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

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killed on GD 18 (plug 5 GD 0) for determination of litter size, fetal weight, and sex ratio. The uterus and right ovary were removed from each dam, fixed in Bouin fluid, and sections were stained with hematoxylin and eosin for light microscopy. Results were analyzed with least significant difference test [apparently on a per fetus basis]. Maternal weight was not altered by treatment. Fetal body weight was decreased in the high-dose group by 14% for males and 12% for females. There was no effect on litter size or sex ratio. There was no treatment effect on dam uterine or ovarian weight. Histopathology of the dam ovary was reportedly not affected by treatment. Histopathology of the dam uterus showed thickening of the endometrium in the 0.05 and 0.5 mg/kg bw groups and uterine muscle damage in the 5 mg/kg bw group. [The damage is not otherwise described. The photomicrographs available in the report were not interpretable due to poor reproduction quality.] The authors concluded that bisphenol A at low doses does not produce reproductive toxicity in mice. [This study was written in Korean with an English abstract and tables. A translation was provided to CERHR by the American Plastics Council.] Strengths/Weaknesses: The use of 3 dose levels is a strength. The lack of information on husbandry conditions, the i.p. dose route, failure to account for litter effects in statistical analyses, and the poor presentation of histopathology results are weaknesses. Utility (Adequacy) for CERHR Evaluation Process: This study is inadequate for the evaluation process. Park et al. (2005a), support not indicated, treated ICR mice during pregnancy. Bisphenol A [purity not indicated] in corn oil was given i.p. at dose levels of 0, 0.05, 0.5, or 5 mg/kg bw on the day of mating, and every 3 days for a total of 6 doses (n 5 3–6/group). Offspring were evaluated on PND 45 for body weight, reproductive organ weight and histopathology, semen analysis, complete blood count, and serum chemistry. [There were 24 female and male offspring evaluated per dose group (not indicated whether 12 of each sex). Litter of origin appears not to have been considered. No information was provided on standardization of litters, diet, or cage/ bedding materials.] Statistical analysis was performed using the least significant difference test. [It was not clear if the litter or offspring was considered the statistical unit.] There was a statistically significant 6% decrease in male body weight in the high-dose group; a comparable body weight decrement in female offspring was not statistically significant. There were no statistically significant treatment effects on the weights of the testis, epididymis, seminal vesicles, coagulating glands, uterus, or ovary. Sperm concentration, viability, motility, and morphology were not affected by treatment. Blood endpoints were not affected by treatment except for a statistically significant 6% increase in erythrocyte count in male offspring and a 2% decrease in serum albumin in female offspring. An 11% increase in blood urea nitrogen in mid-dose female offspring was not dose-related. Histopathology of the testis and ovaries was described as unaffected by treatment. Uterine intimal proliferation was described in the mid- and high-dose female offspring. [The histological methods were not described. The photomicrographs available in the report were not Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 295 interpretable due to poor reproduction quality.] The authors concluded that bisphenol A at low doses does not produce reproductive toxicity in mice. [This study was written in Korean with an English abstract and tables. A translation was provided to CERHR by the American Plastics Council.] Strengths/Weaknesses: The inadequate description of methods, unacceptable small sample size, the i.p. dosing, inappropriate statistical analyses, and the poor presentation of histology results are weaknesses of this study. Utility (Adequacy) for CERHR Evaluation Process: This study is inadequate for the evaluation process due to the reasons stated above. Sato et al. (2001), support not indicated, investigated the effects in mice of in utero exposure to bisphenol A on fetal growth, offspring reproductive and brain development, and behavior. Pregnant Jcl-ICR mice (n 5 20) were given s.c. injections of bisphenol A [purity not indicated] 100 mg/kg bw/day, ethinyl estradiol 0.2 or 0.02 mg/kg bw/day, or olive oil vehicle on GD 11–19 [Plug day was not defined. Information regarding caging material, animals per cage, feed, culling, and weaning was not provided.] Pups were evaluated for onset of pivoting, righting, straight line walking, and grasp reflex. Open field testing was conducted at 40 days of age. Offspring were killed at 40 or 60 days of age and organs were weighed and processed for histology using hematoxylin and eosin [fixation method not given]. Brain myelin was evaluated using Klü ver-Barrera staining. Statistical analyses were performed using the Student ttest. [The pup appears to have been used as the statistical unit.] There were 11/93 stillborn fetuses after in utero exposure to bisphenol A, but no data were provided for the control group. There were no significant effects of bisphenol A treatment on litter size or offspring body weight at birth, 20, or 60 days of age. There were no significant effects of bisphenol A treatment on days at acquisition of pivoting, righting, straight-line walking, or grasp reflexes. In open field testing, mice in the bisphenol A-treated group showed significantly less defecation than controls [39% less]. There was no statistically significant difference between groups in grooming, rearing, line-crossing of inner and outer fields, or latency to first line crossing. At 60 days of age, seminiferous tubules from bisphenol A-exposed male offspring had a significant reduction in mean diameter [k16.6%] and cell layer thickness [k25%] compared to controls. There was no significant bisphenol A effect on brain myelination at 60 days of age or in mean diameter at 40 and 60 days of age of the tractus mamillothalamics. The authors suggest that in utero exposure to 100 mg/kg bw/day bisphenol A induces alterations in behavior similar to that seen at reduced plasma corticosterone levels and that bisphenol A exposure induces gross and cellular changes in seminiferous tubules, suggesting potential perturbation in hormone pathways involved in development. Strengths/Weaknesses: The use of multiple doses of estrogen as a positive control is a strength. Weaknesses include the evaluation of a single dose of BPA, subcutaneous dosing, and lack of details regarding husbandry. Behavioral methods were chosen from less sophisticated screening approaches and data were not analyzed appropriately using the litter as the statistical
296 CHAPIN ET AL. unit. Further, there is no description of sex ratios in groups given behavioral testing, despite established sex differences in endpoints measured in the open field evaluation. As a result, behavioral findings are unreliable. Utility (Adequacy) for CERHR Evaluation Process: This study is inadequate for inclusion in the evaluation process due to the reasons stated above. Rubin et al. (2006), supported by NIEHS, examined sexual differentiation in mice perinatally exposed to bisphenol A. Animals were fed rodent diet 2018 (Harlan Teklad, St. Louis, MO), which was reported to have negligible for estrogenicity (20 fmol 17b-estradiol equivalents/g). Caging and bedding materials were not indicated but were reported to have negligible estrogenic activity in the E-SCREEN assay. Water was supplied in glass bottles. On GD 8 (GD 1 5 day of vaginal plug) through Day 16 of lactation, CD-1 mice were s.c. dosed by osmotic pump with the 50% DMSO vehicle or bisphenol A [purity not reported] at 0.000025 or 0.000250 mg/kg bw/day. [The numbers of dams exposed was not indicated.] Litters were culled to 8 pups (4/sex) on the day following birth. Litters were weaned on PND 22–24 (day of birth not defined). Anatomical examination and assessment of tyrosine hydroxylase neurons in the anteroventral periventricular preoptic area by an immunohistochemistry technique were conducted before puberty (PND 22–24) in 7 or 8 offspring/ sex/group (2/sex/litter). Open-field testing was conducted in 14–17 offspring/group (1 offspring/sex/litter) at 6–9 weeks of age. The study authors expressed concern about possible hormonal effects because their historical records indicated that regular estrous cycles are not observed in group-housed females at 6–9 weeks of age. Therefore, open-field testing was repeated in 27–29-dayold offspring (n 5 10–12/sex/group) exposed to 0 or 0.000250 mg/kg bw/day bisphenol A. Statistical analyses included 2-way ANOVA, t-test, and ANOVA with Bonferroni post-hoc test. In control offspring, the total number of tissue sections through the anteroventral periventricular preoptic area was greater in females than males, but the sexually dimorphic difference was not observed in either treatment group. The number of sections through the anteroventral periventricular preoptic area was significantly lower in females from the high-dose bisphenol A than control group. In the control offspring, the number of tyrosine hydroxylase-positive neurons in the anteroventral periventricular preoptic area was higher in females and in males but this sexually dimorphic difference was not observed in the high-dose group. The number of tyrosine hydroxylase-positive neurons in the anteroventral periventricular preoptic area was lower in females in the high-dose bisphenol A than control group. The results for tyrosine hydroxylase-positive neurons were based on counting of all sections. When counting was limited to 7 sections or 4mid-sections, the sexually-dimorphic difference observed for tyrosine hydroxylase-positive neurons in the control group was not observed in either treatment group. When limited to 3 caudal sections, the sexually dimorphic difference observed for tyrosine hydroxylase-positive neurons was maintained in the low-dose group and was borderline significant (P 5 0.06) in the high-dose group. Bisphenol A exposure had no significant effect on the number of tyrosine hydroxylase-positive neurons in the arcuate nucleus. In open-field testing of 6–9-week-old animals, significant effects in control females compared to control males included more rearing and time spent in the center and less time stopped. Sexually dimorphic differences in rearing and time spent in center were not observed in either bisphenol A treatment group and the sexually dimorphic difference in time stopped was not observed in the low-dose group. In open-field testing conducted at 4 weeks of age, control females compared to males reared more times and spent less time stopped. The sexually dimorphic differences were not observed in animals exposed to 0.000250 mg/kg bw/day (the only dose tested in 4-week-old animals). The number of rearings was significantly lower in 4-week-old females in the 0.000250 mg/kg bw/day group than in controls. The study authors concluded that bisphenol A may alter important events during critical periods of brain development. Strengths/Weaknesses: The strengths of this study are the care taken to control for extraneous estrogenic exposure, the delivery of BPA at 2 doses, both low, delivery from GD 1–PND 16, the reasonable sample sizes, and the inclusion as outcome measurements of behavior, anatomy, and an index of neurochemical effects in the brain. Significant weaknesses include the use of s.c. osmotic pumps, uncertainty about sample size, and whether litter effects were adequately controlled. Utility (Adequacy) for CERHR Evaluation Process: This is inadequate for the evaluation process due to the combination of route of administration and statistical concerns. Toyama (2005), supported in part by the Japanese Ministry of Education, Culture, Sports Science, and Technology, examined the effects of prenatal Bisphenol A exposure in CL/P mice, a strain with a high background rate of cleft lip/palate. The study was published in Japanese and a translation was provided by the American Plastics Council. Mice were fed CA-1 (Japan CLEA, Inc.). [No information was provided about caging or bedding materials.] On GD 9.5 (GD 0 5 day of vaginal plug), 25 dams/group were s.c. dosed with olive oil vehicle or bisphenol A [purity not reported] at 0.001, 0.01, 0.1, 1, or 10 mg/kg bw. Dams were killed on GD 18 and fetuses (169–184/group) were examined for cleft lip/palate or thymic anomaly (i.e., hypoplasia). Data were analyzed by Student t-test and w 2 test. [It appears that offspring were considered the statistical unit.] There were no significant differences for numbers of implantations or fetal survival. The incidence of cleft lip/ palate in fetuses from the control and each respective treatment group was 8.3, 8.0, 6.1, 1.8, 4.9, and 6.2%. There were no differences in the types of cleft palate observed in each group. Incidence of thymic anomaly in the control and each respective dose group was 11.8, 10.8, 6.1, 1.8, 4.9, and 6.2%. Incidence of cleft/lip palate or thymus anomalies was lower in bisphenol A-treated than control groups and was lowest in the 0.1 mg/kg bw bisphenol A group. [Results of statistical analyses for cleft lip/palate and thymic anomaly were difficult to interpret.] A higher tendency for complication of cleft lip/palate and thymus hypoplasia [possibly fetuses with both types of defects] was observed in the bisphenol A groups; respective incidences in the control Birth Defects Research (Part B) 83:157–395, 2008
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National Toxicology Program U.S. De
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NTP.will.transmit.the.NTP-CERHR.<st
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National Toxicology Program U.S. De
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nTp brief tainers.with.internal.epo
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Population Adult General. Populatio
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Table 3. Blood and Breast Milk Biom
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Figure 2b. The weight of evidence t
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in.considering.the.biological.plaus
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isphenol.A.as.efficiently.as.adult.
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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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cutaneous. injection. 20 . vom. Saa
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are CurrenT exposures To bisphenol
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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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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
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
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: 294 CHAPIN ET AL. buffered paraform
Page 221 and 222: 298 CHAPIN ET AL. PND 21 and housed
Page 223 and 224: 300 CHAPIN ET AL. Tando et al. (200
Page 225 and 226: 302 CHAPIN ET AL. Purina Certified
Page 227 and 228: 304 CHAPIN ET AL. high-doses of bis
Page 229 and 230: 306 CHAPIN ET AL. born to those dam
Page 231 and 232: 308 CHAPIN ET AL. average weight we
Page 233 and 234: 310 CHAPIN ET AL. study authors con
Page 235 and 236: 312 CHAPIN ET AL. used for extracti
Page 237 and 238: 314 CHAPIN ET AL. jar, and there we
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
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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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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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