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

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BISPHENOL A Table 93 Treatment-Related Effects in Adult Rats Fed Bisphenol A Through Diet in a Multigeneration Reproductive Toxicity Study a Dose, ppm diet [mg/kg bw/day b ] 0.015 0.3 4.5 75 750 7500 Endpoint [0.0095] [0.019] [0.285] [4.75] [47.5] [475] BMD10 BMDL 10 BMD 1SD BMDL 1SD Terminal body weight F0 males 2 2 2 2 2 k 22% 3554 [225] 3137 [199] 3133 [198] 2701 [171] F1 males 2 2 2 2 k 6% k 26% 2811 [178] 2548 [161] 2443 [155] 2153 [136] F2 males c 2 2 2 2 k 12% k 29% 733 [46] 554 [35] 648 [41] 484 [31] F3 males c 2 2 2 2 2 k 26% 1456 [92] 913 [58] 1260 [80] 786 [50] F0 females 2 2 2 2 2 k 13% 5722 [362] 4753 [301] 4741 [300] 3876 [245] F1 females 2 2 2 2 k 6% k 16% 4600 [291] 3950 [250] 3730 [236] 3142 [199] F2 females c 2 2 2 2 2 k 14% 3863 [245] 1576 [100] 3115 [197] 1291 [82] F3 females 2 2 2 2 2 k 20% 3664 [232] 3194 [202] 3456 [219] 2949 [187] Relative paired kidney weight F0 males 2 2 2 2 2 m 14% 5903 [374] 4555 [288] 6536 [414] 5035 [319] F1 males 2 2 k 5% 2 2 m 10% 5729 [363] 4662 [295] 5053 [320] 4088 [259] F2 males 2 2 2 2 m 5% m 18% 4524 [287] 3893 [247] 3471 [220] 2950 [187] F3 males 2 2 2 2 2 m 16% 6986 [442] 4319 [274] 6720 [426] 3403 [216] F0 females 2 2 2 2 2 m 7% 8008 [507] 7521 [476] 7712 [488] 6578 [417] F2 females Relative paired testis weight 2 2 2 2 2 m 6% 7930 [502] 7515 [476] 7621 [483] 6247 [396] F0 males 2 2 2 2 2 m 27% 2924 [185] 2567 [163] 2998 [190] 2596 [164] F1 males 2 2 2 2 2 m 18% 3287 [208] 2763 [175] 4106 [260] 3428 [217] F2 males 2 2 2 2 2 m 24% 3086 [195] 2874 [182] 3245 [206] 2779 [176] F3 males 2 2 2 2 2 m 19% 4329 [274] 2593 [164] 5010 [317] 3298 [209] Relative paired epididymis weight F0 males 2 2 2 2 2 m 19% 3804 [241] 3072 [195] 5044 [319] 4068 [258] F1 males 2 2 2 2 2 m 19% 2963 [188] 2566 [163] 3255 [206] 2786 [17] F2 males c 2 2 2 2 m 8% m 24% 884 [56] 596 [38] 951 [60] 641 [41] F3 males Relative liver weight 2 2 2 2 2 m 22% 3449 [218] 2516 [159] 4117 [261] 3095 [196] F0 females 2 2 2 2 2 m 11% 7663 [485] 5848 [370] 7965 [504] 7439 [471] F2 females m 2 2 2 2 m 19% 6912 [438] 3650 [231] 7454 [472] 5533 [350] Relative paired ovary weight] F0 females 2 2 2 2 2 k 19% 4103 [260] 3149 [199] 7126 [451] 5387 [341] F1 females 2 2 2 2 2 k 15% 5754 [364] 3964 [251] 10,237 [648] 6966 [441] F2 females k 15% 2 k 15% k 11% 2 k 24% 7053 [447] 3520 [223] 7646 [484] 6360 [403] No. with renal tubule degeneration F0 females 0/12 0/12 0/12 0/14 0/12 4/13 6491 [411] 3848 [244] F1 females 0/10 0/10 0/10 0/10 0/10 8/11 5498 [348] 2470 [156] F2 females 0/11 0/10 0/12 0/11 0/12 7/13 5884 [373] 3018 [191] No. females with chronic liver inflammation F0 females 0/12 1/12 0/12 0/14 1/12 3/13 4867 [308] 3214 [204] F1 females 0/10 0/10 3/10 1/10 1/10 3/11 F2 females No. of implantation sites 1/11 0/10 2/12 2/11 2/12 5/13 3029 [192] 1856 [118] F0 dams 2 2 2 2 2 k16% 4088 [259] 3021 [191] 8020 [508] 5832 [369] F1 dams c 2 2 2 2 2 k26% 6120 [388] 2383 [151] 7000 [443] 4713 [298] F2 dams 2 k8% 2 2 2 k18% 4917 [311] 3597 [228] 7679 [486] 5631 [357] Epididymal sperm concentration, F1 2 2 2 2 2 k18% 5012 [317] 3407 [216] 11,050 [700] 7407 [469] Daily sperm production, F3 2 2 2 2 2 k19% 7399 [469] 4025 [255] 8279 [524] 7596 [481] a Tyl et al. (2002b). b Based on target doses provided by the study authors and expressed as an average of the dose for males and females. c Benchmark dose values were estimated using a polynomial model. m,k Statistically significant increase, decrease, 2 no statistically significant effect. significant effects observed in pups included increased that further studies using a better route of exposure are numbers of live male and total pups and increased needed for bisphenol A. adjusted (for litter size) pup weight in the mid-dose Strengths/Weaknesses: This study appears to have group. Unadjusted and adjusted male and female pup been well conducted. When compared to studies that weights were significantly increased at the high-dose. used the oral route of exposure, this study provides The study authors noted that the effects observed in this evidence that the manifestation of maternal toxicity is study were random and most likely due to chance. They dependent on the route of administration and that routeconcluded that bisphenol A did not induce adverse dependent metabolism may be important for toxicity. effects on fertility in male or female mice. It was noted However, the administration of bisphenol A via silastic Birth Defects Research (Part B) 83:157–395, 2008 361
362 CHAPIN ET AL. Table 94 Treatment-Related Effects in Developing Rats in a Multigeneration Reproductive Toxicity Study of Bisphenol A a Endpoint 0.015 [0.0095] 0.3 [0.019] 4.5 [0.285] Live pups/litter F1 2 2 2 F2 2 2 2 F3 Pup body weight 2 k 11% 2 F1, PND 4 2 2 2 F1, PND 7 2 2 2 F2, PND 7 2 2 2 F3, PND 7 2 2 2 F1, PND 14 2 2 2 F2, PND 14 2 2 2 F3, PND 14 2 2 2 2 c F1. PND 21 2 2 F2, PND 21 2 2 2 c 2 c F 3, PND 21 2 2 Anogenital distance, F 2 females m 3% m 3% m 3% Age of vaginal opening adjusted for body weight F 1 2 2 2 F 2 2 2 2 F 3 2 2 2 Age of preputial separation adjusted for body weight F1 2 2 2 F2 2 2 2 F 3 2 2 2 75 [4.75] 2 2 2 2 2 2 2 2 2 2 2 c 2 c 2 c 2 2 2 2 2 2 2 Dose, ppm diet [mg/kg bw/day b ] 750 7500 [47.5] [475] BMD10 BMDL 10 BMD 1SD BMDL 1SD 2 2 2 2 2 2 2 2 2 2 2 c 2 c 2 c m4% 2 2 2 m 1.7 days 2 2 k 20% k 26% k 26% k 11% k 23% k 15% k 13% k 27% k 20% k 20% k 27% k 20% k 19% 2 m 3.6 days m 4 days m 3.2 days m 4.9 days m 7.4 days m 4 days a Tyl et al. (2002b). b Based on target doses provided by the study authors and expressed as an average of the dose for males and females. c A significant (B5%) decrease in pup body weights observed only in F1 and/or F2 litters was apparently not considered treatmentrelated by study authors. m,k Statistically significant increase, decrease, 2 no statistically significant effect. implants makes the extrapolation for human risk assessment difficult in the absence of an improved pharmacokinetic understanding. Utility (Adequacy) for CERHR Evaluation Process: This study is adequate but of limited utility for the evaluation process. NTP (1985a) and Morrissey et al. (1989) sponsored a continuous breeding study in CD-1 mice exposed to bisphenol A (98% purity). Additional information on ovarian follicle counts in F0 and F1 females was published in a report by Bolon et al. (1997). In this study, mice were fed NIH-07 open formula rodent chow and housed in polypropylene or polycarbonate cages containing Ab-Sorb-Dri litter. The laboratory at which the study was conducted was stated to be in full compliance with GLP regulations. In the preliminary study (Task 1), 8 mice/sex/group (8 weeks old) were fed diet containing bisphenol A at 0, 0.3125, 0.625, 1.25, 2.5, or 5.0% for 14 days. By assuming that a 40-g mouse ingests 7 g feed/ day, the study authors estimated bisphenol intake at 0, 437.5, 875.0, 1750.0, 4375.0, 8750.0 mg/kg bw/day. The aim of the preliminary study was to determine a maximum tolerated dose that induced significant toxicity but resulted in Z90% survival and r10% decrease in weight gain. Statistical analyses included ANOVA, and w 2 test. Lethality was significantly increased in the highdose group. Body weight gain was depressed in groups exposed to Z1.25% bisphenol A. Clinical signs of toxicity were observed in the 2.5 and 5.0% dose groups and 4232 6661 3733 6412 3432 5179 4976 2890 3840 3704 3284 4253 3972 6225 6381 7444 7350 4740 8637 [268] [422] [236] [406] [217] [328] [315] [183] [243] [235] [208] [269] [252] [394] [404] [471] [466] [300] [547] 3033 2405 2742 4473 2891 4059 3854 2570 3302 3224 2621 3566 3423 5422 5307 6325 6485 4025 7466 [192] [152] [174] [283] [183] [257] [244] [163] [209] [204] [166] [226] [217] [343] [336] [401] [411] [255] [473] 8823 7241 5943 8860 4179 6023 6474 2789 3579 3323 3523 4219 3575 3248 4367 6249 2974 3809 3503 [559] [459] [376] [561] [265] [381] [410] [177] [227] [210] [223] [267] [226] [206] [277] [396] [188] [241] [222] 6225 4645 4518 6317 3448 4653 4940 2415 3013 2827 2763 3473 3016 2786 3600 3198 2580 3201 2984 [394] [294] [286] [400] [218] [295] [313] [153] [191] [179] [175] [220] [191] [176] [228] [203] [163] [203] [189] included dehydration, dyspnea, lethargy, tremors, ptosis, piloerection, and diarrhea. In the reproduction and fertility study (Task 2), 11week-old mice were randomly assigned to treatment groups according to body weight. The mice were fed diets containing 0, 0.25, 0.5, or 1.0% bisphenol A. The NTP stated that a 40-g mouse consuming 7 g of feed/day would be exposed to bisphenol A at 437.5, 875, and 1750 mg/kg bw/day. [Based on body weight and feed intake values reported for males at B3 week intervals, CERHR estimated mean bisphenol A intake at B365, 740, and 1630 mg/kg bw/day. Feed intakes were reported only at Week 1 and 18 for females, and Week 18 most likely represented the lactation period. For Week 1, bisphenol A intake by females was estimated at 410, 890, and 1750 mg/kg bw/day. At Week 18, bisphenol A intake by females was estimated at 1090, 1785, and 3660 mg/kg bw/day.] There were 40 mice/sex in the vehicle control group and 20/sex in each bisphenol A group. Exposure to bisphenol A began during a 7-day premating period. Following the premating period, males and females from the same treatment group were randomly paired and housed together for 98 days and following the mating period, each male and female was housed separately for 21 days. Bisphenol A dosing was continued throughout the mating and separation period. Concentration and stability of bisphenol A in feed were verified. During the 98-day cohabitation period, pups born were counted, sexed, and weighed. All litters 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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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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• • Howdeshell.et.al. (55).repo
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and.cystic.endometrial.hyperplasia.
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cutaneous. injection. 20 . vom. Saa
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are CurrenT exposures To bisphenol
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w/day;.95th.percentiles.0.289.-.0.2
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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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12.. Padmanabhan. V,. Siefert. K,.
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In..Research.Triangle.Park,.NC:.RTI
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65.. Alonso-Magdalena. P,. Laribi.
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91.. Calabrese.EJ,.Baldwin.LA.(2003
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Thyroid.Function.in.Juvenile.Female
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droxylase.immunoreactivity..76:423.
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stanceschimiques.gc.ca/challenge-de
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Watanabe.H,.Ohta.Y,.Iguchi.T.(2006)
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226..vom. Saal. FS,. Cooke. PS,. Bu
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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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Page 243 and 244: 320 CHAPIN ET AL. Table 81 Summary
Page 245 and 246: 322 CHAPIN ET AL. Table 82 Continue
Page 251 and 252: 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
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Page 279 and 280: 356 CHAPIN ET AL. concentrations us
Page 281 and 282: 358 CHAPIN ET AL. animals were non-
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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
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Page 297 and 298: 374 Table 101 Summary of High Utili
Page 299 and 300: 376 Table 102 Summary of Limited Ut
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
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Page 315 and 316: 392 CHAPIN ET AL. Ryan BC, Vandenbe
Page 317 and 318: 394 CHAPIN ET AL. Thomas P, Dong J.
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Page 321: appendix iii. publiC CommenTs and p
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