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

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457 lg/L] bisphenol A and malformations (curved tails) were increased by exposure to 20 mM. The effects were similar to those observed with 17b-estradiol, but bisphenol A was less potent. [Very few protocol details were provided, and no data were shown by study authors for mortality and malformation endpoints.] The study authors concluded that bisphenol A could act as a developmental neurotoxicant by upregulating CYP450 aromatase expression but that further studies were needed to determine if there are changes in neural estrogen biosynthesis or CNS development. Strengths/Weaknesses: A weakness of this study for the current evaluation is the lack of morphometric data. The significance of the observed change in aromatase is not clear. Utility (Adequacy) for CERHR Evaluation Process: This study is not useful in the evaluation process. Segner et al. (2003), supported by the European Commission, examined estrogenicity responses and in vivo life cycle effects in zebrafish exposed to bisphenol A. Estrogenicity studies are discussed in Section 2. One hundred fertilized eggs/vessel were exposed to bisphenol A (98% purity) at 0, 94, 188, 375, 750, or 1500 mg/L under semistatic conditions [culture ware not discussed]. Exposures were continued until fish became sexually mature. The numbers of fish/vessel were adjusted to 50 following 42 days of exposure and 30 following 75–78 days of exposure. Two replicates were examined. Bisphenol A concentrations were confirmed by GC/MS. Endpoints evaluated included survival, behavior, growth, time to first spawning, egg production, and fertilization success (percent fertilized eggs/vessel/ day). Statistical analyses included ANOVA and William test. EC 50-values were calculated by probit analysis and analyzed by Kruskal–Wallis and Mann–Whitney U tests. 17b-Estradiol, ethinyl estradiol, and 4-tert-octylphenol were also examined using similar protocols. The authors only discussed results for reproductive success because they stated that it was the most consistent and reproducible effect following exposure of the fish to estrogenic substances. An EC 50-value of 6140 nM [1.4 mg/L] bisphenol A was obtained for fertilization success, and the study authors stated that the value exceeded concentrations typically found in the environment. Bisphenol A had a relative potency of 0.0000006 compared to17b-estradiol and was 45 times less potent than 4-tert-octyl-phenol. The study authors concluded that the in vivo potency of the compounds was overestimated by in vitro estrogenicity assays (described in Section 2). Strengths/Weaknesses: This study was well performed. Utility (Adequacy) for CERHR Evaluation Process: This study is useful in showing a lack of effect on fertilization at environmentally relevant concentrations of bisphenol A, but not useful to the evaluation process. Metcalfe et al. (2001), supported by the Environmental Science and Technology Alliance Canada, the Natural Sciences and Engineering Research Council of Canada, and Health Canada, in glass jars, exposed medaka (Oryzias latipes) from 1 day after hatching until 85–110 days after hatching to bisphenol A [purity not indicated] at 0, 10, 50, 100, or 200 mg/L (n 5 60 fish/treatment). Over the 48 hr between media change, actual concentrations were a mean 59.6% of nominal concentrations. Fish were killed and embedded in paraffin for section. Gonads Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 313 were evaluated to determine the sex of the fish and whether testes contained ova, an intersex condition. Length and weight of the animals and sex ratio were not altered by treatment [statistical methods not reported]. There were 2 instances of intersex gonads in males exposed to bisphenol A 10 mg/L and no instances at higher concentrations. Histologic changes in testes including a reduction in germ cells were noted at 50 mg/L and higher. At 200 mg/L, oogenesis in females was more advanced than in controls. Strengths/Weaknesses: Strengths of this study are the step-sectioning of gonads and the use of several positive control estrogens, which worked as expected. Utility (Adequacy) for CERHR Evaluation Process: This study is not useful to the evaluation process. Yokota et al. (2000), supported by the Japanese Environment Agency, exposed medaka (Oryzias latipes) to bisphenol A (499% purity) at 0, 3.2, 16, 80, 400, or 2000 mg/L from fertilization until 60 days after hatching (n 5 60/treatment) [culture ware not discussed]. Actual bisphenol A concentrations were generally within 3% of nominal concentrations before hatching. After hatching, the lower 2 concentrations were B70–80% of nominal and the higher concentrations were B90% of nominal. Fish were assessed for survival, time to hatching, and growth. Sixty days after hatching, 19 or 20 fish/treatment were killed and sectioned for examination of the gonads using hematoxylin and eosin staining of fixed specimens. Statistical analysis was performed using ANOVA and nonlinear regression. Hatchability was 490% in all treatment groups. Time to hatch and mortality were not affected by treatment, although there was a nonconcentration dependent delay in hatching at 13 mg/L. Body length and weight 60 days after hatching were negatively correlated with bisphenol A concentration, and length and weight at 2000 mg/L were significantly lower than control values on pair-wise comparison. Based on external appearance and gonad examination, there were more females than males at 400 mg/L and there were no males at 2000 mg/L. Control sex ratio was 2:1 (male:female). There were 6 fish with intersex gonads among the 19 examined in the 2000 mg/L group. The authors concluded that bisphenol A adversely affects the early life stage of medaka with alteration of sexual differentiation. Strengths/Weaknesses: This study was well performed. Utility (Adequacy) for CERHR Evaluation Process: This study is not useful to the evaluation process. Pastva et al. (2001), support not indicated, examined the effects of bisphenol A exposure on development of medaka (Oryzias latipes). In a study examining abnormalities in embryos, 5 eggs were placed in individual glass vials containing bisphenol A [purity not indicated] at 0, 20, or 200 mg/L. There were 5 glass vials/exposure concentration, for a total of 25 embryos/group. The exposure period began 5 hr following fertilization and was continued for 9 days. Embryos were examined for malformations daily by observing them through the clear protective membrane of the egg. The severity of malformations was scored and severity indices were determined. In a second study examining mortality, newly hatched larvae were exposed for 96 hr to a method control solution, ethanol vehicle control solution, or 200 mg/L bisphenol A. Ten larvae were added to each
314 CHAPIN ET AL. jar, and there were 3 replicates/test solution (i.e., 30 larvae/concentration). Data were analyzed by t-test. The malformation severity index was increased significantly at 5–8 days following fertilization in embryos exposed to 200 mg/L bisphenol A, but the severity index did differ significantly from the control value on Day 9. Abnormalities consisted of pericardial edema, hemorrhage, and hemostasis. Larval mortality was not affected by exposure to 200 mg/L bisphenol A. The study authors concluded that exposure to environmentally relevant concentrations of bisphenol A resulted in embryonic deformities in medaka, but that the embryos were able to repair the abnormalities before hatching. Strengths/Weaknesses: This study using medaka is similar in design to the FETAX assay, which uses Xenopus. These types of assays have not been demonstrated to have relevance for human risk assessment. Utility (Adequacy) for CERHR Evaluation Process: This study is not useful in the evaluation process. Lee et al. (2003b), supported by Jeonnam Regional Environment Technology Development Center, exposed 51-day-old Korean rockfish (Sebastes schlegeli) fry to bisphenol A in feed at 0, 0.05, 0.5, 5, 50, and 100 mg/kg diet for 29 days [purity of bisphenol A, stability in feed, and culture ware not indicated]. At the end of the experiment, gonads were removed and sex determined by light microscopy of stained sections. There was no effect of bisphenol A on sex ratio compared to controls. [The data presentation and statistical analysis are unclear: the number of female fish and number of male fish in each dose group are presented as averages with an unspecified error and analyzed by Student ttest. Whole numbers would have been expected with v 2 analysis.] The authors concluded that there was no estrogenic effect of bisphenol A on sex differentiation in the Korean rockfish. Strengths/Weaknesses: The use of a positive control, which worked as expected, is a strength of this study. The inadequate presentation of data and statistical analysis is a weakness. Utility (Adequacy) for CERHR Evaluation Process: This study is not useful in the evaluation process. Honkanen et al. (2004), supported by the Finnish Graduate School of Environmental Science and Technology and the Academy of Finland, examined the effects of bisphenol A exposure on yolk-sac fry of landlocked salmon. Ten 8-day-old fry/beaker were exposed to bisphenol A [99% pure] at concentrations of 0, 10, 100, or 1000 mg/L for 42 days, in glass beakers. The ethanol vehicle and pure tap water were used as negative controls. There were 3–4 replicates/dose. One fry/beaker was photographed and killed following 6 days of exposure. After 6 weeks of exposure, all remaining fry were blotted and weighed. Three fry/beaker were photographed and 3 fry/beaker were examined histologically. Statistical analyses included ANOVA and Tukey test. Effects observed in fry exposed to the highest bisphenol A concentration included: yolk sac edema and hemorrhaging around gill arches and the front part of the yolk sac at 6 days of exposure; phlegmatic behavior (lack of activity during siphoning to renew solutions) on Day 8 of exposure; and darkening of color at Day 17 of exposure. No increases in mortality were observed. At the end of the exposure period, wet weights were increased in fry exposed to the highest concentration, and the study authors stated that the effect was due to fluid accumulation. In fry exposed to the mid- and highconcentration of bisphenol A, strongly stained fragments were observed in nuclei and storage substances in liver were decreased. No abnormalities were observed in histological examinations of heart, kidney, and thyroid gland. The study authors concluded that bisphenol A induced toxicity in fry at concentrations rarely found in the environment. Strengths/Weaknesses: The range of concentrations used in this study is a strength. Utility (Adequacy) for CERHR Evaluation Process: The finding of an effect only at a high concentration of bisphenol A may have importance for environmental assessments but is not of utility in the current evaluation process. 3.2.10.4 Reptile and bird: Stoker et al. (2003), supported by the Argentine National Agency for the Promotion of Science and Technology and Argentina Ministry of Health, examined the effects of in ovo bisphenol A exposure on sexual development of the crocodilian reptile Caiman latirostris. A preliminary experiment was conducted to determine the effects of temperature on sex determination, and it was established that incubation at 301C resulted in production of females while incubation at 331C resulted in the production of males. In the main experiment, eggs were collected from 5 nests in Argentina. Half the eggs were incubated at 301C and the other half at 331C. Care was taken to avoid exposing eggs to putative sources of estrogens such as spray paint, plastic, and nesting materials. At each incubation temperature, eggs from each nest were distributed among treatment groups. Twenty days following collection, 1 egg/nest/incubation temperature was opened for stage determination. At developmental stage 20, bisphenol A [purity not indicated] was applied topically to the eggshell at concentrations of 1.4 or 140 ppm (0.09 or 9 mg/egg). Other eggs were treated with 0.014 or 1.4 ppm 17b-estradiol. Control eggs were left untreated or exposed to the ethanol vehicle. Hatchlings were weighed and measured at birth. At 10 days of age, 4 animals/group/incubation temperature were killed for determination of sex by examination of internal genitalia. Sex determination was confirmed by histological evaluation of organs, which were fixed in 10% buffered formalin. Morphometric analysis of seminiferous tubules was also conducted in 10-day-old animals. The remaining animals (6– 11/group/incubation temperature) were raised until 6 months of age, at which time they were killed, measured, and sexed by examination of external genitalia. Evaluators were blinded to treatment conditions. Statistical analyses included Kruskal–Wallis ANOVA and Mann– Whitney U test. At 331C, there was 100% sex reversal in the high-dose bisphenol A and high-dose 17b-estradiol groups at 10 days and 6 months of age. Whereas 100% of control and low-dose animals in the 331C group were male, 100% of animals in the high-dose bisphenol A and 17b-estradiol group were female. Although there was no sex reversal in the low-dose bisphenol A or 17b-estradiol groups incubated at 331C, morphometric evaluations at 10 days of age revealed significantly increased perimeter of seminiferous tubules, which had empty lumens. There 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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12.. Padmanabhan. V,. Siefert. K,.
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In..Research.Triangle.Park,.NC:.RTI
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65.. Alonso-Magdalena. P,. Laribi.
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91.. Calabrese.EJ,.Baldwin.LA.(2003
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Thyroid.Function.in.Juvenile.Female
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droxylase.immunoreactivity..76:423.
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stanceschimiques.gc.ca/challenge-de
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Watanabe.H,.Ohta.Y,.Iguchi.T.(2006)
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226..vom. Saal. FS,. Cooke. PS,. Bu
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solid.phase.extraction-high.perform
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appendix i. nTp-Cerhr bisphenol a e
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158 CHAPIN ET AL. the CERHR Core Co
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160 CHAPIN ET AL. referred to as 4,
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162 CHAPIN ET AL. concentrations in
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164 CHAPIN ET AL. Food (no. sampled
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166 CHAPIN ET AL. Table 6 Continued
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168 CHAPIN ET AL. comparison of the
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170 CHAPIN ET AL. Table 8 Urinary C
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172 CHAPIN ET AL. the blood of male
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174 CHAPIN ET AL. Table 11 Bispheno
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176 CHAPIN ET AL. Table 13 Summarie
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178 CHAPIN ET AL. Table 15 Estimate
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180 CHAPIN ET AL. Table 17 Maximum
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182 CHAPIN ET AL. 2.0 GENERAL TOXIC
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184 CHAPIN ET AL. fetuses (3.572.7
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186 CHAPIN ET AL. Secondary sources
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188 CHAPIN ET AL. Table 25 Maternal
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190 CHAPIN ET AL. Table 27 Bispheno
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192 CHAPIN ET AL. Table 31 Qualitat
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194 CHAPIN ET AL. Table 33 Toxicoki
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198 CHAPIN ET AL. appeared to occur
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200 CHAPIN ET AL. Table 43 Biliary
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202 CHAPIN ET AL. suggesting that 4
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204 CHAPIN ET AL. low following ora
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206 CHAPIN ET AL. scaling and speci
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208 CHAPIN ET AL. 60-100% in each d
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210 CHAPIN ET AL. related. No histo
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212 CHAPIN ET AL. Table 52 Continue
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214 CHAPIN ET AL. Model and exposur
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216 CHAPIN ET AL. Model and exposur
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218 Model and exposure Husbandry a
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220 CHAPIN ET AL. Table 54 Differen
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222 CHAPIN ET AL. Table 56 Anti-And
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224 Table 57 In Vitro Genetic Toxic
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226 CHAPIN ET AL. Table 58 In Vivo
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228 CHAPIN ET AL. Table 59 Developm
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232 CHAPIN ET AL. Table 64 Tissue R
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236 CHAPIN ET AL. treatment conditi
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238 CHAPIN ET AL. clinical signs, b
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240 CHAPIN ET AL. Table 71 Benchmar
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242 CHAPIN ET AL. group, 5 from 1 l
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244 CHAPIN ET AL. least significant
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246 CHAPIN ET AL. group was a reduc
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248 CHAPIN ET AL. 100-151 g for fem
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250 CHAPIN ET AL. 3.2.3.2 Developme
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252 CHAPIN ET AL. weights, bispheno
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254 CHAPIN ET AL. 120 mg/kg bw/day
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256 CHAPIN ET AL. comparisons condu
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258 CHAPIN ET AL. the findings of t
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260 CHAPIN ET AL. analyzed.] Anogen
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
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: 312 CHAPIN ET AL. used for extracti
Page 239 and 240: 316 CHAPIN ET AL. of testes and com
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-
Page 283 and 284: 360 CHAPIN ET AL. following adjustm
Page 285 and 286: 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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