Assessing the Human Health Risks of Trichloroethylene Key Scientific Issues (2006) / Chapter Skim
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3 Kidney Toxicity and Cancer
3 Kidney Toxicity and Cancer
Pages 58-136
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From page 58... ...
. The review focuses on scientific issues raised during the review process that have relevance in carrying out a human health risk assessment.
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From page 59... ...
. The sulfoxidation and toxicity of trichloroethylene S-conjugates (involving hepatic or kidney microsomal sulfoxidation of cysteine and mercapturic acid conjugates)
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. Sulfoxidation was not detected with human kidney microsomes, although only one kidney sample was evaluated (Krause et al.
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were much better microsomal flavin monooxygenase substrates in human kidney and liver and in rabbit liver than were those with less nucleophilic sulfur atoms (the various haloalkyl cysteine and mercapturic acid conjugates)
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Qualitatively, S-(1,2dichlorovinyl) -l-cysteine sulfoxide replicated the rat renal tubular cell injury also caused by S-(1,2-dichlorovinyl)
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. More recently, the effects of the cysteine-S-, mercapturic acid, and corresponding sulfoxide conjugates of the nephrotoxicant fluoromethyl-2,2difluoro-1-(trifluoromethyl)
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Myriad investigations of in vivo trichloroethylene disposition in rodents and humans after controlled as well as occupational exposure (Birner et al. 1993; Bernauer et al.
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From page 65... ...
-l-cysteine exposure in vivo. nonCanCeR toxiCity Animal Studies Tubular Toxicity Trichloroethylene has been shown to cause toxicity to renal tubules in bioassay studies, and mechanisms of this toxicity have been pursued in experimental studies.
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-l-cysteine-induced apoptosis also has been reported in primary cultures of human proximal tubule cells (Lash et al.
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Urinary excretion of albumin was not affected (although the high end of the range was about twice that of the control group) and high-molecular-weight proteins showed an upward trend but were not significantly increased (creatinine at 36 mg/g [4-81 mg/g]
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From page 68... ...
Results from the National Toxicology Program's 2-year cancer bioassays of trichloroethylene administered by gavage to rats and mice are provided in Tables 3-1 and 3-2. Nonneoplastic kidney lesions were found in all animals dosed for 2 years, including mice that did not develop kidney cancer (NTP 1988)
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From page 69... ...
KIDNEY TOXICITY AND CANCER 6 TABLE 3-1 Summary of Renal Toxicity and Tumor Findings in Gavage Studies of Trichloroethylene by NTP (1990) Cytomegaly and Karyomegaly Tumor Incidence Sex Dose (mg/kg)
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From page 70... ...
. No renal effects were reported for mice, but renal adenocarcinomas were found in male rats at the high dose (600 ppm)
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The lesions due to formic acid (induced by trichloroethanol administration) and trichloroethylene exposure differ in the nature and the time course of the lesions.
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The amount of formic acid produced after administration of trichloroethanol or trichloroacetic acid in drinking water was similar at 2-4 weeks (about 20 mg/day for each compound) and was the same at the two doses used (1 and 5 g/L for trichloroacetic acid and 0.5 and 1.0 g/L for trichloroethanol)
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. The trichloroethyleneexposed patients had elevated excretion of 1-microglobin compared with the nonexposed renal cell cancer patients.
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. Some subjects in this study were highly exposed; of the 134 with renal cell cancer, 19 reported past exposures that led to narcotic effects and 18 of the 401 controls, experienced similar effects (odds ratio [OR]
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From page 75... ...
(1972) noted that the relationship between trichloroethylene exposure and urinary trichloroacetic acid was nonlinear at trichloroethylene concentrations above 50 ppm, reaching a plateau at 100 ppm, thus indicating saturation of trichloroacetic acid formation.
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Rather, weight of evidence indicates that proteinuria is occurring at current occupational exposures and that kidney damage is occurring. Although generalized proteinuria and urinary excretion of specific tubular proteins have been used to evaluate renal tubular cell toxicity in animals and humans exposed to trichloroethylene, it should be noted that while proteinuria does result from tubular toxicity, it is not specific for trichloroethylene or tubular nephrotoxins in general (D'Amico and Bazzi 2003; Han and Bonventre 2004; Lane 2004)
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. kidney CanCeR Hazard Identification from Epidemiology Studies The committee was charged with evaluating the strengths and limitations of the body of epidemiologic evidence on trichloroethylene and kidney cancer.
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The design characteristics of 18 cohort studies are presented in Table 3-4 and selected results from the studies are provided in Table 3-5. The committee has attempted to compile a complete list of studies that provide insights into the association between exposure to trichloroethylene and kidney cancer.
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enelyhteorolhcirToterusopxEdnarecnaCneewteBsnoitaicossAtneserPtahTseidutStrohoCdetceleS dnasisylanA tnemtsujdA laitnetoProf srednuofnoC R MS ,ecar,xes,egA ,raeyradnelac fonoitarud ,tnemyolpme htaedforaey R MS ,ecar,xes,egA raeyradnelac deunitnoc dnatnemssessAerusopxE serusopxEtnaveleRrehtO hguorhtdenimretedtnemyolpmE dnasdrocerkrowynapmoc sbojfo %73tuoba;sweivretni nodesab,ECToterusopxedah .stcejbus07 hguorhtdenimretedtnemyolpmE oN.sdrocerkrowynapmoc .tuodeirractnemssessaerusopxe dedulcniserusopxesuodrazaH citsalprebbur,sdiuflgnittuc ,stnevloscinagro,seydtniap yxope,semufgnidlew,stniap ,sotsebsa,srenedrahdnasniser dna,srebfilarenimedamnam gnitset(noitaidargnizinoi cfiicepsoN.) stnenopmocfo .ECTfonoitnem nosirapmoC puorG lareneg.S.U noitalupop larenegnailatI noitalupop puorGydutS )
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80 dnasisylanA tnemtsujdA laitnetoProf srednuofnoC RR,R MS ) nossioP( ,xes,egA doirepradnelac dnatnemssessAerusopxE serusopxEtnaveleRrehtO tnemssessatsineigyhlairtsudnI eneigyh,syevrus,sweivretni morf snoitpircsednoitisop,selfi gnippid morf ybdecalper ECToterusopxE llamsgninaelcdnastrapegral htiwstnenopmoclacirtcele derocserusopxE.selttobezeeuqs -knar;bojrotnemtrapedyb .ytisnetnifoxednideredro draddotS:serusopxerehtO -1,1,1,lohoclalyporposi,tnevlos ,eneulot,enoteca,enahteorolhcirt enelyhtem,enoteklyhtelyhtem .edirolhc ECT,0691-0591:gnisaergeD dnatnevlosdraddotSdecalper .edirolhcartetnobrac fonoitartnecnoc,0691ylraE ehtgnirud mpp004tuoba ECT .gnisaergedfonim51lausu 002tuobaotdecudersawsihT .s0691etalni mpp ECT:8791retfA enahteorolhcirt-1,1,1 ECT:tnevlosetatsdloc:8691 .enahteorolhcirt-1,1,1ybdecalper nosirapmoC puorG etihwhatU noitalupop puorGydutS )
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81 xoC,R MS lanoitroporp ledomsdrazah xes,egA RR,R MS ) nossioP( ,xes,egA fosetad,ecar tsaldnatsrfi tnemyolpme deunitnoc detarenegsecirtamerusopxE lairtsudnidnaseeyolpmeyb ropavnidesu ECT.stsineigyh -2591)
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82 dnasisylanA tnemtsujdA laitnetoProf srednuofnoC ledomxoC rofdetsujda emit,epytyap dna,erihecnis lanoitiddA.ega stnemtsujda rehtorof ,serusopxe gnidulcni .enizardyh cfiiceps-ecaR sRO egA dnatnemssessAerusopxE serusopxEtnaveleRrehtO depolevedxirtamerusopxe-boJ ehtfotnemssessahguorht serocserusopxE.ecalpkrow cilcycylop,enezneb,ECTrof larenim,snobracordyhcitamora erusopxE.enizardyhdna,lio erusopxefoytisnetni=erocs ) hgih,muidem,wol,enon( desopxesraeyforebmun× .sbojllarevodemmus ACT-UrofgnirotinomlacigoloiB otseirotsihrekrowfoegakniL krow;sdroceresu-tnevlostnalp nwonkhtiwaerassecorpni .erusopxeotsetauqeesutnevlos ,creP,ECT:serusopxerehtO ,sahthpan,senelyx,eneulot .lonehp,enoteca,lonahte nosirapmoC puorG lanretnI nosirapmoc lareneghsidewS fo noitalupop %02(633,1 )
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From page 83... ...
83 R MS ,xes,egA raeyradnelac RIS,R MS emit,xes,egA doirep RISdna R MS ,xes,egA ;raeyradnelac -esacdetsen ydutslortnoc recnaclanerno deunitnoc enoN foytilibaborpfosetamitsE fosepyttnereffidoterusopxe detubirttaleuftfarcriayratilim naicinhcettfarcriaroinesayb .selfilennosrep'stcejbus ,57C M,55C morf M:deredisnocsleuF oterusopxefI.52C M,77C M ehtfotrapebdluowtineht,ECT tfarcriaehtfoerutximxelpmoc .sleuf enoN lanretxE htiwnosirapmoc lareneg.S.U noitalupop lareneghsidewS noitalupop lanretxE htiwnosirapmoc lareneg.S.U ;noitalupop lanretni nosirapmoc nemetihw041,2 nemetihwnon67 nemow034 riA nem671,2 morf568,1 ecroF nemetihw567,1 nemkcalb36 nemowetihw912 nemowkcalb3 dnaetihwfoecneirepxeytilatro M 3>,nemowdnanemetihwnon ,3891-7591,tnemyolpmeshtnom sionillInitnalpgnirutcafunamani gnisaergedasa ,77C .4791ot2791gnirud)
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84 dnasisylanA tnemtsujdA laitnetoProf srednuofnoC citsigoL sesylana gnitsujda raey,egarof ,htaedfo rehtodna setairavoc deretlataht erusopxeeht ybetamitse %02> dnatnemssessAerusopxE serusopxEtnaveleRrehtO yberusopxerofdetarseltitboJ adetaercdnatsineigyhlairtsudni cfiicepsrofxirtamerusopxe-boj sadedoc( ECTgnidulcni,stnevlos .) desopxe/desopxenu nosirapmoC puorG lanretnI nosirapmoc puorGydutS )
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From page 85... ...
8 RIS emit,xes,egA doirep lanretnI nosirapmoc ,SRISgnisu detsujda .egarof RIS:lanretxE .snoitaluclac ,thgiewydoB doolb,thgieh ,erusserp foekatni ,sciteruid ,gnikoms lohocladna .dessessa deunitnoc -UrofgnirotinomlacigoloiB fosetilobatemdoolbdna ACT rehtO.enahteorolhcirtdnacreP :gnirotinomoibdnaserusopxe creP,enahteorolhcirt-1,1,1 gninaelcrofdesu,erusopxe ECT nI.5791dna6591neewteb nidesustnevlosrehto,6791 hguorht-kla W.seititnauqllams niserusopxehgiH.yevrusI rewoL.aeraenihcam-draobdrac serusopxesuounitnoctub lacirtcelednahtimskcolni .spohskrow lareneghsinniF noitalupop lanretnI sesunosirapmoc otsetarhsinaD .detcepxeetaluclac lanretxE nosirapmoc dnahsinaDhtiw recnacnamreG ecnedicniyrtsiger esuaC.setar morfhtaedfo ;sdrocerlatipsoh htaedfoesuac setarlanretxerof htaednodesab .setacfiitrec latot479,3 nem050,2 nemow429,1 ;nemdesopxe381 detapicitrap961 lortnoC.ydutsni 091fotrohoc ,nemdesopxenu eganodehctam bojlacisyhpdna desopxeotytivitca raelcnU.trohoc strohoceht woh detutitsnocerew .dewollofdna desabebotsraeppA 5foretsulcano gnidnfiesaC.sesac neebevahtonyam .etauqeda ) 2991-7691(ecneirepxeecnedicnI derotinomyllacigoloibsrekrowfo oterusopxelanoitapuccorof -5691(stnevlosdetanegolah foetutitsnIhsinniFehtta)
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From page 86... ...
86 dnasisylanA tnemtsujdA laitnetoProf srednuofnoC RR,R MS lanoitidnoc( citsigol ) noisserger radnelac,egA ecnisemit,raey yap,derihtsrfi lanretni,epyt lanretxedna esodnoitaidar RIS ,xes,egA ,raeyradnelac tsrfifodoirep ,tnemyolpme tnemyolpme noitarud RISlanretxE ,snoitaluclac rofdetsujda ,ega,xes raeyradnelac dnatnemssessAerusopxE serusopxEtnaveleRrehtO detarenegsecirtamerusopxE lairtsudnidnaseeyolpmeyb ,sdiuflgnittuc,ECTrofstsineigyh defiissalcsrekro ,)
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From page 87... ...
8 R MSlanretxE ,snoitaluclac rofdetsujda ,ega,xes raeyradnelac tastnevloscinagrootserusopxE dna ECToteuderewtnalpeht yramirpehT.enelyhteorolhcrep noitarudsawerusopxefoxedni .tnalpehttatnemyolpmefo sdrocerynapmoconesuaceB sawnoitarud,elbaliavaerew morf:sdrocerecnarusninodesab robalfonoitanimretotnoitpecni snoitaruD.egarevocecnarusni sadetamitserednuylekilerew tnemecnemmocfosetad dna)
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From page 88... ...
88 ASSESSING THE HUMAN HEALTH RISKS OF TRICHLOROETHYLENE TABLE 3-5 Selected Results from Cohort Studies of Kidney Cancer and Occupational Exposure to Trichloroethylene Approximate Exposed Estimated RR Statistical Power Reference Study Population Cases (95% CI) to Detect a RR = 2 Incidence Sinks et al.
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31.9 Zhao et al. Kidney in men 2005 Cumulative exposure score, lag 0 Low (0-3)
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From page 90... ...
33.3 High exposure 7 1.78 (0.72-3.66) 50.1 Peak exposures (reference=none/low)
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a 16.6 Zhao et al. Kidney in men 2005 Cumulative exposure score, lag 0 Low (0-3)
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estimates that nearly 39,000 patients will be diagnosed with kidney cancer in 2006, more than twice the number of patients expected to be diagnosed with liver cancer (see Chapter 4)
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From page 93... ...
Effects of Confounding The impact of confounding by other risk factors also needs to be considered carefully in evaluating the evidence for kidney cancer. In the cohort studies, potentially confounding factors other than accounting for age, sex, and calendar year were not evaluated.
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From page 94... ...
is 2, but the prevalence of smoking in the cohort was not taken into account in its calculation, so that confounding could explain the observed effect. The following equation describes the relationship between incidence and exposure and the confounding effect of smoking: I = I0 ×{1 + ps ×(RRs -1 ,i ,i } where I is the incidence of kidney cancer, I0 represents the baseline rate, RRs ,i represents the rate ratio for smoking (s)
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From page 95... ...
scirte seidutStrohoCdetceleSnienelyhteorolhcirToterusopxEfotnemssessAehtfoscitsiretcarahC MesoD ,evitatitnauq( ,evitatitnauqimes ) evitatilauq rekramoiB seulav rekramoiB deunitnoc seulav erusopxE noitalopartxE ,sdohtem( atad,snoitpmussa ,tcerid[secruos )
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From page 96... ...
6 scirte MesoD rekramoiB seulav evitalumuC ;erusopxe detaluclac stlusertub ;detroperton egareva dnaerusopxe fonoitarud .erusopxe erusopxE noitalopartxE enoN adekIehtgnisU( pihsnoitaler] 2791[ erusopxe ECTrof naidem,ACT-Uot erewserusopxe )
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From page 97... ...
ECTsraeY saerusopxe roenituor ;tnettimretni dnaepytboj fonoitarud .erusopxe evitalumuC yberusopxe thgiew ECT ;shtnomsemit otdesopxe ynasawskaep hgihniemit osla;yrogetac foymotohcida ,desopxereve .onrosey deunitnoc enoN mret-gnoL detarseeyolpme ybserusopxe ;airetirceugav lairtsudniynapmoc ehtdesutsineigyh nadliubotatad ;xirtamerusopxe noitaredisnocon htiwsegnahcfo .emit otdengissasrekro W ,ylbmessa:seilimaf ,noitacirbaf ,gnissecorp rellams;ecnanetniam gnissecorp:spuorg dnasrotarepo ) 044,1(srepleh ropavnodekrow .sresaerged noliatedoN elbissoprolocotorp erusopxe;srorre ;niatrecnusiegnar seirogetaceerht krow,hgih:dengissa 05>(sresaergedno krow,muidem;)
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From page 98... ...
8 scirte MesoD spuorgboJ fonoitaruD tnemyolpme erusopxE noitalopartxE enoN htiwknilon,enoN .serusopxerosboj erusopxE noitacfiitnauQ ruofylnodesu;enoN :spuorgbojdaorb %57ralloceulb lacinhcet,latotfo evitartsinimda,ffats etihwdna,skrelc .ralloc trohocehtrofenoN noitaruD lennosreP ;4591>sdrocer ;doogytilauq dnadetratsry hcaerofdedne naidem;tcejbus :snoitarud tnemyolpme ,ry01tuoba tuobapu-wollof %52ylno,ry71 ry52>dah ,sdrocerkro W ;doogytilauq krowry4> ;ry03 |
From page 99... ...
fosraeY tnemyolpme ninoitaruD tnemtraped deunitnoc noissergeR sawpihsnoitaler ybdepoleved 06: MG.yrtsudni ;9591-7491 -0691 mpp mpp94 mpp02;9691 9791-0791 enoN enoN enoN morfselpmaS ;margorplanoitan :latemdnanori tonnoitatitnauq ytilatromnidesu .yduts gnirotinomerusopxE , MEJtnalp,atad evitatitnauqimes ybstnemngissa stsineigyhlairtsudni .seeyolpmedna enoN enoN 2591trohocnI ,ry3> 6991-1591 1591trohocnI noitarudtrohS ry01tuoba ,seirotsihkro W ,doogytilauq ninoitarud tneicfifus;.stped .ycnetal larenegdetimiL noitpircsed lanoitan morf .secruos ;nawiaT tceridon noitamrofni dedivorpsaw demuserpno crePdna ECT .serusopxe tonegasu ECT .debircsed seinapmocdexi M srekrowgnissecorp-muinarU dnas0591ni ECTgnisu ,sdiuflgnittucosla,s0691 .sdrocerynapmoc,enesorek desu;tnalpscinortceleegraL lacolnidnuof(crePdna ECT .) retawllew ,gnirutcafunamdraobrepaP ,slairetamnitneserp ECT .debircsedtonegasu sgnittesdexi M -uohcsaaR nesleiN 3002.late serusopxe( -uohcsaaRni .latenesleiN )
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From page 100... ...
100 scirte MesoD .svdesopxE desopxenu erusopxE noitalopartxE repapnienoN eirrehC( ] 1002[.late desabdetalopartxe :repapnisliatedno mpp000,2>skaep 002-001 mret-gnol .)
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From page 101... ...
. Because the study population included the area with the cluster, the observed relative risks for kidney cancer were much higher than in any other study (SMR, 7.97; 95% CI, 2.59-18.59; five cases)
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From page 102... ...
A cluster of cases of kidney cancer were used to design the study, and they were included in the analysis (see Swaen 1995; McLaughlin and Blot 1997)
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6. Use of the Danish Cancer Registry to calculate expected values might not be appropriate if rates of renal cell cancer in the region surrounding the plant are very different from those in Denmark.
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From page 104... ...
Case-Control Studies The main methodological points associated with case-control studies are the accuracy of the outcome, estimates of exposure, statistical power, confounding, and selection bias. Tables 3-8 and 3-9 provide the essential design characteristics and selected results of case-control studies on kidney cancer and occupational exposure to trichloroethylene.
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From page 105... ...
10 elbissoPdnarecnaCyendiKneewteBsnoitaicossAtneserPtahTseidutSlortnoC-esaCfonoitpircseD roftnemtsujdA gnidnuofnoC ,thgie W lohocla,ega ,noitpmusnoc ,noitapucco ffuns,gnikoms eeffoc,esu ,noitpmusnoc ,senotsyendik ,noisnetrepyh lacidemrehto srotcaf emitefil,xeS occabot gnikoms deunitnoc sisylanA citsigoL noisserger citsigoL noisserger hguohtlA slortnoc dehctam sesacot ) 1:3oitar( ,latipsohno dna,ega a,xes dehcatam sisylana tonsaw .detcudnoc noitanimreteD erusopxEfo nosrep-nI weivretni gnissessa snoitapucco )
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From page 106... ...
106 roftnemtsujdA gnidnuofnoC gnihcta M selbairav sisylanA dehcta M sesylana noitanimreteD erusopxEfo nosrep-nI htiwsweivretni eriannoitseuq emitefilgnissessa lanoitapucco ;) seltitboj(yrotsih sexednierusopxe ybdenimreted lanoitapucco rotsineigyh tontub,tsimehc ylticilpxedenfied :desuseulaV ",desopxenu" ;1 |
From page 107... ...
10 enoN gnihcta M ,selbairav ,gnikoms eeffoc ,noitpmusnoc ytisebo deunitnoc detsujdanU ,sisylana tub -dehctam detsujdanu lanoitidnoC citsigol noisserger foyrotsiH oterusopxe snobracordyh deniatbo deliamhguorht dnaeriannoitseuq detnemelppus enohpeletyb weivretni .) stroper-fles( delia M roeriannoitseuq weivretnienohp )
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From page 108... ...
108 roftnemtsujdA gnidnuofnoC taega,xeS ,sisongaid ,sutatslativ lanoitacude lausu,level forebmun setteragic ,dekoms lanoitapucco erusopxe ,stnevlosot recnaccfiiceps srotcafksir rofdellortnoc evitcepserni sesylana sisylanA citsigoL noisserger noitanimreteD erusopxEfo esoderusopxE saeranidetamitse detanimatnocfo ,retawgniknird rofgnitnuocca sraeydnanoitacol ,ecnediserfo epip,woflretaw .scitsiretcarahc tnaveleR ) s(erusopxE -orolhcarteT enelyhte forebmuN slortnoC 777 forebmuN sesaC yendik53 fo deunitnoC fonoitpircseD noitalupoPydutS ehtotdetropersesaC recnaCsttesuhcassa M nidesongaid,yrtsigeR stnedisergnoma6891-3891 doCepaCreppuevfifo slortnocgnivil;snwot AFCH morfdetceleserew desaeced;DDRdnasdrocer ehtybdefiitnedislortnoc latiVfotnemtrapeDetats .selfihcraeseRdnascitsitatS %6.08:setaresnopseR AFCHfo DDRfo fotxenfo %9.57,sesac %9.37,slortnoc %8.87,slortnoc .slortnocdesaecedfonik 8-3 ELBAT ecnerefeR uargnehcsA 3991.late
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From page 109... ...
10 ,xes,egA weivretni ,dohtem etteragic ydob,gnikoms ,xednissam ,noitacude esuciseglana gnihcta M ,selbairav ,noitacude ydob,gnikoms xednissam deunitnoc citsigoL noisserger lanoitidnoC citsigol -ni(eriannoitseuQ weivretninosrep htiwdeliamro -wollofenohpelet ssessaot) pu tnemyolpme cfiicepsni dnasnoitapucco roboj(seirtsudni ,)
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From page 110... ...
110 roftnemtsujdA gnidnuofnoC ydob,egA ,xednissam gnikoms ,retnec,egA ssamydob etteragic,xedni gnikoms sisylanA citsigoL noisserger citsigoL noisserger noitanimreteD erusopxEfo nosrep-nI htiwsweivretni eriannoitseuq tsomgnissessa dnatnecer dleh-tsegnol noitapucco dna) seltitboj( oterusopxe stnegacfiiceps .)
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From page 111... ...
111 ydob,egA ,xednissam etteragic ,gnikoms tnednopser sutats deunitnoc citsigoL noisserger citsigoL noisserger htiw nosrep-nI weivretni eriannoitseuq gnissessa ni(erusopxe ) sraey5fossecxe fotsil morf secnatsbuscfiiceps .)
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From page 112... ...
112 roftnemtsujdA gnidnuofnoC ,xes,egA ydob,gnikoms ,xednissam ,erusserpdoolb foekatni sciteruid sisylanA citsigoL noisserger noitanimreteD erusopxEfo ,nosrep-nI dednilbnu ybsweivretni snaicisyhp ) yxorprotcerid( derutcurtshtiw eriannoitseuq gnissessa lanoitapucco boj(yrotsih cfiicepsdna)
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From page 113... ...
113 ,gnikoms,egA ,noisnetrepyh ssamydob xedni gnihcta M ,selbairav gnikoms deunitnoc citsigoL noisserger lanoitidnoC citsigol noisserger nosrep-nI tcerid(sweivretni htiw) yxorpro eriannoitseuq gnissessa lanoitapucco seltitboj;yrotsih dnadedocerew ahtiwdegrem erusopxe-boj eht morfxirtam recnaClanoitaN .etutitsnI nosrep-nI sweivretni emitefilfo lanoitapucco gnisuyrotsih oteriannoitseuq seltitbojssessa detroper-flesdna ,serusopxe serusopxe ybdeniatrecsa erusopxe-boj .secirtam ,enelyhteorolhcirT -orolhcartet stnevlos,enelyhte larenegni -orolhcirT ,enelyhte -orolhcartet cinagro,enelyhte stnevlos 786 892,4 834 lleclaner amonicrac laner539 llec 58-02ega,sesacetih W yllacigolotsihhtiw,sraey lacol fo sisongaiddemrfinoc ehthguorhtdefiitnedi -8891ni recnaCatosenni M metsySecnallievruS defiitnedislortnoc;0991 46-12ega( sdrocer ,sesacfo DDRhguorht AFCHdna)
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From page 114... ...
114 roftnemtsujdA gnidnuofnoC gnihcta M ,selbairav gnikoms sisylanA lanoitidnoC citsigol nodesab( -ycneuqerf ) dehctam noitanimreteD erusopxEfo lanoitapuccO dnayrotsih ,ECTotcfiiceps stroper-fles erusopxefo dna .enelyhteorolhcirt,ECT;gnilaidtigid ECTot perchloroethylene, fostroper citocranerp rofsmotpmys .serusopxekaep -bojdesU xirtamerusopxe dnattennaPfo XERACeht refniot metsys .serusopxe tnaveleR )
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From page 115... ...
KIDNEY TOXICITY AND CANCER 11 TABLE 3-9 Selected Results from Case-Control Studies of Kidney Cancer and Occupational Exposure to Trichloroethylene Exposed Estimated RR Reference Study Population Cases (95% CI) Siemiatycki, Kidney cancer, men, Montreal 1991; Exposure assessed by experts from job Parent et al.
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One possible source of bias that affects all case-control studies to some degree is the nonrepresentativeness of the study population to the target population. This can occur through sampling variation (essentially a ran
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From page 117... ...
As with the cohort studies, an important factor that affects causal inference is how exposure is measured and assigned (validity, reliability) and whether exposure-response relationships are measurable.
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From page 118... ...
Same plants as in Vamvakas (molecular study of von Questionnaire by personal study. Detailed info on TCE Hippel-Lindau gene interview; secondary questions use, area descriptors -- hot mutations in subjects if TCE reported; employer dip baths, small work areas, highly exposed to TCE)
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(1998) study compared 58 renal cell cancer cases diagnosed between 1987 and 1992 with controls to provide an independent assessment of the Henschler et al.
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There were also large differences in the source of exposure, with the use of hot dip tanks (major sources of trichloroethylene vapors) predominating in the highest category and largely rag-and-bucket cleaning (limited local sources of trichloroethylene vapors)
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This could have led to an inaccurate estimate of the exposure distribution. On the other hand, the control subjects who were enrolled when the interviews were conducted might not represent the true exposure distribution of the target population through time.
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(2001) separately estimated the exposure intensities with a suitable engineering model, which estimated peak exposures in the range of 500 ppm and averages about 100 ppm.
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Again, prevalent cases of renal cell carcinoma were identified in 1992-2000 and interviews were conducted in 1999-2000. Controls were identified and interviewed in 1999-2000 and were recruited from noncancer patients having surgery and from a local department of geriatrics.
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tumor suppressor gene in the etiology of renal cell carcinoma arising from exposure to trichloroethylene. Brauch and coworkers have reported additional studies (Brauch et al.
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Thirtyeight of the original 58 patients with renal cell carcinoma were analyzed, and the authors used the original Vamvakas et al. exposure classification.
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. The nephrocarcinogenic effects of trichloroethylene are more pronounced in male rats, compared with female rats and were absent in male and female mice.2 Studies of trichloroethylene metabolism in rodents and humans support a role for bioactivation in the development of nephrotoxicity and nephrocarcinogenicity after exposure to trichloroethylene (Lash et al.
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Genotoxicity Trichloroethylene causes a significant increase in the incidence of renal tumors in rats when administered orally and a marginal incidence of renal tumors when administered via inhalation; on the basis of limited evidence for carcinogenicity in humans and sufficient evidence for carcinogenicity in experimental animals, the International Agency for Research on Cancer (IARC 1995b) classified trichloroethylene as a probable carcinogen in humans (group 2A)
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From page 128... ...
the possibility that kidney cells derived from kidney cancer patients could be more sensitive to DNA-damaging activity due to a more marked expression of enzymes involved in the metabolic activation of kidney procarcinogens and suppression of DNA repair processes. Therefore, the results of the genotoxicity studies must be considered solely as indicating that trichloroethylene might be genotoxic to the human kidney; the authors suggest that the designation of "inadequate evidence for carcinogenicity to humans" might not be tenable in the absence of sufficiently powered and carefully controlled epidemiologic studies.
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More than 80% of sporadic renal cell carcinoma, but not papillary renal cell carcinoma, is associated with inactivation of the VHL gene (Gnarra et al.
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From page 130... ...
, which leads to an OR of 6.5, which remains significant. Collectively, the data support the concept of a genotoxic effect of trichloroethylene leading to VHL gene damage and subsequent occurrence of renal cell carcinoma in highly exposed subjects.
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. A worldwide mutation database compiling VHL mutations in sporadic renal cell carcinoma showed that missense mutations compose about 29% of all mutations; a large majority of base changes (71%)
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1999) .The three reports of trichloroethylene exposure from the same group suggest that trichloroethylene increases VHL mutations and generates a unique genetic signature of trichloroethylene exposure, which leads to the development of renal cell carcinoma.
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Role of Nephrotoxicity in Trichloroethylene Renal Cancer In animal studies, renal cancer occurs at high doses and is preceded by nephrotoxicity affecting the proximal tubule (NTP 1988, 1990)
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findings Although the committee was not charged with performing a risk assessment, it became clear from the epidemiologic evidence that there were sufficient data to make a recommendation about whether the findings of the mortality and incidence studies provided support for or against the hypothesis that exposure to trichloroethylene was associated with the induction of kidney cancer. There is strong evidence that exposure to high doses of trichloroethylene is associated with increased rates of kidney cancer.
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After the discovery of the VHL tumor suppressor gene, it became recognized that homozygous inactivation of the VHL gene was linked to the occurrence of renal clear cell carcinoma, the renal carcinoma preferentially induced by trichloroethylene. In exposed subjects, the genotoxic effect of trichloroethylene likely results from bioactivation pathways leading to renal VHL gene damage and renal cell carcinomas.
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From page 136... ...
· Although correlation of VHL mutations to trichloroethylene exposure and renal cell cancer are persuasive, the findings need to be validated in other populations and geographic areas. Because many risk factors for renal cell carcinoma generate mutation spectra similar to that of trichloroethylene, coexposure to trichloroethylene with other risk factors needs to be seriously considered and accounted for in future epidemiologic studies.
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Key Terms
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