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

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Experiment 1 2 3 4 5 BISPHENOL A 343 Table 89 Conditions Used in Experiments to Study Bisphenol A Effects on Sperm Production in Rats a Bisphenol A doses mg/kg bw/day No. rats/group Diet/water Caging 0, 0.020, 2, or 200 0, 0.020, 2, or 200 0, 0.020, 2, or 200 0, 0.020, 2, or 200 0 a Ashby et al. (2003). 10 10 10/bisphenol A group 20/control group 10/bisphenol A group 20/control group 10 To obtain more dose–response information, Sakaue et al. (2001) repeated the study in 8 rats/group dosed [assumed by gavage as in the first study] with 0.000002, 0.00002, 0.0002, 0.002, 0.020, 0.200, or 2 mg/kg bw/day bisphenol A. [It is assumed that ages of rats, treatment period, and observation periods were the same as in the first study.] Body and testis weights were not affected by bisphenol A treatment at Week 18. At Week 18, significant decreases in daily sperm production and daily sperm production/g tissue were observed at 0.020, 0.200, and 2 mg/kg bw/day. [The decrease compared to control was estimated from a graph. For daily sperm production, the decreases were B30% at 0.020 mg/kg bw/day, B34% at 0.200 mg/kg bw/day, and B32% at 2 mg/kg bw/day. For daily sperm production/g tissue, the decreases were B24% at 0.020 mg/kg bw/day, B32% at 0.200 mg/kg bw/day, and B28% at 2 mg/kg bw/day.] In a third experiment, rats were given a single oral dose of 0.020 mg/kg bw bisphenol A. Six hours later, the rats were killed, the right testis was homogenized, and the cytosol was examined for protein expression using two-dimensional polyacrylamide gel electrophoresis. Changes in intensity and mobility were noted for 3 unidentified proteins. The study authors concluded that the dose–response curve for bisphenol A affects on spermatogenesis in the adult rat was monotonic rather than having an inverted U-shape. Strengths/Weaknesses: This study used a relevant route of administration and multiple doses. A weakness is the brief exposure period. Variability in control daily sperm production between the first and second study is disturbing; given the small sample (5 or 8/group), this variability severely decreases confidence in the data. No histopathologic correlate was presented. Utility (Adequacy) for CERHR Evaluation Process: This study is adequate but of limited utility due to small sample and variable control values between experiments. Ashby et al. (2003), support not indicated, examined the effects of bisphenol A exposure on sperm production in rats. The study attempted to replicate earlier findings from Sakaue et al. (2001). Five independent experiments were conducted, and the conditions for each experiment are summarized in Table 89. Some of the experiments used the same conditions as the Sakaue et al. (2001) study, including stainless steel cages with no bedding, CE2 diet (CLEA, Tokyo, Japan), and glass water bottles. In the first 4 studies, 10–20 adult (B13-week-old) Sprague–Dawley rats/group were gavaged with bisphenol A (99% purity) at 0 (ethanol/corn oil vehicle), 0.020, Birth Defects Research (Part B) 83:157–395, 2008 RM3/Automatic system 5002/Glass bottles 5002/ Glass bottles CE2/ Glass bottles RM3, 5002, or CE2/not specified Stainless steel, unspecified bedding Stainless steel, no bedding Stainless steel, no bedding Stainless steel, no bedding Not specified 2, or 200 mg/kg bw/day for 6 days. Concentrations of dosing solutions were verified. In the fifth study, rats fed different diets were gavaged with vehicle for 6 days. Rats were fed 1 of 3 diets as indicated in Table 89. Phytoestrogen aglycone content of the feed was measured. Respective concentrations of daidzein, genistein, and coumestrol in each feed were reported at 94, 62, and 0.6 mg/g diet for Rat and Mouse No. 3 (RM3; Special Diet Services Ltd.); 40, 23, and 0.1 mg/g diet for 5002 (Purina Mills); and 157, 106, and 2.2 mg/g CE2 diet. Ten rats were used in each group, except in third and fourth studies, where 20 control rats were split into 2 groups before dosing. Rats were administered drinking water through an automatic system in the first study and via glass bottles in the other studies. In the first study, rats were housed 3/cage at the start of the study and 2/cage later in the study. In the other 4 studies, rats were housed 2/ cage. Rats were weighed during the study. Animals were killed at 18 weeks of age, 5 weeks after the start of dosing. Liver, kidney, and reproductive organs were weighed, and sperm counts were obtained. In the first 4 studies, data were analyzed by ANOVA, ANCOVA for organ and body weights, and Dunnett test. Results from all 4 studies were also analyzed by ANOVA in an attempt to increase study power. Data from the fifth study were analyzed by Fisher least significant difference test. In the 4 studies that compared the effects of bisphenol A exposure to a vehicle control group, there were no significant effects of bisphenol A exposure on sperm count, daily sperm production, or weights of body, liver, kidney, testis, prostate, epididymis, or seminal vesicle. One animal exposed to 200 mg/kg bw/day bisphenol A in the third study was reported to have unexpectedly small testes and epididymides, but the study authors indicated that inclusion of this animal in later statistical analyses had no effect on outcome. One animal in the 200 mg/kg bw/day group in the fourth study had a small testis. No significant effects were observed when data from the first 4 experiments were pooled and analyzed. The study authors noted that some endpoints were variable from one experiment to the other. It was noted that prostate weights were 10% lower in animals from Experiment 1 than from Experiments 2–4. Sperm counts and daily sperm production were reportedly different in control animals from Experiment 1 compared to Experiment 2. It was noted that rats were fed different diets in Experiment 1 (RM3) and Experiment 2 (5002), and a study to examine the effects of feed was conducted. In the study examining effects in rats fed
344 CHAPIN ET AL. different diets but exposed to vehicle, no effects of diet on daily sperm production were observed. The only significant effect reported was a 9% lower weight of right epididymis in rats fed CE2 compared to RM3 or 5002 feed. The study authors stated that the effect was likely spurious due to lack of effect on other endpoints, no effect on left or total epididymis weight, and lack of the effect in the first 4 experiments. The study authors concluded that there was no evidence in their study that bisphenol A affected reproductive organ weights or daily sperm production. Lack of bisphenol A-induced effect on daily sperm production was in contrast to observations of the Sakaue et al. (2001) study, which reported a decrease in this endpoint. Subtle genetic differences in the rats were suggested as a possible reason for differences in results between the 2 studies. Given the robustness and comprehensiveness of this study, it is highly useful. It strongly suggests that the NOAEL for potential bisphenol A-mediated effects on the adult rat reproductive system exceeds 200 mg/kg/ day. Absence of confirmation of the work of Sakaue et al. (2001) led to an extensive study of the potential variables (e.g., diet, housing, etc.) that might account for the discrepancies. These data suggests that subtle changes in study endpoints, especially daily sperm production and organ weights, may occur by random chance or genetic differences in the respective lab’s supplier of rats may play a role. These data also strongly suggest bisphenol A administered orally has no effect on sperm production albeit following only 6 days of administration. Strengths/Weaknesses: This study reports a well conducted, comprehensive assessment of the potential effects of bisphenol A delivered by 6 daily doses on daily sperm production. The 6-day treatment period is a (understandable) weakness. Utility (Adequacy) for CERHR Evaluation Process: This study is adequate and useful for the evaluation process. Tohei et al. (2001), supported in part by the Japan Society for the Promotion of Science, examined the effects of bisphenol A exposure on testicular function of Wistar–Imamichi rats. [No information was provided about composition of chow, bedding, or caging.] In a series of studies, rats were dosed with bisphenol A [purity not indicated] in sesame oil by s.c. injection for 2 weeks. Bisphenol A doses were 0.1 or 1 mg/day [B0.3 or 3 mg/kg bw/day based on the reported body weights of 300–350 g]. The dose of 1 mg/day bisphenol A was stated to be similar to the highest exposures reported in humans, which were based on saliva levels measured in patients receiving composite dental sealants. Doses and exposure duration were based on results of preliminary studies. Five or 6 animals/dose group were used in each experiment. Statistical analyses included ANOVA, Fisher protected least significant difference test, and Mann–Whitney U test. In the first study conducted to examine testicular and pituitary function, LH, FSH, prolactin, testosterone, and inhibin were measured in plasma, pituitary, and/or testis by RIA in rats s.c. dosed with 1 mg/day bisphenol A for 2 weeks. Statistically significant effects [percent differences compared to controls, as estimated from a graph] included increases in plasma levels of LH [150%] and prolactin [1067%] and decreases in levels of plasma testosterone [29%] and testicular inhibin [36%]. In a second experiment to examine testicular response, rats were s.c. dosed with 0.1 or 1 mg/day bisphenol A for 2 weeks. The rats then received 10 IU hCG through an atrial cannula. Blood samples were drawn for measurement of progesterone and testosterone levels before and at various time intervals between 30 and 180 min following the hCG challenge. Plasma progesterone and testosterone levels were increased following the hCG challenge in control rats. In the bisphenol A-treated rats, only a slight increase in progesterone levels occurred 30 min following challenge, and plasma progesterone levels were significantly lower compared to the control group at 60–150 min following challenge. There was an increase in plasma testosterone level following challenge of the bisphenol A group, but values were significantly lower than control values at 90–120 min following the challenge. In a third experiment examining pituitary response, adult male rats were castrated 5 days before bisphenol A treatment. Castrated rats were s.c. injected with 1 mg/ day bisphenol A and 75 mg/day testosterone propionate for 2 weeks. The rats then received 250 ng gonadotropinreleasing hormone by s.c. injection. Plasma LH was measured before and at various time intervals between 0.25 and 4 hr following the gonadotropin-releasing hormone challenge. No statistically significant effects were observed. In a fourth study, males were dosed with 1 mg/day bisphenol A for 2 weeks and then paired with females in proestrus. Sexual function was evaluated by scoring mounts, intromissions, and ejaculations. No significant effects were observed for sexual function. Based on the findings reported in all studies, the study authors concluded that ‘‘The testis is probably a more sensitive site for [bisphenol A] action than the hypothalamuspituitary axis.’’ Strengths/Weaknesses: RIAs appear to have been conducted competently. Subcutaneous is not a relevant route of exposure, and the sample size was limited. Blood collection via decapitation is not appropriate, because decapitation stress affects plasma prolactin and LH secretion. No mention is made of the order of killing. If controls were killed first and the guillotine was not cleaned between uses (and animals were not in separate rooms), there may be serious confounding of the data. Because rat plasma testosterone levels are normally highly variable, the low degree of variability in this study, given the small sample size, is remarkable (B70.12 ng/mL). No functional consequence of the alterations in hormone levels were described. Weaknesses include use of two doses delivered subcutaneously, critically small sample sizes, use of an inappropriate method of plasma collection, the stressful nature of cannula insertion just one day before measurement, and inappropriate statistical analyses that did not account for temporally repeated measures. Utility (Adequacy) for CERHR Evaluation Process: This study is inadequate for the evaluation process. Kim et al. (2002b), supported by the Korean Ministry of Health and Social Welfare, examined the effects of bisphenol A exposure on the male reproductive system. A translation of the study was provided by the American Plastics Council. Four-week-old male F344 rats (7/group) were given bisphenol A in drinking water at 0 (ethanol vehicle), 0.1, 1, 10, or 100 ppm for 13 weeks. According to the study authors, Birth Defects Research (Part B) 83:157–395, 2008
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National Toxicology Program U.S. De
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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
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248 CHAPIN ET AL. 100-151 g for fem
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250 CHAPIN ET AL. 3.2.3.2 Developme
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252 CHAPIN ET AL. weights, bispheno
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254 CHAPIN ET AL. 120 mg/kg bw/day
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256 CHAPIN ET AL. comparisons condu
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258 CHAPIN ET AL. the findings of t
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260 CHAPIN ET AL. analyzed.] Anogen
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262 CHAPIN ET AL. purposeful confou
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264 CHAPIN ET AL. increased lordosi
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266 CHAPIN ET AL. that there was a
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268 CHAPIN ET AL. duration of adver
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270 CHAPIN ET AL. doses of potent e
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272 CHAPIN ET AL. Table 74 Effects
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274 CHAPIN ET AL. reproductive orga
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276 CHAPIN ET AL. tyrosine-hydroxly
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278 CHAPIN ET AL. include small sam
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280 CHAPIN ET AL. males/group. [It
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282 CHAPIN ET AL. termination, whic
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284 CHAPIN ET AL. provided a reliab
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286 CHAPIN ET AL. grooming, and out
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288 CHAPIN ET AL. method of oral do
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290 CHAPIN ET AL. reared by their d
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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
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Page 263 and 264: 340 CHAPIN ET AL. Schirling et al.
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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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Page 287 and 288: 364 CHAPIN ET AL. Table 97 Effects
Page 289 and 290: 366 CHAPIN ET AL. Table 99 Treatmen
Page 291 and 292: 368 CHAPIN ET AL. Therefore the NTP
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Page 297 and 298: 374 Table 101 Summary of High Utili
Page 299 and 300: 376 Table 102 Summary of Limited Ut
Page 303 and 304: 380 CHAPIN ET AL. from other suppli
Page 305 and 306: 382 CHAPIN ET AL. U.S. populations.
Page 307 and 308: 384 CHAPIN ET AL. 10. Critical desi
Page 309 and 310: 386 CHAPIN ET AL. Engel SM, Levy B,
Page 311 and 312: 388 CHAPIN ET AL. alpha and beta ex
Page 313 and 314: 390 CHAPIN ET AL. Murray TJ, Maffin
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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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