Monograph on the Potential Human Reproductive and ... - OEHHA
Monograph on the Potential Human Reproductive and ... - OEHHA
Monograph on the Potential Human Reproductive and ... - OEHHA
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nTp brief<br />
c<strong>on</strong>sidered.“positive”.(52)..Overall,.<strong>the</strong>.NTP.<br />
c<strong>on</strong>sidered.<strong>the</strong>.rat.data.to.indicate.that.“low”.<br />
doses.of.bisphenol.A.do.not.affect.<strong>the</strong>.<strong>on</strong>set.<br />
of.puberty.in.female.rats..A.total.of.six.“low”.<br />
dose.mouse.studies.were.identified.<strong>and</strong>.evaluated.by.<strong>the</strong>.NTP..Of.<strong>the</strong>se,.two.reported.effects.<br />
c<strong>on</strong>sistent. with. accelerated. puberty. <strong>and</strong>. <strong>on</strong>e.<br />
showed.an.alterati<strong>on</strong>.in.events.related.to.sexual.<br />
maturati<strong>on</strong>.in.females.<strong>and</strong>.were.interpreted.as.<br />
“positive”.<strong>and</strong>.<strong>the</strong>.o<strong>the</strong>r.three.were.c<strong>on</strong>sidered.<br />
“negative.”.<br />
The.NTP.strategy.for.evaluating.<strong>the</strong>.entire.“low”.<br />
dose.literature.<strong>on</strong>.puberty.in.female.rodents.was.<br />
to. first. c<strong>on</strong>duct. a. detailed. assessment. of. <strong>the</strong>.<br />
mouse.studies.to.determine.whe<strong>the</strong>r.any.aspect.<br />
of.study.design.could.account.for.<strong>the</strong>.apparently.<br />
c<strong>on</strong>tradictory.results.in.this.species..The.most.<br />
c<strong>on</strong>sistent.difference.between.<strong>the</strong>.“positive”.<strong>and</strong>.<br />
“negative”.studies.in.mice.is.<strong>the</strong>.approach.used.<br />
to.measure.a.puberty-related.event..Age.at.first.<br />
estrus.is.<strong>the</strong>.most.accurate.indicator.of.puberty.in.<br />
rodents..This.occurs.at.<strong>the</strong>.same.time.as.vaginal.<br />
opening.in.rats..However,.in.mice,.vaginal.opening.does.not.correlate.well.with.puberty.<strong>and</strong>.<strong>the</strong>.<br />
first.day.of.detecting.cornified.cells.in.a.vaginal.<br />
smear,.a.sign.of.first.estrus,.is.<strong>the</strong>.preferred.measure.used.to.indicate.<strong>the</strong>.<strong>on</strong>set.of.puberty.(208)..<br />
Although. accelerated. vaginal. opening. is. an.<br />
expected.resp<strong>on</strong>se.to.estrogens.in.mice,.<strong>the</strong>.lack.<br />
of.simultaneous.occurrence.of.vaginal.opening.<br />
<strong>and</strong>.first.estrus.suggests.that.<strong>the</strong>se.events.may.be.<br />
differentially.regulated.even.though.<strong>the</strong>y.are.both.<br />
estrogen.resp<strong>on</strong>sive..Thus,.<strong>the</strong>.NTP.c<strong>on</strong>siders.<br />
vaginal.opening.to.be.a.marker.of.sexual.maturati<strong>on</strong>,.but.not.a.surrogate.measure.of.puberty,.<br />
i.e.,.first.estrus..The.three.mouse.studies.that.<br />
reported.effects.c<strong>on</strong>sistent.with.an.accelerati<strong>on</strong>.<br />
of.a.puberty-related.event.used.first.estrus.as.<strong>the</strong>.<br />
marker.of.puberty.(48, 55, 189)..In.c<strong>on</strong>trast,.<strong>the</strong>.<br />
“negative”.studies.used.vaginal.opening.(41, 178,<br />
197)..Each.study.also.has.its.own.limitati<strong>on</strong>.that.<br />
complicates.a.straight-forward.interpretati<strong>on</strong>.of.<br />
<strong>the</strong>.results,.e.g.,.small.sample.size,.positive.c<strong>on</strong>trol.resp<strong>on</strong>se,.or.use.of.subcutaneous.injecti<strong>on</strong>.<br />
27<br />
to.pregnant.dams..Based.<strong>on</strong>.<strong>the</strong>.analysis.outlined.<br />
below,.<strong>the</strong>.NTP.c<strong>on</strong>cluded.that.<strong>the</strong>.“positive”.<br />
mouse.studies.provided.limited.evidence.of.an.<br />
accelerati<strong>on</strong>.of.puberty.<br />
In.c<strong>on</strong>trast,.<strong>the</strong>.NTP.c<strong>on</strong>cluded.that.<strong>the</strong>.rat.studies.do.not.indicate.an.effect.<strong>on</strong>.puberty.at.“low”.<br />
doses..The.differences.in.outcomes.cannot.be.<br />
attributed. to. <strong>the</strong>. use. of. an. insensitive. strain.<br />
or.stock.because.a.variety.of.rat.models.were.<br />
used.in.<strong>the</strong>.“negative”.studies:.Sprague-Dawley,.<br />
Wistar,.Wistar-Furth.rats,.Wistar-derived.Alderley.Park,.CD,.<strong>and</strong>.D<strong>on</strong>ryu..Moreover,.three.of.<br />
<strong>the</strong>.“negative”.rat.puberty.studies.reported.o<strong>the</strong>r.<br />
“low”.dose.effects.(53, 122, 173)..The.effects.of.<br />
bisphenol.A.<strong>on</strong>.puberty.in.rats.at.“high”.doses.<br />
are.more.inc<strong>on</strong>sistent.than.<strong>the</strong>.“low”.dose.studies..Only.<strong>on</strong>e.study.has.reported.an.effect.<strong>on</strong>.puberty.in.<strong>the</strong>.predicted.directi<strong>on</strong>,.i.e.,.accelerati<strong>on</strong>.following.subcutaneous.treatment.<strong>on</strong>.postnatal.days.0.to.9.(120)..O<strong>the</strong>r.studies.reported.<br />
no.effect.(116 – 119).or.a.delay.in.puberty.at.≥.50.<br />
mg/kg.bw/day.(37, 43)..Four.of.<strong>the</strong>se.studies.<br />
used.a.positive.c<strong>on</strong>trol.group.(43, 116, 118, 120)..<br />
In.<strong>the</strong>se.studies,.resp<strong>on</strong>ses.to.potent.estrogens.<br />
based.<strong>on</strong>.age.at.vaginal.opening.ranged.from.no.<br />
effect.(116),.to.a.statistically.significant.small.or.<br />
moderate.accelerati<strong>on</strong>.[1.7.days.(43);.2.4.days.<br />
(120);.3.6.days.(118, 119)].<br />
Mouse Studies<br />
“Positive” Mouse Studies<br />
•<br />
The.largest.magnitude.of.effect.<strong>on</strong>.puberty.<br />
in.female.mice.was.reported.by.Ryan.et al.<br />
(48)..In.this.study,.age.at.first.estrus.was.accelerated.by.4.5.days.in.C57BL/6.mice.whose.<br />
dams.were.orally.dosed.with.0.2.mg/kg/day.<br />
bisphenol.A. during. gestati<strong>on</strong>. <strong>and</strong>. lactati<strong>on</strong>.<br />
(GD3.–.PND21).(48)..Accelerati<strong>on</strong>.in.puberty.of.approximately.6.days.was.reported.in.<br />
<strong>the</strong>.ethinyl.estradiol.positive.c<strong>on</strong>trol.group..<br />
The. major. limitati<strong>on</strong>. of. this. study. was. <strong>the</strong>.<br />
relatively. small. sample. sizes. used. for. this.<br />
endpoint.(4.–.5.dams.per.treatment.group)..
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