Monograph on the Potential Human Reproductive and ... - OEHHA

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adioimmunoassay (RIA). Statistical analyses included Bartlett test, analysis of covariance (ANCOVA), Dunnett test, and Bonferroni test. Exposure to bisphenol A did not affect weights of the ventral prostate, seminal vesicles, glans penis, or levator ani plus bulbocavernosus muscle; or serum concentrations of LH or testosterone. Testosterone increased the weights of accessory reproductive organs. Flutamide increased serum LH concentrations and inhibited testosterone-induced increases in accessory reproductive organ weights. Study authors concluded that bisphenol A did not exhibit androgenic or antiandrogenic effects in rats. Yamasaki et al. (2003) conducted a Hershberger assay in rats exposed to bisphenol A or 1 of 29 other chemicals. In this study, which was conducted according to GLP, animals were housed in stainless steel wire-mesh cages. Assuming these males were fed the same diets as rats used in an uterotrophic assay also described in this study, they received MF Oriental Yeast feed. Rats were randomly assigned to treatment groups. Beginning at 56 days of age and continuing for 10 days, 6 castrated male Brl Han: WIST Jcl (GALAS) rats/group were administered bisphenol A by stomach tube at doses of 0 (olive oil vehicle), 50, 200, or 600 mg/kg bw/day. An additional group of rats was administered the same vehicle and doses of bisphenol A in addition to 0.2 mg/ kg bw/day testosterone propionate by s.c. injection. Dose selection was based on results of preliminary studies. A positive control group was given 10 mg/kg bw/day flutamide in addition to 0.2 mg/kg bw/day testosterone propionate. Rats were killed 24 hr after receiving the final dose. Ventral prostate with fluid, seminal vesicles with fluid, bulbocavernosus/levator ani muscle, glans penis, and Cowper gland were collected and weighed. Data were analyzed by Student t-test. Bisphenol A did not affect body weight and there were no clinical signs of toxicity. The only statistically significant effect on relative organ weight was a [24%] increase in glans penis weight in rats given 600 mg/kg bw/day bisphenol A without coadministration of testosterone. In contrast, rats treated with flutamide plus testosterone propionate experienced increases in weights of ventral prostate, seminal vesicle, bulbocavernosus/levator ani muscle, glans penis, and Cowper gland. [Absolute organ weights were not reported. It is assumed but was not stated that relative weights were based on body weight.] Study authors noted that because glans penis weights were variable in control rats and weights of other accessory reproductive organs were not affected, bisphenol A could not be clearly determined to have androgen agonistic properties. Nishino et al. (2006) performed a Hershberger assay in Wistar rats. At 2 weeks of age, rats were given ssniffR 10 diet and housed in Makrolon cages with ssniff bedding. Seven days after orchiectomy, rats were placed in groups of 13 [randomization not discussed] and treated orally [gavage assumed] with bisphenol A [purity not indicated] in propylene glycol at 0, 3, 50, 200, or 500 mg/kg bw/day for 7 days or s.c. with testosterone propionate 1 mg/kg bw. Another group was given oral bisphenol A 500 mg/kg bw/day and flutamide 3 mg/kg bw/day. Rats were killed by decapitation after treatment. Seminal vesicles and prostates were weighed and fixed in 4% neutral buffered paraformaldehyde. Immunohistochemical evaluation of androgen receptor, PCNA, and MIB-5 Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 223 was performed. Epithelial cell height and duct luminal area were determined morphometrically. Review by the Expert Panel indicated that this study was inadequate due to methodological issues. 2.3 Genetic Toxicity Assessment of mutagenicity associated with bisphenol A was based primarily on reviews by the European Union (2003) and Haighton et al. (2002). CERHR summarized a limited number of studies that were not included in reviews. Results of in vitro genetic toxicity testing are summarized in Table 57, and results of in vivo genetic toxicity tests are summarized in Table 58. The European Union (2003) noted that bisphenol A demonstrated aneugenic potential and micronuclei formation in in vitro tests without metabolic activation. However, there was no evidence of micronuclei formation in an in vivo mouse study. Other studies demonstrated disruption of microtubule formation and the presence of DNA adducts. In the studies reviewed by the European Union, there was no evidence of gene mutations or structural chromosomal aberrations in in vitro tests and negative results were obtained in a dominant lethal test in rats; however, the European Union noted several limitations for those studies. Based on their review of genotoxicity data and the lack of significant tumors reported in animal studies, the European Union (2003) concluded that bisphenol A does not appear to have significant mutagenicity potential in vivo. Because aneugenic potential was apparently observed only in in vitro tests, it was judged to be of no concern. The relevance of DNA adduct formation was unclear, but based on weight of evidence, i.e., negative findings for gene mutation and clastogenicity in cultured mammalian cells, DNA adduct formation was thought unlikely to be of concern for humans. Haighton et al. (2002) concluded that results of standardized and validated genetic toxicity tests demonstrated the lack of mutagenic and genotoxic activity of bisphenol A in vivo. Studies demonstrating disrupted microtubule formation or DNA adduct formation were noted, but because the studies used high-doses, they were judged to be of limited relevance. The lack of activity in an in vivo micronucleus assay in mice was said to confirm negative results observed in in vivo tests. Lastly, it was concluded that bisphenol A (parent) had no structural features that suggested mutagenic activity. Subsequent to the release of the European Union (2003) and Haighton et al. (2002) reviews, Hunt et al. (2003), published a study examining meiotic aneuploidy potential of bisphenol A in female mice. In 1998, a large increase in background rate of congression failure (from 1–2 to 40%) and in aneuploidy (from 0.7 to 5.8%) was observed in the study authors’ laboratory. The increase was found to coincide with damage to polycarbonate caging material. Removal of the most damaged cages and change to polysulfone cages resulted in decreased background rates of congression failure. Intentionally damaging polycarbonate cages and water bottles resulted in increased rates of congression failure. As noted in Table 58, congression failure rates were increased in juvenile female mice orally exposed to Z20 mg/kg bw/ day bisphenol A for 6–8 days or 20 mg/kg bw/day for 7
224 Table 57 In Vitro Genetic Toxicity Studies of Bisphenol A Concentration Cell Endpoint Results Reference Haworth et al. (1983) a,b Negative Schweikl et al. (1998) a,b Negative Takahata et al. (1990) a,b Negative Dean and Brooks (1978) a,b Negative JETOC (1996) a,b Masuda et al. (2005) Salmonella typhimurium strains TA98, TA100, Mutagenicity TA1535, TA1537 Salmonella typhimurium strains TA97a, TA98, Mutagenicity TA100, TA102 Salmonella typhimurium strains TA97, TA98, Mutagenicity TA100, TA102 Salmonella typhimurium strain TA1538 and Mutagenicity Escherichia coli strains WP2 and WP2uvrA Salmonella typhimurium strains TA98, TA100, Mutagenicity TA1535, TA1537, and Escherichia coli strain WP2uvrA Salmonella typhimurium strains TA98 and TA100 Mutagenicity 3.3–333.3 mg/plate, with and without metabolic activation 50–500 mg/plate, with and without metabolic activation r5000 mg/plate with and without metabolic activation r1000 mg/mL, with and without metabolic activation Negative 5–1250 mg/plate, with and without metabolic activation Negative Schweikl et al. (1998) a,b Negative Chinese hamster V79 cells, hprt locus Mutagenicity Myhr and Caspary (1991) a,b Negative (results questioned due to possible inability to count small colonies) Mouse lymphoma L5178Y cells, tk 1/- locus Mutagenicity CHAPIN ET AL. Honma et al. (1999) a,b ; Moore et al. (1999) a,b Tsutsui et al. (1998) a,b Inconclusive without and negative with metabolic activation Negative Mouse lymphoma L5178Y cells, tk 1/- locus Mutagenicity Takahashi et al. (2001) m at all doses Syrian hamster embryo cells (Na1/K1 ATPase Mutagenicity and hprt loci) Human RSa cells Mutagenicity Dean and Brooks (1978) a,b Iso et al. (2006) Negative Saccharomyces cerevisiae strain JDI Mutagenicity m at Z10 -6 M [0.2 mg/L] 1mM [228 mg/L], with and without metabolic activation 0.1–0.2 mM [23–46 mg/L], without metabolic activation 5–60 mg/L without metabolic activation, 25– 200 mg/L with metabolic activation, or 5–60 mg/L with and without metabolic activation d Concentrations not specified, with and without metabolic activation 25–200 mM [5.7–46 mg/L], without metabolic activation 10 -8 –10 -5 M [0.002–2 mg/L], without metabolic activation r500 mg/L, with and without metabolic activation 10 –8 –10 -4 M [0.002–23 mg/L], without metabolic activation 10 -4 M[23 mg/L], without metabolic activation m MCF-7 cells DNA damage (assessed by comet assay) MDA-MB-231 cells DNA damage (assessed by comet assay) Chinese hamster ovary (CHO) cells Chromosomal aberration Ivett et al. (1989) a,b ; Tennant et al. (1986, 1987) b Hilliard et al. (1998) a Negative (inconsistent m at high dose with metabolic activation) Positive at Z400 mM [91.3 mg/L] without metabolic activation c ; negative with metabolic activation CHO cells, clone WBL Chromosomal aberration Galloway et al. (1998) a Positive c Tsutsui et al. (1998) a,b Negative Dean and Brooks (1978) b Tsutsui et al. (1998) a,b Negative CHO cells, clone WBL Chromosomal aberration Syrian hamster embryo cells Chromosomal aberration Epithelial-type rat liver cell line (RL1) Chromosomal aberration Syrian hamster embryo cells Aneuploidy/ polyploidy 20–40 mg/L, without metabolic activation and 30–50 mg/L with metabolic activation 350–450 mM [80–103 mg/L], without metabolic activation and r250 mM [57 mg/L] with metabolic activation 400 and 450 mM [91 and 103 mg/L], without metabolic activation 25–200 mM [5.7–46 mg/L], without metabolic activation 10–30 mg/L 25–200 mM [5.7–46 mg/L], without metabolic activation Birth Defects Research (Part B) 83:157–395, 2008
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National Toxicology Program U.S. De
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[This page inTenTionally lefT blank
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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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isphenol.A.as.efficiently.as.adult.
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isphenol.A..For.example,.this.raise
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laboRaToRy aNImal STudIeS In.contra
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of.normal.sex-based.differences.bet
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death.(168),.synaptic.plasticity.(1
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gland.carcinogen.or.that.bisphenol.
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understand.the.possible.long-term.c
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strategies.to.improve.the.sensitivi
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cutaneous. injection. 20 . vom. Saa
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are CurrenT exposures To bisphenol
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nTp ConClusions The.NTP.reached.the
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appendix a: inTerpreTaTion of blood
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µg/kg.bw/day.based.on.the.assumpti
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concentrations.from.maternal,.fetal
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65.. Alonso-Magdalena. P,. Laribi.
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Thyroid.Function.in.Juvenile.Female
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droxylase.immunoreactivity..76:423.
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Watanabe.H,.Ohta.Y,.Iguchi.T.(2006)
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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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Page 97 and 98: 174 CHAPIN ET AL. Table 11 Bispheno
Page 99 and 100: 176 CHAPIN ET AL. Table 13 Summarie
Page 101 and 102: 178 CHAPIN ET AL. Table 15 Estimate
Page 103 and 104: 180 CHAPIN ET AL. Table 17 Maximum
Page 105 and 106: 182 CHAPIN ET AL. 2.0 GENERAL TOXIC
Page 107 and 108: 184 CHAPIN ET AL. fetuses (3.572.7
Page 109 and 110: 186 CHAPIN ET AL. Secondary sources
Page 111 and 112: 188 CHAPIN ET AL. Table 25 Maternal
Page 113 and 114: 190 CHAPIN ET AL. Table 27 Bispheno
Page 115 and 116: 192 CHAPIN ET AL. Table 31 Qualitat
Page 117 and 118: 194 CHAPIN ET AL. Table 33 Toxicoki
Page 121 and 122: 198 CHAPIN ET AL. appeared to occur
Page 123 and 124: 200 CHAPIN ET AL. Table 43 Biliary
Page 125 and 126: 202 CHAPIN ET AL. suggesting that 4
Page 127 and 128: 204 CHAPIN ET AL. low following ora
Page 129 and 130: 206 CHAPIN ET AL. scaling and speci
Page 131 and 132: 208 CHAPIN ET AL. 60-100% in each d
Page 133 and 134: 210 CHAPIN ET AL. related. No histo
Page 135 and 136: 212 CHAPIN ET AL. Table 52 Continue
Page 137 and 138: 214 CHAPIN ET AL. Model and exposur
Page 139 and 140: 216 CHAPIN ET AL. Model and exposur
Page 141 and 142: 218 Model and exposure Husbandry a
Page 143 and 144: 220 CHAPIN ET AL. Table 54 Differen
Page 145: 222 CHAPIN ET AL. Table 56 Anti-And
Page 149 and 150: 226 CHAPIN ET AL. Table 58 In Vivo
Page 151 and 152: 228 CHAPIN ET AL. Table 59 Developm
Page 155 and 156: 232 CHAPIN ET AL. Table 64 Tissue R
Page 159 and 160: 236 CHAPIN ET AL. treatment conditi
Page 161 and 162: 238 CHAPIN ET AL. clinical signs, b
Page 163 and 164: 240 CHAPIN ET AL. Table 71 Benchmar
Page 165 and 166: 242 CHAPIN ET AL. group, 5 from 1 l
Page 167 and 168: 244 CHAPIN ET AL. least significant
Page 169 and 170: 246 CHAPIN ET AL. group was a reduc
Page 171 and 172: 248 CHAPIN ET AL. 100-151 g for fem
Page 173 and 174: 250 CHAPIN ET AL. 3.2.3.2 Developme
Page 175 and 176: 252 CHAPIN ET AL. weights, bispheno
Page 177 and 178: 254 CHAPIN ET AL. 120 mg/kg bw/day
Page 179 and 180: 256 CHAPIN ET AL. comparisons condu
Page 181 and 182: 258 CHAPIN ET AL. the findings of t
Page 183 and 184: 260 CHAPIN ET AL. analyzed.] Anogen
Page 185 and 186: 262 CHAPIN ET AL. purposeful confou
Page 187 and 188: 264 CHAPIN ET AL. increased lordosi
Page 189 and 190: 266 CHAPIN ET AL. that there was a
Page 191 and 192: 268 CHAPIN ET AL. duration of adver
Page 193 and 194: 270 CHAPIN ET AL. doses of potent e
Page 195 and 196: 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)
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330 CHAPIN ET AL. (Nagao et al., 19
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332 CHAPIN ET AL. antinuclear antib
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334 CHAPIN ET AL. least 6 animals.
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336 CHAPIN ET AL. Utility (Adequacy
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338 CHAPIN ET AL. stomach weight wa
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340 CHAPIN ET AL. Schirling et al.
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342 CHAPIN ET AL. Endpoint Table 88
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344 CHAPIN ET AL. different diets b
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346 CHAPIN ET AL. with 40 mg vitami
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348 CHAPIN ET AL. the bisphenol A v
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350 CHAPIN ET AL. and determining t
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352 CHAPIN ET AL. expression [to B6
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354 CHAPIN ET AL. indicated] at 0 (
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356 CHAPIN ET AL. concentrations us
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358 CHAPIN ET AL. animals were non-
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360 CHAPIN ET AL. following adjustm
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362 CHAPIN ET AL. Table 94 Treatmen
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364 CHAPIN ET AL. Table 97 Effects
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366 CHAPIN ET AL. Table 99 Treatmen
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368 CHAPIN ET AL. Therefore the NTP
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370 CHAPIN ET AL. weeks before mati
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374 Table 101 Summary of High Utili
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376 Table 102 Summary of Limited Ut
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380 CHAPIN ET AL. from other suppli
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382 CHAPIN ET AL. U.S. populations.
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384 CHAPIN ET AL. 10. Critical desi
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386 CHAPIN ET AL. Engel SM, Levy B,
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388 CHAPIN ET AL. alpha and beta ex
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390 CHAPIN ET AL. Murray TJ, Maffin
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392 CHAPIN ET AL. Ryan BC, Vandenbe
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394 CHAPIN ET AL. Thomas P, Dong J.
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appendix iii. publiC CommenTs and p
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