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ased composites and sealants used in dentistry. Environ Health Perspect 104:298–305. Olsen CM, Meussen-Elholm ET, Hongslo JK, Stenersen J, Tollefsen KE. 2005. Estrogenic effects of environmental chemicals: an interspecies comparison. Comp Biochem Physiol C Toxicol Pharmacol 141:267–274. Olsen CM, Meussen-Elholm ET, Samuelsen M, Holme JA, Hongslo JK. 2003. Effects of the environmental oestrogens bisphenol A, tetrachlorobisphenol A, tetrabromobisphenol A, 4-hydroxybiphenyl and 4,4 0 -dihydroxybiphenyl on oestrogen receptor binding, cell proliferation and regulation of oestrogen sensitive proteins in the human breast cancer cell line MCF-7. Pharmacol Toxicol 92:180–188. Onn Wong K, Woon Leo L, Leng Seah H. 2005. Dietary exposure assessment of infants to bisphenol A from the use of polycarbonate baby milk bottles. Food Addit Contam 22:280–288. Ortiz-Zarragoitia M, Cajaraville MP. 2006. Biomarkers of exposure and reproduction-related effects in mussels exposed to endocrine disruptors. 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Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 391 Pickford DB, Hetheridge MJ, Caunter JE, Hall AT, Hutchinson TH. 2003. Assessing chronic toxicity of bisphenol A to larvae of the African clawed frog (Xenopus laevis) in a flow-through exposure system. Chemosphere 53:223–235. Porrini S, Belloni V, Della Seta D, Farabollini F, Giannelli G, Dessi-Fulgheri F. 2005. Early exposure to a low dose of bisphenol A affects sociosexual behavior of juvenile female rats. Brain Res Bull 65:261–266. Pottenger LH, Domoradzki JY, Markham DA, Hansen SC, Cagen SZ, Waechter Jr JM. 2000. The relative bioavailability and metabolism of bisphenol A in rats is dependent on the route of administration. Toxicol Sci 54:3–18. Pritchett JJ, Kuester RK, Sipes IG. 2002. Metabolism of bisphenol a in primary cultured hepatocytes from mice, rats, and humans. Drug Metab Dispos 30:1180–1185. Quesada I, Fuentes E, Viso-Leon MC, Soria B, Ripoll C, Nadal A. 2002. 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Environ Toxicol Pharmacol 20:42–47. Rankouhi TR, Sanderson JT, van Holsteijn I, van Leeuwen C, Vethaak AD, van den Berg M. 2004. Effects of natural and synthetic estrogens and various environmental contaminants on vitellogenesis in fish primary hepatocytes: comparison of bream (Abramis brama) and carp (Cyprinus carpio). Toxicol Sci 81:90–102. Rankouhi TR, van Holsteijn I, Letcher R, Giesy JP, van Den Berg M. 2002. Effects of primary exposure to environmental and natural estrogens on vitellogenin production in carp (Cyprinus carpio) hepatocytes. Toxicol Sci 67:75–80. Razzoli M, Valsecchi P, Palanza P. 2005. Chronic exposure to low doses bisphenol A interferes with pair-bonding and exploration in female Mongolian gerbils. Brain Res Bull 65:249–254. Recchia AG VA, Gabriele S, Carpino A, Fasanella G, Rago V, Bonofiglio D, Maggiolini M. 2004. Xenoestrogens and the induction of proliferative effects in breast cancer cells via direct activation of oestrogen receptor alpha. Food Addit Contam 21:134–144. Rivas A, Fisher JS, McKinnell C, Atanassova N, Sharpe RM. 2002. Induction of reproductive tract developmental abnormalities in the male rat by lowering androgen production or action in combination with a low dose of diethylstilbestrol: evidence for importance of the androgen-estrogen balance. Endocrinology 143:4797–4808. Roepke TA, Snyder MJ, Cherr GN. 2005. Estradiol and endocrine disrupting compounds adversely affect development of sea urchin embryos at environmentally relevant concentrations. Aquat Toxicol 71:155–173. Romero J, Ventura F, Gomez M. 2002. Characterization of paint samples used in drinking water reservoirs: identification of endocrine disruptor compounds. J Chromatogr Sci 40:191–197. Routledge EJ, White R, Parker MG, Sumpter JP. 2000. Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) alpha and ERbeta. J Biol Chem 275:35986–35993. Roy P, Salminen H, Koskimies P, Simola J, Smeds A, Saukko P, Huhtaniemi IT. 2005. Screening of some anti-androgenic endocrine disruptors using a recombinant cell-based in vitro bioassay. J Steroid Biochem Mol Biol 88:157–166. Rubin BS, Lenkowski JR, Schaeberle CM, Vandenberg LN, Ronsheim PM, Soto AM. 2006. Evidence of altered brain sexual differentiation in mice exposed perinatally to low, environmentally relevant levels of bisphenol A. Endocrinology 147:3681–3691. Rubin BS, Murray MK, Damassa DA, King JC, Soto AM. 2001. Perinatal exposure to low doses of bisphenol A affects body weight, patterns of estrous cyclicity, and plasma LH levels. Environ Health Perspect 109:675–680. Rudel RA, Brody JG, Spengler JD, Vallarino J, Geno PW, Sun G, Yau A. 2001. Identification of selected hormonally active agents and animal mammary carcinogens in commercial and residential air and dust samples. J Air Waste Manag Assoc 51:499–513. Rudel RA, Camann DE, Spengler JD, Korn LR, Brody JG. 2003. 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392 CHAPIN ET AL. Ryan BC, Vandenbergh JG. 2006. Developmental exposure to environmental estrogens alters anxiety and spatial memory in female mice. Horm Behav 50:85–93. Saito D, Minamida G, Izukuri K, Tani-Ishii N, Kato Y, Ozono S, Kawase T, Teranaka T, Koshika S. 2003a. Effects of pubertal treatment with bisphenol A and Bis-GMA on sex hormone level in male rats. Environ Sci 10:55–61. Saito D, Minamida G, Tani-Ishii N, Izukuri K, Ozono S, Koshika S, Teranaka T. 2003b. Effect of prenatal exposure to dental composite resin monomers on testosterone production in the rat testis. Environ Sci 10:327–336. Sajiki J, Miyamoto F, Fukata H, Mori C, Yonekubo J, Hayakawa K. 2007. Bisphenol A (BPA) and its source in foods in Japanese markets. Food Addit Contam 24:103–112. Sajiki J, Takahashi K, Yonekubo J. 1999. Sensitive method for the determination of bisphenol-A in serum using two systems of high-performance liquid chromatography. J Chromatogr B 736:255–261. Sakamoto H, Yokota H, Kibe R, Sayama Y, Yuasa A. 2002. Excretion of bisphenol A-glucuronide into the small intestine and deconjugation in the cecum of the rat. Biochim Biophys Acta 1573:171–176. Sakaue M, Ohsako S, Ishimura R, Kurosawa S, Kurohmaru M, Hayashi Y, Aoki Y, Yonemoto J, Tohyama C. 2001. Bisphenol-A affects spermatogenesis in the adult rat even at a low dose. J Occup Health 43:185–190. Samuelsen M, Olsen C, Holme JA, Meussen-Elholm E, Bergmann A, Hongslo JK. 2001. Estrogen-like properties of brominated analogs of bisphenol A in the MCF-7 human breast cancer cell line. Cell Biol Toxicol 17:139–151. Santos NC, Figueira-Coelho J, Martins-Silva J, Saldanha C. 2003. Multidisciplinary utilization of dimethyl sulfoxide: pharmacological, cellular, and molecular aspects. Biochem Pharmacol 65:1035–1041. Sasaki N, Okuda K, Kato T, Kakishima H, Okuma H, Abe K, Tachino H, Tuchida K, Kubono K. 2005. Salivary bisphenol-A levels detected by ELISA after restoration with composite resin. J Mater Sci Mater Med 16:297–300. Sashihara K, Ohgushi A, Ando R, Yamashita T, Takagi T, Nakanishi T, Yoshimatsu T, Furuse M. 2001. Effects of central administration of bisphenol A on behaviors and growth in chicks. J Poult Sci 38: 275–281. Sato M, Shimada M, Sato Y. 2001. The effects of prenatal exposure to ethinyl estradiol and bisphenol-A on the developing brain, reproductive organ and behavior of mouse. Congenit Anom41: 187–193. Savabieasfahani M, Kannan K, Astapova O, Evans NP, Padmanabhan V. 2006. Developmental programming: differential effects of prenatal exposure to bisphenol-a or methoxychlor on reproductive function. Endocrinology 147:5956–5966. Schaefer WR, Hermann T, Meinhold-Heerlein I, Deppert WR, Zahradnik HP. 2000. Exposure of human endometrium to environmental estrogens, antiandrogens, and organochlorine compounds. Fertil Steril 74:558–563. Schafer TE, Lapp CA, Hanes CM, Lewis JB, Wataha JC, Schuster GS. 1999. Estrogenicity of bisphenol A and bisphenol A dimethacrylate in vitro. J Biomed Mater Res 45:192–197. Schirling M, Bohlen A, Triebskorn R, Kohler HR. 2006. An invertebrate embryo test with the apple snail Marisa cornuarietis to assess effects of potential developmental and endocrine disruptors. Chemosphere 64:1730–1738. Schönfelder G, Flick B, Mayr E, Talsness C, Paul M, Chahoud I. 2002a. In utero exposure to low doses of bisphenol A lead to long-term deleterious effects in the vagina. Neoplasia 4:98–102. Schönfelder G, Friedrich K, Paul M, Chahoud I. 2004. Developmental effects of prenatal exposure to bisphenol A on the uterus of rat offspring. Neoplasia 6:584–594. Schönfelder G, Wittfoht W, Hopp H, Talsness CE, Paul M, Chahoud I. 2002b. Parent bisphenol A accumulation in the human maternalfetal-placental unit. Environ Health Perspect 110:A703–707. Segner H, Navas JM, Schafers C, Wenzel A. 2003. Potencies of estrogenic compounds in in vitro screening assays and in life cycle tests with zebrafish in vivo. Ecotoxicol Environ Saf 54:315–322. Seidlová-Wuttke D, Jarry H, Christoffel J, Rimoldi G, Wuttke W. 2005. Effects of bisphenol-A (BPA), dibutylphtalate (DBP), benzophenone 2 (BP2), procymidone (Proc), and linurone (Lin) on fat tissue, a variety of hormones and metabolic parameters: A 3 months comparison with effects of estradiol (E2) in ovariectomized rats. Toxicology 213:13–24. Seidlová-Wuttke D, Jarry H, Wuttke W. 2004. Pure estrogenic effect of benzophenone-2 (BP2) but not of bisphenol A (BPA) and dibutylphtalate (DBP) in uterus, vagina and bone. Toxicology 205:103–112. Sharpe RM, Rivas A, Walker M, McKinnell C, Fisher JS. 2003. Effect of neonatal treatment of rats with potent or weak (environmental) oestrogens, or with a GnRH antagonist, on Leydig cell development and function through puberty into adulthood. Int J Androl 26:26–36. Sheeler CQ, Dudley MW, Khan SA. 2000. Environmental estrogens induce transcriptionally active estrogen receptor dimers in yeast: activity potentiated by the coactivator RIP140. Environ Health Perspect 108:97–103. Shibata N, Matsumoto J, Nakada K, Yuasa A, Yokota H. 2002. Malespecific suppression of hepatic microsomal UDP-glucuronosyl transferase activities toward sex hormones in the adult male rat administered bisphenol A. Biochem J 368:783–788. Shikimi H, Sakamoto H, Mezaki Y, Ukena K, Tsutsui K. 2004. Dendritic growth in response to environmental estrogens in the developing Purkinje cell in rats. Neurosci Lett 364:114–118. Shilling AD, Williams DE. 2000. Determining relative estrogenicity by quantifying vitellogenin induction in rainbow trout liver slices. Toxicol Appl Pharmacol 164:330–335. Shimizu M, Ohta K, Matsumoto Y, Fukuoka M, Ohno Y, Ozawa S. 2002. Sulfation of bisphenol A abolished its estrogenicity based on proliferation and gene expression in human breast cancer MCF-7 cells. Toxicol In Vitro 16:549–556. Shin BS, Kim CH, Jun YS, Kim DH, Lee BM, Yoon CH, Park EH, Lee KC, Han SY, Park KL, Kim HS, Yoo SD. 2004. Physiologically based pharmacokinetics of bisphenol A. J Toxicol Environ Health A 67:1971–1985. Shin BS, Yoo SD, Cho CY, Jung JH, Lee BM, Kim JH, Lee KC, Han SY, Kim HS, Park KL. 2002. Maternal-fetal disposition of bisphenol a in pregnant Sprague-Dawley rats. J Toxicol Environ Health A 65: 395–406. Shioda T, Wakabayashi M. 2000. Effect of certain chemicals on the reproduction of medaka (Oryzias latipes). Chemosphere 40: 239–243. Silva E, Rajapakse N, Kortenkamp A. 2002. Something from "nothing"— eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol 36:1751–1756. Singleton DW, Feng Y, Chen Y, Busch SJ, Lee AV, Puga A, Khan SA. 2004. Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol 221:47–55. Singleton DW, Feng Y, Yang J, Puga A, Lee AV, Khan SA. 2006. Gene expression profiling reveals novel regulation by bisphenol-A in estrogen receptor-alpha-positive human cells. Environ Res 100:86–92. Smeets JM, Rankouhi T, Nichols KM, Komen H, Kaminski NE, Giesy JP, Van Den Berg M. 1999. In vitro vitellogenin production by carp (Cyprinus carpio) hepatocytes as a screening method for determining (anti)estrogenic activity of xenobiotics. Toxicol Appl Pharmacol 157:68–76. Snyder RW, Maness SC, Gaido KW, Welsch F, Sumner SC, Fennell TR. 2000. Metabolism and disposition of bisphenol A in female rats. Toxicol Appl Pharmacol 168:225–234. Sohoni P, Sumpter JP. 1998. Several environmental oestrogens are also anti-androgens. J Endocrinol 158:327–339. Sohoni P, Tyler CR, Hurd K, Caunter J, Hetheridge M, Williams T, Woods C, Evans M, Toy R, Gargas M, Sumpter JP. 2001. Reproductive effects of long-term exposure to Bisphenol A in the fathead minnow (Pimephales promelas). 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Bisphenol A concentrations in receiving waters near U.S. manufacturing and processing facilities. Chemosphere 40: 521–525. Staples CA, Dorn PB, Klecka GM, O’Block ST, Harris LR. 1998. A review of the environmental fate, effects, and exposures of bisphenol A. Chemosphere 36:2149–2173. Steinmetz R, Brown NG, Allen DL, Bigsby RM, Ben-Jonathan N. 1997. The environmental estrogen bisphenol A stimulates prolactin release in vitro and in vivo [see comments]. Endocrinology 138:1780–1786. Birth Defects Research (Part B) 83:157–395, 2008
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National Toxicology Program U.S. De
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NTP.will.transmit.the.NTP-CERHR.<st
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National Toxicology Program U.S. De
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nTp brief tainers.with.internal.epo
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Population Adult General. Populatio
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Table 3. Blood and Breast Milk Biom
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Figure 2b. The weight of evidence t
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in.considering.the.biological.plaus
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concentrations.from.maternal,.fetal
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droxylase.immunoreactivity..76:423.
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solid.phase.extraction-high.perform
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appendix i. nTp-Cerhr bisphenol a e
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158 CHAPIN ET AL. the CERHR Core Co
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160 CHAPIN ET AL. referred to as 4,
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162 CHAPIN ET AL. concentrations in
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164 CHAPIN ET AL. Food (no. sampled
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166 CHAPIN ET AL. Table 6 Continued
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168 CHAPIN ET AL. comparison of the
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170 CHAPIN ET AL. Table 8 Urinary C
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172 CHAPIN ET AL. the blood of male
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174 CHAPIN ET AL. Table 11 Bispheno
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176 CHAPIN ET AL. Table 13 Summarie
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178 CHAPIN ET AL. Table 15 Estimate
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180 CHAPIN ET AL. Table 17 Maximum
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182 CHAPIN ET AL. 2.0 GENERAL TOXIC
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184 CHAPIN ET AL. fetuses (3.572.7
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186 CHAPIN ET AL. Secondary sources
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188 CHAPIN ET AL. Table 25 Maternal
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190 CHAPIN ET AL. Table 27 Bispheno
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192 CHAPIN ET AL. Table 31 Qualitat
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194 CHAPIN ET AL. Table 33 Toxicoki
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198 CHAPIN ET AL. appeared to occur
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200 CHAPIN ET AL. Table 43 Biliary
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202 CHAPIN ET AL. suggesting that 4
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204 CHAPIN ET AL. low following ora
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206 CHAPIN ET AL. scaling and speci
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208 CHAPIN ET AL. 60-100% in each d
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210 CHAPIN ET AL. related. No histo
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212 CHAPIN ET AL. Table 52 Continue
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214 CHAPIN ET AL. Model and exposur
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216 CHAPIN ET AL. Model and exposur
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218 Model and exposure Husbandry a
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220 CHAPIN ET AL. Table 54 Differen
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222 CHAPIN ET AL. Table 56 Anti-And
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224 Table 57 In Vitro Genetic Toxic
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226 CHAPIN ET AL. Table 58 In Vivo
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228 CHAPIN ET AL. Table 59 Developm
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232 CHAPIN ET AL. Table 64 Tissue R
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236 CHAPIN ET AL. treatment conditi
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238 CHAPIN ET AL. clinical signs, b
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240 CHAPIN ET AL. Table 71 Benchmar
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242 CHAPIN ET AL. group, 5 from 1 l
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244 CHAPIN ET AL. least significant
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246 CHAPIN ET AL. group was a reduc
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248 CHAPIN ET AL. 100-151 g for fem
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250 CHAPIN ET AL. 3.2.3.2 Developme
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252 CHAPIN ET AL. weights, bispheno
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254 CHAPIN ET AL. 120 mg/kg bw/day
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256 CHAPIN ET AL. comparisons condu
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258 CHAPIN ET AL. the findings of t
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260 CHAPIN ET AL. analyzed.] Anogen
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262 CHAPIN ET AL. purposeful confou
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264 CHAPIN ET AL. increased lordosi
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266 CHAPIN ET AL. that there was a
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268 CHAPIN ET AL. duration of adver
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270 CHAPIN ET AL. doses of potent e
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272 CHAPIN ET AL. Table 74 Effects
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274 CHAPIN ET AL. reproductive orga
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276 CHAPIN ET AL. tyrosine-hydroxly
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278 CHAPIN ET AL. include small sam
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280 CHAPIN ET AL. males/group. [It
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282 CHAPIN ET AL. termination, whic
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284 CHAPIN ET AL. provided a reliab
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286 CHAPIN ET AL. grooming, and out
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288 CHAPIN ET AL. method of oral do
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290 CHAPIN ET AL. reared by their d
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292 CHAPIN ET AL. has been informed
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294 CHAPIN ET AL. buffered paraform
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296 CHAPIN ET AL. unit. Further, th
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298 CHAPIN ET AL. PND 21 and housed
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300 CHAPIN ET AL. Tando et al. (200
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302 CHAPIN ET AL. Purina Certified
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304 CHAPIN ET AL. high-doses of bis
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306 CHAPIN ET AL. born to those dam
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308 CHAPIN ET AL. average weight we
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310 CHAPIN ET AL. study authors con
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312 CHAPIN ET AL. used for extracti
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314 CHAPIN ET AL. jar, and there we
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316 CHAPIN ET AL. of testes and com
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318 CHAPIN ET AL. differentiation o
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320 CHAPIN ET AL. Table 81 Summary
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322 CHAPIN ET AL. Table 82 Continue
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328 CHAPIN ET AL. 600 mg/kg bw/day)
Page 253 and 254:
330 CHAPIN ET AL. (Nagao et al., 19
Page 255 and 256:
332 CHAPIN ET AL. antinuclear antib
Page 257 and 258:
334 CHAPIN ET AL. least 6 animals.
Page 259 and 260:
336 CHAPIN ET AL. Utility (Adequacy
Page 261 and 262:
338 CHAPIN ET AL. stomach weight wa
Page 263 and 264: 340 CHAPIN ET AL. Schirling et al.
Page 265 and 266: 342 CHAPIN ET AL. Endpoint Table 88
Page 267 and 268: 344 CHAPIN ET AL. different diets b
Page 269 and 270: 346 CHAPIN ET AL. with 40 mg vitami
Page 271 and 272: 348 CHAPIN ET AL. the bisphenol A v
Page 273 and 274: 350 CHAPIN ET AL. and determining t
Page 275 and 276: 352 CHAPIN ET AL. expression [to B6
Page 277 and 278: 354 CHAPIN ET AL. indicated] at 0 (
Page 279 and 280: 356 CHAPIN ET AL. concentrations us
Page 281 and 282: 358 CHAPIN ET AL. animals were non-
Page 283 and 284: 360 CHAPIN ET AL. following adjustm
Page 285 and 286: 362 CHAPIN ET AL. Table 94 Treatmen
Page 287 and 288: 364 CHAPIN ET AL. Table 97 Effects
Page 289 and 290: 366 CHAPIN ET AL. Table 99 Treatmen
Page 291 and 292: 368 CHAPIN ET AL. Therefore the NTP
Page 293 and 294: 370 CHAPIN ET AL. weeks before mati
Page 295 and 296: 372 CHAPIN ET AL. Table 100 Summary
Page 297 and 298: 374 Table 101 Summary of High Utili
Page 299 and 300: 376 Table 102 Summary of Limited Ut
Page 301 and 302: 378 CHAPIN ET AL. Table 103 Summary
Page 303 and 304: 380 CHAPIN ET AL. from other suppli
Page 305 and 306: 382 CHAPIN ET AL. U.S. populations.
Page 307 and 308: 384 CHAPIN ET AL. 10. Critical desi
Page 309 and 310: 386 CHAPIN ET AL. Engel SM, Levy B,
Page 311 and 312: 388 CHAPIN ET AL. alpha and beta ex
Page 313: 390 CHAPIN ET AL. Murray TJ, Maffin
Page 317 and 318: 394 CHAPIN ET AL. Thomas P, Dong J.
Page 319 and 320: [This page inTenTionally lefT blank
Page 321: appendix iii. publiC CommenTs and p
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