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

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nTp brief behavior.(116, 122, 143)..For.instance,.responses. to.novelty.and.exploratory.behavior.are.sexually. dimorphic.behaviors.where.female.mice.tend.to. display.more.of.these.behaviors.than.males.(46, 135)..Bisphenol.A.seems.to.dampen.this.sexdifference.by.reducing.the.expression.of.these. behaviors.in.female.mice.(“defeminization”.or. “masculinization”).exposed.during.development,. either.through.gestation.via.the.dam.with.oral. doses.of.0.01.mg/kg.bw/day.or.through.gestation. until.weaning.at.0.04.mg/kg.bw/day.(46, 135).. While.a.loss.of.sexual.dimorphism.seems.to. be.one.general.trend.observed.in.the.behavior. literature,.findings.for.other.effects.can.be.more. difficult.to.interpret..A.number.of.studies.have. looked. at. the. relationship. between. developmental.exposure.to.bisphenol.A.and.increased. activity..The.studies.that.most.directly.support.an. effect.of.increased.activity.administered.bisphenol.A.directly.into.the.brain.(133, 134, 144, 145).. This.route.of.administration.limits.the.ability.to. interpret.these.studies.in.relation.to.human.exposure.levels.as.well.as.to.compare.the.findings.to. results.from.other.studies.that.use.more.typical. routes. of. administration.. Other. studies. using. similar.behavior.assessments.have.not.reported. differences.in.spontaneous.motor.activity.in.the. offspring.of.dams.orally.treated.with.a.range.of. doses.from.0.1.–.400.mg/kg.bw/day.(50, 146).. Indications.of.increased.activity.based.on.other. types.of.behavioral.tests.are.also.mixed..Some. studies.report.no.impact.of.bisphenol.A.treatment. on.activity.(107, 142, 147),.increased.morphineinduced.locomotion.in.animals.treated.during. development.with.bisphenol.A.(136, 148),.no. difference.between.control.and.bisphenol.A. treated.animals.in.response.to.methylphenidate,. a.drug.used.to.treat.attention.deficit.hyperactivity.disorder.(ADHD).(147),.and.decreased.amphetamine-induced.activity.in.bisphenol.Atreated.male.rats.(46)..The.literature.provides. more. consistent. support. for. a. loss. of. sexual. dimorphism. in. locomotor. activity.. Bisphenol. A.exposure.during.development.eliminated.sta- 19 tistically.significant.sex.differences.observed.in. control.animals.where.females.are.more.active. than. males. (122, 125),. or. caused. significant. differences.in.activity.consistent.with.a.loss.of. sexual.dimorphism,.i.e.,.increased.activity.in. male,.but.not.female.rats.(149). Certain.behavioral.effects.such.as.alterations.in. locomotor.activity,.reward.behavior,.response. to.novelty,.motivation,.cognition,.and.attention. can.display.some.degree.of.sexual.dimorphism. but.also.implicate.involvement.of.the.dopaminergic.system,.a.monoaminergic.neurotransmitter..Interactions.with.the.dopaminergic.system. are.supported.by.findings.that.bisphenol.A.can. alter.the.gene.expression.of.D1,.D3,.and.D4. dopamine.receptors.(137, 145, 150).and.dopamine.transporters.(145, 151, 152)..In.addition,. several.studies.report.that.perinatal.exposure.to. bisphenol.A.can.alter.(usually.decrease).expression.of.the.rate.–.limiting.enzyme.for.dopamine.synthesis,.tyrosine.hydroxylase.(TH),.that.catalyzes.the.conversion.of.tyrosine.to.a.pre-cursor. of.dopamine,.dihydroxyphenylalanine.(DOPA),. in.several.regions.of.the.brain.including.the.substantia.nigra.(145,153),.the.anteroventral.periventricular.nucleus.of.the.hypothalamus.(AVPV). (124),.midbrain.(151),.limbic.area.(152),.and. rostral.periventricular.preoptic.area.(125). Additional.support.for.the.brain.as.a.target.of. bisphenol.A.is.provided.by.a.number.of.studies.that.report.neural.alterations.at.the.cellular. level.including.interactions.with.or.changes.in. measures.of.expression.of.a.number.of.receptors.involved.in.brain.function,.such.as.estrogen. receptors.ERα.and.ERβ (47, 154 – 156),.gammaaminobutyric.acid.type.A.(GABA A).(157, 158),. progesterone.(159, 160),.aryl.hydrocarbon.receptor.(AhR),.retinoic.acid.receptor.(RAR).alpha,. retinoid. X. receptor. (RXR). alpha. (161 – 163),. and. thyroid. receptors. (82 – 86).. Other. studies. report.effects.on.neuronal.migration.or.organization.(164, 165),.synaptogenesis.(166, 167),. GABA-induced. currents. (158),. neuronal. cell.
death.(168),.synaptic.plasticity.(169);.thyroid. receptor-mediated.differentiation.of.oligodendrocytes.(170),.and.reduced.proliferation.of. neural.progenitor.cells.(171). The.NTP.concurs.with.the.CERHR.Expert.Panel. on.Bisphenol.A.that.the.results.of.neurological. and.behavioral.studies.of.exposures.of.laboratory.animals.to.bisphenol.A.during.development. raise.questions.about.possible.risks.to.human. development..Although.the.technical.merit.of.the. scientific.literature.on.brain.and.behavior.varies,. a.number.of.the.“low”.dose.studies.have.been. considered.by.various.evaluation.groups.to.be. experimentally.well-conducted. 11 .For.example,. the.CERHR.Expert.Panel.on.Bisphenol.A.classified.the.studies.by.Kwon.et al. (116),.Negishi. et al. (50),.Della.Seta.et al. (49),.Palanza.et al. (44),.and.Ryan.and.Vandenbergh (48).as.having. “high.utility”.in.its.evaluation. The.NTP.also.concurs.with.the.CERHR.Expert. Panel.on.Bisphenol.A.that.additional.research. is.needed.to.more.fully.assess.the.functional,. long-term.impacts.of.exposures.to.bisphenol.A. on.the.developing.brain.and.behavior..Overall,. the.current.literature.cannot.yet.be.fully.interpreted.for.biological.or.experimental.consistency.or.for.relevance.to.human.health. 12 .Part. of.the.difficulty.for.evaluating.consistency.lies. in.reconciling.findings.of.different.studies.that. use.different.experimental.designs.and.different. specific.behavioral.tests.to.measure.the.same. dimension.of.behavior.. 11 The.studies.by.Negishi.2004.et al. (50),.Carr.et al. (132),.Ryan.and.Vandenberg.(48),.and.Adriani. et al. (135). were. described. as. sufficiently. reliable.for.regulatory.use.in.a.minority.opinion. expressed.by.Denmark,.Sweden,.and.Norway.in. the.latest.European.Union.risk.assessment.(6).. Dr.. Michael. Baum,. an. ad hoc. reviewer. in. the. NTP.Board.of.Scientific.Counselors.peer.review,. considered.the.studies.by.Ryan.and.Vandenberg. (48),.Gioiosa.et al. (46),.and.Rubin.et al. (125). to.be.exceptionally.well-conducted.. 20 For.some.of.the.reported.effects,.there.is.some. degree.of.consistency.in.the.rodent.studies.(96).. For.example,.Rubin.et al. (125).reported.that. perinatal.exposure.to.low.doses.of.bisphenol. A.significantly.reduced.the.number.of.tyrosine. hydroxylase. (dopaminergic). neurons. in. the. AVPV.of.female.mice.to.the.values.observed.in. control.and.bisphenol-treated.males..Because. the.AVPV.is.involved.in.regulating.ovulation.in. rodents.this.finding.is.consistent.with.an.earlier. study.by.this.same.group.that.reported.disrupted. estrous.cyclicity.in.adult.female.mice.following. perinatal.exposure.to.bisphenol.A.(173)..However,.the.manifestation.or.translation.of.these. effects.to.primates.or.humans.is.unclear.because. there.is.no.homologous.hypothalamic.structure. to.the.AVPV.in.humans. 12 . Another.issue.that.complicates.translation.of. the.rodent.findings.to.primates.and.humans.is. species.differences.in.the.role.of.estradiol.in. regulating. sexual. differentiation. of. the. brain. 12 The.following.“low”.dose.studies.were.cited.in. the.“Characterization.of.Risk.to.Human.Health”. section. of. the. Health. Canada. Draft. Screening. Assessment. for. Bisphenol.A. (172):. Palanza. et al..2002.(44),.Laviola.et al..2005.(45),.Gioiosa. et al..2007.(46),.Farabollini.et al..2002.(130),. Della.Seta.et al..2005.(112),.Adriani.et al..2003. (135),.Negishi.et al..2004.(50),.and.Carr.et al.. 2003.(132)..From.these.studies,.Health.Canada. concluded.that.“While.collectively.these.studies. provide. evidence. that. exposure. to. bisphenol.A. during.gestation.and.early.postnatal.life.may.be. affecting.neural.development.and.some.aspects. of.behaviour.in.rodents,.the.overall.weight.of.evidence.was.considered.limited.from.the.perspective.of.rigour.(e.g.,.study.design.limitations.such. as.conduct.of.behavioural.assessments.at.a.single. time.point);.power.(e.g.,.limited.number.of.animals.per.test.group),.corroboration/consistency. (limited. consistency. of. studies). and. biological. plausibility.(e.g.,.certain.studies.involve.use.of.a. single.dose,.lack.of.dose.response.relationship).. These.limitations.make.it.difficult.to.determine. actual.significance.of.findings.to.human.health. risk.assessment.” nTp brief
Page 1: National Toxicology Program U.S. De
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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: of.normal.sex-based.differences.bet
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 and 42: • • Howdeshell.et.al. (55).repo
Page 43 and 44: and.cystic.endometrial.hyperplasia.
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
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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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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
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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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