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

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There is sufficient evidence in rats and mice that bisphenol A causes male reproductive toxicity, characterized as delayed preputial separation, with subchronic or chronic oral NOAEL of 4.75 mg/kg bw/ day and a LOAEL of 47.5 mg/kg bw/day (Tyl et al., 2002b). There is inconsistent evidence in rats and mice that bisphenol A alters testosterone and gonadotropin levels in males after oral postnatal exposure. There is inconsistent evidence in male and female mice that bisphenol A produces aneugenic effects in germ cells after exposure. 5.0 SUMMARIES, CONCLUSIONS, AND CRITICAL DATA NEEDS 5.1 Developmental Toxicity No data on the effects of human developmental exposure to bisphenol A are available. There is a large literature describing studies in rodents and some work in other species. A large experimental animal literature was reviewed, assessed for its utility, and weighed based on the criteria established by this Panel. From the rodent studies we can conclude that bisphenol A: * Does not cause malformations or birth defects in rats or mice at levels up to the highest doses evaluated: 640 mg/kg/day (rats) and 1250 mg/kg/ day (mice). * Does not alter male or female fertility after gestational exposure up to doses of 450 mg/kg bw/day in the rat and 600 mg/kg bw/day in the mouse (highest dose levels evaluated). * Does not permanently affect prostate weight at doses up to 475 mg/kg/day in adult rats or 600 mg/kg/day in mice. * Does not cause prostate cancer in rats or mice after adult exposure at up to 148 or 600 mg/kg/day, respectively. * Does change the age of puberty in male or female rats at high doses (ca. 475 mg/kg/day). Rodent studies suggest that bisphenol A: * Causes neural and behavioral alterations related to disruptions in normal sex differences in rats and mice. (0.01–0.2 mg/kg/day). The data on bisphenol A are insufficient to reach a firm conclusion about: * A change in the onset of puberty in male rats or mice at doses up to 475–600 mg/kg/day. * An acceleration in the age of onset of puberty at a low dose in female mice at 0.0024 mg/kg/day, the only dose tested. * Whether Bisphenol A predisposes rats toward prostate cancer or mice toward urinary tract deformations. 5.2 Reproductive Toxicity There are insufficient data to evaluate whether bisphenol A causes male or female reproductive toxicity in humans. A large experimental animal literature was reviewed, assessed for its utility, and weighted based on Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 381 the criteria established by this expert panel, including an evaluation of experimental design and statistical procedures. These animal data are assumed relevant for the assessment of human hazard. Female effects: There is sufficient evidence in rats and mice that bisphenol A causes female reproductive toxicity with subchronic or chronic oral exposures with a NOAEL of 47.5 mg/kg bw/day and a LOAEL of Z475 mg/kg bw/day. Male effects: There is sufficient evidence in rats and mice that bisphenol A causes male reproductive toxicity with subchronic or chronic oral exposures with a NOAEL of 4.75 mg/kg bw/day and a LOAEL of Z47.5 mg/kg bw/day. 5.3 Human Exposures Bisphenol A is FDA-approved for use in polycarbonate and epoxy resins that are used in consumer products such as food containers (e.g., milk, water, and infant bottles) food can linings (Staples et al., 1998; SRI, 2004) and in dental materials (FDA, 2006). Resins, polycarbonate plastics, and other products manufactured from bisphenol A can contain trace amounts of residual monomer and additional monomer may be generated during breakdown of the polymer (European-Union, 2003). Environmental Exposures: Bisphenol A emitted from manufacturing operations is unlikely to be present in the atmosphere in high concentrations. However, it was found in 31–44% of outdoor air samples with concentrations of oLOD (0.9) to 51.5 ng/m 3 (Wilson et al., 2006). Indoor air samples found concentrations r29 ng/m 3 (Rudel et al., 2001, 2003; Wilson et al., 2003). Limited U.S. surface water sampling found bisphenol A in 0–41% of samples ranging from o0.1 to 12 ug/L (Kolpin et al., 2002; Boyd et al., 2003). Twenty-five to 100% of indoor dust samples contained bisphenol A with concentrations of odetectable to 17.6 mg/g (Rudel et al., 2001, 2003; Wilson et al., 2003, 2006). Exposures Through Food: The highest potential for human exposure to bisphenol A is through products that directly contact food such as food and beverage containers with internal epoxy resin coatings and through the use of polycarbonate tableware and bottles, such as those used to feed infants (European-Union, 2003). Studies examining the extraction of bisphenol A from polycarbonate infant bottles in the U.S. found concentrations o5 mg/L. Canned infant formulas in the U.S. had a maximum levels of 13 mg/L in the concentrate that produced a maximum of 6.6 mg/L when mixed with water (FDA, 1996; Biles et al., 1997a). Breast milk studies in the U.S. have found up to 6.3 mg/L free bisphenol A in samples (Ye et al., 2006). Measured bisphenol A concentrations in canned foods in the U.S are o39 mg/ kg (FDA, 1996; Wilson et al., 2006). Limited drinking water sampling in the U.S. indicates that bisphenol A concentrations were all below the limit of detection (o0.1 ng/L) (Boyd et al., 2003). Biological Measures of Bisphenol A in Humans: The panel finds the greatest utility in studies of biological samples that use sensitive and specific analytical methods (LC-MS or GC-MS) and report quality control measures for sample handling and analysis. The panel further focused on biological monitoring done in
382 CHAPIN ET AL. U.S. populations. In the U.S, adult urine concentrations of free bisphenol A are o0.6 mg/L and total bisphenol A concentrations are o19.8 mg/L (Calafat et al., 2005; Liu et al., 2005; Ye et al., 2005). The 95th percentile total bisphenol A concentration for 394 adult volunteers (males and females; 20–59 years old) from the NHANES III survey was 5.18 mg/L (Calafat et al., 2005). Girls age 6–9 in the U.S. have concentrations of total bisphenol A o54.3 mg/L, with median concentrations ranging from 1.8–2.4 mg/L (Liu et al., 2005; Wolff et al., 2006). No U.S. studies have examined blood or semen concentrations of bisphenol A. Amniotic fluid total bisphenol A concentrations in the U.S are o1.96 mg/L. Dental sealant exposure to bisphenol A occurs primarily with use of the dental sealant bisphenol A dimethylacylate. This exposure is considered an acute and infrequent event with little relevance to estimating general population exposures. Bisphenol A Intake Estimates: The panel found that previous oral intake estimates for infants fed formula and breast milk did not use levels reported for the U.S. population, so the panel estimated intake based on typically-used parameters. The panel found the food intake estimates made by the European Commission (2002) used concentrations of bisphenol A comparable to U.S. food concentrations in their intake estimates, so have included these estimates as well (Table 104). Estimates from duplicate diets in U.S. children (Wilson et al., 2003, 2006) found lower bisphenol A concentrations in foods than those estimated by the European Commission, therefore the aggregate estimates of intake by Wilson et al. were somewhat lower than those estimated by the European Commission. However, the aggregate intake estimates by Wilson et al. (2003, 2006) are in line with the estimates based on urinary metabolite measurements for children described above. Estimates of intake based on occupational air concentrations of bisphenol A from U.S. powder paint workers suggest exposures up to 100 ug/kg bw/day (USEPA, 1988). Estimates of intake based on urinary metabolite levels among Japanese workers spraying epoxy coatings resulted in a mean estimate of exposure of 0.043 mg/kg bw/day (o0.002 pg to 0.45 mg/kg bw/day) (Hanaoka et al., 2002). 5.4 Overall Conclusions The panel spent a considerable amount of time attempting to interpret and understand the inconsistent findings reported in the ‘‘low dose’’ literature for bisphenol A. Conducting low dose studies can be challenging because the effects may be subtle and small in magnitude and therefore more difficult to statistically distinguish from background variability. The inherent challenge of conducting these types of studies may be exacerbated with bisphenol A because the endpoints of concern are endocrine-mediated and potentially impacted by factors that include phytoestrogen content of the animal feed, extent of bisphenol A exposure from caging or water bottles, and the alleged sensitivity of the animal model to estrogens. The Panel believed that highdose studies are less susceptible to these types of influences because the toxicologic response should be more robust and less variable. While the Panel did not necessarily expect a specific effect to display a monotonic dose response (e.g., consistently increasing organ size), many members of the panel expected the high-dose studies with bisphenol A to detect some manifestation of toxicity (e.g., altered weight, histopathology) in tissues reported to be affected at low doses even if the study could not replicate the reported low dose effect. There are several large, robust, well designed studies with multiple dose groups using several strains of rats and mice and none of these detected any adverse reproductive effects at low to moderate dosage levels of BPA administered via the relevant route of human exposures. Further, none of these studies detected changes in prostate weight, age at puberty (rat), pathology or tumors in any tissue, or reproductive tract malformations. For this reason, Panel members gave more weight to studies that evaluated both low- and high-doses of bisphenol A compared to low-dose-only studies in cases where the target tissues were comparably assessed. Every chemical that produces low dose cellular and molecular alterations of endocrine function also produces a cascade of effects increasing in severity resulting in clearly adverse alterations at higher doses, albeit the effects can be different from those seen at low doses. With these endocrine disrupters, but not BPA, the low dose effects are often causally linked to the high-dose adverse effects of the chemical. This is true for androgens like testosterone and trenbolone, estrogens like DES, 17bestradiol and ethinyl estradiol, xenoestrogens like methoxychlor and genistein, and antiandrogens like vinclozolin, for example. Hence, the failure of BPA to produce reproducible adverse effects via a relevant route of exposure, coupled with the lack of robustness of the many of the low dose studies (sample size, dose range, statistical analyses and experimental design, GLP) and the inability to reproduce many of these effects of any adverse effect strains the credibility of some of these study results. They need to be replicated using appropriate routes of exposures, adequate experimental designs and statistical analyses and linked to higher dose adverse effects if they are to elevate our concerns about the effects of BPA on human health. The lack of reproducibility of the low dose effects, the absence of toxicity in those low-dose-affected tissues at high-doses, and the uncertain adversity of the reported effects led the panel to express ‘‘minimal’’ concern for reproductive effects. In contrast, the literature on bisphenol A effects on neural and behavioral response is more consistent with respect to the number of ‘‘positive’’ studies although it should be noted that the high-dose studies that proved to be the most useful for evaluating reproductive effects did not adequately assess neural and behavioral responses. In addition, even though different investigators assessed different neural and behavioral endpoints, the Panel concluded that the overall findings suggest that bisphenol A may be associated with neural changes in the brain and behavioral alterations related to sexual dimorphism in rodents. For this reason, the Panel expressed ‘‘some’’ concern for these effects even though it is not clear the reported effects constitute an adverse toxicological response. Concerns are expressed relative to current estimates of general population exposure levels in the U.S. 1. For pregnant women and fetuses, the Expert Panel has different levels of concern for the different 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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isphenol.A.as.efficiently.as.adult.
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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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µg/kg.bw/day.based.on.the.assumpti
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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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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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302 CHAPIN ET AL. Purina Certified
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304 CHAPIN ET AL. high-doses of bis
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306 CHAPIN ET AL. born to those dam
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308 CHAPIN ET AL. average weight we
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310 CHAPIN ET AL. study authors con
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312 CHAPIN ET AL. used for extracti
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314 CHAPIN ET AL. jar, and there we
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316 CHAPIN ET AL. of testes and com
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318 CHAPIN ET AL. differentiation o
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320 CHAPIN ET AL. Table 81 Summary
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322 CHAPIN ET AL. Table 82 Continue
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328 CHAPIN ET AL. 600 mg/kg bw/day)
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Page 265 and 266: 342 CHAPIN ET AL. Endpoint Table 88
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Page 297 and 298: 374 Table 101 Summary of High Utili
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Page 311 and 312: 388 CHAPIN ET AL. alpha and beta ex
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