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

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0.002, 0.02, and 2 mg/kg bw/day for 6 days. Epididymal sperm were collected 22 days after the end of bisphenol A treatment and multicolor fluorescent in situ hybridization was used to evaluate decondensed sperm for aneuploidy. Sperm count was decreased by bisphenol A 0.002 mg/kg bw/day, but there was no increase in the frequency of hyperhaploidy or diploidy. Bisphenol A was negative in a bone marrow micronucleus test at dose levels up to 2 mg/kg/day for 2 days. 2.4. Carcinogenicity No human data examining the carcinogenicity of bisphenol A were identified. NTP (1982) and Huff (2001) examined carcinogenicity of bisphenol A in F344 rats and B6C3F1 mice. Animals were randomly assigned to treatment groups. Bisphenol A(o98.2% purity) was administered through feed for 103 weeks to 50 rats/sex/dose at 0, 1000, or 2000 ppm, 50 male mice/group at 0, 1000, or 5000 ppm, and 50 female mice/group at 0, 5000, or 10,000 ppm. NTP estimated mean bisphenol A intakes of 74 and 148 mg/kg bw/day for male rats and 74 and 135 mg/kg bw/day for female rats. [Data on bisphenol A intake, food intake, and body weights were not provided for mice.] Using default values, the European Union (2003) estimated bisphenol A intakes of 120 and 600 mg/kg bw/day in male mice and 650 and 1300 mg/kg bw/day in female mice. Concentration and stability of bisphenol A in feed were verified. Body weights and clinical signs were observed during the study. Following the exposure period, animals were killed and necropsied. Organs, including seminal vesicle, prostate, testis, ovary, and uterus, were preserved in 10% neutral buffered formalin and examined histologically. Statistical analyses included Cox and Tarone methods, 1-tailed Fisher exact test, Bonferroni inequality criterion, Cochran-Armitage test, and life table methods for linear trend. In rats, body weights of males and females from both dose groups were lower than controls throughout the study. Feed intake was decreased in females of both dose groups beginning at Week 12. No adverse effects on survival were observed. There were no non-neoplastic lesions [including in male and female reproductive organs] that appeared to be treatment-related. The incidence of leukemia was increased in males (13 of 50, 12 of 50, and 23 of 50 in control and each respective dose group) and females (7 of 50, 13 of 50, and 12 of 50). In males the trend for leukemia was significant by Cochran- Armitage test, but statistical significance was not shown by life table analysis for trend or incidence in the highdose group, according to the unpublished version of the study. The published version of the study indicated statistical significance at the high-dose. Statistical significance was not attained for leukemia incidence in female rats. An increased incidence of testicular interstitial cell tumors (35 of 49, 48 of 50, 46 of 49) was statistically significant in both dose groups. An increased incidence of mammary fibroadenomas in males of the high-dose group (0 of 50, 0 of 50, and 4 of 50) achieved statistical significance for trend by Cochran-Armitage test but not by Fisher exact test. In bisphenol A groups, there were decreased incidences of adrenal pheochromocytomas in males, adrenal cortical adenomas in females, and uterine endometrial stromal polyps. The Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 227 NTP concluded that none of the increases in tumor incidence in rats was clearly associated with bisphenol A exposure. In mice, body weights were lower in high-dose males and in females of both dose groups. Feed intake could not be accurately determined because of spillage. Bisphenol A did not affect the survival of mice. Incidence of multinucleated hepatocellular giant cells was increased in treated males (1 of 49, 41 of 49, and 41 of 50). [A review of the data indicated no increases in incidence of non-neoplastic lesions in the reproductive organs of male or female mice.] The incidence of leukemia or lymphoma in male mice by dose group (2 of 49, 9 of 50, and 5 of 50) was not statistically significant. The published version of the report indicated an increasing trend for lymphoma. The linear trend for increased pituitary chromophobe carcinomas in male mice (0 of 37, 0 of 36, 3 of 42) was reported to be statistically significant by Cochran-Armitage test but statistical significance was not shown by Fisher exact test. The study authors concluded that none of the increases in tumor incidence in mice could be unequivocally associated with bisphenol A exposure. NTP concluded that under the conditions of this study, there was no convincing evidence the bisphenol A was carcinogenic in F344 rats or B6C3F 1 mice. However, study authors stated that there was suggestive evidence of increased cancer in the hematopoietic system based on marginally significant increases in leukemia in male rats, non-statistically significant increases in leukemia in female rats, and a marginally significant increase in combined incidence of lymphoma and leukemia in male mice. A statistically significant increase in testicular interstitial cell tumors in aging F344 rats was also considered suggestive evidence of carcinogenesis. The effect was not considered conclusive evidence because of the high incidence of the testicular neoplasm in aging F344 rats (88% incidence in historical controls). The NTP study was reviewed by the European Union (2003) and Haighton et al. (2002). For increases in leukemia, mammary gland fibroadenoma, and Leydig cell tumors in male rats, both groups noted the lack of statistical significance using the appropriate analyses and the common occurrence of these tumor types in F344 rats. The European Union (2003) concluded, ‘‘Overall, all of these [tumor] findings in rats and mice are not considered toxicologically significant. Consequently, it is concluded that bisphenol A was not carcinogenic in this study in both species.’’ Haighton et al. (2002) concluded, ‘‘Overall, the results of this bioassay did not provide any compelling evidence to indicate that [bisphenol A] was carcinogenic in F344 rats or in B6C3F 1 mice.’’ Based on the experimental animal data, the European Union concluded that ‘‘ythe evidence suggests that bisphenol A does not have carcinogenic potential.’’ Using a weight of evidence approach, Haighton et al. (2002) concluded that bisphenol A was not likely to be carcinogenic to humans. This conclusion was based on NTP study results; lack of activity at noncytotoxic concentrations in both in vitro genetic toxicity tests and in an in vivo mouse micronucleus test; and data from metabolism studies that show rapid glucuronidation and no formation of possibly reactive intermediates, with the possible exception of reactive intermediates potentially generated as a result of saturated detoxification pathways at high-doses.
228 CHAPIN ET AL. Table 59 Development of UDPGT Activity in Humans a UDPGT activity, nmol/min/mg protein Age Bilirubin Testosterone 1-Napthol 30 weeks gestation 0.05 0 0.56 30 weeks gestation 0.4; 1 0.14; 0.85 3.0; 1.8 with 10 weeks survival Full-term infants 0.0770.04 0.1070.06 0.7570.68 surviving 1–10 days (n 5 7) Full-term infants 0.6470.32 0.1270.05 2.471.1 surviving 8–15 weeks (n 5 6) Full-term infants 0.9971.1 0.0970.06 3.672.1 surviving 22–55 weeks (n 5 5) Adult males (n 5 3) 0.7670.43 0.4670.61 7.272.2 a Coughtrie et al. (1988). Data presented as individual values or mean7SD. 2.5 Potentially Susceptible Subpopulations As noted in Section 2.1.1.3, one pathway of bisphenol A metabolism in humans and experimental animals is glucuronidation. Studies in experimental animals demonstrated that both the intestine and liver can glucuronidate bisphenol A. UGT2B1 was identified as the isoform involved in bisphenol A glucuronidation in rat liver (Yokota et al., 1999). The UDPGT isoform involved in human intestinal glucuronidation of bisphenol A is not known to have been identified. Despite uncertain isoform identification, studies in humans and experimental animals demonstrate developmental changes in expression of activities of several UDPGT isoforms that potentially affect bisphenol A metabolism. Coughtrie et al. (1988) examined the ontogeny of UDPGT activity in human liver microsome samples obtained postmortem from adults and premature or full-term infants. Results of this analysis are listed in Table 59. Activities for isoenzymes catalyzing glucuronidation of bilirubin, testosterone, and 1-napthol were very low at birth in premature and full-term infants. Activities increased with age for the isoenzymes catalyzing glucuronidation of bilirubin (B80% of adult levels by 8–15 weeks of age) and 1-naphthol (B30% of adult levels at 8–15 weeks of age). During the first 55 weeks of life, no consistent increase in activity was noted for the isoenzyme catalyzing glucuronidation of testosterone. Using an immunoblot technique with antibodies developed toward liver testosterone/4-nitrophenol and kidney naphthol/bilirubin, 1 immunoreactive protein was observed in microsomes of 18- and 27-week-old fetuses and 3 immunoreactive proteins were observed in microsomes of full-term infants. Most isoenzymes present in adults were observed in infants within 3 months of age at levels B25% those of adults. Strassburg et al. (2002) used a reverse transcript (RT)polymerized chain reaction (PCR) technique to examine developmental changes in expression for 13 UDPGT genes in liver samples obtained from 16 pediatric patients undergoing liver transplant for extrahepatic biliary atresia (6–24 months old) and 12 adults undergoing liver transplant for carcinoma (25–75 years). Changes in gene expression were also assessed in hepatic RNA samples for two 20-week-old fetuses. No transcripts for UDPGT were detected in samples from 20week-old fetuses. In infant and adult livers, transcripts were detected for UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B4, UGT2B7, UGT2B10, and UGT2B15; there were no age-related differences in expression. Expression of UGT1A9 and UGT2B4 mRNA was lower in the pediatric samples. Western blot analyses of protein expression for UGT1A1, UGT1A6, and UGT2B7 were consistent with findings for mRNA expression. Activities toward 18 specific substrates were assessed in microsomes. In 13–24-month-old children compared to adults, glucuronidation activity was lower for ibuprofen (24fold), amitriptyline (16-fold), 4-tert-butylphenol (40-fold), estrone (15-fold), and buprenorphine (12-fold). Cappiello et al. (2000) compared uridine 50-dipho sphoglucuronic acid concentrations in livers and kidneys of human fetuses and adults and in placenta. In adults undergoing surgery, liver samples were obtained from 1 man and 4 women (23–72 years of age) and kidney samples were obtained from 1 woman and 4 men (55–63 years of age). Fetal livers and kidneys were obtained from 5 fetuses legally aborted between 16 and 25 weeks gestation. Five placenta samples were obtained on delivery at 17–25 weeks gestation. Compared to adults, fetal uridine 50-diphosphoglucuronic acid concentrations were 5-fold lower in liver and 1.5-fold lower in kidney. Concentrations of uridine 50-diphosphoglucuronic acid in placenta were 3–4-fold lower than in fetal liver. Based on these findings, study authors concluded that glucuronidation is potentially limited in the human fetus. As noted in Sections 2.1.2.2 and 2.1.2.3, rat fetuses appear to have no or low ability to glucuronidate bisphenol A (Miyakoda et al., 2000; Matsumoto et al., 2002; Domoradzki et al., 2003). Although rats glucuronidate bisphenol A at birth, glucuronidation capacity appears to increase with age (Matsumoto et al., 2002; European-Union, 2003; Domoradzki et al., 2004). Some possible interindividual or sex-related differences in the ability to produce the bisphenol A sulfate conjugate were identified in a limited number of human studies. As discussed in more detail in Section 2.1.1.3 and shown in Table 8, higher amounts of urinary bisphenol A sulfate were detected in 15 adult women than in 15 adult males (Kim et al., 2003b). In a study examining bisphenol A metabolism by human hepatocytes, an B10-fold higher concentration of a bisphenol A glucuronide/ sulfate conjugate was observed in the sample from 1 female than in samples from 2 other females and 2 males (Pritchett et al., 2002). Yang et al. (2003) examined the effects of polymorphisms in sulfotransferase enzymes on urinary excretion of total bisphenol A (conjugated and free) in Korean volunteers. Urinary bisphenol A concentrations were measured by HPLC and a PCR method was used to determine sulfotransferase genotype. The SULT1A1 * 1 allele was reported to have greater enzyme activity than the SULT1A1 * 2 enzyme and it was expected that individuals with the SULT1A1 * 1 allele would be able to rapidly eliminate bisphenol A. However, no significant differences in urinary bisphenol A concentrations were observed between 57 individuals with the SULT1A1 * 1 allele (geometric mean7SD 5 10.1078.71 mg/L) and 15 Birth Defects Research (Part B) 83:157–395, 2008
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National Toxicology Program U.S. De
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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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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
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 and 146: 222 CHAPIN ET AL. Table 56 Anti-And
Page 147 and 148: 224 Table 57 In Vitro Genetic Toxic
Page 149: 226 CHAPIN ET AL. Table 58 In Vivo
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
Page 197 and 198: 274 CHAPIN ET AL. reproductive orga
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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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