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

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nTp brief • Tyl.et al..(41).reported.no.effect.of.bisphenol. days.earlier.than.control.animals..In.the.Ryan. A.on.age.at.vaginal.opening.in.CD-1.mice. et al..study,.two.of.the.five.animals.in.the.0.200. using. a. multigenerational. study. design. at. mg/kg.bw/day.group.that.had.a.~4.5.day.statisti- dietary.doses.that.ranged.from.0.003.to.600. cally.significant.acceleration.in.puberty.showed. mg/kg. bw/day.. The. positive. control. group. a.much.greater.acceleration.than.the.other.ani- used.in.the.bisphenol.A.study,.17β-estradiol. mals.in.that.group,.i.e.,.~.10.days.early.onset.of.(0.08.mg/kg.bw/day).caused.the.expected.ef- first.estrus.compared.to.the.mean.of.the.control. fect.of.accelerated.vaginal.opening..However,. group.(public.comment.on.the.draft.NTP.Brief. the.experimental.model.used.in.this.study.did. not.appear.to.be.sensitive.in.detecting.estro- from.Dr..Earl.Gray,.received.May.23,.2008).. genic.effects.at.low.doses..In.a.separate.multi Other Effects Considered generational. study. designed. to. characterize. A.variety.of.other.effects.in.laboratory.animals. the.response.in.CD-1.mice.to.17β-estradiol. have.been.linked.to.“low”.dose.bisphenol.A.expo- (0.0002.–.0.1.mg/kg.bw/day),.the.authors.did. sure.during.development,.including.decreased. not.report.any.effect.on.vaginal.opening.at. sperm.quantity.or.quality,.obesity,.disruption. doses.below.~.0.03.mg/kg/day.(210)..In.ad- of.meiosis,.changes.in.reproductive.hormone. dition,. estrous. cycle. length. was. unaffected. levels,.or.cellular.effects.in.reproductive.tissues.. at.all.doses..Thus,.detecting.an.estrogenic.ef- These.effects.had.less.impact.in.shaping.NTP’s. fect.of.a.weaker.estrogen.such.as.bisphenol.A. conclusions.on.potential.risks.to.humans.from. at.very.low.doses.(≤.~.0.03.mg/kg.bw/day). bisphenol.A.exposure.than.the.developmental. would.not.be.expected.in.this.animal.model.. effects.observed.at.“high”.doses.on.survival.and. growth.and.the.“low”.dose.effects.on.brain.and. behavior,.mammary.gland,.prostate.gland,.and. onset.of.puberty.in.females.described.above. Species Differences There.are.other.indications.of.species.differences.between.rats.and.mice.that.may.contribute.to.the.inconsistent.literature.for.bisphenol. A..Research.on.the.effects.of.pheromones.in. regulating.puberty.suggests.that.puberty.may. be.more.easily.perturbed.in.mice.compared.to. rats..Puberty.in.female.mice.can.be.accelerated. when.the.mice.are.exposed.to.urine.from.a.male.. This.effect.has.been.reported.more.often.and. more.consistently.for.mice.than.for.rats.(211, 212)..In.addition,.the.IUP.effect,.which.was.an. important.factor.in.the.Howdeshell.et al..study,. is.better.documented.in.mice.compared.to.rats. suggesting.that.this.effect.may.be.more.robust. in.mice.(209)..IUP.was.not.considered.in.other. studies.in.the.bisphenol.A.literature,.but.it.is. worth.noting.that.the.studies.by.Markey.et al. (178).and.Ryan.et al. (48).also.show.indications.of.a.subpopulation.of.mice.that.may.be. more.responsive.to.bisphenol.A..As.discussed. earlier,.Markey.et al..commented.that.a.portion. of.mice.exhibited.partial.vaginal.opening.~.4. 29 In. some. cases,. the. relationship. between. a. specific.cellular-.or.tissue-level.finding.and.a. potential.health.effect.in.the.whole.organism.is. unclear..This.is.because.there.is.often.uncertainty.about.the.functional.impact.of.a.cellular.or. mechanistic.finding,.such.as.the.altered.level.of. a.receptor.protein.or.change.in.enzyme.activity.. For.example,.the.potential.health.impact.that. may.result.from.uterine.changes.characterized. by.altered.ERα.and.ERβ.expression.and.from. an.increase.in.the.number.and.appearance.of. uterine.epithelial.cells.is.unclear.(213).. In.other.cases,.the.literature.is.not.sufficiently. developed.. Newbold. et al. (214). recently. described.a.number.of.morphological.changes. in.the.ovaries.and.uteri.of.18-month.old.mice. that. had. received. subcutaneous. injections. of. bisphenol.A.at.doses.of.10,.100,.or.1000.µg/kg. on.days.1.–.5.of.life..Increases.in.cystic.ovaries.
and.cystic.endometrial.hyperplasia.were.statistically.significant.in.the.100.µg/kg.dose.group.but. not.at.1000.µg/kg..Non-statistically.significant. increases.in.the.incidence.of.a.variety.of.other. ovarian. and. uterine. proliferative. lesions. and. cysts.were.also.reported..Replication.of.these. findings.and.further.study.of.the.linkage.of.early. and.late.occurring.events.will.be.important.in. establishing.a.better.understanding.of.any.longterm.consequences.of.exposures.of.the.developing.organism.to.bisphenol.A. As.mentioned.earlier,.NTP.Briefs.are.not.meant. to.serve.as.comprehensive.reviews.of.the.scientific.literature..Only.key.study.findings.and.issues.that.relate.to.NTP.conclusions.on.concerns.for.potential.reproductive.and.developmental.health.effects.in.humans.are.typically. presented..However,.three.reported.“low”.dose. health.effects.(obesity,.decreased.sperm.count. or.quality,.and.abnormalities.of.meiosis).that. ultimately.had.less.impact.in.determining.the. NTP’s.conclusions.are.briefly.discussed.below. in.order.to.illustrate.the.interpretive.challenges. associated.with.this.literature..Two.examples. of.such.effects,.obesity.and.impacts.on.sperm,. demonstrate.findings.that.are.not.reported.consistently.enough.to.be.considered.reproducible.. The.third.example.relates.to.abnormalities.of. meiosis.and.is.presented.to.demonstrate.that. effects.predicted.from.in vitro studies.are.not. necessarily.observed.in.the.in vivo.studies.. Obesity There.is.currently.insufficient.evidence.to.conclude.that.bisphenol.A.exposure.during.development.predisposes.laboratory.animals.to.develop. obesity.or.metabolic.diseases.such.as.diabetes,. later.in.life..Obesity.and.metabolic.disruption. have.become.a.research.focus.for.bisphenol.A. based.on.several.reports.of.increased.postnatal. growth.following.“low”.dose.exposure.during. development.and.several.in vitro and.in vivo. studies.that.report.effects.related.to.altered.carbohydrate.and.lipid.regulation. 30 The.NTP.concurs.with.the.CERHR.Expert.Panel. on.Bisphenol.A.that.the.effects.of.bisphenol.A. on.body.weight.at.“low”.doses.are.inconsistent. (2)..A.number.of.studies.in.rats.and.mice.report. increases.in.postnatal.growth.following.developmental.exposure.to.bisphenol.A.at.oral.doses. of.0.0024.–.1.2.mg/kg.bw/day. (55, 155, 173, 215).or.a.subcutaneous.dose.of.0.5.mg/kg.bw/ day.(179)..Other.“low”.dose.(≤.5.mg/kg.bw/day). studies.in.rats.and.mice.have.either.not.detected. any.significant.effect.on.body.weight.(43, 48, 50, 52, 107, 116, 122, 200, 214, 216).or.reported. growth. reductions. (37, 115, 146, 189, 217).. Differences.in.study.outcomes.cannot.easily.be. attributed.to.the.use.of.a.potentially.insensitive. rodent.model.or.experimental.protocol.because. several.studies.that.did.not.detect.any.significant. difference.in.body.weight.reported.other.effects. at.“low”.dose.levels.(48, 50, 52, 122, 217)..The. bases.for.the.inconsistent.findings.are.unclear,. but.may.relate.to.factors.such.as.diet.and.differences.in.experimental.design.or.analysis. The.data.are.currently.too.limited.to.conclude. that. developmental. exposure. to. bisphenol.A. causes. diabetes. or. other. metabolic. disorders. later.in.life..Two.studies.in.laboratory.animals. have.assessed.endpoints.related.to.carbohydrate. or.lipid.regulation..In.adult.male.mice,.a.single. subcutaneous.dose.of.0.010.or.0.100.mg/kg.bw/ day.bisphenol.A.caused.decreased.blood.glucose. and.increased.plasma.insulin.(218)..Additionally,.increased.pancreatic.insulin.content.and. insulin.resistance.were.reported.at.0.100.mg/kg. bw/day.(administered.orally.or.by.subcutaneous. injection).after.a.slightly.longer.period.of.dosing. (4-.days).(218)..A.recent.study.by.Miyawaki.et al. (215).assessed.a.variety.of.endpoints.related. to.carbohydrate.and.lipid.regulation.in.1-month. old.mice.that.were.exposed.through.maternal. treatment.during.gestation.and.lactation.with. 0.001.or.0.010.µg/ml.bisphenol.A.in.drinking. water.(~0.26.and.2.42.mg/kg.bw/during.gestation)..Endpoints.included.body.weight,.adipose. tissue.weight,.and.blood.concentrations.of.leptin,. nTp brief
Page 1: National Toxicology Program U.S. De
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Page 8 and 9: NTP.will.transmit.the.NTP-CERHR.<st
Page 10: National Toxicology Program U.S. De
Page 15 and 16: nTp brief tainers.with.internal.epo
Page 17 and 18: Population Adult General. Populatio
Page 19 and 20: Table 3. Blood and Breast Milk Biom
Page 21 and 22: Figure 2b. The weight of evidence t
Page 23 and 24: in.considering.the.biological.plaus
Page 25 and 26: isphenol.A.as.efficiently.as.adult.
Page 27 and 28: isphenol.A..For.example,.this.raise
Page 29 and 30: laboRaToRy aNImal STudIeS In.contra
Page 31 and 32: of.normal.sex-based.differences.bet
Page 33 and 34: death.(168),.synaptic.plasticity.(1
Page 35 and 36: gland.carcinogen.or.that.bisphenol.
Page 37 and 38: understand.the.possible.long-term.c
Page 39 and 40: strategies.to.improve.the.sensitivi
Page 41: • • Howdeshell.et.al. (55).repo
Page 45 and 46: cutaneous. injection. 20 . vom. Saa
Page 47 and 48: are CurrenT exposures To bisphenol
Page 49 and 50: w/day;.95th.percentiles.0.289.-.0.2
Page 51 and 52: nTp ConClusions The.NTP.reached.the
Page 53 and 54: appendix a: inTerpreTaTion of blood
Page 55 and 56: µg/kg.bw/day.based.on.the.assumpti
Page 57 and 58: concentrations.from.maternal,.fetal
Page 59 and 60: 12.. Padmanabhan. V,. Siefert. K,.
Page 61 and 62: In..Research.Triangle.Park,.NC:.RTI
Page 63 and 64: 65.. Alonso-Magdalena. P,. Laribi.
Page 65 and 66: 91.. Calabrese.EJ,.Baldwin.LA.(2003
Page 67 and 68: Thyroid.Function.in.Juvenile.Female
Page 69 and 70: droxylase.immunoreactivity..76:423.
Page 71 and 72: stanceschimiques.gc.ca/challenge-de
Page 73 and 74: Watanabe.H,.Ohta.Y,.Iguchi.T.(2006)
Page 75 and 76: 226..vom. Saal. FS,. Cooke. PS,. Bu
Page 77 and 78: solid.phase.extraction-high.perform
Page 79 and 80: appendix i. nTp-Cerhr bisphenol a e
Page 81 and 82: 158 CHAPIN ET AL. the CERHR Core Co
Page 83 and 84: 160 CHAPIN ET AL. referred to as 4,
Page 85 and 86: 162 CHAPIN ET AL. concentrations in
Page 87 and 88: 164 CHAPIN ET AL. Food (no. sampled
Page 89 and 90: 166 CHAPIN ET AL. Table 6 Continued
Page 91 and 92: 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
Page 109 and 110:
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
Page 173 and 174:
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
Page 179 and 180:
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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Page 249 and 250:
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328 CHAPIN ET AL. 600 mg/kg bw/day)
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330 CHAPIN ET AL. (Nagao et al., 19
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332 CHAPIN ET AL. antinuclear antib
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334 CHAPIN ET AL. least 6 animals.
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336 CHAPIN ET AL. Utility (Adequacy
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338 CHAPIN ET AL. stomach weight wa
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340 CHAPIN ET AL. Schirling et al.
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342 CHAPIN ET AL. Endpoint Table 88
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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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374 Table 101 Summary of High Utili
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376 Table 102 Summary of Limited Ut
Page 301 and 302:
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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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Page 321:
appendix iii. publiC CommenTs and p
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