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

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Utility (Adequacy) for CERHR Evaluation Process: This study is inadequate for the evaluation process based on the limitations noted above. Matsumoto et al. (2004), support not indicated, examined the effect of maternal bisphenol A exposure on growth of offspring in mice. Mice were fed standard rodent chow (CE-2, Japan Clea). [No information was provided on caging and bedding materials.] Mice of the ddY strain were exposed to bisphenol A (Z97% purity) through feed at 0 or 1% from GD 14–PND 7. The study authors stated that the bisphenol A dose was equivalent to 1000 mg/kg bw/day. [The number of dams treated was not indicated. Day of vaginal plug and day of birth were not defined]. Mice delivered pups on PND 21. During the postnatal period, body weight was monitored in 31 pups from the control group and 61–89 pups from the bisphenol A group. Serum prolactin levels were measured by RIA in 3 dams/group 4 days following delivery. Pups were killed on PND 7, and stomach weight was measured. Data were analyzed by Student ttest. [It was not clear if the litter or offspring was considered the statistical unit.] No differences were reported for live pups at birth. During the postnatal period, body weights of pups in the bisphenol A group were significantly lower [by B40%] than control group pups. No deaths were reported for pups in the control group, but 30% of pups in the bisphenol A group died before PND 7. On PND 1, milk could be seen in stomachs of pups from the control group, but not the bisphenol A group. [The number of pups evaluated for milk in stomach was not reported.] On PND 7, stomach weight was significantly lower [by 40%] in pups from the bisphenol A than control group. Serum prolactin level was significantly reduced [by 46%] in dams from the bisphenol A group. The authors concluded that administration of a high bisphenol A dose to mice resulted in suppressed postnatal growth of offspring that probably resulted from an insufficient supply of milk, which might have been due to decreased prolactin secretion. [Because of the implications of this study for lactation competence, this study will be discussed again in Section 4.2.] Strengths/Weaknesses: Weaknesses of the study are the difficulty in calculating bisphenol A intake, the likely high exposure level, the lack of information on dam number and husbandry, and the high level of pup body weight decrement and mortality. Utility (Adequacy) for CERHR Evaluation Process: This study is inadequate for the evaluation process due to the reasons stated above. Suzuki et al. (2003), supported by the Japanese Ministry of Health, Labor, and Welfare and the Ministry of Education, Culture, Sports, Science, and Technology conducted a study to determine the effect of prenatal bisphenol A exposure on dopamine-receptor mediated actions in mice. Female ddY mice were fed chow containing bisphenol A at 0.002, 0.5, or 2 mg/g feed from mating through weaning of offspring. [No information was provided on the number of dams treated, purity of bisphenol A, or the type of chow, bedding, or caging materials. Assuming a female mouse eats B0.2 kg feed/kg bw/day (USEPA, 1988), bisphenol A intake would have been 0.4, 100, or 400 mg/ kg bw/day.] Male offspring were subjected to a series of tests [age at testing not stated]. In a conditioned place- Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 299 preference test, groups of 6–10 mice were injected with 0.5 mg/kg bw methamphetamine and placed in either the dark or light area of the test apparatus for 3 days. On the other 3 days, males were injected with saline and placed in the other compartment of the testing apparatus. On Day 7, the divider in the apparatus was raised and the time spent in each compartment was measured. Activity was measured in groups of 9–10 mice for 3 hr following injection with saline or 2 mg/kg bw methamphetamine. Dopamine-induced binding of 35 S-guanosine-5 0 [g-thio]-triphosphate in the limbic system was measured (n 5 3 samples/group). Protein levels of dopamine and vesicle monoamine transporters in brain were determined by Western blot (n 5 6 samples), and mRNA levels of dopamine receptor in brain were determined by RT-PCR. Data were analyzed by ANOVA with Bonferroni/Dunnett test. [It was not clear if the litter or offspring was considered the statistical unit.] In conditioned-preference testing, exposure to all 3 bisphenol A doses resulted in a significant and doserelated increase in preference for compartments associated with methamphetamine exposure. [Control mice showed no compartment preferences while the times spent in the methamphetamine-associated compartment were B150, 200, and 275 sec by animals in each respective dose group.] Preference for the methamphetamine compartment was eliminated by injecting the animals with SCH23390, A dopamine D 1 receptor antagonist. In mice exposed to the high-dose of bisphenol A, activity was significantly increased [by B80% at peak] compared to the control group following methamphetamine challenge, and sensitization to methamphetamine-induced activity was also enhanced. Dopamineinduced binding of 35 S-guanosine-5 0 [g-thio]-triphosphate in the limbic system was potentiated [increased by B15%; not clear if statistically significant] and Gprotein activation was increased [by B75%] in mice exposed to the high bisphenol A dose. The effects on Gprotein activation were eliminated following injection with SCH23390 or sulpiride, a dopamine D2 receptor antagonist. No changes were observed for expression of dopamine and vesicle monoamine transporter proteins. Expression of dopamine D 1 receptor mRNA was upregulated significantly to 130% of control levels in the highdose bisphenol A group. [For all endpoints except for conditioned preference, only the data from the highdose bisphenol A group was shown. It was not clear if that was the only dose tested for those endpoints or if the high-dose data were shown because it was the only dose that resulted in a statistically significant effect.] The study authors concluded that ‘‘prenatal and neonatal exposure to bisphenol A can potentiate central dopamine D1 receptor-dependent neurotransmission, resulting in supersensitivity of methamphetamine-induced pharmacological actions related to psychological dependence on psychostimulants.’’ Strengths/Weaknesses: Strengths include a wide range of doses administered orally. Weaknesses include absence of adequate experimental details, inappropriate statistical procedures that did not account for litter or repeated measurement, inadequate presentation of body weight data, and use of high-doses. Utility (Adequacy) for CERHR Evaluation Process: This study is inadequate for the evaluation process due to the reasons stated above.
300 CHAPIN ET AL. Tando et al. (2007), supported by the Japanese Ministries, investigated the effects of bisphenol A exposure in the maternal diet during the prenatal and lactational period on the long-term development of the cortex and substantia nigra. ddY mice were maintained under a 12-hr/12-hr light/dark cycle before mating. From GD 0 through weaning on PND 21, dams had free access to a diet containing bisphenol A (purity 499%) at 0, 3, or 8000 mg/kg feed. Pups were weaned on PND 21 to a diet without bisphenol A. [The basal feed, cage, and bedding were not specified. Daily feed consumption was not reported. Assuming a pregnant mouse eats B0.15 kg feed/kg bw/day and a lactating mouse eats B0.45 kg feed/kg bw/day, bisphenol A intake would have been B0, 4.5, or 1200 mg/kg bw/day during gestation and B0, 1.35, or 3600 mg/kg bw/day during lactation.] At 8–11 weeks of age, male and female offspring (n 5 4 and 5/sex/treatment group) were killed and formalin-perfused. Brains were harvested and embedded in paraffin. Immunohistochemical detection for tyrosine hydroxylase, calbindin D-28 K, calretinin, and parvalbumin proteins were performed. In situ TUNEL was also performed. Statistical analyses use ANOVA and post-hoc test using the Bonferroni/Dunn multiple comparison test. [It was not clear if the litter or offspring was considered the statistical unit.] No cytoarchitectural anomalies were seen in brain sections of either sex across treatment groups, based on hematoxylin-eosin and Kluver-Barrera stains. [Data were not shown.] The distribution and density of immunopositive staining for calbindin D-28 K, calretinin, and parvalbumin showed no statistically significant differences in low or high-dose bisphenol A exposed groups. Female offspring exposed to the lower dose level of bisphenol A exhibited a significant decrease in the volume of the substantia nigra. The number of tyrosine hydroxlyasepositive nuclei and fibers in this region was significantly reduced in low-bisphenol exposed female mice compared to control females and high-dose bisphenol A-exposed females [k18%, and 16%, respectively, estimated from a graph]. No significant differences in number of tyrosine hydroxylase positive cells were identified in bisphenol Aexposed males. Decreased values in immunopositive staining could not be attributed to apoptosis, based on TUNEL staining [data not shown]. The authors concluded that there were sex- and dosespecific sensitivities of the developing substantia nigra, in the DDY mice with females exposed to a low but not a high-dose of bisphenol A showing a significant reduction in the number of tyrosine hydroxylase-positive nuclei. They indicated that the functional significance of this reduction was unknown. The authors suggested a putative mechanism involving interaction of bisphenol A with ERb, which is abundantly present in the developing substantia nigra. Strengths/Weaknesses: Strengths of this study are that BPA was delivered orally to the dams during the gestational and lactational period and the use of appropriate methods for assay of the anatomical and some molecular aspects of brain development. Weaknesses include the lack of specification of the feed, broad range of the two doses used, small sample size given high variability of endpoints (4 and 5/sex/treatment group), and absence of expected sexually dimorphisms in measures in the controls. Utility (Adequacy) for CERHR Evaluation Process: This study is inadequate and not useful for the evaluation process for the reasons stated above. Mizuo et al. (2004), supported by the Japanese Ministry of Health, Labor, and Welfare and the Ministry of Education, Culture, Sports, Science, and Technology, examined the effect of perinatal bisphenol A exposure on morphine-induced rewarding effects and hyperlocomotion in mice. Testing was conducted in offspring of ddY mice that received chow containing 0, 0.002, 0.5, or 2 mg bisphenol A/g feed [0, 2, 500, or 2000 ppm] during gestation and the neonatal period of pup development. [No information was provided on the number of dams treated/group, purity of bisphenol A, or feed, caging, or bedding materials.] In place-conditioning testing, 6–10 offspring/group were placed in one compartment of a testing apparatus following saline injection and in a second compartment of the apparatus following morphine injection; on the second day, mice were given free access to both compartments and the time spent in each compartment was measured. Locomotor activity was measured after injecting 9–10 mice/bisphenol A group with saline or 10 mg/kg bw morphine. Guanosine-5 0 diphosphate binding and expression of m-opioid receptor mRNA were measured in 3 independent samples/group. Statistical analyses included 2-way ANOVA with Bonferroni/Dunnett test. [No information was given on the ages that testing was conducted and the sex of mice tested. It was not clear if the litter or offspring was considered the statistical unit.] In place-preference conditioning testing, a dose-dependent increase was observed for the time spent in the compartment associated with morphine exposure and statistical significance was attained at the two highest dose levels. [The time spent in the morphine-associated compartment was B15 sec for controls, 150 sec for the mid-dose group, and 175 sec for the high-dose group.] Locomotion in the high-dose bisphenol A group was significantly increased following morphine injection [B130 compared to 10 activity counts in high-dose bisphenol A group compared to the control]. Bisphenol A treatment had no effect on guanosine-5 0 -diphosphate binding (i.e., m-opioid receptor mediated G-protein activation) or expression of m-opioid receptor mRNA. The study authors concluded that chronic exposure to bisphenol A induces morphine-induced rewarding effect and hyperlocomotion that does not occur through activation of the m-opioid receptor. Strengths/Weaknesses: Strengths of this study are that BPA was delivered orally to the dams during the gestational and lactational period. Weaknesses include the lack of specification of the feed, broad range of the two doses used, small sample size (n 5 6–10) and inappropriate statistics that do not account for litter or repeated measures. Utility (Adequacy) for CERHR Evaluation Process: This study is inadequate and not useful for the evaluation process. Miyatake et al. (2006), supported by the Japanese Ministry of Health, Labor, and Welfare and the Ministry of Education, examined the effects of developmental bisphenol A exposure on morphine-induced rewarding effects in male ddY mice. Maternal mice were orally exposed to olive oil vehicle, bisphenol A [purity not indicated] at 0.003 or 200 mg/kg bw/day, or 17b 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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concentrations.from.maternal,.fetal
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appendix i. nTp-Cerhr bisphenol a e
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158 CHAPIN ET AL. the CERHR Core Co
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160 CHAPIN ET AL. referred to as 4,
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162 CHAPIN ET AL. concentrations in
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164 CHAPIN ET AL. Food (no. sampled
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166 CHAPIN ET AL. Table 6 Continued
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168 CHAPIN ET AL. comparison of the
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170 CHAPIN ET AL. Table 8 Urinary C
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172 CHAPIN ET AL. the blood of male
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174 CHAPIN ET AL. Table 11 Bispheno
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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
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 and 218: 294 CHAPIN ET AL. buffered paraform
Page 219 and 220: 296 CHAPIN ET AL. unit. Further, th
Page 221: 298 CHAPIN ET AL. PND 21 and housed
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
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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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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