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Summary

ドキュメント内 Styrene(原文) (ページ 85-90)

Styrene. is. absorbed. through. the. respiratory. tract. of. humans. and. pulmonary. retention. of. inhaled.

styrene.is.reported.at.60.–.70%.(reviewed.in.(2, 4))..Studies.in.rats.demonstrated.absorption.of.styrene.

through.the.respiratory.and.gastrointestinal.tracts.(reviewed.in.(2))..Limited.dermal.absorption.studies.

in.humans.and.rats.suggest.that.styrene.is.absorbed.through.skin.(reviewed.in.ATSDR.(2)).

In.humans,.rats,.and.mice,.styrene.is.widely.distributed.throughout.the.body.and.the.highest.concen-trations.are.initially.found.in.fat.(reviewed.in.IARC.(4))..Styrene.is.distributed.to.fetuses.of.rats.(39).

and.reproductive.organs.of.rats.and.mice.(reviewed.in.(38))..Volume.of.distribution.in.humans.was.

reported.as.99.L.or.1.4.L/kg.(31)..

The.main.pathway.of.styrene.metabolism.in.humans.begins.with.conversion.of.styrene.to.styrene.

oxide.by.CYP.enzymes..Styrene.oxide.is.metabolized.to.styrene.glycol.by.epoxide.hydrolase..Styrene.

glycol. is. metabolized. to. mandelic. acid,. which. is. then. converted. to. phenylglyoxylic. acid.. These.

metabolites.are.excreted.in.urine.and.are.often.used.as.biomarkers.of.exposure.to.styrene..In.humans,.

mandelic.acid.represents.57.–.80%.of.a.styrene.dose,.and.phenylglyoxylic.acid.represents.10.–.33%.of.

the.dose.(reviewed.in.(2, 32))..Small.amounts.of.styrene.oxide.are.conjugated.with.glutathione..The.

glutathione.conjugates.are.converted.to.mercapturic.acid.products..Metabolites.generated.through.ring.

••

a ppendix II

epoxidation.of.styrene.(i.e.,.vinylphenol),.conversion.of.styrene.to.1-phenylethanol.(i.e.,.ultimately.

leading.to.formation.of.hippuric.acid),.glutathione.conjugation.of.styrene.oxide,.and.glucuronidation.

of.phenylethylene.glycol.represent.<1%.of.the.styrene.dose.(reviewed.in.(4))

Styrene.metabolism.in.mice.and.rats.is.similar.to.that.of.humans,.but.some.differences.were.noted..It.

appears.that.the.capacity.to.generate.styrene.oxide.is.greater.in.rodents.(reviewed.in.(4))..In.addition.

to. converting. styrene. oxide. to. styrene. glycol. and. ultimately. mandelic. acid,. rodents. metabolize. a.

significant.portion.of.styrene.oxide.by.conjugating.it.to.glutathione..The.glutathione.conjugates.are.

converted.to.mercapturic.acid.products..It.is.estimated.that.≥ 10%.of.the.styrene.dose.is.converted.

to.mercapturic.acid.in.rats.inhaling.≤ 300.ppm.styrene.or.ip.injected.with.≤ 250.mg/kg.bw.styrene.

and.in.mice.ip.injected.with.400.mg/kg.bw.styrene..Though.not.described.as.a.major.pathway,.the.

pathway.involving.conversion.of.styrene.to.1-.and.2-phenylethanol.and.ultimately.to.hippuric.acid.

was.described.as.more.important.in.experimental.animals.than.humans.

According.to.a.PBPK.model.developed.by.Ramsey.and.Andersen.(35),.saturation.of.styrene.metabo-lism.in.humans.occurs.at.styrene.blood.levels.exceeding.1.7.mg/L..The.saturation.point.based.on.

styrene. levels. in. air. is. 200. ppm. in. humans,. rats,. and. mice.. Below. those. concentrations,. the. rate.

of.styrene.metabolism.is.limited.by.perfusion.of.blood.in.liver.or.other.organs.involved.in.styrene.

elimination..The.model.was.verified.using.actual.blood.concentrations.of.styrene.in.humans.and.rats..

In.experimental.animal.studies.involving.a.range.of.exposures.from.80.–.1200.ppm,.the.slope.of.the.

relationship.between.blood.styrene.concentration.and.air.concentration.increased.above.about.300.

ppm.in.rats.and.mice.

A.more.recent.mode.of.action-based.PBPK.model.by.Sarangapani.et.al..(36).compared.dosimetry.of.

styrene.and.styrene.oxide.in.the.lung.of.rats.and.mice..The.model.predicted.~10-fold.lower.styrene.

oxide.concentrations.in.the.terminal.bronchioles.of.rats.versus.mice.

In.humans,.the.most.active.isoforms.involved.in.styrene.metabolism.are.CYP2E1.in.liver.and.lung.

(4)..CYP2B6.is.also.active.in.the.metabolism.of.styrene.in.liver.and.lung.of.humans..In.mice,.the.

most.active.isoform.in.the.lung.is.CYP2F2.

In.metabolism.of.styrene.by.humans,.pulmonary.microsomal.activity.is.far.below.that.of.hepatic.

microsomal.activity,.and.nasal.tissues.were.found.to.have.no.activity.(reviewed.in.(4))..In.contrast,.

rodents.(especially.mice).have.a.high.capacity.to.metabolize.styrene.in.lung.and.nasal.tissues..

In.humans,.styrene.clearance.rate.is.reported.at.1.7.L/minute,.a.rate.similar.to.that.of.total.blood.

flow.through.liver.(31)..Styrene.is.highly.metabolized.and.the.majority.of.metabolites.are.eliminated.

through.urine..A.limited.amount.of.styrene.(0.7.–.4.4%).is.present.in.exhaled.air.unchanged.(reviewed.

in.(2, 4)).. Styrene. clearance. from. blood. is. biphasic,. indicating. a. two-compartment. toxicokinetic.

model..Half-lives.for.inhaled.styrene.were.reported.at.0.6.hours.for.the.first.elimination.phase.and.

13.hours.for.the.second.elimination.phase.(reviewed.in.(2))..Half-lives.for.urinary.elimination.of.

mandelic.acid.in.humans.were.reported.at.3.–.4.hours.and.25.–.40.hours.for.each.respective.phase.

(reviewed.in.(2, 32))..The.half-life.for.the.first.urinary.elimination.phase.of.phenylglyoxylic.acid.was.

reported.at.11.hours.(reviewed.in.(2))..As.in.humans,.styrene.elimination.in.rats.and.mice.occurs.

mainly.through.biphasic.urinary.excretion.of.metabolites.(reviewed.in.ATSDR.(2)).

a ppendix II

2.6.2 General Toxicity

Acute.effects.that.have.been.observed.in.workers.exposed.to.styrene.are.irritation.of.the.eyes.and.

upper.respiratory.tract.and.CNS.depression.characterized.by.drowsiness,.dizziness,.headache,.and.

impaired.balance.(reviewed.in.(7))..Irritation.was.reported.at.styrene.levels.exceeding.24.ppm and.

CNS.depression.has.been.reported.at.concentrations.>100.ppm.(reviewed.in.IARC.(4))..Impaired.

color.vision.discrimination.is.another.potential.effect.in.styrene-exposed.workers.and.the.effect.was.

found.to.correlate.with.urinary.levels.of.mandelic.acid.(reviewed.in.(4, 7))..These.effects.were.noted.

at.air.styrene.levels.at.20.–.50.ppm.and.higher.(7, 48)..Hearing.impairment.was.observed.in.styrene-exposed.workers,.but.the.effect.was.mainly.reported.in.inadequately.controlled.studies..IARC.(4).

concluded.that.neurological.effects.usually.occur.at.styrene.concentrations.exceeding.100.ppm.but.

have.been.reported.with.exposures.as.low.as.10.–.30.ppm..Additional.neurological.effects.were.noted.

in.occupational.and.clinical.studies..Although.the.studies.were.noted.to.be.inconsistent,.poorly.con-trolled,.and.lacking.in.dose-response.information,.they.suggested.that.styrene.exposure.could.lead.

to.slower.reaction.time,.impaired.short.term.memory,.and.reduced.manual.dexterity.(reviewed.in.

(7))..A.review.by.Rebert.and.Hall.(32),.sponsored.by.the.Styrene.Information.and.Research.Center,.

disputed.claims.that.neurotoxicity.occurs.in.humans.at.concentrations.below.50.ppm.styrene,.citing.

inadequacy.in.study.designs.or.interpretations..The.authors.also.concluded.that.there.are.no.indica-tions.of.persisting.damage.to.the.nervous.system.as.a.result.of.styrene.exposure..

Consistent.with.human.findings,.evidence.of.neurological.effects.have.been.observed.in.repeat.dose.

experimental. animal. studies. reviewed. by. IARC.(4). and. to. a. limited. extent,. Harvard.(7).. Styrene.

inhalation.studies.reported.decreased.brain.dopamine.levels.and.increased.homovanillic.acid.levels.

in.rabbits.(≥ 750.ppm),.depletion.of.retinal.dopamine.levels.in.rats.(300.ppm),.increased.brain.glial.

fibrillary.acidic.protein.in.rats.(320.ppm),.and.mild.neurobehavioral.disturbances.in.rats.(1400.ppm).

and.mice.(425.ppm)..Similar.effects.were.observed.in.rats.orally.exposed.to.≥ 0.5.mg/kg.bw.styrene..

Hearing.impairment.was.observed.in.rats.following.repeated.inhalation.exposure.to.850.ppm.styrene.

but.not.to.200.ppm.styrene.in.a.second.study..It.is.not.known.if.studies.examined.multiple.dose.levels,.

and.a.LOAEL.for.neurotoxic.effects.is.therefore.not.known..The.Styrene.Information.and.Research.

Center.review.noted.that.few.studies.exposed.the.animals.to.less.than.300.ppm.styrene.(32)..

Additional. effects. that. have. not. been. observed. in. humans. were. reported. in. experimental. animal.

studies..Inhalation.of.styrene.vapors.produced.nasal.lesions.in.rats.and.mice.and.pulmonary.lesions.

in.mice.(reviewed.in.(4, 7))..The.effects.occurred.with.styrene.exposures.≥ 20.ppm.in.mice.and.≥ 50.

ppm.in.rats.and.were.thought.to.result.from.local.conversion.of.styrene.to.styrene.oxide..Some.studies.

reported.liver.effects.(e.g.,.glutathione.depletion,.changes.in.liver.enzyme.activities,.and/or.necrosis).

in.rats.and.mice;.effects.were.seen.at.≥ 50.ppm.in.mice,.the.more.sensitive.species.(4)..

Some.studies.provided.limited.evidence.of.immunotoxicity.in.humans.(e.g.,.alterations.in.lymphocyte.

numbers. and T-lymphocyte. response). and. rodents. (e.g.,. impaired. immune. response. or. reduced.

resistance. to. viral. or. parasitic. infections). exposed. to. styrene. (reviewed. in.(4)).. Based. on. limited.

evidence.of.lymphocyte.effects.in.workers.and.effects.in.experimental.animal.studies,.Harvard.(7).

concluded.that.styrene.should.be.investigated.further.as.a.potential.immunotoxicant.

2.6.3 Genetic Toxicity

Styrene.does.not.interact.with.DNA,.but.its.metabolite.styrene.oxide.forms.stable,.persistent.adducts.

a ppendix II

with.DNA.in.humans.and.experimental.animals.(reviewed.in.(7))..Adducts.indicate.styrene.exposure,.

but.implications.regarding.possible.health.effects.are.not.known..Increased.frequency.of.DNA.strand.

breaks.were.observed.in.white.blood.cells.of.workers.exposed.to.styrene,.but.the.breaks.appeared.to.

be.repaired.from.the.end.of.one.work.shift.to.the.beginning.of.the.next.day’s.work.shift.

Variable. results. were. obtained. in.in vitro. and.in vivo. studies. examining. styrene. exposure. on.

chromosomal.aberrations,.SCEs,.and.micronuclei.frequencies..The.majority.of.in vivo.experimental.

animal.studies.resulted.in.negative.chromosomal.aberration.and.micronuclei.findings,.but.positive.

SCE. findings.. Genotoxicity. occurred. only. at. high. dose. levels. and. usually. following. more. than. 1.

day.of.exposure..In.contrast.to.experimental.animal.studies,.the.majority.of.in vivo.human.studies.

suggested.positive.chromosomal.aberration.findings.and.negative.SCE.results..Human.studies.were.

complicated. by. confounders. such. as. other. occupational. exposures.. Harvard. conducted. additional.

statistical.evaluations.on.human.studies.(7).and.concluded.that.evidence.of.a.possible.association.

between. occupational. styrene. exposure. and. chromosomal. aberrations. was. compelling,. while. the.

association. with. SCEs. was. less. certain.. None. of. the. studies. provided. evidence. of. an. association.

between. styrene. exposure. and. micronuclei. frequency.. Mutagenicity. studies. in. several. strains. of.

Salmonella.usually.produced.negative.findings.in.the.absence.of.metabolic.activation.and.occasionally.

positive.results.with.metabolic.activation.(reviewed.in.(7)).

2.6.4 Carcinogenicity

Studies. in. reinforced. plastics. workers. were. judged. to. be. most. informative. for. evaluating. cancer.

effects.in.humans.because.styrene.exposures.were.generally.the.highest,.and.confounding.by.other.

chemical.exposures.was.less.likely.(reviewed.in.(4, 7))..Though.not.consistently.observed.among.

different.studies,.lung/respiratory.and.lymphatic/hematopoietic.cancers.were.most.often.reported.in.

reinforced.plastics.workers..However,.increases.in.lung/respiratory.cancers.were.often.not.related.to.

estimated.exposure.level.or.duration.and.may.have.been.confounded.by.smoking..Interpretation.of.

lymphatic/.hematopoietic.cancers.was.difficult.due.to.low.numbers.of.observed.and.expected.deaths,.

possible.confounding,.lack.of.consistent.dose-response.patterns,.and.small.size.of.subgroups.with.

high.levels.and.durations.of.exposure..It.was.noted.that.findings.were.not.robust.and.may.have.been.

due.to.chance.or.bias.in.addition.to.confounding..IARC.concluded.(4),.“There.is.limited evidence.in.

humans.for.the.carcinogenicity.of.styrene.”

In.studies.examining.carcinogenicity,.rats.and.mice.were.exposed.through.oral.and.inhalation.routes..IARC.

(4).and.Harvard.(7).concluded.that.there.was.no.compelling.evidence.that.styrene.exposure.increased.

tumor.frequency.in.rats..Both.groups.noted.evidence.of.increased.pulmonary.adenomas.in.male.and.

female.mice.and.an.increase.in.pulmonary.carcinomas.in.female.mice.following.inhalation.exposure.to.

styrene..IARC.concluded.“There.is.limited.evidence.in.experimental.animals.for.the.carcinogenicity.of.

styrene.”.A.review.of.styrene.oxide.data.indicated.that..3.gavage.studies.in.rats.and.1.in.mice.consistently.

demonstrated.an.increase.in.forestomach.tumors.following.exposure.to.≥ 50.mg/kg.bw.

Mechanism.of.styrene-induced.lung.tumors.in.mice.is.not.known,.but.IARC.(4).stated.that.the.most.

likely.mechanism.is.cytotoxicity.and.increased.cell.proliferation.resulting.from.in.situ.formation.of.

styrene.oxide..However,.IARC.noted.that.effects.from.circulating.styrene.oxide.and.DNA.adduct.

formation. cannot. be. excluded.. IARC. noted. that. the. proposed. mechanism. involving. conversion.

of. styrene. to. styrene. oxide. by. mouse. pulmonary. Clara. cells. is. probably. not. relevant. to. humans,.

a ppendix II

who.have.far.fewer.Clara.cells.than.mice;.however,.a.similar.mechanism.in.other.organs.cannot.be.

ruled.out..Metabolism.of.styrene.oxide.by.epoxide.hydrolase.is.comparable.or.moderately.higher.in.

humans.than.in.mice..Toxicokinetics.differences.between.rats.and.mice.were.noted,.including.greater.

production.of.styrene.oxide.with.higher.levels.of.the.R-enantiomer.in.lung,.and.increased.sensitivity.

to. glutathione. depletion. by. mice.. It. was. thought. that. the. differences. could. account. for. increased.

tumor.sensitivity.in.mice..However,.it.was.reported.that.differences.were.not.of.sufficient.magnitude.

to.explain.the.increased.susceptibility.of.mice..In.their.overall.evaluation.of.carcinogenicity,.IARC.

concluded. that.“Styrene is possibly carcinogenic to humans (Group 2B).” The. Harvard. Panel.(7).

concluded.that..“…styrene’s.carcinogenicity.in.humans.is.only.suggestive.but…styrene’s.carcinogenic.

potential.in.humans.cannot.be.ruled.out.”

2.6.5 Potentially Sensitive Subpopulations

The.main.styrene-metabolizing.enzymes.identified.in.humans.are.CYP2B6,.CYP2E1,.and.epoxide.

hydrolase..There. is. some. information. regarding. ontogeny. and. polymorphisms. of. those. enzymes,.

which.may.affect.levels.of.styrene.and.its.metabolites..However,.the.roles.of.genetic.polymorphisms.

and.ontogenetic.differences.in.determining.sensitive.subpopulations.is.complex..This.Expert.Panel.

has.not.evaluated.the.role.polymorphisms.may.play.in.forming.sensitive.subpopulations,.nor.has.it.

seen.information.regarding.other.potentially.sensitive.subpopulations.

a ppendix II

ドキュメント内 Styrene(原文) (ページ 85-90)

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