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

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Utility (Adequacy) for CERHR Evaluation Process: This study is inadequate and not useful due to critically small sample size, route of administration, lack of clarity of design, and inappropriate statistical procedures. 3.2.9 Sheep. Evans et al. (2004), supported by the British Council, Irish Health Research Board, and the Royal Society, examined the effects of bisphenol A exposure on gonadotropin secretion on prepubertal female lambs. [No information was provided about feed or composition of bedding or caging materials.] Starting at 3 weeks of age, female Poll Dorset lambs were weighed weekly, and blood samples were collected 2 times/week for measurement of LH and FSH levels. At 4 weeks of age, lambs were assigned to treatment groups according to body weight. From 4–11 weeks of age, 6 lambs/group received biweekly i.m. injections with the 10:1 corn oil/alcohol vehicle, 3.5 mg/kg bw bisphenol A [purity not reported], 0.175 mg/kg bw diethylstilbestrol [listed as 0.0175 in the legend for Figure 1 of the study], or 3.5 mg/kg bw octylphenol. Lambs were ovariectomized at 9 weeks of age. [The text of the methods sections reported ovariectomy at the beginning of treatment, but that statement appears to be an error because it is not indicated elsewhere in the study.] On the last day of treatment, blood was collected every 15 min for 6 hr to assess pulsatile LH secretion. All lambs were then killed. Adrenal glands, kidneys, and ovaries were weighed. Uteri were examined as discussed in Morrison et al. (2003). Data were analyzed by ANOVA, Dunnett multiple comparison post-hoc test, regression analysis, Munro algorithm, and paired t-tests. Compared to the control group, the bisphenol A group did not experience significant changes in body, kidney, adrenal, or ovarian weights. [No data were shown for body, kidney, and ovarian weights in the control vs. bisphenol A group.] Uteri from the bisphenol A group were reported to be visually larger, but no uterine weights were provided. Over the 7-week treatment period, bisphenol A did not significantly affect blood LH or FSH levels compared to controls. Compared to controls, the bisphenol A group experienced significant decreases [% change compared to controls] in concentration [48%], amplitude [77%], and frequency [66%] of pulsatile LH secretion. Octylphenol did not have any effect on the endpoints examined. Diethylstilbestrol treatment resulted in decreased blood levels of LH and FSH over the treatment period, including the period following ovariectomy. Concentration, amplitude, and frequency of pulsatile LH secretion were also lower in the diethylstilbestrol group, with a greater magnitude of effect compared to bisphenol A. The study authors concluded that the bisphenol A dose tested can inhibit LH secretion in lambs. Strengths/Weaknesses: The unique animal model and the use of LH pulsatile response are uncommon but interesting. The high-dose level via i.m. injection is a weakness as are small sample sizes (n 5 6). The statistical tests for LH trends did not appear to take into account the repeated nature of the sampling leading to over stating the significance of trend effects. Utility (Adequacy) for CERHR Evaluation Process: This study is adequate for inclusion but of limited utility for the evaluation process. Morrison et al. (2003), supported by the Wellcome Trust, Dr. Ferranti, and the Irish Health Research Board, Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 307 examined the effects of bisphenol A exposure on the lamb uterus. [No information was provided on feed or composition of bedding or caging materials.] At 4 weeks of age, female Poll Dorsett lambs were randomly assigned to treatment groups according to body weight. Beginning at 4 weeks of age and continuing for 7 weeks, 6 lambs/group received biweekly i.m. injections with the 10:1 corn oil:alcohol vehicle, 3.5 mg/kg bw bisphenol A [purity not reported], 0.175 mg/kg bw diethylstilbestrol, or 3.5 mg/kg bw octylphenol. Lambs were ovariectomized during the fifth week of exposure. Throughout the study, blood was collected for measurement of gonadotropin levels and the results of those analyses were reported in the study by Evans et al. (2004). Lambs were killed following 7 weeks of exposure. Uteri and cervices were fixed in Bouin solution for histopathological examination, morphometric measurement, and immunohistochemical detection of ERa and ERb. Statistical analyses included ANOVA with Fisher protected least significant difference. Significant effects observed with bisphenol A treatment [% change compared to controls] were increased uterine/cervical tract weight [87%], endometrial area [154%], and endometrial/myometrial ratio [65%]. Qualitative histopathological observations in uteri from bisphenol A-treated lambs included endometrial edema, decreased endometrial gland density compared to controls, and crowding of cells in the uterine epithelium, which contained substantial amounts of eosinophilic, non-vacuolated cytoplasm. In contrast to uteri from control lambs, mononuclear cell exocytosis was not a common observation in uteri from the bisphenol A group. The cervical epithelium was keratinized in the bisphenol A group. Qualitative analyses revealed that diffuse intracellular staining for ERa and ERb in the uterine subepithelium was most pronounced in the bisphenol A and diethylstilbestrol groups. Similar to animals treated with bisphenol A, the diethylstilbestrol group had increased uterine weight, keratinized cervical epithelium, changes in uterine histology, and keratinized cervical epithelium, but there was no change in endometrial/myometrial ratios. No changes were observed following exposure to octylphenol. The study authors concluded that bisphenol A exposure altered the uterocervical environment of lambs. Strengths/Weaknesses: This is a companion to the study of Evans et al. (2004) with similar strengths. The single high-dose level via i.m. injection is a weakness as is the exclusion of data from 2 lambs based on responses for E/M ratio endpoints, thus reducing the n to 5 and potentially biasing the data. The statistical analyses do not appropriately account for the number of multiple comparison made which can increase the probability of detecting an effect by chance. Utility (Adequacy) for CERHR Evaluation Process: This study is adequate for inclusion but of limited utility in the evaluation process. Savabieasfahani et al. (2006), supported by the U.S. Public Health Service, NIH, and the University of Michigan, used Suffolk ewes to investigate the effects of maternal exposure to bisphenol A or methoxyclor [not discussed here] during gestation. Pregnant Suffolk ewes used in this experiment were exposed to a natural photoperiod in the same pasture and fed a diet of 1.25 kg alfalfa/grass hay. Pregnant ewes (n 5 10) of similar
308 CHAPIN ET AL. average weight were injected s.c. on GD 30–90 with 5 mg/kg bw day bisphenol A (991% purity) dissolved in cottonseed oil. Control pregnant ewes (n 5 16) were administered vehicle injections. Lambs were born over about a 1-month interval in early spring. Birth outcome measurements included number and gender of offspring, weight, height, chest circumference, genital development, and measurement of blood insulin and insulin-like growth factor-1. Lambs were cross-fostered and group housed on PND 3. Lactating ewes were fed a diet of corn and alfalfa hay. Lambs had free access to standardized Shur Gain feed pellets. [The authors note the presence of phytoestrogens in the feed but did not provide quantification.] At weaning, female were separated from male offspring, and the females were housed in open air pens under natural photoperiod with free access to feed pellets, as described above. Maternal blood samples were taken on GD 50, 70, and 90 for measurement of bisphenol A using HPLC. The number and sex of offspring in each treatment group, weight, height, chest circumference, and genital development were noted. Blood levels of insulin and insulinlike growth factor 1 were assayed by RIA on PND 1. In female offspring [n not indicated], blood was drawn biweekly during the first 2 postnatal months for determination of LH by RIA. Timing of puberty onset was estimated through twice weekly blood draws for progesterone (n 5 11/group). Estrus cycling patterns were determined by frequent measurement of FSH, LH, and progesterone by RIA in 3 female offspring/group after synchronization with prostaglandin F2a at 40 weeks of age. Statistical analyses were performed using ANOVA, repeated measures ANOVA, or a linear mixed model. A cluster algorithm was used to identify LH pulses, with Student t-test to determine LH nadirs. Blood levels of bisphenol A were significantly higher in exposed pregnant ewes than controls at all sampling times. The levels reached (37.473.3 mg/L) were compared to exposure levels reported in pregnant women [0.3–18.9 mg/L (Schönfelder et al., 2002b)]. No statistical difference was reported in gestation length, number of offspring, or sex. There were no significant differences in female lambs in anogenital distance, insulin, or insulinlike growth factor levels on PND 1. In female offspring, prenatal bisphenol treatment significantly decreased birth weight [by B11%], height [by B5%], and chest circumferences [by B7%, all comparisons estimated from a graph]. In male offspring exposed to bisphenol A, there were no significant differences from control in birth weight, height, chest circumference, or anogenital distance, but anoscrotal:anonavel ratio was increased significantly [by 21%]. Bisphenol A treatment increased significantly levels of circulating LH [by B89%, estimated from a graph] during the first 2 months of life in female offspring. Onset of puberty was not affected by treatment in bisphenol A-exposed female offspring, but these females had a significantly longer first breeding season [by B2 weeks] and larger number of cycles during the first breeding season). Estrous cycle length and progesterone levels were not different from controls. The bisphenol A group had significantly lower peak and total LH, and the amplitude of LH pulses was increased significantly, whereas frequency showed no difference from control group. No differences in FSH were seen between groups. Progesterone secretion pattern showed no difference between groups, despite perturbations in LH patterns. The authors concluded that prenatal exposure to bisphenol A impairs growth in female fetuses and is associated with dampening of the LH surge. Although there was no apparent effect on progesterone production, the authors suggested that the changes induced by prenatal exposure of females could interfere with fertility. Strengths/Weaknesses: This study appears to have been well-conducted with the utilization of multiple endpoints in sheep. Weaknesses are the use of a single dose level and the relatively small sample size. The single time point for bisphenol A plasma determination at an unknown time relative to s.c. injection is a weakness. Utility (Adequacy) for CERHR Evaluation Process: This study is adequate though of limited utility. 3.2.10 Non-mammalian species. Although these studies in non-mammalian species can be quite useful for understanding mechanisms and environmental impacts, the studies are not considered useful for the evaluation process, because of the uncertain relationship between human biology and that of the model species. 3.2.10.1 Invertebrates: Hill et al. (2002) supported by the Council on Undergraduate Research and the Association for Biological Laboratory Education, examined the effects of bisphenol A on the development of 2 freshwater sponge species. (Heteromyenia sp. and Eunapius fragilis). Sponge gemmules were incubated in tissue culture wells containing bisphenol A [purity not indicated] at 0, 0.16, 16, 80, or 160 ppm [mg/L]. The control group was incubated in the spring water vehicle. There were 5 replicates/treatment. Nonylphenol and ethylbenzene were also examined. Growth was measured on Days 3, 6, and 9. Because growth patterns were similar at all 3 evaluation periods, statistical analyses were conducted only for Day 6 data. Data were analyzed by ANOVA and Tukey multiple comparison test. In both species, abnormal development or malformation of the water vascular system was observed at a bisphenol A dose of 16 ppm and germination was completely inhibited at 80 and 160 ppm. Significantly reduced growth rates were observed in Heteromyenia sp. at 160 ppm. Similar effects were observed with nonylphenol and ethylbenzene. The study authors stated that sponges may prove useful for examining endocrine-disrupting compounds. Strengths/Weaknesses: This study used a unique model with a focus on the aquatic system. Utility (Adequacy) for CERHR Evaluation Process: This study may have utility for environmental assessment, but is not useful for human risk assessment. Roepke et al. (2005), supported by the National Oceanic and Atmospheric Administration, examined the effects of bisphenol A exposure on development of two species of sea urchin, Strongylocentrotus purpuratus and Lytechinus anamesus. In dose–response studies, sea urchin embryos were incubated from 1–96 hr postfertilization in media containing bisphenol A [purity not indicated] at 0, 250, 500, 750, or 1000 mg/L [culture ware not discussed]. Development toxicity was assessed at 96 hr by examining larvae at the pluteus stage. The larvae were categorized as normal, delayed, abnormal, elongated, or hatched. Data were obtained in 3 replicates. Birth Defects Research (Part B) 83:157–395, 2008
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National Toxicology Program U.S. De
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Population Adult General. Populatio
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Table 3. Blood and Breast Milk Biom
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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
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
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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
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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
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Page 233 and 234: 310 CHAPIN ET AL. study authors con
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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)
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
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Page 275 and 276: 352 CHAPIN ET AL. expression [to B6
Page 277 and 278: 354 CHAPIN ET AL. indicated] at 0 (
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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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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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