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

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BISPHENOL A Fig. 2. In vitro estrogenic potency (log10) inER a and b binding and transcriptional assays and estrogen-dependent cell proliferation assays) distributions of bisphenol A and estrogen responses in vivo in rats, mice and fish. Each data point represents one bisphenol A study in which bisphenol A was compared to a reference estrogen in rats, mice, fish, or in vitro. Data summarized from Table 52 and Table 53, midrange values used when a range is given in the table. response half maximal response comparator estrogen test estrogen 10 9 8 7 6 5 b a log molar concentration Fig. 3. Alternative approaches to comparing estrogenic potency. In this example, the half-maximal response to the comparator estrogen occurs at 10 -8 M. A similar response occurs with the test estrogen at 10 -5 M, suggesting a 1000-fold difference in potency. If the magnitudes of response at equimolar concentrations are compared, the apparent potency may be much different. The response to the test estrogen at 10 -7 M (a) is about half the response to the comparator estrogen at 10 -7 M (a1b). bisphenol A given by gavage increased uterine weight by approximately 25% while the same dose given s.c. increased uterine weight by approximately 170% (Laws et al., 2000). A greater response by the s.c. than oral route was also shown by Yamasaki et al. (2000) and Kanno et al. (2003b) in the OECD multilaboratory study who showed a lowest effective bisphenol A dose of 8 mg/kg bw/day by the s.c. route and 160 mg/kg bw/day by the oral route. The greater activity per unit dose of s.c. than oral bisphenol A is due presumably to glucuronidation of the orally administered compound with consequent loss of estrogenicity (Matthews et al., 2001). A few studies could not confirm the greater effect of Birth Defects Research (Part B) 83:157–395, 2008 219 s.c. compared to oral bisphenol A on uterine weight. Ashby and Tinwell (1998) concluded that the magnitude of uterine weight response was similar for s.c. and oral routes. [The Expert Panel notes a greater numerical magnitude of response after s.c. than oral exposure in most of the experiments reviewed in this report, and that statistical comparison of the dose routes was not reported.] Matthews et al. (2001) found a similar increase in uterine weight in rats given s.c. or oral bisphenol A at 800 mg/kg bw/day. Nagel et al. ([1997, 1999) noted that 17b-estradiol is extensively protein-bound in vivo and bisphenol A is minimally protein-bound. A recent study indicated more extensive binding of bisphenol A to plasma binding proteins (Teeguarden et al., 2005). Nagel suggested that estrogenicity of BPA (as well as other steroid hormones) can be predicted more accurately in rats by considering the free fraction of a chemical in human serum. [The Expert Panel notes that Figure 2 does not suggest that bisphenol A is more potent than 17b-estradiol in vivo than in vitro. The developmental effects of bisphenol A in the prostate are discussed in Section 3.2.] Inter-strain variability in rats has been evaluated as a source of variability in estrogenicity assays. Inspection of Table 53 does not suggest large sensitivity differences between Sprague–Dawley, Wistar, and Long-Evans rats. Greater sensitivity of F344 than Sprague–Dawley rats has been shown with respect to uterine weight and epithelial cell height (Steinmetz et al., 1998), where 17b-estradioladjusted potencies differed by 20–37% between the strains. BrDu labeling of vaginal epithelium was 3 times greater in F344 than Sprague–Dawley rats in another study (Long et al., 2000), and a third study (Steinmetz et al., 1997) showed that both bisphenol A and 17bestradiol increase serum prolactin in ovariectomized F344 but not ovariectomized Sprague–Dawley rats. Diel et al. (2004) evaluated estrogenic response to bisphenol A
220 CHAPIN ET AL. Table 54 Differences Between Laboratories in Rat Uterotrophic Assay With Bisphenol A a Laboratory Rat strain Immature, gavage x 3 days 2 7 12 13 Immature, s.c. x 3 days 2 6 7 8 12 13 15 18 20 21 Adult, s.c. x 3 days 2 6 7 8 12 Adult, s.c. x 7 days 2 7 a Kanno et al. (2003b). CD(SD)IGS CD(SD)IGS CD(SD)IGS BR Wistar CD(SD)IGS CD(SD)IGS BR CD(SD)IGS Alpk:ApfSD CD(SD)IGS BR Wistar Wistar Sprague–Dawley Sprague–Dawley CD(SD) BR CD(SD)IGS CD(SD)IGS BR CD(SD)IGS Alpk:ApfSD CD(SD)IGS BR CD(SD)IGS CD(SD)IGS Lowest effective dose level (mg/kg bw/day) 200 10 x x x 10 10 375 x x 100 x x x 100 x x x x x 100 x x 600 x 300 x x x 300 300 1000 x 600 x 600 600 1000 1000 1000 in juvenile ovariectomized DA/Han, Sprague–Dawley, and Wistar rats. After 3 days of treatment with bisphenol A 200 mg/kg bw/day, there were small statistically significant increases in uterine weight in DA/Han and Sprague–Dawley rats but not in Wistar rats. There were no alterations in uterine or vaginal epithelium or in uterine clusterin mRNA expression in any of the strains after bisphenol A treatment. Inter-laboratory variation in the uterotrophic assay was evaluated by the Organization for Economic Cooperation and Development (OECD) (Kanno et al., 2003b). Coded chemicals, including bisphenol A, were sent to up to 212 different laboratories. Four assay protocols were evaluated including oral treatment of intact immature rats for 3 days, s.c. treatment of intact immature rats for 3 days, s.c. treatment of ovariectomized 6–8-week-old rats for 3 days, and s.c. treatment of ovariectomized 6–8-week-old rats for 7 days. Not all laboratories used all protocols or tested all compounds. Rat strains and suppliers were not standardized across laboratories. Comparisons were made between labs based on the lowest dose level at which body weightadjusted blotted uterine weight was significantly different from the control. Results are summarized in Table 54. The lowest effective dose of bisphenol A was uniformly identified for the assays performed in ovariectomized adults. Assays performed in immature animals varied in identification of the lowest effective bisphenol A dose Multiple of control value 6.0 5.5 5.0 PCNA labeling 4.5 3.0 2.5 Vaginal opening PND 26 2.0 Epithelial cell height 1.5 Uterine wet weight 1.0 Body weight 0.5 0.0 0.1 1.0 10.0 100.0 Bisphenol A dose, mg/kg bw/day Fig. 4. Dose–response curves for endpoints of estrogenic activity in s.c.-dosed mice. On pair-wise testing, body weight was increased at 0.5 mg/kg bw/day and decreased at 100 mg/kg bw/day; vaginal opening was advanced at 0.1 and 100 mg/kg bw/day; epithelial cell height was increased at 5, 75, and 100 mg/kg bw/day; PCNA labeling was increased at 75 and 100 mg/kg bw/day; and uterine wet weight was increased at 100 mg/kg bw/day. Data from Markey et al. (2001b). level. There was no apparent effect of strain on sensitivity of the uterotrophic response in immature (intact or castrate) or adult female rats. Intra-laboratory variability has been noted for the bisphenol A uterotrophic assay in immature mice (Tinwell and Joiner, 2000). Of 8 studies performed over a 2-year period at s.c. bisphenol A dose levels up to 200 or 300 mg/kg bw/day, 4 showed a significant increase in uterine weight at 200 mg/kg bw/day. The other 4 studies, including the 2studies that went to 300 mg/kg bw/day, showed no effect of bisphenol A treatment on uterine weight despite the expected response to diethylstilbestrol. Study authors noted that reducing the permissible body weight of the mice selected for study resulted in lower and less variable control uterine weights and greater likelihood of bisphenol A effect (Tinwell and Joiner, 2000; Ashby et al., 2004). [The Expert Panel notes that these studies all used high s.c. doses of bisphenol A.] Markey et al. (2001b) proposed that the rodent uterotrophic assay is relatively insensitive to the estrogenic effects of bisphenol A. These authors treated immature CD-1 mice with bisphenol A in s.c. minipumps and evaluated uterine weight, relative area of uterine compartments, epithelial height, expression of lactoferrin and proliferating cell nuclear antigen (PCNA), and induction of vaginal opening. Dose–response curves for the endpoints that showed significant changes from control are illustrated in Figure 4. The study authors also noted that significant alterations in some endpoints were observed at much lower doses (0.1 mg/kg bw/day for vaginal opening and 5 mg/kg bw/day for epithelial cell height), giving rise to a U-shaped dose–response curve. [The assertions of some investigators notwithstanding, the Expert Panel notes that oral bisphenol A does not consistently produce robust estrogenic responses and, when seen, estrogenic effects after oral treatment occur at high-dose levels.] Transgenic reporter mice have permitted in vivo identification of activation of the estrogen response Birth Defects Research (Part B) 83:157–395, 2008
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National Toxicology Program U.S. De
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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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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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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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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
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Page 135 and 136: 212 CHAPIN ET AL. Table 52 Continue
Page 137 and 138: 214 CHAPIN ET AL. Model and exposur
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Page 145 and 146: 222 CHAPIN ET AL. Table 56 Anti-And
Page 147 and 148: 224 Table 57 In Vitro Genetic Toxic
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
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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
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Page 173 and 174: 250 CHAPIN ET AL. 3.2.3.2 Developme
Page 175 and 176: 252 CHAPIN ET AL. weights, bispheno
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Page 179 and 180: 256 CHAPIN ET AL. comparisons condu
Page 181 and 182: 258 CHAPIN ET AL. the findings of t
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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)
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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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