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

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were no significant effects reported for bisphenol A following incubation at 301C. The study authors concluded that bisphenol A induced estrogenic effects in caiman as evidenced by reversed gonadal sex and disrupted gonadal histoarchitecture. Strengths/Weaknesses: This study appears to have been well performed and the use of a positive control is a strength. A weakness is the expression of exposure level in terms of total egg weight, which precludes easy comparison to human exposure levels. Utility (Adequacy) for CERHR Evaluation Process: This study has no utility in the evaluation process. Berg et al. (2001), supported by the Foundation for Strategic Environmental Research and the Swedish Council for Forestry and Agricultural Research, examined the effects of bisphenol A exposure on development of sex organs in quail and chicken embryos. The effects of tetrabromobisphenol A were also examined but will not be discussed. Bisphenol A (99.4% purity) was injected into yolk of Japanese quail eggs on the third day of incubation and into chicken (domestic fowl) eggs on the fourth day of incubation at doses of 0 (propylene glycol vehicle), 67, and 200 mg/g egg. Eggs were also injected with diethylstilbestrol at doses of 2, 20, and 200 ng/g egg [culture ware not discussed]. Two days before the anticipated hatching date, embryos were examined for mortality (32–43 quail embryos and 34–91 chicken embryos/group examined) and mü llerian duct abnormality or testicular histopathology (8–15 quail embryos/group and 7–30 chicken embryos/group examined). Testes were fixed in 4% formalin. Data were analyzed by Fisher exact probability test. Exposure to bisphenol A did not increase mortality in quail embryos. Incidence of females with abnormal mü llerian ducts was increased in quail embryos exposed to the high bisphenol A dose but the incidence of ovotestis in males was not increased by bisphenol A exposure. Mortality of chicken embryos was increased following exposure to both bisphenol A dose levels. The incidence of male chicken embryos with ovotestis was increased at the high-dose of bisphenol A but there was no effect on females with abnormal müllerian ducts. Effects observed in one or more diethylstilbestrol groups included increased incidence of females with abnormal mü llerian ducts in quail embryos and males with ovotestis in quail and chicken embryos. Based on study findings, the study authors concluded that bisphenol A can cause estrogen-like malformations in reproductive organs of birds. Strengths/Weaknesses: The detailed evaluation of genital tract morphology is a strength, but the expression of exposure level in mg per g egg makes it difficult to compare to human exposure levels. Utility (Adequacy) for CERHR Evaluation Process: This study is not useful to the evaluation process. Halldin et al. (2001, 2005), supported by the European Union and numerous Swedish agencies, examined the effect of in ovo exposure to bisphenol A on sexual behavior of male Japanese quail. On Day 3 of incubation, the yolks of an unspecified number of quail eggs were injected with vehicle (emulsion of peanut oil, lecithin, and propylene glycol) or Bisphenol A (499% purity) at 67 or 200 mg/g egg, and eggs were incubated at 37.51C at 60% relative humidity. After hatching, male and female chicks were housed together. Males were Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 315 individually housed at 7 weeks of age. At 9 weeks of age, 17 control and 4–7 treated males/group were examined for sexual behavior. Behavior with a sexually receptive female was evaluated by observing actions such as neck grab, mount attempt, mounts, and cloacal contact movement. Testing was conducted for 2 min/day over 5 consecutive days. At the completion of testing, testis weight was measured, gonado-somatic index was determined, and plasma testosterone levels were measured by RIA. Females exposed in ovo (n 5 5–8/group) were evaluated for numbers of eggs laid over 5 days and oviduct morphology. Statistical analyses included Kruskal–Wallis test, or w 2 test for trend. No effects of bisphenol A exposure were reported for any of the effects examined including sexual behavior of males, testicular weight, gonado-somatic index in males, plasma testosterone levels, or numbers of eggs produced. Numbers of females with retained right oviduct were increased in the bisphenol A groups (2 of 5 and 4 of 7 in each respective bisphenol A group vs. 1 of 8 in controls) but the effect did not achieve statistical significance. Sexual behavior was reportedly affected at an ethinyl estradiol dose of 0.006 mg/g egg and diethylstilbestrol doses of 0.019 and 0.057 mg/g egg. The study authors concluded that, with the possible exception of a trend for retained right oviduct in females exposed to 200 mg/g egg, bisphenol A was not shown to affect any of the endpoints examined in Japanese quail, which were demonstrated to be a well-suited model for studying effects of estrogenic compounds. Strengths/Weaknesses: The use of 2 positive controls and the attention to sexual behavior are strengths. Weaknesses are the expression of exposure level in mg per g egg, making it difficult to compare to human exposure levels, the lack of detail in the reporting of methods and results, and the lack of apparent statistical analysis. Utility (Adequacy) for CERHR Evaluation Process: This study is not useful to the evaluation process. Panzica et al. (2005), supported by the University of Torino and Region Piemonte, conducted a study that intended to examine the effects of in ovo bisphenol A exposure on the vasotocin system and sexual behavior of Japanese quail. In 2 sets of experiments, quail eggs were injected with bisphenol A [purity not indicated] at 50, 100, or 200 mg/egg following 3 days of incubation [culture ware not discussed]. Exposure to bisphenol A resulted in a dramatic decrease in the number of live chicks hatching (8–11% vs. 55–60% in controls). Chicks that hatched survived less than a week. Dissection of non-hatched embryos indicated that development was blocked immediately following injection in most embryos. A high rate of malformations was observed in chicks that died following hatching. [No further information was presented for methods, and no data were presented for individual doses.] Strengths/Weaknesses: Weaknesses are the expression of exposure level in mg per g egg, making it difficult to compare to human exposure levels, and the lack of data presentation. Utility (Adequacy) for CERHR Evaluation Process: This study is not useful in the evaluation process. Furuya et al. (2002), supported by the Japanese Ministry of Education, Science, Sports, and Culture, examined the effects of bisphenol A exposure on growth
316 CHAPIN ET AL. of testes and combs of male chickens. Beginning at 2 weeks of age, male white Leghorn chicks were orally dosed weekly with corn oil vehicle (n 5 5) or 200 mg bisphenol A [purity not indicated] (n 5 12). [The specific method of oral dosing was not reported. It is assumed that birds were dosed until they were killed.] Chickens were killed at 16 weeks of age. Combs and testes were weighed. Testes were fixed in 4% paraformaldehyde and examined histologically. [Statistical methods were not discussed, and the levels of statistical significance were not reported.] Bisphenol treatment did not affect body weight, but comb and testis weight were significantly lower in the chickens exposed to bisphenol A. Spermatogenesis was disturbed in the chickens of the bisphenol A group, as observed by small seminiferous lumen and scarcity of spermatids and mature sperm. Diameter of seminiferous tubules and incidence of seminiferous tubules with mature sperm were significantly lower in the bisphenol A group. The study authors concluded that bisphenol A might disturb the growth of comb and testes in male chickens, possibly through an endocrine mechanism. Strengths/Weaknesses: The study of male puberty in chickens is a strength. Weaknesses are the use of a single dose level and the lack of information on dosing and statistical analysis. The study would have been strengthened by measurement of hormone levels. Utility (Adequacy) for CERHR Evaluation Process: This study is not useful to the evaluation process. Sashihara et al. (2001), supported by the Japan Ministry of Education, Science, and Culture and the Uehara Memorial Foundation, examined the effects of early life exposure to bisphenol A on growth and behavior in male chicks. Layer type (Julia) chicks were obtained from a local hatchery, housed in windowless rooms [no further housing details provided], given ad lib access to water and feed (Toyohashi Feed and Mills Co.), and provided continuous lighting. Birds were group housed based on weight. At 4 days of age, 0, 100, or 200 mg of bisphenol A [purity not given] dissolved in 10% ethanol and sesame oil, was injected into the brain (n 5 12 or 13 per group). Chicks were followed for growth up to 20 days after treatment. A subset of 7 chicks/group was used for behavioral testing 8 days after treatment. Birds were placed under isolation distress condition and for a 5-min period were observed in a cage for motor activity and vocalization. At 20 days of age, birds were killed and liver, kidney, testis, and brain were weighed. Statistical analyses were performed using ANOVA and Duncan multiple range tests. There were no treatment effects on food intake 6 hr after injection or on body weight gain measured 3 days after exposure. In the behavioral test, there were no treatment effects on jumping, locomotor activity, and duration of crouching. There was a statistically significant dose-dependent increase in the frequency of distress vocalizations. There were no treatment effects at 20 days on body or organ weights. The authors concluded that an acute early life exposure of the chick brain to 100 or 200 mg bisphenol A may affect stress-induced behavior, which may involve an estrogen-mediated pathway. Strengths/Weaknesses: The rationale for the selection of the test animal and dosing procedures are not provided. Given that acute doses were injected directly into the brain, specific rationale for the method and selection of dose are critical to understanding the relevance of the study to human health or to wildlife or livestock concerns. This provides a vacuum for the interpretation of the dose-related increase in vocalizations that were reported. Utility (Adequacy) for CERHR Evaluation Process: This study is not useful to the evaluation process. Furuya et al. (2006), supported by the Japanese Ministry of Education, Science, Sports, and Culture, examined the effects of bisphenol A exposure on development of male chicks. Beginning at 2 weeks of age, male white Leghorn chicks were orally dosed every 2 days with bisphenol A at 0 (alcohol/corn oil vehicle) 0.002, 0.020, 0.200, 2, or 200 mg/kg bw. The high-dose level was considered to be a positive control based on previous observations in the laboratory. [No information was provided about the specific method of oral dosing, number of birds treated, purity of bisphenol A, or the type of feed or caging and bedding materials used. It was implied but not clearly stated that exposures were continued until the birds were killed.] The birds were killed at 5, 10, 15, 20, and 25 weeks of age. The comb, wattle, and testes were weighed. Part of the testicular tissue was used to isolate mRNA for evaluation of ERa and aromatase expression by RT-PCR. Additional testicular tissue was fixed in 10% buffered formalin for histopathology analysis and assessment of spermatogenesis by using immunohistochemistry techniques to measure proliferating cell nuclear antigen levels. [Methods for statistical analyses were not reported.] Although responses were not dose-related, significant decreases in weight (doses at which effects were observed) were reported for comb and wattle at 10 weeks of age (Z0.002 mg/kg bw), testis at 10 weeks of age (200 mg/kg bw), comb and testis at 15 weeks of age (Z0.020 mg/kg bw), wattle at 15 weeks of age (Z 0.2 mg/kg bw), comb at 20 weeks of age (Z0.200 mg/ kg bw), testis at 20 weeks of age (200 mg/kg bw), and comb and testis at 25 weeks of age (200 mg/kg bw). There were no effects on body weight. Histopathological observations in testis (doses at which effects were observed) included significant and dose-related reductions in the number of spermatogonia at 5 weeks of age (Z 2 mg/kg bw) and number of spermatogonia, spermatocytes, and spermatids at 10–25 weeks of age (Z0.02 mg/kg bw, except for decreases in spermatocytes at 10 weeks of age, which occurred at Z0.200 mg/kg bw). Seminiferous tubule diameter was significantly reduced at all ages in groups exposed to Z0.020 mg/kg bw. Significant and dose-related reductions in testicular proliferating cell nuclear antigen levels were observed at Z0.200 mg/kg bw at 10 weeks of age and Z0.020 mg/kg bw at 15–25 weeks of age. ERa mRNA was significantly increased according to dose (doses at which effects were observed) at 10 weeks of age (Z0.020 mg/kg bw), 15 and 20 weeks of age (Z0.200 mg/kg bw/day), and 25 weeks of age (200 mg/kg bw). Significant and dose-related increases were also observed for aromatase mRNA expression (doses at which effects were observed) at 5 weeks of age (Z0.002 mg/kg bw), 10 weeks of age (0.200 mg/kg bw), and 15 weeks of age (200 mg/kg bw). The study authors concluded that exposure to bisphenol A at environmentally relevant levels may affect male chicken phenotypes and result in unbalanced gene expression in the testis. 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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laboRaToRy aNImal STudIeS In.contra
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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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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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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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Page 189 and 190: 266 CHAPIN ET AL. that there was a
Page 191 and 192: 268 CHAPIN ET AL. duration of adver
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Page 195 and 196: 272 CHAPIN ET AL. Table 74 Effects
Page 197 and 198: 274 CHAPIN ET AL. reproductive orga
Page 199 and 200: 276 CHAPIN ET AL. tyrosine-hydroxly
Page 201 and 202: 278 CHAPIN ET AL. include small sam
Page 203 and 204: 280 CHAPIN ET AL. males/group. [It
Page 205 and 206: 282 CHAPIN ET AL. termination, whic
Page 207 and 208: 284 CHAPIN ET AL. provided a reliab
Page 209 and 210: 286 CHAPIN ET AL. grooming, and out
Page 211 and 212: 288 CHAPIN ET AL. method of oral do
Page 213 and 214: 290 CHAPIN ET AL. reared by their d
Page 215 and 216: 292 CHAPIN ET AL. has been informed
Page 217 and 218: 294 CHAPIN ET AL. buffered paraform
Page 219 and 220: 296 CHAPIN ET AL. unit. Further, th
Page 221 and 222: 298 CHAPIN ET AL. PND 21 and housed
Page 223 and 224: 300 CHAPIN ET AL. Tando et al. (200
Page 225 and 226: 302 CHAPIN ET AL. Purina Certified
Page 227 and 228: 304 CHAPIN ET AL. high-doses of bis
Page 229 and 230: 306 CHAPIN ET AL. born to those dam
Page 231 and 232: 308 CHAPIN ET AL. average weight we
Page 233 and 234: 310 CHAPIN ET AL. study authors con
Page 235 and 236: 312 CHAPIN ET AL. used for extracti
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Page 241 and 242: 318 CHAPIN ET AL. differentiation o
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
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-
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Page 285 and 286: 362 CHAPIN ET AL. Table 94 Treatmen
Page 287 and 288: 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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372 CHAPIN ET AL. Table 100 Summary
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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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378 CHAPIN ET AL. Table 103 Summary
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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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