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

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Hiroi et al. (2004), supported by the Japanese Ministry of Health, Labor, and Welfare, the National Institute for Environmental studies, and the Japan Science and Technology Agency, compared blood bisphenol A levels in women with and without endometrial hyperplasia. Volunteers were recruited from an outpatient clinic in Japan. Women included in the study consisted of 11 controls with normal endometrium, 19 with endometrial hyperplasia, and 7 with endometrial carcinoma. The hyperplasia group was further divided according to severity: 10 with simple hyperplasia and 9 with complex hyperplasia. Mean ages were 48.4–48.9 years in groups without cancer, and the mean age was 63.1 years in the group with endometrial cancer. Blood samples were collected at the time of endometrial examination. Serum bisphenol A levels were measured by ELISA. Data were analyzed by Student t-test, with the exception of gravidity and parity, which were analyzed by w 2 test. There were no significant differences in age, gravidity, parity, or body height, weight, or mass index between the groups without endometrial cancer. Women with endometrial cancer were significantly older and had significantly lower values for gravidity, parity, height, and weight. Mean7SD serum bisphenol A levels were reported at 2.571.5 ng/mL in controls, 2.271.6 ng/mL in women with hyperplasia, and 1.470.5 ng/mL in women with endometrial cancer. When the group with hyperplasia was divided according to severity, serum bisphenol A blood levels were reported at 2.972.0 ng/ mL in the group with simple hyperplasia and 1.470.4 ng/mL in the group with complex hyperplasia. Serum bisphenol A levels were significantly lower in women with complex endometrial hyperplasia or endometrial cancer than in controls. The study authors concluded that their preliminary findings demonstrated a possible link between bisphenol A exposure and endometrial hyperplasia or cancer. It was noted that modes of action for bisphenol A may be more complex than expected and that these contradictory results might provide a clue about mechanisms of production of estrogen-dependent diseases. Strengths/Weaknesses: Because this was a small, cross-sectional study, it is not possible to determine whether this association preceded disease, or could have been associated with the disease process. As noted in Section 1.1.5, ELISA may over estimate bisphenol A. Utility (Adequacy) for CERHR Evaluation Process: The cross-sectional study design is adequate but of limited utility for this evaluation, but raises research questions regarding mechanisms of production of estrogen-dependent diseases. Sugiura-Ogasawara et al. (2005), supported by the Japanese Ministry of Health, Labor, and Welfare, conducted a study to determine if there is an association between recurrent miscarriage and bisphenol A levels in blood. The cases in this study were 45 patients with a history of 3 or more (3–11) consecutive first trimester miscarriages. Mean7SD age of the cases was 31.674.4. None of the cases had a history of live birth. All were seen at a Japanese hospital between August, 2001– December, 2002. Half of the cases were housewives and half were employed in various occupations. A hysterosalpingography analyses was conducted in cases, and chromosome analyses were conducted for both cases and their partners. Women were excluded from the study if Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 331 uterine anomalies were observed or chromosomal abnormalities were detected in either partner. Serum bisphenol A levels were determined by ELISA. Immunological endpoints examined included antinuclear antibodies, antiphospholipid antibodies, and natural killer cell activity. Blood testing for hypothyroidism, diabetes mellitus, and hyperprolactinemia was conducted. Blood samples were obtained 5–9 days following ovulation in at least 2 cycles. Blood samples to determine progesterone and prolactin levels were taken at 3 months following the last miscarriage and before the next conception. For subsequent pregnancies, ultrasounds were conducted, and spontaneously aborted embryos/fetuses were karyotyped. Serum levels of bisphenol A in cases were compared to those of 32 healthy non-pregnant hospital employees with no history of live birth, infertility, or miscarriage. Mean7SD age of controls was 32.074.8. None were taking oral contraceptives. Like the cases, the controls lived near Nagoya City. Statistical analyses included Welch test, Mann–Whitney test, and Pearson correlation coefficient. Bisphenol A levels (mean7SD) were reported to be significantly higher in women with recurrent miscarriages (2.5975.23 ng/mL) compared to healthy controls (0.7770.38 ng/mL). In the 45 cases, incidences of abnormal conditions were 15.6% for hypothyroidism, 13.3% for antiphospholipid antibodies, 22.2% for antinuclear antibodies, 11.1% for hyperprolactinemia, and 20.5% for luteal phase defect. Serum levels of bisphenol A were significantly higher in patients who tested positive versus negative for antinuclear antibodies (mean7SD 5 7.38279.761 vs. 1.22271.54 ng/mL). Thirty-five of the patients became pregnant and 48.6% had another miscarriage. Serum bisphenol A levels in patients who miscarried were 4.3978.08 ng/mL, and serum bisphenol A in patients with successful pregnancies were 1.2271.07 ng/mL (not statistically significant). The study authors concluded that exposure to bisphenol A is associated with recurrent miscarriage. In a letter to the editor, Berkowitz (2006) stated that this study did not support an association between bisphenol A blood levels and recurrent miscarriage. Several limitations were noted for the study. Timing and numbers of blood samples collected were not defined clearly. It was noted that because bisphenol A has a short half-life, it would be critical to know if blood samples were obtained in a timeframe relevant to the occurrence of miscarriage. Although differences in serum bisphenol A levels in cases compared to controls achieved statistical significance, it was noted that median levels of bisphenol A in serum were nearly identical in patients with recurring miscarriages (0.71 ng/mL) and controls (0.705). The similarities in median values suggested there were no differences between the two groups, and it was suggested that apparent differences in mean serum levels of bisphenol A were due to a few individuals, as was demonstrated in Figure 1 of the Sugiura-Ogasawara et al. (2005) report. Berkowitz (2006) stated that the Welch test was inappropriate for statistical analyses and noted that the two evaluation groups could not be considered comparable because of differences in occupation (housewives compared to medical workers) and unknown fertility of controls. Because the controls were not evaluated for factors such as hypothyroidism and systemic lupus erythematosus (associated with
332 CHAPIN ET AL. antinuclear antibodies), the conditions may have been over represented in cases and may have been the cause of the reported differences between the 2 groups. Although mean bisphenol A levels were (non-significantly) lower in women who subsequently became pregnant and had a successful pregnancy compared to those who miscarried, Berkowitz (2006) noted that the median level of bisphenol A was actually higher in women with the successful pregnancies. Last, the ELISA method for measuring bisphenol A levels has not been validated and is subject to inaccuracy due to extensive cross-reactivity. In a response to the comments by Berkowitz (2006), Sugiura-Ogasawara (2006) stated that although measurement of bisphenol A levels at various time points would have been ideal, obtaining samples every day during pregnancy would have been difficult. Sugiura-Ogasawara (2006) clarified that bisphenol A values were based on a single sample in each individual, but that similar tendencies were observed for a second blood sample. With respect to the use of women with live births as controls, Sugiura-Ogasawara (2006) explained that the same blood samples were used for measurements of other environmental compounds, some of which are known to decrease after delivery. It was noted that none of the cases had systemic lupus erythematosus, and that use of controls with hypothyroidism or antinuclear antibodies was not considered important for the study. Superiority of the HPLC method compared to the ELISA method for measuring serum bisphenol A levels was acknowledged, but the authors stated that the ELISA method was used because of limited funding, reiterated that the study was preliminary and used a small number of volunteers, and that additional studies using a larger sample and more appropriate analytical methods were needed. Strengths/Weaknesses: The letter from Berkowitz (2006) summarizes many of the weaknesses of this study. No quality assurance information was given for the biomarker/hormone measurements. As the Berkowitz letter points out, the ELISA method is not standardized for human sera (and may overestimate bisphenol A due to nonspecific binding), the distribution of exposure was not normal, and median values of the two groups were similar, with two women skewing the mean. Little information was provided on the characteristics of the two study groups or response rates. Age and body-mass index were controlled in the analyses, but other potential confounders and effect modifiers were not. The time between exposure and observation was not appropriate. Spontaneous abortions have been associated with many factors which have not been addressed here. The authors’ conclusions require the assumption that bisphenol A measurement levels represent those present during the important time frame for the spontaneous abortion. The authors do not report the time frame for collection of the blood samples. Nonnormal data were not appropriately transformed for analysis. Welch’s test was used ‘‘yto compare bisphenol A levelsybecause the distribution of the two groups might have differed.’’ Welch’s test is a t-test for groups with unequal variance, not different distributions (both should be normal, which was probably not the case). Utility (Adequacy) for CERHR Evaluation Process: Because of limitations in the design and analysis of this work, this study is inadequate has no utility in this evaluation. Yang et al. (2006), supported by the Korean FDA, measured urine bisphenol A in 172 Korean men and women and evaluated the relationship of these values with UDP-glucuronosyl- and sulfotransferase polymorphisms, with sister-chromatid exchange testing, and with self-reported symptoms of possible endocrine origin. First-morning urine samples were collected at the time of a routine physical examination, as was a blood sample, and a questionnaire was completed. Urine bisphenol A was measured using reverse phase HPLC. DNA was isolated from blood samples and polymorphisms were determined at SULT1A1 and UGT1A6. Sister chromatid exchange in response to N-methyl-N 0 -nitro-Nnitrosoguanidine (MNNG) was evaluated in blood cells [not otherwise specified]. The relationship between urine bisphenol A and continuous variables was assessed with simple or multiple regression analysis and the relationship with categorical variables assessed with the Wilcoxon test. None of the subjects reported occupational exposure to bisphenol A. The median urine bisphenol A concentration was 7.86 mg/L. Urine bisphenol A was not different in men and women. Urine bisphenol A was associated with body-mass index (P 5 0.06) and self-reported frequency of alcohol consumption (P 5 0.08). SULT1A1 and UGT1A6 polymorphisms were not associated significantly with urine bisphenol A concentrations. No significant associations were observed between urine bisphenol A and MNNG-induced sister-chromatid exchange, although they were associated when lower levels of MNNG were used. There were no significant associations between urine bisphenol A and self-reported symptoms of possible endocrine origin, including thirst/frequent urination, dizziness, neck mass, heat intolerance, sweating, hot flashes, swelling of lymph nodes, dysmenorrhea, menstrual irregularity, or menorrhagia. The authors concluded that even though they had been unable to associate an endocrine disorder with urine bisphenol A, continuous biologic monitoring of bisphenol A would be prudent. Strengths/Weaknesses: Bisphenol A was measured in urine using HPLC. No information was given regarding any selection criteria or response rates and some outcome measures were self-reported. Utility (Adequacy) for CERHR Evaluation Process: While small, this study is useful for providing descriptive exposure information on BPA urinary levels (see Section I). This study does not have utility for evaluation of reproductive endpoints. 4.1.2 Male. Luconi et al. (2001), supported by the Italian Public Health Project, examined the effects of in vitro exposure of human spermatozoa to bisphenol A. Semen was collected from normozoospermic men, and spermatozoa were separated. Intracellular calcium was measured using a spectrofluorometric method in cells treated with 1 mM bisphenol A, 1 mM 17b-estradiol, 10 mM progesterone, [17 b-estradiol is noted as 10lM in Figure 6, text states 1lM] or the same concentrations of bisphenol A in combination with 17b-estradiol or progesterone. Effects on acrosome reaction were examined using a fluorescent staining method in cells exposed to 1 mM [0.23 mg/mL] bisphenol A for 2 hr, with and without exposure to 10 mM progesterone. [In the study figures summarizing results, sample numbers in studies involving bisphenol A were listed at 5–11. It 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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• • 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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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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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
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
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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 239 and 240: 316 CHAPIN ET AL. of testes and com
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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)
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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 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
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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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