M Sivapathasundaram , S . 1997 . Evaluation of a recombinant yeast cell estrogen screening assay . Environ Health Perspect , 105 : 734 – 42 .
   PubMed Web of Science ®Google Scholar
• Colerangle , JB and Roy , D . 1997 . Profound effects of the weak environmental estrogen-like chemical bisphenol A on the growth of the mammary gland of Noble rats . J Steroid Biochem Mol Biol , 60 ( 1–2 ) : 153 – 60 .
   PubMed Web of Science ®Google Scholar
• Cook , JC , Kaplan , AM Davis , LG . 1997 . Development of a Tier I Screening Battery for Detecting Endocrine-Active Compounds (EACs) . Regul Toxicol Pharmacol , 26 ( 1 ) : 60 – 8 .
   PubMed Web of Science ®Google Scholar
• de Wildt , SN , Kearns , GL Leeder , JS . 1999 . Glucuronidation in humans. Pharmacogenetic and developmental aspects . Clin Pharmacokinet , 36 : 439 – 52 .
   PubMed Web of Science ®Google Scholar
• Deschamps , JC , Ott , RS McEntee , K . 1987 . Effects of zeranol on reproduction in beef bulls: Scrotal circumference, serving ability, semen characteristics, and pathologic changes of the reproductive organs . Am J Vet Res , 48 : 137 – 47 .
   PubMed Web of Science ®Google Scholar
• Dodds , EC and Lawson , W . 1936 . Synthetic oestrogenic agents without the phenanthrene nucleus . Nature , 137 : 996
   Google Scholar
• Dodge , JA , Glasebrook , AL Magee , DE . 1996 . Environmental estrogens: Effects on cholesterol lowering and bone in the ovariectomized rat . J Steroid Biochem Mol Biol , 59 : 155 – 61 .
   PubMed Web of Science ®Google Scholar
• Elswick , BA , Welsch , F and Janszen , DB . 2000 . Effect of different sampling designs on outcome of endocrine disruptor studies . Reprod Toxicol , 14 : 359 – 67 .
   PubMed Web of Science ®Google Scholar
• Ema , M , Fujii , S Furukawa , M . 2001 . Rat two-generation reproductive toxicity study of bisphenol A . Reprod Toxicol , 15 ( 5 ) : 505 – 23 .
   PubMed Web of Science ®Google Scholar
• European Union . 2003 . European Union Risk Assessment Report Accessed: 2004, Available at
   Google Scholar
• Faber , KA and Hughes , CL . 1992 . Anogenital distance at birth as a predictor of volume of the sexually dimorphic nucleus of the preoptic area of the hypothalamus and pituitary responsiveness in castrated adult rats . Biol Reprod , 46 : 101 – 4 .
   PubMed Web of Science ®Google Scholar
• Gill , WB , Schumacher , GF and Bibbo , M . 1977 . Pathological semen and anatomical abnormalities of the genital tract in human male subjects exposed to diethylstilbestrol in utero . J Urol , 117 : 477 – 80 .
   PubMed Web of Science ®Google Scholar
• Gill , WB , Schumacher , GFB Bibbo , M . 1979 . Association of diethylstilbestrol exposure in utero with cryptorchidism, testicular hypoplasia and semen abnormalities . J Urol , 122 : 36 – 9 .
   PubMed Web of Science ®Google Scholar
• Gould , JC , Leonard , LS Maness , SC . 1998 . Bisphenol A interacts with the estrogen receptor alpha in a distinct manner from estradiol . Mol Cell Endocrinol , 142 ( 1–2 ) : 203 – 14 .
   PubMed Web of Science ®Google Scholar
• Graham , JD and Wiener , J . 1995 . Risk vs. Risk: Tradeoffs in Protecting Health and the Environment , Cambridge, MA, , USA : Harvard University Press .
   Google Scholar
• Gray , GM , Baskin , SI Charnley , G . 2001 . The Annapolis accords on the use of toxicology in risk assessment and decision-making: An Annapolis Center workshop report . Toxicol Methods , 11 ( 3 ) : 225 – 31 .
   Google Scholar
• Gray , GM , Cohen , JT and Rhomberg , L . 2004 . Weight of the Evidence Evaluation of Low-Dose Reproductive and Developmental Effects of Bisphenol A: Online Supplement Material Boston, MA, , USA Harvard Center for Risk Analysis. Available at
   Google Scholar
• Gupta , C . 2000 . Reproductive malformation of the male offspring following maternal exposure to estrogenic chemicals . Proc Soc Exp Biol Med , 224 ( 2 ) : 61 – 8 .
   PubMed Web of Science ®Google Scholar
• Haighton , LA , Hlywka , JJ Doull , J . 2002 . An evaluation of the possible carcinogenicity of bisphenol A to humans . Regul Toxicol Pharmacol , 35 : 238 – 54 .
   PubMed Web of Science ®Google Scholar
• Haseman , JK , Bailer , AJ Kodell , RL . 2001 . Forum: Statistical issues in the analysis of low-dose endocrine disruptor data . Toxicol Sci , 61 : 201 – 10 .
   PubMed Web of Science ®Google Scholar
• Herbst , AL , Ulfelder , H and Poskanzer , DC . 1971 . Adenocarcinoma of the vagina: Association of maternal stilbestrol therapy with tumor appearance in young women . N Engl J Med , 284 : 878 – 88 .
   PubMed Web of Science ®Google Scholar
• Highman , B , Norvell , MJ and Shellenberger , TE . 1977 . Pathological changes in female C3H mice continuously fed diets containing diethylstilbestrol or 17-beta estradiol . J Environ Pathol Toxicol , 1 : 1 – 30 .
   PubMedGoogle Scholar
• Highman , B , Greenman , DL Norvell , MJ . 1980a . Neoplastic and preneoplastic lesions induced in female C3H mice by diets containing diethystilbestrol or 17-beta estradiol . J Environ Pathol Toxicol , 4 : 81 – 95 .
   PubMed Web of Science ®Google Scholar
• Highman , B , Greenman , DL Norvell , MJ . 1980b . Pathological changes in female C3H mice fed diets containing diethylstilbestrol or 17b-estradiol . J Environ Pathol Toxicol , 1 : 1 – 30 .
   Google Scholar
• Howdeshell , KL , Hotchkiss , AK Thayer , KA . 1999 . Exposure to bisphenol A advances puberty . Nature , 401 ( 6755 ) : 763 – 4 .
   PubMed Web of Science ®Google Scholar
• Howdeshell , KL and vom Saal , FS . 2000 . Developmental exposure to bisphenol A: Interaction with endogenous estradiol during pregnancy in mice . Am Zool , 40 ( 3 ) : 429 – 37 .
   Google Scholar
• Huff , J . 2001 . Carcinogenicity bioassays of bisphenol A, 4-vinylcyclohexene diepoxide, and 4-vinylcyclohexene . Toxicol Sci , 64 : 282 – 3 .
   PubMedGoogle Scholar
• Kim , H , Han , S Yoo , S . 2001 . Potential estrogenic effects of bisphenol A estimated by in vitro and in vivo combination assays . J Toxicol Sci , 26 ( 3 ) : 111 – 8 .
   PubMedGoogle Scholar
• Krishnan , AV , Stathis , P Permuth , SF . 1993 . Bisphenol-A: An estrogenic substance is released from polycarbonate flasks during autoclaving . Endocrinology , 132 ( 6 ) : 2279 – 86 .
   PubMed Web of Science ®Google Scholar
• Kubo , K , Arai , O Ogata , R . 2001 . Exposure to bisphenol A during the fetal and suckling periods disrupts sexual differentiation of the locus coeruleus and of behavior in the rat . Neurosci Lett , 304 : 73 – 6 .
   PubMed Web of Science ®Google Scholar
• Laws , SC , Carey , SA Ferrell , JM . 2000 . Estrogenic activity of octylphenol, nonylphenol, bisphenol A and methoxychlor in rats . Toxicol Sci , 54 ( 1 ) : 154 – 67 .
   PubMed Web of Science ®Google Scholar
• Leary , FJ , Resseguie , LJ Kurland , LT . 1984 . Males exposed in utero to diethylstilbestrol . JAMA , 252 ( 21 ) : 2984 – 9 .
   PubMed Web of Science ®Google Scholar
• Long , X , Steinmetz , R Ben-Jonathan , N . 2000 . Strain differences in vaginal responses to the xenoestrogen bisphenol A . Environ Health Perspect , 108 ( 3 ) : 243 – 7 .
   PubMed Web of Science ®Google Scholar
• Lucier , GW . 1976 . Perinatal development of conjugative enzyme systems . Environ Health Perspect , 18 : 25 – 34 .
   PubMed Web of Science ®Google Scholar
• Lucier , GW , Lui , EM and Lamartiniere , CA . 1979 . Metabolic activation/deactivation reactions during perinatal development . Environ Health Perspect , 29 : 7 – 16 .
   PubMed Web of Science ®Google Scholar
• Markey , CM , Luque , EH De Munoz , M . 2001 . In utero exposure to bisphenol A alters the development and tissue organization of the mouse mammary gland . Biol Reprod , 65 ( 4 ) : 1215 – 23 .
   PubMed Web of Science ®Google Scholar
• Matthews , JB , Twomey , K and Zacharewski , TR . 2001 . In vitro and in vivo interactions of bisphenol A and its metabolite, bisphenol A glucuronide, with estrogen receptors alpha and beta . Chem Res Toxicol , 14 : 149 – 57 .
   PubMed Web of Science ®Google Scholar
• McLachlan , JA , Newbold , RR and Bullock , B . 1975 . Reproductive tract lesions in male mice exposed prenatally to diethylstilbestrol . Science , 190 : 991 – 2 .
   PubMed Web of Science ®Google Scholar
• Milman , HA , Bosland , MC Walden , PD . 2002 . Evaluation of the adequacy of published studies of low-dose effects of bisphenol A on rodent prostate for use in human risk assessment . Regul Toxicol Pharmacol , 35 ( 3 ) : 338 – 46 .
   PubMed Web of Science ®Google Scholar
• Miyakoda , H , Tabata , M Onodera , S . 1999 . Passage of bisphenol A into the fetus of the pregnant rat . J Health Sci , 45 : 318 – 23 .
   Google Scholar
• Munro , IC , Haighton , LA Hlywka , JJ . 2002 . Carcinogenicity bioassay of bisphenol A . Toxicol Sci , 66 : 356
   PubMed Web of Science ®Google Scholar
• Nagao , T , Saito , Y Usumi , K . 2002 . Low-dose bisphenol A does not affect reproductive organs in estrogen sensitive C57BL/6N mice exposed at the sexually mature, juvenile, or embryonic stage . Reprod Toxicol , 16 : 123 – 30 .
   PubMed Web of Science ®Google Scholar
• Nagel , SC , vom Saal , FS Thayer , KA . 1997 . Relative binding affinity-serum modified access (RBA-SMA) assay predicts the relative in vivo bioactivity of the xenoestrogens bisphenol A and octylphenol . Environ Health Perspect , 105 ( 1 ) : 70 – 6 .
   PubMed Web of Science ®Google Scholar
• National Toxicology Program . 1982 . “ Technical Report on the Carcinogenesis Bioassay of Bisphenol A in F344 Rats and B6C3F1 Mice (Feed Study) ” . In National Toxicology Program , Bethesda, MD, , USA : National Institutes of Health .
   Google Scholar
• National Toxicology Program (NTP) . 2001 . National Toxicology Program's Report of the Endocrine Disruptors Low-Dose Peer Review Research Triangle Park, NC
   Google Scholar
• Neumann , H . 1976 . Dose-dependent kinetics of diethylstilbestrol in the rat . J Toxicol Environ Health (Suppl) , 1 : 61 – 76 .
   Google Scholar
• Nonneman , DJ , Ganjam , VK Welshons , WV . 1992 . Intrauterine position effects on steroid metabolism and steroid receptors of reproductive organs in male mice . Biol Reprod , 47 : 723 – 9 .
   PubMed Web of Science ®Google Scholar
• Pottenger , LH , Domoradzki , JY Markham , DA . 1997 . Bioavailability of 14C-bisphenol A (BPA) in F344 rats following oral (po), subcutaneous (sc) or intraperitoneal (ip) administration . Toxicology , 36 : 143
   Google Scholar
• Pottenger , LH , Domoradzki , JY Markham , DA . 2000 . The relative bioavailability and metabolism of bisphenol A in rats is dependent upon the route of administration . Toxicol Sci , 54 ( 1 ) : 3 – 18 .
   PubMed Web of Science ®Google Scholar
• Prins , GS . 1997 . “ Developmental estrogenization of the prostate gland ” . In Prostate: Basic and Clinical Aspects , Edited by: Naz , RK . 245 – 266 . Boca Raton, FL, , USA : CRC Press .
   Google Scholar
• Pritchett , JJ , Kuester , RK and Sipes , IG . 2002 . Metabolism of bisphenol A in primary cultured hepatocytes from mice, rats, and humans . Drug Metab Dispos , 30 : 1180 – 85 .
   PubMed Web of Science ®Google Scholar
• Ramos , JG , Varayoud , J Kass , L . 2001 . Prenatal exposure to low doses of bisphenol A alters the periductal stroma and glandular cell function in the rat ventral prostate . Biol Reprod , 65 : 1271 – 7 .
   PubMed Web of Science ®Google Scholar
• Rane , A and Tomson , G . 1980 . Prenatal and neonatal drug metabolism in man . Eur J Clin Pharmacol , 18 : 9 – 15 .
   PubMed Web of Science ®Google Scholar
• Reinisch , JM and Sanders , SA . 1992 . Effects of prentatal exposure to diethylstilbestrol (DES) on hemispheric laterality and spatial ability in human males . Horm Behav , 26 : 62 – 75 .
   PubMed Web of Science ®Google Scholar
• Ring , JA , Ghabrial , H Ching , MS . 1999 . Fetal hepatic drug elimination . Pharmacol Ther , 84 : 429 – 45 .
   PubMed Web of Science ®Google Scholar
• Risbridger , G , Wang , H Frydenberg , M . 2001 . The metaplastic effects of estrogen on prostate epithelium: Proliferation of cells with basal cell phenotype . Endocrinology , 142 : 2443 – 50 .
   PubMed Web of Science ®Google Scholar
• Sakaue , M , Ohsako , S Ishimura , R . 2001 . Bisphenol-A affects spermatogenesis in the adult rat even at a low dose . J Occup Health , 43 : 185 – 90 .
   Web of Science ®Google Scholar
• Santti , R , Pylkkanen , L Newbold , R . 1990 . Developmental oestrogenization and prostatic neoplasia . Int J Androl , 13 : 77 – 80 .
   PubMedGoogle Scholar
• Scientific Committee on Food . 2002 . Opinion of the Scientific Committee on Food on Bisphenol A , European Commission Health & Consumer Protection Directorate-General . SCF/CS/PM/3936 Final, Available at
   Google Scholar
• Spearow , JL , Doemeny , P Sera , R . 1999 . Genetic variation in susceptibility to endocrine disruption by estrogen in mice . Science , 285 : 1259 – 61 .
   PubMed Web of Science ®Google Scholar
• Spearow , JL , Henley , P Doemeny , P . 2001 . Genetic variation in physiological sensitivity to estrogen in mice . APMIS , 109 : 356 – 64 .
   PubMed Web of Science ®Google Scholar
• Steinmetz , R , Mitchner , NA Grant , A . 1998 . The xenoestrogen bisphenol A induces growth, differentiation, and c-fos gene expression in the female reproductive tract . Endocrinology , 139 ( 6 ) : 2741 – 7 .
   PubMed Web of Science ®Google Scholar
• Takahashi , O and Oishi , S . 2000 . Disposition of orally administered 2,2-bis(4-hydroxyphenol)propane (bisphenol A) in pregnant rats and the placental transfer to fetuses . Environ Health Perspect , 108 : 931 – 5 .
   PubMed Web of Science ®Google Scholar
• Thayer , KA , Ruhlen , RL Howdeshell , KL . 2001 . Altered prostate growth and daily sperm production in male mice exposed prenatally to subclinical doses of 17-alpha ethinyl oestradiol . Hum Reprod , 16 ( 5 ) : 988 – 96 .
   PubMed Web of Science ®Google Scholar
• Timms , BG , Petersen , SL and vom Saal , FS . 1999 . Prostate gland growth during development is stiumulated in both male and female rat fetuses by intrauterine proximity to female fetuses . J Urol , 161 : 1694 – 701 .
   PubMed Web of Science ®Google Scholar
• Tinwell , H , Joiner , R Pate , I . 2000 . Uterotrophic activity of bisphenol A in the immature mouse . Regul Toxicol Pharmacol , 32 ( 1 ) : 118 – 26 .
   PubMed Web of Science ®Google Scholar
• Tinwell , H , Haseman , J Lefevre , PA . 2002 . Normal sexual development of two strains of rat exposed in utero to low doses of bisphenol A . Toxicol Sci , 68 : 339 – 48 .
   PubMed Web of Science ®Google Scholar
• Tunn , U , Senge , T Schenck , B . 1979 . Biochemical and histological studies on prostates in castrated dogs after treatment with androstanediol, oestradiol and cyproterone acetate . Acta Endocrinol (Copenh) , 91 : 373 – 84 .
   PubMedGoogle Scholar
• Tyl , RW , Myers , CB Marr , MC . 2002 . Three-generation reproductive toxicity study of dietary bisphenol A in CD Sprague-Dawley rats . Toxicol Sci , 68 : 121 – 46 .
   PubMed Web of Science ®Google Scholar
• USEPA (Environmental Protection Agency) . 2003 . Integrated Risk Information System (IRIS) Accessed: 2003. Available at
   Google Scholar
• Vandenbergh , JG and Guggett , CL . 1995 . The anogenital distance index, a predictor of intrauterine position effects on reproduction in female house mice . Lab Anim Sci , 45 ( 5 ) : 567 – 73 .
   PubMedGoogle Scholar
• Völkl , W , Colnot , T Csanády , GA . 2002 . Metabolism and kinetics of bisphenol A in humans at low doses following oral administration . Chem Res Toxicol , 15 : 1281 – 87 .
   PubMed Web of Science ®Google Scholar
• vom Saal , FS , Timms , BG Montano , MM . 1997 . Prostate enlargement in mice due to fetal exposure to low doses of estradiol or diethylstilbestrol and opposite effects at high doses . Proc Natl Acad Sci U S A , 94 ( 5 ) : 2056 – 61 .
   PubMed Web of Science ®Google Scholar
• vom Saal , FS , Cooke , PS Buchanan , DL . 1998 . A physiologically based approach to the study of bisphenol A and other estrogenic chemicals on the size of reproductive organs, daily sperm production, and behavior . Toxicol Ind Health , 14 ( 1–2 ) : 239 – 60 .
   PubMed Web of Science ®Google Scholar
• vom Saal , FS and Welshons , WV . 2000 . NIH panel confirms that endocrine disrupting chemicals cause effects at very low doses . Risk Pol Rep 2000 , November 30 : 47 – 50 .
   Google Scholar
• Weijman , J , Ramaekers , FC Elsinghorst , TA . 1992 . Changing cytokeratin expression patterns in diethylstilbestrol dipropionate-induced metaplastic lesions of the goat prostate . Vet Q , 14 ( 1 ) : 2 – 7 .
   PubMed Web of Science ®Google Scholar
• Wilcox , AJ , Baird , DD Weinberg , CR . 1995 . Fertility in men exposed prentatally to diethylstilbestrol . N Engl J Med , 332 ( 21 ) : 1411 – 6 .
   PubMed Web of Science ®Google Scholar
• Witorsch , RJ . 2002 . Low-dose in utero effects of xenoestrogens in mice and their relevance to humans: An analytical review of the literature . Food Chem Toxicol , 40 : 905 – 12 .
   PubMed Web of Science ®Google Scholar