M<'thod. fQ' ~"1N'i"ll R,sk Qf Cbtmo<al tOJUlY H"""," ..cll<on·~"""," Boo....cl Eco<y"<rIlO£0"'" by V B V""k, G C. B"k". D. G. Hod ,.0 D. B. P",bllClt~~SCOPE

Quantitative Effects of Chemicals onFertility

Allen J. Wilcox

ABSTRACT

Human fertility i. a c<>mplex b,<>logi(:~1 ~ltribut. that can be afTectro byu~ur¢t<> ch.mic~ls. M.asur.m.nt <>f f.rtility can be bas.e<l on the f.nililing capacity' of'perm, prevalence of o"ulator)' cycl.... demographoc ass..SSmenr of tim. 10

p~gnancy. ~"d bioch.mical i"dicators of the likelihood of conception i" eachcycl•. In theory'. a"y of th~ m.asur•• could be us.e<l to quanrify the effe<:t$ ofch.mocal$. In praC1ice. the difficulties of mea$Uflng both .xposur. to chemical'and f.rtility have oev.rely Iimitroth••stimalion ofdo<c-respo"oe relationships.Th. Ulilny of a~imal .Iudies in estimat,ng huma~ ris~ i' discu,sed and nN>approaches to the .tudy and measu~ment of human fertilny a~ con.iderro,

1 INTRODUCTION

Femhzat,on " rhe cytoplasmic a~d nuel.~r union oflwo llam.t.... and fertility isbroadly defin.d as th. ~apacit)' to r.produce, Chemical. lhat impair f.rtility maydirectly obstruct fertilization or may interfere with procesoe. that prec.de Orfolio'" fertilization. Thu,. effect$ on fenility includ. but are not limit.d to eff""t.on fertiliulion.

S.,..ral common chemical$ m~y disrupt the fertility' of laboratory animal.(D,xon. 1980), The fenility of human. i' prohably at least as $u$C.ptibl•• ~nd )'.tth.re a~ f.w.r ch.m,cals thar are kno"'n to affect human f.rtihty. On. ~a<onmay be Ihat m.thod. for m.a.unng damage to human fertility are not )'.t ",.nestabl,.hro. Ther. ~re the u.ual difficulties of mea$u"ng human e'~u"" tochom,cab. In addition, human fert,lity ha$ >e'o.. r~l po"ibl. measurementendpoinr., not all of which are cl.arly u"dentood, Unlike canc.r, "'hich can bedefinro by' e,sentially the sam. cnroria in anim~ls and huma"., f.rtilitycan rarelybe mea.ured in animals and human. ,n the sam. way. Thi. papor ",'ilI.mphasiz<di"e= components of fertility and doscribe >e'o'eral approach.s 10 measurin8fertilny. Aproposed new method tOI measuring hU1ll.\ln fertility may a\'otd romecommon probkm$. finally', "'hat liul. i. ~no...n about dose-re,ponoe relat,on·

458 Methods 1M Esli"""ing R"k <>/ Ch.mkal fnjury

,hlp, for chemical, affecting fertility will be dilCu~>ed, Including the problem ofasafe dOK

2 A MODEL OF FERTILITY

In thi' >eelion, the qde ofhuman reproduclion "ill be oUllined, and .n.tom,ca!.physiologic.1 .nd beh"'ioural "pe<lS of fenilit) will be ,umm.rized in a modelThIS model pro' ides a frame"orl for ,ub",quenl di""us,ion of elT"'ts ofchemicals on fonilit)

2.1 A R.,·i.,,· or Ih. Human R.produClj,.. C,'d.

The germ cell line lh.l e,'enlu.ny produces ,~rm or eggs;n lhe ",xuall) matu~po"on ha< ,I' Origln< ,n prenatal life. Distincl primordial gerin cells maydilTerenti.le as earl) a, the ninth day after ConCepUon (O,d201\sk" 1%1), Inmales. lhe'" germ cell. lran,form after birth into .~rmalogoOia. which aredormant until pubeny At pubeny Ihere begm, a <onlinuou~ prollfera"on ofma,ure s~rm. in"ol'ing mito'i' and lhen mei""i. Thi. >Oquence of tr.n.form­aUon~ i~ weil <haranefl,ed and requires about 12 "eek< from >lem cell 10 malure,~rm, Up 10 200 million human sperm a,. generalW daily

The kmale germ hne expen=, an ent"ely differenl '"'!uence of e"ent•. Theproliferation of Ihe oogonia. including milO'is and pan of meiosis, tah' placebefore birth. Unlike lhe male, the female does nol produce germ cells after binh,In raCI, the 'otal number of gametes in the human female slead,ly d",hnes fromabout 1 million al 5 month" ge.lation 10 250 000 al puberty aDd abou' 2S 000 atage 30. Only a "'lati"el) fe" OOC)'tCS go on. under hormon.1 $Iimulauon of 'hemenmual cyd., 1o resume 'heir m"ot,c di,..ion and develop inlo o"a.Normally. a .ingle 0'-'01 i$ released in each cyde Thu,. while men producehundred' ofbillio", of malure garneles in Iheir Iifelime. w'omen 'ypically producearound 400,

Fertilizalion i' a dOKI) spaced .....uence of e,,,nt> in which a $ingle <permpenelrates tho eu membrane, ,he eucompletes me,"'is, and lhe genetic malerialof Ihe ,perm and o"um are fu"'d. Ordinarii}' thi~ occur-< in lhe o"tduct. The newz,.gol. proctt,ls down lhe o"duCl and inlO the uterm "'here, 7-10 da). laler, ilimplanls in lhe endomelrium. Onl) a fe"" da)'s laler. the developing .mbt)'o w;11h"'e differentia'ed IhOK primordiaillerm cells 'ha' t".nluan,. go on to producelhe nexi generalion

2.2 O..-elopipg a Mod.l of F.rtility

Fenility d.pend, no' only On biological capaci,}' bul on approprIate behav,ourFigu... 1 inlegral'" biolol',al and beh,,',oural elemenl' of fenility into t,,·oll'OUps: factor-< lhal precede fenilization, and factor-< lhal occur around the ,imeof fenilization, The lhird >ee'ion of the model define. ",veral fen;lit) endpo,nl$,

Prefen, 'ZOllO!'facIO's

FoclO's l'lflJ' lhe1''tIt offerl,loZOIIO"

22. l'ufnl~1l1_F.~

The ftl'JrOd1X'\1\e tflCt of males 'lid femaleseollSlW or• JWf ororp... I"1COIIt.I.UI 1M~ md $UUClllrQ for tnnsporu... tho pmctes Tbc lDCII:.....

me:.l IIIte,.lI~ of this "ruc:tllral $)"= n esomt..:J to fmobl): the SlIllpiest

460 MeIA<>d< jor EsrinUlring Risk oj CllemlC~i {njury

mrilization procedurc for men or ","omcn I~ to ot!stTuctthe tract In addl(ion (0haroouri~g gamete~, Ihe leSlC~ or o"arie' al'" acl a, cndocrine gland"DISruplion of hormonc production. dir<:ctly or throup, the C<~lral ncn'OU''ySicm. can likcwi'" afT..:t fertilily.

Another eleme~l in fenihl) i' Ihe qualil) of the germ cell•. In its profligateproduclion ofgarnet... thc male reproduC\l"e system produces many irregular orimmature .penn. Some of Ihe'" are pre,umably lcss capable of fertilizalion,Irregular l)'pe' are det<:ctable hy ",men analy~i', O"a arc nol '" d"ecllyoh"''''able. hOI presumahl) "ary in quality a, well

Ferlihly depend, on malure sexual function and beha.'iour, Sexual imercourserequir.. both m,oluntary and mlunlary ne..ou, system aeli"il)', In human~,

cultural norm, and Ihe socializalion of the i~di"tdual fun her affecl r.adin." andcapacity for intercou~.

],2.2 Fac/(}rJ N.~r IA. Time of Fertilization

Frequ.ncy ofcoilu, ha' a major .fT..:t on the probahililY offerti"zatlon (Barren.1971; Bongaarts. 1975a), There i' ",m. nideno:e Ihal 'perm antibodies in thefemale reproductive tract may inlenere with f.rtilily (An.bacher <I ~I.. 1973).Finally, the u.. of contraception po"'cnully influence' fer"hly.

2.2.3 Ferriliry Endpoims

li"c birth' prN'ide a coO\'en..nt endpoinl for .stimaling fertihty. parhcularl)'when ~tudYlng Ih. fenihty ofla'so groups of people. The advantage of using hebirth' a, an endpointl~ that data are easily obtained; .irtuany all ,,"e bIrths areroutin.ly reg"lered, Th. di..d"antaso i. that ",'e hirth' do not repre",nl allpregnancies, For ....mple. aooul 1S%of pregnancies .nd "lth a mi",a"iage orstillbirth (ltndon. 1977). Thus, when u.ing live birth. as an omcom•. one cannot",parale failure 10 concei"e from failure to carry a pregnancy, ",'en though Iheset"'o af¢ biologICally d"linct,

Pregnancy would be mOre specific than Ii"e births a. an .ndpoint fo' ftnllit},HowC\-cr. thtr. 1$ no routine regimation of pregnanC}'. SpeeifiCl\lly, pregnanciestnding;n spontaneous aoortlon art nol documented except in ,peeial studies. Asa resulL dala de$C,ibing pregnancies a,e Ie" avallahle and often less reliable thanIi". binh data

To complicale malle". thtr. i. probahly a large amount of fetal 10$' thatoccu" "ery early aner con~ption,hefore pregnane)' is tvtn recognIZe<!. Miller el

~I. (1980) found Ihat one-third of prtgnancies diagno",d b}' urine a'sayterminate<! before becoming chnically apparent, In other word$. the occurrenctofall clinically recognized pregnaneles " 'till an undereslimate of th. OCCurrenc.of ftni"zatlon,

The true ineideflCc of human fertihzation i' unknown. Under natural

Quanti/ali'''' £1f~clJ ofCA~mi(al$ on FeNiii'J 461

rondition~, human fenili'ation i' ,;nually an unob$e"abl. "enl. The mO$tr.oph"ttcated of lh. proven lests for hurrutn p,egnan9 i. Ihe ,adioimmunoassa)'of human chorionic gonadotropin (hCG), The radioimmuno.assay Can det«:1hCG around the lime of implantation, 7-10 day. followIng cOllCOption. Oth..aS$lll"' of hCG are boinS dO"elop«! including enl:yme_linked sy'tems, E...nearli.. det«:l;on ofconceplion may bo possible using a serum assay for an -earllprepancy factor' Thi' experimenlal as",y has been reponed to det..:t ,'hanS"in ,he maternal immune response "'ithin hours follo"'inS conception (Monon nal.. 1977; Shaw and Morton. 1980),

There i. a .pectrum, then, of f..hllly endpo,nls, rans,ns from l"'e birth dala'" hlch are eaSIly aeees'ible and lack sensiliv'ily. 10 biochemical data ""hich are Ie..accessible and more precise While none can pinpoim the ,,'em of f.nilizalton.any of th.", endpo,nB could bo u",ful,n lhe approprial< ",uing,

Z,) O<cu".nce eI CouS« of r"'lllt)' Impolrll1<B'

r,gure 1 presents ,ious factors ",'h;ch. if disrupled, can impair rertili,y, Ho""common IS fertility Impalrmenl In lhe gonoral population? A World HealthOrganization's Scientific Group used the following operational definitions forepidemIological analy.is

(I) prima,)' infertility: lhe "'oman has nover concoiv'ed desp"e CohabItation and..po,ure '0 pregnancl for a period or 2 )'Oars, (The Scientific Group, aflerrO\-.."'ing the subj«:t, concluded lhat 'exposure 10 prognancy' is dtfficult 10define and >landardize excepl In the cont..t of specific local conditions):

(2) secondary infertil;l)': Ihe wom.n ha, prev'iou,lj concei...d but is sub­",quenlly unable to cOllCO"e despite coh.bilallon and exposure 10 prog­nancy foe a period of2 ;-ea1'$: If the woman has breasl fed. p,n'IOU' infan'­then expo,ure 10 prcgnanC)' 'hould bo caiculated from the end of the periodof lacl'lional amenorrhoea (WHO, 1975),

According 10 lhi. report, primary Infenility is as high a, J.O~. in areas of theworld where gonorrhoea. genilal,uborculO$i, and other infeclions are pre".lent

Using lhe loame cr;leeia, a Sludy of. carefully selected sample of Danishwomen bolw«n Iheages of25 and 45 found Ihal9\ met the cequirem.nt fOfprimary inferhlllY and 7~. mOfe "'..,re secondarily' infenile (Rachoolin andOlsen. 1981), A SIud}' of a nalionalloample of US "omen 18-39 yearl oldclassified 21 ~~~ of couples as 'involunlarily ,ubfenile', and e.timaled thal 6-8 ~/.

US roupl.. "'ere inYolun,arily 'terile fOf lh..e" hole It..., (Whelpton ~I aI., 1%6).These numbors undoreslim..e lhe aClual prevalence of impai,ed fe"ilily inthegeneral population in Ih.t lhey \nclude only Ihose who WISh 10 haye. child andcannoL Un,ecognl>ed secondary infenilily no doubl OCCIIrs among couples" hohave Compl.led lh.t, family .nd are using long-I.rm conlracopllOn,

In developed counlries, the causes ofrertl),ly impaIrment aro largely unknown

462 M~lhodJ for Es'imOli"!J RiJk of C~mjrol Inju.y

I'h)'sicians '/lho trw infenll( couples classify patlems mto clinical categoriesmduding rmn ",th abnoTIIlal semen analy,i" women witb abnormal ovulauon.endomeui"'is or OMlructed lUbes. a few" "b defeu, of the ulereS 0' ~en'ix. anda group wIth no obvIous problem (Dor n 01.. 1977). How,,·er. few of Iheserondilion' b..'e obvious aeliologles. Among known cause" inf«lion isfrequently m"oked (M",Leod, 1951: WHO, 1975). Olher less common causeSare radIation exposure (A,b, 1980), genelic dIsease $uch a, sickle cell anaemia(Osegbe el 01" (981), chromosomal anomahes (Chandley, 1979). or severtmalnmritlon (StelO and Susser. (975), These aecount for a 'mall number of allea.... Umil recentl}'. the possibility of efTect' of chemIcal' on fen,htl has notbeen given much con"deratlon.

3 MECHANISMS 8" WHICH CHEMICALS AFFECT HUMANFU.T1UTY

While it is difficuh 10 detect wual efTec1S on hUllUln fertilily, Ibere are chem;cal$known to affect mMI of the biological and bebavioural fwors tbat lO turn affectfertillly. Oweral prin~iple, of reproductiw toxlCQlogy have been di",us>edelsewbere (Vouk and Sheehan, 1983), Some ,pecifie examples of effe<:1' ofchemical' on human reprodUCli'.. funnion are mentioned here.

Most oflbe buman fertilily·related factors lO FIgure I are kno"'n 10 be affenedby chemical exposures. Even Ihe structure of tbe reproduct,,'e IraCt ~an beahered. fo. e.ample, by prenalal exposure to dleth~lslilboestrol: StellCb....r" 0/.(1981) found abnonnalitles of (be rep,odllC1i"e organ. among 13 of t 7 younllmen exposed 10 dietb}'lstilboemol in ulero,

Fortlgn chemical$ Can imerfere with the oUlput of 1"C!lroducti,'e hormones,Many rommonly prescribe<! medicallons aller rep,oducti'.. hormone produc_t;on througb eilher central nervous system "'tion or peripheral effe<:1$ (Soykaand Mallison, (981), In lheir r..'iewofcbemlcal efTtt($ on Teproduction, Sulhanand B..low (1979) cite So"iet lileratUrt in whiCh women work;nll with phthalaleplasticizers "ere found 10 have low oeslrogen I..'e!s

The effect of chemical' on tbe qualily of sperm production bas been ofparticular intere't because charaCle,;stics of the spenn art ~on"enteml}'mea.ur­able. A dttrease lO numbet'S of sperm has been a,socialed "'tb lead upo,ure(Lan~ranjanU oJ" 1975), peslicide exposure (dlb.omochloropropane) (Wbo'ton" 0/.. 1977), and rolton!«d ""'al (gossypol) (POW tl 01., 1980). In~rea ... ;nabnormat .penn are ,"ported wilb lead ~xposu ... (Laneranjan tl 01" 1975),C;llarelle smokinll (Evan, tl 01" 1981) and earbon di.ulphide (Laneranjan. 1912).Human eggs a ... nol so accessible, and Ihu'lh~ effttl of chemical. on ooqte' i,not so ea.ily measured. Matti"'n and Thorgei,..",n (1978) 'uggeSt lhal lhedec'ea>ed aile at menopause aSSOCIated with ,moking is an indlrecl mea,ure ofooqt~ destruc"on.

lmpolence or lo,s oflibido can be side efTecl> of man)' preSCribed m«hcallom

QU"'n/ital;"~ Effeas 0/ C~m;"als "" Fe"i!il)' 463

(Soyka and Manison. 19S1). Kepon. (chlordeeon.) (Sulli"an and Barlow. 1979)and perhaps oth.r pesllcld., Or herbIcIdes (Esplc" 01.. 1970).

Th. effeelS c<Jnsid.red so far ar'lhose ,,'hich "'ould tend to impair fertilit}', II i,not impos,;bl. that .xpo,ures to .n,';ronm.ntal as.nt' could ha,', th. oppo,il<effect, Lo"'-dooe radiation in ultra ha' been reponed to increase f.rlilily.possIbly b)' accd.raling OOC}1t maturation (M.yer and Tonascia. 19S1), Ach.mical might beh.-'. ,imilarly. although no 'uch .ffecl frem accIdentalexposure' 1$ ~nown.

In ,urn, there i$ ",'id""'" of qualltatlv••ffeet$ of ch.mlcals on mO$\reproduction-r.lated proce>se' in human, as ,,-.11 as in laboratory an;mal'. In lh.following sections. quanti13ti," effeelS ofchemical' on fertlhl)' w\1I be du;cuosed.

4 QUANTITATIVE ASSESS~ENTOF THE EFFECTS OFCHEMICALS ON FERTILITY

Glv.n that ch.micals can dlS,,-,ptth. prace..... leading to f.nilization, how cando....r.lated .fTeet' be a$"'ssed? In lhe laborato')'. (hi' problem Can beapproach.d under controlled condilions: dose can be re!!u!at.d and nearly anystage of the reproducti,·. proce>' obser-..ed. Th. hmltalion of lhi' approach i,thaI it calt be applied only' to non-human species. In the 'ludy of human$.ch.mical .xposure and f.nility efTee" are hard.r to quantify. and lhe r..ull. areles, ct-rtain. Thu" n.ilher the laboralory nor the ,pld.miologlCal approach isenlirely samfauary. The pufalls of .xtrapolaling from laboralory ,pec;es 10

humans may be no Ie" lhan the problem, of .xtrapolaling frem one humanstudy 10 all exposed person,.

In thlS section. various approache, to inf.rtihly ri,t a.....'m.nt in anImals andhumans ,,"';11 be con$id.red. ThIs S<C1ion <o",lude, with a discussion of th.problems of establishing saf. or acceplabl. 1",.1, of exposure ";th regard tofenility

4.1 Qunl;laI;U E";",al;nn of Ibe Eff«:l$ or Chemical' On AnimalFerlilily

Laborato')' tests of f."ihty invol"e dosing one or both parent animal' andobser.'lng subsequ.nt pregnancies. In ",nal matmg. th. male" dosed and lh.ncag.d ,,"';lh a senes of pre,'iou.ll' unmated r.males o'-.r se"eral w.eks. Th.f.males ar. usually kilied and rertlllty' .,se,sed in l.rm, of numbers ofdead and"iabl. r.tuse,. Th" method can deteet lhe tran.ionl mal. inf.nility thaIaccompan,es damage to a partlCula< 'tage of 'permal0!!.nem, With ~m.

ch.mical,.•xpo.ure may !la,'. 10 be ..t.nded to ,'.ry young males in order 10

d.tecl ad"e~ effeet, on adult r.nllit}" For oxampl., lopical exposure of infantmale rati 10 huachloroph~ne l~ads to decreased fertility "hen they become adult(Gell.n" ai, 1978).

464 Me/hOOslor Eslim(l/illg Risk oICh",,,callnju'y

Wilen [.mal.! art doXd, a fOf'Cd·bfcrolni d.Sli" is often uled: hl1ers artrt1no,'.d immediat.ly aftor birth, which eneourag.~ rtpeat«l pr.gnancies,Fenility i' asse5sed in terms of frequency of pregnancies and size of Iillers, A,with mal... the exposure offemal.. ma~ have 10 be ....nded to .arly hf. in order10 delect effect> on fenihty. Even "posure in ulao can have effect' on,ubsequenl fertlliw D..th~!'tllboe",ol••posure in alera produces a cl<ar dose­related e/fecl on th. fertilily of fmul. mice: (McLachlan alld Dixon. 1976).Benzo(aJpyrenc ,imilarly cause, se....re Impa"men, of fen,hly among both mal<and femal< mice w'ho are ••posed a, f.lU..' (MacKenzi. and Ang.vine. 1981).

Th. posilbl< ,mportance 10 forlillty of \'try .arly .xposures f,,'ours Ih. use ofmuhillenoralion .ludi••, In thi. 'ludy de.illn, bolh parents are do,.,d and lhenmaled. Their offsprinll (F,) are conlinuously dosed and th.n maled withun..pooed pann.rs, In ""m. ca..s, animals from lhe n..l g.n.ration (F,) areal"" dosed and mated. F.,-lillty of .ach g.neralion is llisesoed using ,uchmea'ures a, number of copula lion' per oestrou, cycl., number of pregnanciesper copulalion. proportion ofmal.. that imprell"81" proportion offemales lhalare Impregnated. and numbeT of offspnng per pregnancy,

Multi\lenoralion 'lUdies of<q>roducli'-e fu ....tion are perfonned fOf "\lulatorypul'J'OS"'. Many of th.,., have nol been published (Clegg, 1979), Amongpubli,hed report> offenili'y impairment m muillgenerwon studIes. lhe effecl$on fcrti!ily are "ncrall}' more mark.d among th. f 1 and f, gen.ralion. lhan inthe Fo. Thi' .. lrue for polychlonnaled bIphenyl, (Linder ., 01.. 19,4).organophosphate pesticides (Ambr"" el 01.. 1970). and. Ie.. cleariy. for carba'}'!(Collins .1 01.. 1971). The,., findin" underscore lhe importance: of remoteexpo,ur.. for lhe effecl' ofeh""'ica!' "n fertilit)', The magnitude ofan effect maydepend n"t only on lhe d"" and on the age al which lhe dose is gl\'en, bUI als<> "nwhether the parent' and grandparents w'ere exposed.

4.1 Quutilali... E'li""lioll of tltt Effects of Cbutk.1s all HumurertUh)'

Accurale measuremeal of chemica! effec" on human ferlilny i. limited b~

uncertam,y in ..limatmg eh""'ical ..posure. a. well as by dillkuhies ofmea,uring fertilit}' endpoint',

4.2.1 M~a$llFiTl{j Human EX~SIir~ 10 Ch~miral.

The exposure of a pelS<ln 10 chemical. can rarely be determined exacll}', Whenlhe chemical i' a pre>Cfiplion drug. medical record. may prOVIde documenlat,onof lhe prescribed d",.,. Estimal.. "f expo,ure are al"" pos.ible with nOn­prescription deu" and "ther self-admlOl!lered !ub<lanccs, for "hlOh the d""rale may be den"ed from per""ns' repom of Iheir ow'n oonsumplion.Occupational "posur.. are even 10$$ definne_ Pnwns may be unaware of lhe

Quan/ita'iu EJJ~clS ofChrmicilis on Fmili'y 465

kmd or amount of their eXp"'ure Furthermore. occupational eXj>05ure> Canin>'ol'" complex mixtures of chemicals. such tbat 'he ~parate elf<:<ts oflnd"idual ch.micals cannol be .asily isolated. Where jol>-.peclfic "p"'urc dataarc a'-ailahl•. individual 'Xj>05urc can be eltlrna,e<! on the baSI< ofjoh type andduration, Other environmental eXp"'ure>, such as .xposure to pe.ticides, are th.mo" .Iu,i,-. This i. especially true if Ih...posure has taken plaa SOme time mthc pa,t. Laboratory methods for estImating chemical ..posures, mcludtnghiological monitoring. are ".adily impro>'ing hut provide only partial anSwers '0th... prohlem. (Rollan, 1981).

There are .pecific aspeclS of e,polure to be taken Into a«ount whenconsidering fertility as an outcome. To aff<:<1 feniht)', a ch.mical must gainac<:cu to germ cell. or to the accessory organ> tbat rellula" reproduction. Thus.the route of exposure (gastrointestinal tract. skin, lung,) may inlluence thepotency of .If<:<!. Timinll of cxposure is paramount for .ffect' on f.rtility, A~hemlCalthat damages one I'age of .pennatOllenelis or collenest< rna}' produceinf."ilit}' only durinll a ,pecific inte"'al after exposure, Extremely 10nlllatenC)effects a'" poUlhle. as m the ,mpalnnen, offerlilu) repone<! wl1h fetal ..posure10 diethylstilboemol (DES) (Manll"n tI al.. 1982). Unfortunately. remote <au..·and-.,ffect relation,hips are hard to rec"gnlze m humanl. The damalle apparentlyinlliCte<! hy DES on fenility would probably have gone unnoticed w'e", it not forthe auention already drawn to DES a. a tran,placental carcinogen,

4.2.1 M~asuTln~ Human Fertill',

E.-ery method for measurinll human fertihty i' arbotrary ,n 'hat each methodtake. into account some factors and disTellard. oth.... This is demonstrate<! Inthe fo110")08 sectiOn>. which summarize approaches that ha>'. been or could beused to measure human fertility.

~.1,2,1 Mewu'in~ P"f~",'/;;alion Fac'a'S

A chemical that totally disrupts I pref.rtiliZlltlon factor can produce sterility.lncomplet. disruption of lhese facton may only partilll)' Impair fertility. Th.ad"anlage of prefertiliZlltion factors i. Iha, th.y are usually' .a.i.. to measurethan th. f."ility .ndpo,nts (Figure 1), For thi' reason. prcfenililation facto .. a",sometimes u..d as substitute endpoints fOT f.rtili\)' in th. >ludy of the elf..,,, ofchemICals on fertility, How",'er, the d.gree to which chemical damage 10 aprefenilization factoT will actually impair fertility is not ea,)' to predICt.

Semen Anal,-.;.. The relation ofthe pr"perties of..men to fertility i, nN certainMacleod (19:10. 1955) and Macleod and Gold (l9S la.b.c. 1952. 1953) anal)'sedejaculate volume. spenn number. spenn motility and 'perm morphology, and thertlallon oflhe>e properhCS to fenihl)', They concluded that ejaculate volume andspenn morphology were unrelated ta th.l.ngth of lime reqUIred for a COUpl.1O

466 MahodJjor Esri/t1o/mg R"k o[Ch'",icol Inju,y

achiele pregnancy Similar]). sperm number Ins unrelated 10 fertility excel'll"'hen lhe .pe,m count wa' b' than 20 million ml, The besl predictor offen iIi I}'was lhe fraclion of acti"e .perm and the quality of sperm acliv"y. although eventho'" were nol hil1hl}' oo=lat«l ""th lime 10 prel1nancy, Thirty inter"eninl1 yearsof ,"search ha"e nOI greatly' ad"anced our undemanding of lhe\.<' ,e!ahon,h,p>(Mann and lUlv..ak·Mann. 1981).

In addilion to Ihe" ,ndirect relalion to fertility ...men characteri"ics are nOI a,simple to mea,ure a. Ihey might S«m. The ,",ullS depend on method' ofcollection and sample preparat,on. and on Ihe ",Ieclion crileria for donors, Tocomplicale n""te... ""men charaClen'lics ftuCtual. w,lh the t,me of day. ",ason."mperalure and olher faCloli (Mann and LUlwak-Mann. 1981), The labilit}' of",m.n compo"lion and "a'ialion' in an.ly'ical method' ha'" led to disal1ree·m.nt o"er ,uch ba"c que>lions as "helher ""m.n charact.ristics ha'.. changed0"" Illne (Nel'on and Bunge. 1914: Macleod and Wans. 1919), Th.""uncenainlies make ,t hard to know whal .rr""l a ch.mICal lhal alt... 'permcharacter,'tics m;l1hl ha'" on rep'odUCll'" capaCily

More comple~ a.loays of 'penn h.". been d.".loped. Wyrobek and B,uce(I91ll) ~on,\dered that abnormal spenn ,h.pe' "ould mdic.t••xposur. to

mUlal1.n•. Yanag,maeh, e' "I. (1916) d"..l"ped an a",,}' in ",hi~h hum.n ,perm"'er. '<Sled for Ih." capacily 10 pen.I,.te h.m"er ova. While thi' a,saj directlyaddresses Ih. que't,on of f.rt,lizalion, it has not yet been .".bh,he<l th.t ,Ipredict' f.rtil;t}' more ,.Ii.bly lhan other ""m.n p,operties.

Anol'u!olOrr C)Y:/rs Th. male h., million' of malure l1enn cell' al any IliHntim•. Th. fem.l. Ij pically h•• only one. If no egg i' p,oduced. Ih. ,,'oman i.'Ieril. for Ih.. cy~l•. The occurrence ofanon,lalory cycles i. commonl}' o!>sen.-.damons ~ouples "'ho are inf.nil•. 0o, el 01. (1911) .nribuled 'he Inferlilily of32 /~ ofcouples ..ekon£ medical c.re 10 .no,'ul.lory cy~le" Anovul.lory cyclesoccur in the general popula"on. bUI .. a 10..... frequency. Vollman (1911)collectedbasal body tempe,alure, in a lonlli,udinal 'tudy of m.nstruat;ng .....om.n. Amons",'om.n ,n Ih.ir I".nlies and Ihirt;es. 4 /'~ of men,lroal cycles f.iled 10 produce Ihe..mperalure ,pike of o"ulalion.

Anovul.,ory cycles are apparenlly common .monl1 ,nfertile .....om.n, bUI the~, ..nl 10 which .xposure 10 ch.mieal, may conlribu1e 10 ano"ulalion i' notXno"'·n. Th. rel.t,,,, .... "ilh .....hieh o"ulat;on Can be monilored (u"nl1 d.ilyt.mperalures or urine assay' of menstrual hormone.). and Ih. direcl relation ofo,'ulalion {o fertihty, ""ould ...m 10 make Ih" a p,om",nl1 endpoont in Ih. 'tudyof Ih••ffects of ch.mICals on fert,h,y

4.2.2,2 M."""ing Faelo" MO' 1M TIme oj Few/,oa/ion

Ch.micals th.1 affect a faClor n.ar Ihe "m. offer1llizalion ,,'ill h",'e • more direcl.ffecl on f.nility, Ho.......'er, ,h... facIO" ". 1"" likely 1"l1et' for chemicalint.rference lhan pleferliliza,;on fa~'o"

Quant;ta1ir~ E/ftet. QjCMmieal. on Futility 467

Frequency of coitus i••trongly rrlaled 10 lhe probab;lity of concepllon(MacLeod and Gold: 1953. Gla,.er and Lachenbruch, 1%8, Bongaarl' 1975a).The dechne ;n ferlilily found "'ilh I1>:Tea~ingage i. allea.t partly due 10 a decline;n frequency of ,ntercou,...,. While chemicals are ho"'n 10 alTert l,b\do and..,ual performance, many other cond;lions alTec\ 'hr.e al>o. The ,nherentpri"acy ,urrounding sexual beha' ,our mak.. it difficult 10 study .uch behav,our'" an rndpoinl.

In de"e1oped countries. the u.e of contracepl;'" is the mojor T'Cgula'or offerlility. Secondary infenility due 10 chcnllcal exposures .. auld occur 10contracepung coupl.. ",ilhoUl being recognized, In theO')',;1 might be possll,1e10 detect ,uch inferlilily by Mudying raleS ofcomracepuve fa,lure (pregnancy) in..posed and unexpo<ed u.ers ofcontracepti"". In practice. 0 prohibitively largenumber of contnilcepling couple~ "'ould be reqUired 10 ob'a,n the number ofunintended pregnanei., requ,red to eSlimale ferlillly. The opposite hypothesi. i.al>o pos,ible: a chemical might imerfere "'ith lhe mechanism ofaclion of 'he oralcontraceplive or in'raul<nne d",lC<. leadlOg to an lOCrra.e in the failure rateWhile hath are plau,ible, neither i' likely 10 prove u.eful in det",'ing ,be elTecl'of chcnucal.

4,2,2.3 Me(lJurin~ H",IorJ Endpcmrs

The 10Iai number ofchildren or pregnancies is nol a .en'iti"e mea,ure of fertilityin a contracepting population. The average reproducli... capacity of human, is'" much ilreater than the a"erage desired family size that ",'en coupl" "'ith,mpaIred fert,hl~ are often able 10 ach,eve 'heir d"'red number ofchildren. gi ...nenough lime When mea,uring partial impairment of fenilil}'. a more .en'iti"emea,ure of fertihty i. the probability of pregnancy or birth occurring underdefined condnion. and "'nhlO a bed t,me. Th,s probab,hly can be ..limatedfrom data a••imple a. "i'al .tatistic,. or a. ",phi'ticated as the 'adioim­munoassa}' of human chorionic gonadotropin. In lh,s =tion .everal 'tudjmethods "'ill be re"e",ed. and a ne'" method proposed,

DeftW9TapMc Meth<>ds Demoiraphers define fenihl}' in term. of hve birth,.and rely hea,';ly on routme vnal 'tati'lic., A couple's capacity 10 conceive i,called 'fecundabihty'. and i. distingu,sh<:<.! from 'ferlility', or acl\llli number ofchildren. While fecundabihty ha' not been a pnme Concern of demolIIaphers,there hu been ",me elTort to "tnna'e this underlying capacity based on apopulation', panorn of live bmh' and "'10' assumplion. ahaut f.tal loss, Thebest ..limates of fecundab,hly are obtained eilher from the time required forpregnancy to occur or the number of hirth. within a ""rtain 'ime penod(Mustafa, 1913). Lee and Lin (1976) and Pullam and W,lhams (977) ha"e\'lIOIlO>ed melhod~ ba>ed on the inter"'als bel",een live births, lam" (1%3, 19;3),Suchindran and Lachenbruch (1975) and Bongaart. (l975b) have d"",r;bed

.wi MrlllD<U fiN u/;,...,/u., RiJk of CltrmkaJ /"IWY

methods baRd on the \lint reqUIred for eol\Ctl)lJOll of. b\'t bll1h 10 0Cl:\I. IneeneraJ. lbe5c moIbod. prod~~n.r""mateS of f«v.lldabilily based oa IarFpopu!alJOftS.. 1lw moslooplnwcllCd work in 1his.rea .... been llw <k\"t'Iopmmlofmod<k to sanublll' Ibe relllJOllSh,Pf t>tr..WIl f«v.ndabilily lDd bonh SJIKlDI ortoW number of~ blnhI (Potier n a'~ I96&; Bonparts. 1915l. 1916)

0.""", apluc ID01bod1 l1li... rcomlly been adapu:d 10 the PUI"p<>K ofcoumal1ftllbe dl"CI of OQ;\I:pellOll'll uJlC:'RUa oa fcrtihly (I.hal Il. b... bulhs).Oollbim n a', (1m) d.IJtuiIcd • AlrVIVOnIup .pproadl to the 1I11C'rV&1 be\..'UI\

h" births for .... II1OCC1lpelJOAal $('lUll&$- l.z>lDe ria' (1980, 19l11)pr~.mnhod for standard...... lhe <WX... I"<WX ofln" 1IIrIhi by~f ofbu11L 1'Xe, and....!tTtIll •. 10 oOwlllll 'apen<d' fcrtihly Wl ..U Ibm compared "'ib IbeobIion"ed fmilll) ...."nber of Ibex ID01bod1 toot "'10 _Ill poIIlbie

drlJ<ttrICeS ," the alml of bu11l COI>uol. l.z>'ine ..P ........ WI the .... of IImhC<llItrol indo:poada>1 of lIC'CUt-tiolW apoPlfe••nd Ihndore 1l1li1 lhettmnhod Ullboawd_ nus may br I"'" fo< OCCIlpationally upooed men bul ISnot neceuarily l() for OttIlpalJOAally apooed "'OfJIor\l .. bole decl_. reprd."I,JnpwlC) an he'nIlu.mced by emplo)-.nml and \'>CeYOna funhennon:.oI>&h1dllf"reneeo ""'..""n lI0uPJ 1I11he pre...1ence of .lerilJDUoa may lead 10 IarF' (,funlHaied) dlSlurbat'ol;a III lllcw _U"," of fmilil)'

The Slmulanon lechn"luel ~nbed b) Bonparn (l97», 1976) and olhers",ould be uorful for ",.. lIiahnl the UUlll)' of these applied detnoIf1IphH: me,"Ul'e$of fenihly. for "umple. If. c!>emieal ".p05U,"" redllCtl l!>e probabllllY of<:on<:eplion by one-lh....:!. how mlJ,hllhi. aff«11ime 10 pr"gnatlC)', Of lpaclnl ofIi.'e binh.? How many porsons would hav" 10 be included in a study dell'" I""has uvin,,'1 in ord"r to delecl • fertilily decline of Ihat mal'lilude?

In sum. demographic melhod. usually as.ume larlle samples, often invol~ lheinterprelallon of paltern. of live blrlhs, and are mo,"" advanced in I!>eOry lhan inpractice. They have only recenlly bttn applied ;n Iludie> of t!>e eff<C11 ofchmllClll. on (milily, .nd lhe" _fulness in this conle.l has nOl )"t'l """'nnahiIShed.

0,,," ApPToaellrs 1lw ume req\ilred For PrqD&!K'Y 10 OttIlran~mealUred ,n100"" J'lfMor ....).... for Inll.""". "'omm an be asked Ibe Imllh of the 110ft.

co,utaCqlIi... Inlm-allhal POe<:eOes pttpaI>Cy.ln 0111< Rudy~ for otherPurpnoes, 93·. of ..omen enrolled .1 prqnaDCy an: able 10 spoafy the ImIJ\h oflhe ~llllllOfl-(:OQ~'" lftten-al (B. Su-ollono. Columbta UOIvaJlly.penooaI rommWiI",:a1lOfl) nus l)'pt of mfonolliion _ nrily adudes..-omen..ho an: lIllI.ble 10 COClOOlve lDd 1Ulder..... po ..C111S .."l)mtll. ..'bose subfemilly ladsthem 10 have f.,.",. pl't'JnliflOellbaJI desired. Noae lhe Jess. 1M uxf'uI_ oflhilIDOIbod ro< dn.eatq IlOpalflllIIIft\ of rmibf) .x"",.,'OS 10 b<~

Tk bial tDbereol ID lbe JlO""I'lS aP\lloadl 0lMIid he .voDd by ...................... before or .1 1M Ilqtruu.nf: of lbetr llOfl-(:OQ1f'8OeJ'Wl1 IDten..l andf......lIllthem until lbey Ire prqnan.f_ 0"., ....y 10 do 10 would be 10 tnbst

... _- --------

Qu<mI;I~,jU EffurJ of Chemictl/s tin Fertility 469

women of rcproouc{;,'. age' into a hi'tory-keeping study in .,bieb menstrualbi'tori•• and cOnlra<:epli'-. use ""ould be cominuously re<:or<led. A pre";o",study, using meMlrual cycl. calendar card., has been SUCtt"ful in coll"'lingpro'pe<;ti". data on prcsnancies (Treloar n al., 1%7: Wik". n aI., 1981). Suchan approach would offer complete mUI on the \ime r~uired for recognizedpregnancy 10 occur, a. wen as on lb. numbers "r ..omen who rail to conce;.e.One disa,hamage 10 thi' approach is lhal il require, a large number ofparticipant' oyer an extended period of lime in ordor to identify enoughpregnaneie, for analy1i,.

A smaller number of ,ubject< would be required for a 'tudy lhal enrolledwomen al the lime lhey arc first vulnerable to pregnancy. Women could befollowed from ,he lime they di",ontinue contraception. for example. unlillhO)'become pregnant. This approach could be furlher refined by using a biochemicala,oay 10 continuou,ly monilor for pregnancy. R"""nt de"elopment' in theradioimmunoas...y of human chorion'" gonadOlropm (hCG) make it feasible 10detect "ef)' early pregnancies u,mg a''ll'' of urine. The sensilivily and specificityof the radioImmunoassay ofhCG has been sleadily imp","ing (Wehmann eI al"1981) to Ihe poinl lhal its applicalion now seem, practical for epidemiologicalin"esliption,.

A case<ontrol study design. ordinanly used for ,nvestipung rare diseaS($.millhl rea",nably be applied 10 UJX»ur.. Ihat may affect fertilily, Couples wilhinfert,lIly of unknown cause could be compared with fert'le couples fordifference' in exJX»ure 10 chemical•. T1te seleclion of ca"" depends on lhedefinilion of infertility, Ca"" could be chosen by broad crileria such a>SUUesledby WHO (1975). or could be confined to particular das"" of infertllily. such a,anovulatory women or men Wilh abnormal semen analysis. This probkm ofdefininll a case is furlher complicaled by lhe selecti'-e manner in which in­fertile pe""ns pre",nl tl>emsel".. for medical care (Rachoolin and Olsen.1981).

A very different approach to the measuremenl offertilily useS women who arebeinll artificially insem,naled by donor sperm (for e>ample. Federalion CECOSor aL 19112). These are wi"e' of men wilh kno"ll fertilil}' impairment andlherefore represent a supposedly normal group of "'omen. (In fac!. lh,s llroupprobably includes a 'lii.ht excess of subfertile women (Emperaire er 01.. 1982).)The fertility of lhese women is expressed ;n the number of cycles .-equinnllart,ficial inseminalion before pregnancy occurS, The quasi..xperimenlal sel1mllofartificial insemination makes il possible to mon,lor faclors (sliCh as lhe tim..ofovulat'on and mseminalion) that olherw,se are nol accessible. The applicalionOflh.. approaCh 10 Ihe sludy ofenvlfonmental factors on fertility has begun in alle"l one centre (J_ O\'01'$l«<t. L:ni'-ersitl of Callforn\a at Davis. personalcommunicalion). Such a method could explore lhe effect ofcommon e'JX»uressuch as smoking. colfee or lea. and alcohol on female fertihty. However. it couldnol easily be eXlended 10 sludy lhe effeels of less Common exposures,

470 MnMdsjo, £Sljrntlling Risk ojChtmir"llnjl<ry

Most of the approaches d,scus<ed abo.'e cannot distmguish between infertilityand early p"'g.nanq 1"". With thi' in mind. a method i' propo<ed he'" whichwould provide a ",Iam'ely specific mea,ure of the capacity to conceive. TheIntrau'erine device (IUD) is a widely used contracepti"e that may not becontraceptive in the mirtest sense, It was once thought 'ha' the IUD p,..'entsf..ullZ.lltion. but mD'" recently it ha' been ,uggested that it act' 10 disruptimplantation. Human .horiDn,. gonadotropIn" p,oduced by trophoblastic,issue afler implantatloo. In the late 1970:1. there began to appear reports ofhCGdetected ft""tingly among women uSIng IUDs. In 1979. Saxena and Landesman","lOwed p"'iti'" and negali'e finding, Df hCG among IUD users. Theysuggested that implantation could indeed be occurring among IUD use". andlha"he ,",consistencies in hCG assay /indinss might in pan be due '0 the use ofIOsen,ili" assays. Since then. lwo studies applylns'!Ie most ad.'anced methodsof early pregnancy dete<'ion Ita.'e fDund persuasi"e evidence Df frequentp",gnancy among IUD use", Hodsen and hi. colleagues (1(78) Ilmultaneouslyapplied lhr« urme assays to hIghly concentrated u'ines. and found brier butdIStInct ,pike, of hCG amDng five of 26 "'omen u"ng IUDs. Smart andcolleagues (1982) detected the ,ecently identified 'ea,ly pregnancy factor' In (} Df23 eycles OCClJrrinllto Iun women> but in none of II cycles OCClJrrinllto ste'ile orsexually inaetl,," women. These studies,uggeS1that an IUD user has a 2O-2S~~

chance of a dete<:table pregnancy many lli.'en cycle.If women concei.'e while u,instbe IUD, then thei, ra'es of conception Dlfe' a

dire<t mu,ure Df tbei, fertility. MD",o.'er. thl> measure is a"ailable continu­ou,I}', rather than helnll confined 10 the non-<;ontracep,ing interval precedlnll abirth. IUD, are used by about 14 \ of contracepung women in the US betw«nIbe age' of 20 and 40 (US Vital and Healtb Slatistic>, 1(81), Tbe propo,tlon ofuse" does not "aI)' sreatl}' by race, age. panty. educalional le"el Dr familyincDme. This ,uggestS that a pool of Iun u.." <ould be found \n mostpopulation, exposed to a ,mpected hazard '0 fefuli'y

4.3 Quutitatl•• Estimation of Rid: E"trapolltloD froDl Anim.ls 10HUDlans

There Ire few if any da<a f'om y,bich to cDmtfUCt a dose-""ponse cur.-e for anad"e.-se elTect ofchemicals on human fenility. Inference' concerning quantital·i.'e effects on fertility' can be draY,n from antmal stud,os. One oftbe best e",mplesof animal do..-""pon.. data is the fetalion of ill u,ero "p"'ure 10 diethylstll­hoeslrol. and .ubsequent fenility. In a laboratory study p""'iously ciled(McLachlan and n"on. 1(76) fertility"'", measured In ,erms of li"e birtb' toforce-bred female mice A decline in fertilily ""as dire<t1y related to prior fetal

Q"""'ilotit", E/fN:lS of CMmkoJ, on F...."li'y 471

Table I F<rtihty of r.mal. moe< ••po«<! '0 DES pren,,,aUy

•'",",..

'00

No. ofoff.print

.,"•'"...."

Tmal reproducti,.. <;apocityor f.....le olf'p'1I\1I

l·.rontroll

'00'"'76.049.422.6•••"

dos... (Table I). Th. h'lhesl dose I,,'.n in this >ludy (per un" body wc,g1Il) ioabout on.-t"..nti.th of Ih. a,..r'I' dose prescribed to prelnant wom.n in the1950..

Th.re are t,,·o ol>so:rva\lons 10 be made reprdina th..... data, On•. the .ffect onf.rhl"y does nol rapidly approach ze,o ..-en at the lo",est doses tested. Thi' mayindica.. tha'th••ffec1 of DES on f.rtility has no lo"...r threshold. Tht absence ofan a!'P"rent Ihreshold .ffec1 ",Ih on. chemICal is notabl•. but does not reliabl)predicl "'hat might be found "'''h oth.r chemi<:.JJ•. consid.rina the '-ariety ofmech.nl,m. by which f.nilit) can he imp.aired. Th. second obser...."on" ,hatlh••trona effec1 on fertilit}' <><:curs at doses rouah1y comp.arabl. to dose'previou.ly .xpe,ienced by human,. ThIS off.,. an opportunity to compare theint.nsi'}' of anlmlll and human responses to a chemICal exposure. The,. ha,"been .....ral "udi.. ofpregnaneies amona women exposed to DES in ""'(} (fore...."'pl<, Barnes.'oJ., 1980: Manpn., 01" 1982), These ""omen produce s1iaJttl}'10"'''' numbers of Iiv. birth,. (Specifically, DES i. associa'ed ""th an increas... ill.pontaneou. abortion, ectopic preanancies. and prema'ur. birth•.) While DESdoes produce a delectabl. elfect In human•. thl< elTect does not appr"""h themagn'lud. observed in the comparabl. animal stud)', Thi' e....mple ,ugg.'" thalhuman reproduction mIght be less s...nsilive th.n lhal of Laboralory anImal,Ho""..·." olher evid.nce .U&&<SIS human' ma}' oometime. be a more sen.itiv.spec..'. Three chemical. ""Ih a kno"''11 dose-dependen, effect on renihty 11\ bothhuman. and laboratory animal. (ethylene dibromide. carbon di.ulpbid•. anddibromochloropropane) affect human. al 10""" doocs than animal. (CEQ.1980· Furthermore, look"" at panlCUlar tep,odllCli'e processes, humanf.nilily appears le.. robust lhan that of lo",..r mammal" For aample. buman'perm production " only 20-50~_... effie,.nt .s tbal or I.boratory anlmllls(Amann, 1981). and Ihe proportion ofabnormal.perm type' io hiJ,her in buman.Ihan 11\ non-primates. SimiLarl}'. ""omon 1)pK:all) produce onl}' on. f.rtilizabl••" at a time. and the occurrence of early f.tallO$s seem' 10 be bighe' lhan

472 Me/hods/or Eslinu"ing Risk o/ehtmieal Injury

ob!iCmd in animab, In corn:lu\ion, thc rclatiyc \Cn\itiYit)' of animal and humanfertility rcmllins 10 be eslablished,

5 CONCLUSIONS A:"D RECO:'I:\IENDATIONS

Sc,enhfic Inleml In chem'cal lo~icity in ,.Ialion 10 fe'tilit)' i' ,elam'ely rean!.There are promi,in~m.thods fo' stud)',ng human fe'1I1i')' that h"e no' y.t beenapplied Sune"ion. for funher research a,e summafiled below

(I) P,efenilization facl0r> a,e often .a,ie, '0 me..ure than fert,ht)· endpo,nt.,and may be suitable 'Ubslltutes fo' an.ssin, 'h. impac' of chemical' onrep'odu<ti,-. funeuon, (KClion 4 2,2.1), Ther. is a need for furth.r d.".lopmentof 'perm a,says lhal rna) p,edict fenih,) ffor example, ,n "iITo fertiliUlIontechn,que.). The monttOfing of ovulation may also p,o"ide a means ofd.tectin,.ffeels of ch.mical, on fertilny proce"es

0) Specific ehem,eals haw been 'hown to .ff",t krtj]it), to animal' andhumans, Ho"'ever. it i' not dear ""hether th. f.rtili') of humans or of annnals IS

lhe more sensili," '0 disrupuon (sect,on 4 3), Some assessment of lhei' 'elali"esen,ili.'i')' is necessaf}' in order 10 eXlrapola.. accurately from an,mals tohumans, A lhorough ,,,'i.w and compa,ison of animal and human data "'ouldbe helpful. although Ihe ,horlage of human data mal pre<lude sound g.ner_alo2.11ion<,

(3) There are ...w,al feasibl. mel hod' for quantifying human fenilily thalha,·. )'d '0 bo applied (section 4.2.2.3). Th.se "'dud. the use of ,im. 10

pr.gnancy a. an .ndpoint. moni'o,ing women for p,egnanci•• by u... ofmenstrual record-ketping. and monitorinl! for pregnancle, by ufln. ""'y'Artificially in ...minaled wOmen and wom.n USing IUDs offe' opportunilies fo'<pecial sludies of fertility (seclion' 4,2.2.3 and 4.2,2.4). Computor 'imulalion'rna)' pro"ide a 1001 fo' making th. complica'ed romparison, nec....f}· toe,aluate demol!raphic method" biol"l!ical monitoring m.thods and oth.r way'of m.asu,ing f.,-tilil)

(4) The estimation of a safe dose i. difficult for any chemical. [n the ca ... offenilil)'. IhlS p,oblem ,s complicated by the apparen, amplificat'on ofeffeclS $«1\

,n multigen.rational $tudies ("""lion 4.1). The mechanism of thi, cumulati"eeffect o"er ..."erall!eneralion, need' fun her ",udy, This ph.nomenon also needs10 be explored in human population•. allhough th.,.. ar. limited opponunilies todo so,

($) Where"er ad"e'se eff",t or chemicals on renility ;s d,sco,'ered, 'I i.necessa,y '0 identify the m¢chanism of ,clion The .ffecl of some a,en" onrenilit) i' so ,pecific .nd transient (for example. tho d;s'upuon of 'pe'­matogenesis by go,,)'pol) that it rnay be judged innocuous, or O\'en d..irabl. as am.thod ofcontrac.plion On the olher hand. an ad" ..... effecl on renilily may be.ccompanied by perman.n' .ffel'1S on ferhhty, as ""en as Olher adve.... effeclS\like mUlagenesis) lhal h,," implicalions beyond f.nilit)",

Quantilati," EjJfflS of Chemicals on hTlililJ 473

6 REFERENCES

Amann, R. P. (19gl) A critic.1 n:";'~ of"""hod. fo..,...lnat;on of .porm.tog,,,,'" from..mln.1 chara<teri"ic>, J. Anm-o.. l. 3J-58

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