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

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oth] was significantly decreased at the highest dose level. There were no other significant effects on microsomal enzymes examined. The study authors concluded that wild mammals such as field voles could be more susceptible to bisphenol A-induced toxicity than laboratory rodents. Strengths/Weaknesses: Strengths include the use of a non-rodent species and multiple doses. Weaknesses include small sample sizes and limited nature of reproductive endpoints as well as the use of the subcutaneous route of administration. Utility (Adequacy) for CERHR Evaluation Process: This study is inadequate for the evaluation. 4.2.2.4 Fish and invertebrates:: Although studies in fish and invertebrates may be important for understanding mechanisms of action and environmental impact, the Panel views these studies as not useful for the evaluation process. Shioda and Wakabayashi (2000), supported by the Japanese Ministry of Education, examined the effects of bisphenol A exposure on reproductive capability of male medaka (Oryzias latipes). Adult male medaka were housed for 2 weeks in glass beakers containing distilled water and bisphenol A [purity not indicated] at 0, 0.3, 1, 3, or 10 mM [0, 0.07, 0.23, 0.69, or 2.3 mg/L]. [The number of male fish treated was not reported. Though not specifically stated, it was suggested that fish in the negative control group were exposed to the acetone vehicle.] Following exposure, each male was housed with two females in beakers containing distilled water. The numbers of eggs spawned, fertilized, and hatched were determined. Statistical analyses included F test followed by t-test or Welch test. Exposure to bisphenol A 10 mM [2.3 mg/L] significantly reduced the number of eggs produced and hatched compared to the negative control group. Additional compounds were also examined, and it was reported that eggs and hatchings were significantly reduced following exposure to 17b-estradiol (Z 3 nM), but not nonylphenol or diethylhexyl phthalate. The study authors concluded that the reproductive effects induced by bisphenol A in this study occurred at a higher concentration than results observed in a yeast estrogen screen. Strengths/Weaknesses: This study appears to have been well conducted study and suggests that bisphenol A 2.3 mg/L in water decreases the number of medaka eggs produced and hatched. Utility (Adequacy) for CERHR Evaluation Process: This study was not considered useful for the evaluation process. Kinnberg and Toft (2003), supported by the Danish Environmental Research Programme, examined the effects of bisphenol A exposure on the reproductive system of male guppies (Poecilia reticulata). Thirty sexually mature male guppies/group were exposed for up to 30 days to bisphenol A [purity not indicated] at nominal concentrations of 0 (acetone vehicle) 5, 50, 500, or 5000 mg/L. Levels of bisphenol A in water were verified. Exposure to the 5000 mg/L concentration was stopped after 21 days because of a high mortality rate. All fish in the high-dose group and 6 fish/group in the lower dose groups were killed and fixed in neutral buffered formalin. Histopathological examination was conducted in whole fish. The mortality rate in the 5000 mg/L group was 77%, but no increase in mortality was observed in the Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 353 lower concentration groups. Testes of fish from the highdose group contained spermatozeugmata (bundles of spermatozoa with heads pointing outward and tails in the center) in ducts, and the authors stated the effect indicated blocked spermatogonial mitosis. [No information was provided on incidence or severity of testicular lesions, and it does not appear that statistical analyses were conducted.] Additional compounds were also tested, and it was indicated that effects induced by flutamide, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene, and 4-tert-octylphenol were similar to those observed with bisphenol A exposure. In contrast, exposure to 0.03 and 0.1 mg/L 17b-estradiol resulted in hypertrophy of Sertoli cells and efferent duct cells. The study authors concluded that a high bisphenol A concentration induced adverse effects on testicular structure. Strengths/Weaknesses: This study appears to have been well conducted. The metabolism of bisphenol A in fish is unknown. It appears the bisphenol A does not exhibit the typical 17b-estradiol-like effect on the testis. Findings occurred at high relative exposures. There was no apparent low-dose effect. Utility (Adequacy) for CERHR Evaluation Process: This study was not considered useful for the evaluation process. Oehlmann et al. (2000), supported by the Berlin Federal Environmental Agency, reported the effects of bisphenol A on reproductive organs in the freshwater ramshorn snail (Marisa cornuarietis) and the marine dog whelk (Nucella lapillus). Details of this study are discussed in Section 4.2.1.4, and most of the findings pertained to female snails. Adult ramshorn snails did not show abnormalities of male sexual organs or gonads after exposure to bisphenol A [purity not indicated] concentrations up to 100 mg/L for 5 months or after exposure for the first year of life. In the dog whelk, a 1-month exposure to 1, 25, or 100 mg/L bisphenol A significantly decreased the proportion of males with sperm in the seminal vesicles compared to the vehicle-exposed control. The length of the penis and prostate gland were also reduced by all concentrations of bisphenol A in this animal. The authors concluded that bisphenol A toxicity occurs in invertebrates at environmentally relevant concentrations. Strengths/Weaknesses: The study appears to have been well conducted and suggests that bisphenol A has an effect on the dog whelk. The potential stability/ biotransformation was discussed in the introduction but not determined during the exposure period. Utility (Adequacy) for CERHR Evaluation Process: This study was not considered useful for the evaluation process. 4.2.2.5 In vitro: While cell culture studies can provide useful insights into cellular and subcellular mechanisms, most of these studies are considered of no utility for the evaluation process. The study by Akingbemi et al. (2004) should nevertheless be considered for mechanistic value, and is considered adequate but of limited utility by the Panel for the evaluation process. Nikula et al. (1999), support not indicated, examined the in vitro effects of bisphenol A on steroidogenesis in mouse Leydig tumor cell cultures. Octyl phenols were also examined in this study, but results will not be discussed. In the first experiment, cells were incubated for 48 hr in media containing bisphenol A [purity not
354 CHAPIN ET AL. indicated] at 0 (ethanol vehicle) or 10 -7 –10 -4 M [0.023– 23 lg/L] or estradiol at 10 -8 M [culture ware type not indicated]. Production of cyclic adenosine monophosphate (cAMP) and progesterone was measured following the incubation period and at 1 and 3 hr following a challenge with 10 ng/mL hCG. In additional experiments, the cells were exposed to bisphenol A at 0 or 10 -6 M [0.23 lg/L] or 17b-estradiol or diethylstilbestrol at 10 -8 M. Production of cAMP and progesterone was measured following the incubation period and at 1 and/or 3 hr following challenge with hCG, forskolin, cholera toxin, or 8-bromo-cAMP. An additional study measured binding of 125 I-hCG to the LH receptor following a 48-hr exposure to bisphenol A at 0 or 10 -6 M [0.23 lg/L]. Each experiment contained 5–8 replicates, and results from 3 independent experiments were pooled. Data were analyzed by ANOVA followed by Fisher test. Bisphenol A had no effect on basal cAMP or progesterone production. At 3 hr following the hCG challenge, the increase in cAMP production was attenuated following previous exposure to bisphenol A at concentrations Z10 -7 M [0.023 lg/L] and increase in progesterone production was reduced at bisphenol A concentrations Z10 -6 M [0.23 lg/L]. At 3 hr following challenge, 10 -6 M [0.23 lg/L] bisphenol A decreased hCG-induced cAMP production but had no effect on forskolin- or cholera toxin-induced cAMP production. Following 3-hr challenges, hCG-induced progesterone production was reduced following exposure to 10 -6 M [0.23 lg/L] bisphenol A, but there were no effects on forskolin-, cholera toxin-, or 8-bromo-cAMP-induced progesterone production. Generally, 17b-estradiol and diethylstilbestrol attenuated hCG-, forskolin, and 8bromo-cAMP-induced progesterone production. Bisphenol A exposure had no effect on binding of 125 I-hCG to the LH receptor. The study authors concluded that bisphenol A appears to inhibit cAMP formation and steroidogenesis in rat Leydig tumor cells by preventing coupling between the LH receptor and adenylate cyclase. Because no inhibition of cAMP production was observed following incubation of cells with 17b-estradiol, the study authors concluded that the effects of bisphenol A may not be estrogen-related. Strengths/Weaknesses: This appears to be a well conducted in vitro study. Stimulation occurred in the absence of steroid-rich fetal bovine serum. There was no mention of whether phenol red-free media were used. Cell viability does not appear to have been determined. Because this study used an in vitro system, the effects of metabolism were limited. Nonetheless, this study provides compelling evidence that the actions of bisphenol A may be non-estrogen mediated. Utility (Adequacy) for CERHR Evaluation Process: This study was not considered useful for the evaluation process. Murono et al. (2001), from the Centers for Disease Control and Prevention, examined the effects of bisphenol A exposure on steroidogenesis in cultured rat Leydig cells. Leydig cell cultures were prepared from testes of 55–65-day-old Sprague–Dawley rats (n 5 8–10). Cells were incubated in 0 or 1–1000 nM [0.23–230 lg/L] bisphenol A [purity not indicated] in DMSO vehicle, with and without 10 mL U/mL hCG for 24 hr [culture ware not indicated]. Following the incubation period, testosterone level was measured by RIA and 125 I-hCG binding to LH receptors was assessed. Media containing hydroxycholesterol was then added to the cultures, and testosterone production following a 4-hr incubation period was measured. The effects of 17b-estradiol and 4-tert-octylphenol were also examined, but will not be discussed. Cell viability was evaluated by trypan blue exclusion and found to be unaffected at the bisphenol A concentrations used in this study. Three experiments with 4 samples/experiment were conducted. Data were analyzed by ANOVA and Student-Newman–Keuls test. Bisphenol A had no effect on basal or hCG-induced testosterone production or hCG binding to LH receptors. [Data were not shown by study authors.] Conversion of hydroxycholesterol to testosterone was also unaffected by exposure of Leydig cells to bisphenol A. No effect on testosterone production was observed following exposure of cells to 17b-estradiol. The study authors noted the similarity of effect between bisphenol A and 17bestradiol, which differed from the modest effects observed with 4-tert-octylphenol exposure. Strengths/Weaknesses: This study appears to have been well conducted. Phenol red-free media were used and cell viability after treatment was assessed. There was likely limited metabolism of bisphenol A, and the activity of metabolites cannot be assessed. Utility (Adequacy) for CERHR Evaluation Process: This study was not considered useful for the evaluation process. Akingbemi et al. (2004), supported by NIEHS, U.S. EPA, NICHHD, and NIH, conducted in vitro studies to examine the effects of bisphenol A exposure on Leydig cell cultures. In vivo studies were also conducted and are described in Section 3 because exposures were commenced in immature animals. In a series of studies, testosterone production by Leydig cells was assessed following incubation of cells with various doses of bisphenol A or bisphenol A in combination with other compounds. Leydig cells were obtained from 90-day-old rats. In a dose–response study, testosterone and 17bestradiol levels were measured in Leydig cells that were incubated with bisphenol A [purity not indicated] at 0 (ethanol vehicle), 0.01, 0.1, 1, 10, 100, or 1000 nM [0, 0.0023, 0.023, 0.23, 2.3, 23, and 230 mg/L] bisphenol A for 18 hr [culture ware not indicated]. To determine if bisphenol A induces estrogenic effects on Leydig cells, testosterone production was also measured in cells incubated with diethylstilbestrol or 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane, a metabolite of methoxychlor, at the same concentrations as bisphenol A. In mechanistic studies, Leydig cells were incubated with 0.01 nM [0.0023 mg/L] bisphenol A, with and without the addition of LH or the antiestrogenic compound ICI 182,780. Endpoints assessed included testosterone and 17b-estradiol production and expression of mRNA for steroidogenic metabolizing enzymes, ER, and steroidogenic acute regulatory protein, a substance that transports the cholesterol used in testosterone synthesis. Levels of hormones in media were measured using RIA methods, and mRNA expression was evaluated using RT-PCR techniques. Statistical analyses included ANO VA and the Duncan multiple range test. In the concentration–response study, production of testosterone by Leydig cells was decreased following exposure to bisphenol A at 0.01 nM [0.0023 lg/L] but not at higher doses. Diethylstilbestrol reduced testosterone 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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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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292 CHAPIN ET AL. has been informed
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294 CHAPIN ET AL. buffered paraform
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296 CHAPIN ET AL. unit. Further, th
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298 CHAPIN ET AL. PND 21 and housed
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300 CHAPIN ET AL. Tando et al. (200
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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
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Page 253 and 254: 330 CHAPIN ET AL. (Nagao et al., 19
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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.
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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Page 289 and 290: 366 CHAPIN ET AL. Table 99 Treatmen
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Page 307 and 308: 384 CHAPIN ET AL. 10. Critical desi
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Page 311 and 312: 388 CHAPIN ET AL. alpha and beta ex
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