Document 3NGJowN0JY6y0m5E1BVx23jdn

HUMAN TOXICOLOGY An International Journal Volume 7 Number 6 November 1988 Human Toxicol (ll)NX). 7, 517--S27 Human Male Exposure to Vinyl Chloride and Possible Teratogenic and Mutagenic Risks: A Review L. Uzvcli 103 Canterbury Drive. Walltnglord. PA I'tOSfi, USA Introduction Vinyl chloride, also known as vinyl chloride monomer (VCM). chlorocthylcne. and chlorocthcnc. was first synthesized in 1833.' Sonic years later in the nnd 1030s. the polymerization process was discovered in Germany. The vinyl chloride related industries have developed rapidly in Europe, which accounts for about 3(1% of world production, and in the United States, which accounts for an estimated 23% of world production. Annual world production of vinyl chloride exceeds 10 billion kg.2 Total world-wide employment in the VCM and polyvinyl chloride (PVC) producing industries is estimated to be well over 7IUXKJ workers. The number of workers employed in industries using PVC as a basic element is estimated to total in the millions. Data pertaining to the possible toxicity of vinyl chloride were published in the literature as early as 1930. At that lime, Patty era/.3 reported gross patho logical changes in guinea pigs that died during exposure to vinyl chloride, including intense congestion and oedema of the lungs and a hyperemia of the kidneys and liver. Vinyl chloride may further be associated with reproductive related risks. Workplace policies, in fact, have been instituted prohibiting females from working in vinyl chloride polymerization areas, based on the belief that vinyl chloride may pose a health risk to females and to their unborn children. Lawsuits have subsequently been filed charging that such policies arc discriminatory because vinyl chloride exposure may also adversely affect male reproductive functioning/'3 A growing body of data indeed suggest that the exposure of human males to vinyl chloride in the workplace, and elsewhere, may be associated with various chromosomal aberrations in lymphocytes and sister chromatid exchanges. Paternal exposure to vinyl chloride may further be associated with various adverse effects on pregnancy and possibly spermatic alterations. This review is intended to examine critically selected, available data concerning paternal exposure to vinyl chloride and possible reproductive related risks. The references included in the review date to 1983. lt should be understood that these references were selected from among the best available published data known ;o the author. ChrtnnoMminl aberrations Data in the published hlvi.uuiv ale eonllieting regarding possible chromosomal aberrations associ ated with the exposure ot human males to vinyl chloride. Some investigators nave reported negative findings for chromosomal alvri.iiions in vinyl chloride exposed males, JTeig A Tliiess" ip 1978 reported data from chromosome analysis undertaken on lymphocyte Cultures from male workers showing no symptoms of vinyl chloride illness. Compared with controls, there was no significant difference in the rale of chromo some aberrations; the frequency of aberrant meta phases totalled 3.1%, excluding gaps, and 7.5%, including gaps for exposed workers, corresponding values in the control group were 2.1 and 5.5%, respectively. Several factors confound the analysis of the Flcig data. The sample population of workers was relatively small (it = 10). A relatively small sample size raises questions about statistical 'power', or an investigator reporting no association, when in fact one exists. In general, the smaller the sample size, the greater the chance that an association between an exposure and an effect will not be detected.7 Precise data on level of vinyl chloride exposure were not presented for all the cases. Data concerning possible alcohol con sumption were not presented. Although data were reportedly collected concerning age, occupational exposures, medical X-rays, recent viral diseases, drug consumption, and smoking habits, specific values were not given in the paper. Duration of exposure of cases ranged from 4 to 26 years. The age range of cases was 34 to 57. The controls were described as 'healthy' persons who were not exposed to vinyl chloride or to any other `known' (not specified) chromosome damaging agent but worked in the same factory. This may raise the possibility that the controls were exposed to various clastogenic agents in the factory. Fleig & Thicss further investigated 20 workers The Macmillan Press Ltd 1988 showing sy ntptnmx of vinyl chloride illness. Compared with 'he same control group, there was a significant diffc'cncc tn the rate of chromoMime aberrations. The rate of aberrant mciaphascs in eases was 5.2%. excluding gaps, ami 11.2%. including gaps; in the control group, the corresponding values were 2.1 and 5.5%. The further data are confounded by the lact that the 20 cases had tin unknown rate ol exposure In addition, duration of exposure in the cases ranged from 4 to 30 years. Cases ranged in age from 32 to <34. in 1980. Rossncr c:/.5 reported data following the investigation of 31 males occupationally exposed to vinvl chloride monomer. A group of males from the same plant, but reportedly not exposed to vinyl chloride monomer, were chosen as matching Controls, Several categories of chromosomal aberrations were analysed: chromatid and chromosome breaks, and chromatid and chromosome exchanges. Gaps were not included among aberrations. Two bk>od samplings were conducted, about a year apart. In all subjects, onlv breaks were detected. No significant differences were found between the cases and controls, or between the first and second sample taking. Exact levels of vinyl chloride monomer exposure are not certain. Rosner ci ul, reported 'on average' the levels of vinyl chloride monomer concentration in the atmosphere of the workplace ranged below the Czechoslovak MAC level of 10 mg/m\ and that the peak concentration did not exceed 30 mg/nr'. At the time of blood sampling, the workers being followed had been exposed to vinyl chloride monomer for 2 and 3 years. Cases ranged in age from 25 to 55. An analysis for drug and alcohol consumption habits was reportedly conducted for all subjects. Data for these parameters were not presented. There is no indication that subjects were questioned concerning smoking habits, or X-ray or other radiation exposure. Some published studies reporting negative findings for chromosomal aberrations in vinyl chloride exposed workers do not state the sex of cases and controls Kilian & Picciano1' reported preliminary data on 121 workers occupationally exposed to vinyl chloride and vinylidcne chl&ridc. Prc-cmployment examination records from 75 persons were used as control data. Compared with cytogenic data from the pre-employ ment examinations, the vinyl chloride workers showed less chromatid breakage, a greater frequency of dicentric chromosomes and a lower percentage of abnormal cells. Data on the sex distribution of cases and controls are not presented by the investigators. The investi gators stated that only about 50% of the vinyl chloride workers at the pertinent facility were included in the study. Cases and controls were not age-matched insofar as the pre-employment group contained only 2 persons over 50 years of age whereas the vinyl chloride group contained 30 persons more than 5(l-vearx-old Picciano ci ul.'"' reported cytogenic findings trom 209 workers emplovcd at a vmvl chloride plant. Coinrol data were obtained from a gioup of 295 'preemployment examinees' who it.id chromosome evaluation done as part ol the routine preemnloymeni examination. Data from the two groups were scored and compared on the basis ol chromatid breaks, chromosome breaks, rings, dicentrics, exchange figures and the proportion of abnormal cells. The investigators stated that results, expressed in terms ol the mean percentage for these categories ol aberrations, showed no major differences between cases and controls for any of the classifications. Although Picciano a ul. indicate that eases and controls were matched as much as possible lor various factors, including sex. the investigators do not provide exact data on the sex distribution of cases and controls. Cases and controls were not age-matched. The as erage age of cases was 39.5 sears (range of IN to 67); the n 'rage age of controls was 25.1 years (ranee of IS to 50 years). Duration of occupational exposure of cases, at the lime of investigation, ranged from I to .332 months (average of 4S.3 months). Several studies have reported positive findings for chromosomal aberrations in human males exposed to vinyl chloride. In 1975 Ducatman ci ul." presented data findings for 11 males exposed to vinyl chloride in a polyvinyl chloride polymerization plant. In com parison with 10 'healthy' male controls, without known vinyl chloride exposure, cases showed a non significant increase in cells with simple aberrations, such as breaks and gaps, when using a r-test for the comparison of means, and marginally significant increases of such aberrations using a I' ratio for the comparison of variance. The differences in cells with 'stable' chromosome aberrations, such as monosomies trisomies. deletions and exchanges, were also non significant. However, cells with unstable' chromo some changes, such as fragments, dicentrics and rings, were observed significantly more frequently in the cultures from cases. The total of simple breaks, including those from multiabcrrant cells, was increased but not significantly in the exposed workers. Complex breaking events were significantly more frequent in eases, and total breaking events were also significantly increased in cases. The relatively small size of the sample population (/> = Jl) affects the statistical significance of the Ducatman eial. data. Exact data on levels of exposure of the workers are not provided. The investigators state that there is no record of ambient gas levels at the pertinent facility, but it was assumed that the levels must have exceeded 500 ppm at times, based on reports of dizziness, odour detection and headaches. Duration of vinyl chloride exposure of cases ranged I Ir ! | i I I R&S 024845 from 414)28 years (average of 15 yeai ->). Cases ranged in age from 25 to 61. Cases ami controls were mn age matched. The average ace of cases was 40, the cortexponding figure lor controls was 27 Bccju'C chromosomal aberrations may be associated with various factors, it is vitally important to question subjects about prior am! current exposure to Known and suspected nun.teens. X-ray and other radiation exposure, drug use. smoking history, akohol con sumption. and infectious diseases, particularly those of viral origin. Due.iiman e/ at, did not provide data for cases and conttols regarding these \niiahlcs. lunevGavioioe/u/.1'' m 1975 reported an increased frequency of chromosomal aberrations m seven males occupationally exposed to vinyl chloride. Three `mmexposed' control subjects, from the same factory as the cases, were also studied. The frequency of abnormal cells in cases (9.52"i>) was significantly greater than m the controls (/' < 0 (H)l), 'I'lte small si/e of eases (// 7) a Meets the epidemio logic significance of this study. Funcs-('ravjoto ct ol do not provide precise data on levels ol exposure to vinyl chloride. It is stated that the level til" exposure to vinyl chloride had `continuously decreased' during past years, and that in the weeks preceding blood sample collection for chromosomal analysis, the air concentration in the polymerization department was estimated to be 2M-O0 ppm. Duration of vinyl chlondc exposure ranged from 9 to 29 years. A problem ot relevant controls is raised. Since the three *iu>nexposed' controls were employed in the same factory as the cases, there is the possibility that thev may have been exposed to vinyl chloride. Also, data for the control subjects showed that 11/566 cells contained chromosomal aberrations, Funcx-Cravioto or ot. hypothesized that this finding might be associated with previous diagnostic X-ray exposure. Also in 1975. Purchase ctaL,? reported findings for chromosomal aberrations in vinyl chloride-exposed workers. The investigators studied 80 workers. Fiftysix had been exposed to vinyl chloride monomer: the remaining workers worked in plants and laboratories where exposure to vinyl chloride reportedly did.not occur. A comparison of chromosomal aberrations in the vinyl chloride exposed workers compared to controls not exposed to vinyl chloride showed a signifi cantly increased (/' < 0.05) percentage of B, Cu, and Cs cells (using the classification of Uuckion & Pike, Journal of Radiation Biology 1964; 8: 439-52) in the exposed workers. Purchase ct at. did not state the sex of cases and controls. Data concerning levels of exposure and duration of exposure were also not provided. The mean age* and age range* of cases and controls were not given. Information about the smoking habits and alcohol consumption of cases and controls was also not included in the published study. In 1976. S/cn(eM t'! at'1 icpwrmd data mi chromo somal abet r.itions in 4* P\ ( workers (41 nudes), 1 oiiV'fuur 'industrial controls' (19 males) engaged in 'ther chemical plants .uk! reportedly not exposed to PV(' bu' `mdifetriv ' exposed to `other' (not sfvehied) chemicals as well as 49 `normal' controls {34 males) with no reported occupational exposure to chemicals were lurther examined The investigators concluded that the rate ot chromosomal aberrations did not dilfer sigiiitieamb between PVC workers and controls. I lowever. the frequency ol chiomuiid-iypc aben.itions was higher in PVC woikers computed to the two controls (I* < (I (KM), in addition unstable chromosomc-ivpe abet rations were Mgmfic.inilv higher in PVC workers (/' -J (),()!) Several factors confound the analysis ot the S/cntesi i/ al. dal.1.1 )uration o! exposm _ of cases t anged trom 0.5 to 12 vears, The imestigatois do not pros ide data on the level ol exposure ot v.ihv A problem ot lelevant controls exists smeo the 44 'mdnsiruil controls' were `uuliteuly' exposed to `other' (unspeciliedj chemicals. Addition,'1'> cases wcic nos age matched with the industrial sonttoK 1 he me.in .me ol the industrial controls was 43 9 wheicas [he value for cases was 27.3 Data are not presented lor such potential confoundcrs as smoking history, alcojiof use. exposure to X-rays and other radiation, possible drug use, and viral or other infectious diseases. Purchase //.n in 1976, reported data on chromo somal abnormalities m 80 workers, including exposed workers, non-e.xposed workers from the same industrial site, and non-exposed workers from a different environment. The population of exposed workers was further divided into groups, base on the type of work earned out. Autoclave operators anil main tenance workers had higher percentages of B and C cells (classified according to Huckton ik Pike. 1964), compared to those who worked in PVC production but not with autoclaves and the non-exposed control subjects from another environment. The difference between the combined results from the exposed groups and the control group was reported to be MaiBncally significant. Purchase a ot. do not specify the sex of the cases and controls. The only information given concerning level of exposure to vinyl chloride was that the auto clave workers had the `highest ' exposure and workers employed in PVC production but not with autoclaves and maintenance workers in the same area had the `lowest' exposure. The duration of exposure of cases is not given. Information about the age range of cases and controls is not presented. In addition, data were not given regarding smoking history* alcohol use and viral infections of cases and controls. Some studies have presented cytogenetic data findings confounded by the fact that cases may have been exposed to vinyl chloride as well as other ':' ii0Z" mm* MM * ", ?4 '',i i !# f$Js I R&S 024847 y^r . k4 ^ t:~*1r<.>".. Vibt IMi n** l :<!' jje ':m I &>S% ' hZ$/, S20 L. UZYCH poicmial mutagens. Heath e/ at."' in 1977, reported chromosomal damage in men occupationally exposed to vinyl chloride monomer and other chemicals. Cytogenetic analysis, primarily designed to measure ' frequencies of chromosomal breakages, were per formed on peripheral blood lymphocytes of 35 males, in three different job categories: 14 in PVC poly merization, 4 in PVC processing, and 17 in rubber tyre manufacture (industry controls). When initial ' analysis showed no significant differences among the three industry groups, a further control group was selected, consisting of 4 males employed at the Center for Disease Control and reportedly `not exposed directly' to any laboratory chemicals (CDC controls). Levels of breakage in all three industry groups were increased significantly over levels in the CDC controls. However, no significant differences were observed between the three industry groups them selves. Chromatid gaps comprised the majority (86%) of observed aberrations. It is difficult to interpret the data of Heath et at. Levels of exposure of cases and controls to vinyl - ' chloride, and other potential mutagens, are not clear. ; The 14 PVC polymerization workers had `presumed ' , - high'exposure to VCM, the 4 PVC processing workers had 'presumed low' VCM exposure, while the 17 , ' workers in rubber tyre manufacture had `presumed ;/ negligible' exposure to VCM. In the opinion of the gP;;/ investigators, the fact that overall breakage levels m'S^v^' wereisimilar in workers exposed heavily, lightly or K/i'^^- ncgligibly to VCM may imply the presence of other Wi'y ' .Clastogenic agents.'Heath et at. concluded that, ' because of the wide range of chemicals to which ft.;; v'lfiy- rubber workers were exposed, primarily solvents, it Tip;'' > V was 'impossible' to relate any particular agents to the ' p . 1 observed' abnormalities. The average number of :v, months worked for the 14 PVC polymerization v,`; g;/ ' '7 &&>> ' workers ranged ffom 215 to 346, for the 17 industry controls the range was 114 to 357. The industry controls 'r ranged in age from 31 to 58; the CDC controls had an age range of 37 to 51. Data were not given pertaining to smoking history, alcohol consumption, drug use, radiation exposure, or viral infections affecting cases and controls/:. ; V,f. . /31 - 7 In the Heather of. study, cells were cultured for 72 1 _ - h in the presence of phytohaemagglutinin. The length Z '/- - of culture time may have affected the frequency of ' observed chromosomal aberrations. In general, cells ^/''pslfwill enter mitosis for the first time in about 48 h; in v C- - approximately 72 h, there will be a second division." In; the' judgment offsome'investigators, the 48-h -^/culture time may allpwfor a relatively more accurate indication'^of S inducedaberrations,;, because some Ganges may be lost or'modified with each'ccll division.. \7/:/.However/ the 72 h culture'may allow recovery of a T-V/ /.v greater number of cells for analysis. - -TM 5 ' from cultured peripheral lymphocytes from 81 men. Fifty-seven of the workers (eases) were employed at plants manufacturing vinyl chloride or PVC. 19 of the workers were on-site controls, and the remaining 5 were off-site controls. The 57 eases were further - .;-j divided into six groups. The on- and off-site controls ` were combined into a single control group, because / :;'H no significant 'differences w:crc observed between ;: ; them. In a study published in 1978, Purchase et at. ` - ! ` reported that the subgroup of eases consisting of 'J, autoclave workers had the greatest number of signifi- . cantly increased values for chromosomal abnor-'/-,/ malitics. The values for total B cells, total Cu cells / and total C cells (classified according to Buckton &. - Pike) were significantly higher than control values (P ` < 0.01). Purchase cl at. further reported a significant correlation between smoking habits and total C cells. Data pertaining to exposure levels in the Purchase et at. study were imprecise. Any experience in a specified ` one-year time period, 7/73-7/74, of exposure to vinyl chloride for short-term excursion which could be - : detected by smell was recorded. The group of eases who operated and cleaned the autoclaves were con sidered, by virtue of theirjobs. as likely to be exposed to the highest average levels of vinyl chloride. The ` investigators gave figures for estimated average operator exposure to vinyl chloride on PVC plants. ` ` :1 , ranging from approximately 1000 ppm (1945-1955) - / to approximately 5 ppm (in 1975). Average duration , ! of exposure to vinyl chloride ranged from 6.1 to 15,5 v years, in the six groups of eases. There was an interval. of about 18 months between the time of blood sampling, and the obtaining of smoking histories. No ' data were provided on alcoholic habits in cases and - ; '-.I controls. However, subjects with recent X-ray e VJvs' gws: exposure, 'prolonged' drug treatment, or recent viral '/ i, infections were excluded from the study. , ,, Some studies have presented data suggesting a ' Z possible relationship between a reduction in exposure ' 7. to vinyl chloride and `normalized' chromosomal / breakage frequency. The blood sampling in the 1978 study by Purchase et at. was carried out in July 1974. V , ' Since that time, threshold limit values for vinyl chloride , and plant exposure levels were reportedly reduced. m In a study published in 1980, Anderson el at. reported: two further samples from the same population of workers analysed for chromosomal aberrations 18 . /;,*/, and 42 months after the initial sampling. ; 'Zj, The second sampling consisted of 21 workers employed or formerly employed in plants manu--vZ ^>y; facturing either vinyl chloride or PVC. re-examined in January 1976, together with 6 off-site controls/ATA third sampling, examined in January 1978, consisted ' of23 workers employed as before together with 8 on-' , site controls. In both the second and third sampling,^ the populations were classified into four groups. -The investigators reported that, in comparing the results' :'V. '' ; ` 'j t; , ;j.,' ij.*, 9**>r .I HUMAN MALE EXPOSURE TO VINYL CHLORIDE 521 ` ' '.t;1' /'- ', v-'r 4 , : 'j y \: ,'f ' ' lbhae,,dtjw_ree_em_n_.a1in9e7j4d a_an_s_ds_u_1c9.h76s..h.t.oh..w.e.ead.ut_aocsltaavteistwicoarlklyerss*ign-hifoi {actors, such as radiation and drugs, which may ^influence breakage frequency. 4 workers were omitted. cantly (P .< 0.05) larger increase than controls in B The mean breakage frequency for the remaining 35 cells, total abnormalities and abnormalities excluding workers was then 3.41%. compared with a control gaps (classified using an adaptation of the method of value of 1.79%. The mean breakage frequency for Buckton & Pike). the heavily exposed workers (3.79%), was higher In the third sampling, the investigators reported a than the value for the rest of the workers (3.15%). . tendency to a decrease in the percentage of cells with All tests for cases compared to controls showed that chromosomal aberrations of various types in com- workers scored significantly higher on a 2.5% signifi . parison with both prior samplings. When the results cance level in the initial study. However, in the ' of the 1978 sampling were considered alone, Anderson repeat cytogenetic study, no significant differences etol. reported that the exposed workers had a similar were found between chromosome breakage frequen percentage of all types of abnormalities compared to cies in eases versus matched controls. The chromosome the control group, in contrast to the 1974 and 1976 breakage frequencies for the three groups of workers samplings. The investigators further stated that the were back to normal. No significant difference was incidence of chromosomal aberrations had returned found between the Control group in 1974 and the to control values during the time that levels of exposure matched controls. Hanstcen eta/, concluded that the had been reduced below 5 ppm. In the judgment of repeat study demonstrated that the chromosome the investigators, it appeared that by reducing exposure . breakage frequency was back to normal after a to vinyl chloride, chromosomal abnormalities had 'significant' reduction in exposure for 2 years. returned to values similar to those of controls. Imprecise data concerning vinyl chloride exposure Lack of precise data concerning levels of exposure levels affects the epidemiologic significance of the to vinyl chloride make it/difficult to evaluate the Hanstcen era/, study. Exact measurements of exposure - possible/'normalization', occurrence reported by in the PVC plant were provided for 1974 (25 ppm). AndersonV/of. The investigators state that although , However, for other years, the air concentration of ` `no accurate' data on exposure levels were available vinyl chloride monomer in the PVC plant was csti- . at the time of the 1974 sampling,`marked'reductions mated, based on the level of production jind the \ , in vinyl chloride levels had supposedly occurred since ' number and types of autoclaves used in a particular ' that time due to modifications and control measures., time period. The estimated values were quite widc- Subjects^ completed a questionnaire, including details .. ranging (from 2000 ppm, for 1950-1954 to 1 ppm, for V . of 'recent high' exposures,"or exposures which could ( 1975). Employment in years ranged from 1 to 18.5 in /Tli be detected by smelling. In the second sampling, it was , the workers chosen at random, 4 to 21 in the workers 'if- reportedly not possible to exclude persons suffering ' examined on clinical grounds, and from 10.5 to 24 in \ from viral 'infections? as* 1T sample members were i'.the heavily exposed workers. The age range in the * '',r:' suffering from colds. However, Anderson era/, stated cases and controls was considerable: 23 to 66 in the That there was no evidence of increased aberrations in randomly chosen workers; 26 to 67 in the workers individuals with colds; this infection was not considered, examined on clinical grounds; 39 to 63 in the workers : .v-in thc third sampling./-1 heavily exposed; and 27 to 66 in controls. Hanstcen er ' data on the subject of normalized chromosome a/. reported that matching for age between cases and breakage frequency were published in a 1978 article, . controls was attempted, but was `not entirely' suceess- >' yjy by Hanstcen ttol.^Cytogenetic studies were carried / ful.V. Although a medical history, including viral: Fourteen /., infections, radiation exposure and drug intake, was ' 13 were '/'reportedly obtained for all participants in both studies,, ' chosen because they had been `heavily' exposed to,-!?; no specific data are presented regarding drug use, a, vinyl chloride monomer for years; and 12 were workers Hsmoking history, alcohol use, radiation exposure, or ; whose first' health screening revealed abnormalities viral infections, ip K but on clinical re-examination all laboratory tests -Chromosomal changes may be reversible. Based --s9.-K'^.SStiacfcjmrbved?normal. -Sixteen;heallhy;males, -with moV on data.f.r.o..m...th..e..A..n..d.e..rson era/ and Hanstcen era/. t V/V*,. I yv&y/fe I ^exSrs^clistribmion7'ofxcasc5 ;and controls is not^aberrations in/vinyl chloride exposed workers. The ..c..l.e..a. rr"eplacement of aberrant cells'by normal L,, WM`SThe mean breakage frequency for the 39 workers t'cells'may'occur at the rate of 1 to 2% per year/ K?was 3.7%in the initial, study.' Becauseof different|j;Thus, ifvery high levels of aberrant cells are observed . 'V-'3ks| '| i'r' Vv-",lV;/ 1I v&*->A?>*"/,: |I H-h> iVV1:1 <1 --rS' II x1 '' Ki1ft'V'. .ftI !#;*: mm Mm ' ' "i: Cv'.*?'- hi: r-p ' r * h\ -S/, >y fe- . 522 L, UZYCH Table 1 Summary; chromosomal aberrations in human males exposed to vinyl chloride Average Reference Duuiminml" No. of Cates n mala duration of eiposure {years) |j Dose of eiposure inexact No of controls Major finding! Significant increase in total breaking arid complex breaking events and 'unstable' Study fimirurjpru Small sample sue; > inexact exposure data;1 ; no age matching " chromosomal changes: non-vgniiicam increase in simple and 'stable1 aberrations j Mr1;.'. . fev.;/ - fciy'is'' 4?:< ' Furtes-Cravioio11 7 males .r.r< Kilim Si PjCciano* J2I 16.5 Not given Inexact Varying 3 75 Significant increase in abnormal cells , Less chromatid breakage, lowers of abnormal cetlv; greater Small sample size; inexact exposure data Sex distribution of cases/ controls not given fe,' frequency of dicentric chromosomes Purchase ei c/,M 56 ,n .. Purchase etal.1* r... . I jJ; i' , SXenICii Hal.' 56 41 males; * other iifev - . '- , Hemhrial,'* 15 nuks Not given Not given Not given Not given Not given; but ra/ipf o/ o.s-ii years Not given Varying Inexact 24 24 44 `industrial* 4V 'normal' 17 `industry' 4 -CDC' Significant increase in B. Cu and Cs cells Significant mutagenic effect Higher frequency of chromatid-type aberrations; significantly higher `unstable' aberrations Significant increase in bwakage levels compared to CDC controls r. Sex ofcavcs/cnnuolv not given: no exposure data Scx of cavcs/controls not given; no exposure data . No dose data; inexact ' duration data: some controls'indirectly' exposed to'other' chemicals Small sample size; ``k\ inexact exposure data li; m '. `' SV-' ' Picciano et a/,10 ,4'*..*j^.,S*Ki1'\' f';.'"' /w,V ' , > 209 45.3 months Inexact 295 No major differences * reported for mutagenic effects Exact sex distribution of : J ', i cascs/controix not given; Inexact exposure data 15.4 12.4 ` ;v-; ` 'v": , fSfci, H.niictn/.*" KWrefc' r'. 'S*'.-.v*i..- * ` /-.- 39 (initial) 37 (repeat) Varying 'if-';.IVreliw M at. '* 57 mi,, Inexact Not known Inexact 10 NO significant ' ' ` - ,`^e? ' Small sample size: J v-_ '^ 4 20 difference in rate of inexact exposure data vX v';.-"v, s chromosomal aberrations; ,, Significant difference in Unknown exposure rate r`. 'X''7#/' rate of chromosomal aberrations ' , "' "* 16 (initial) 32 + 6 (repeat) Significant mutagenic effect: Exact sex distnbution of / cases/controlx unclear; 1' V No significant difference.. inexact exposure data; :.*, *r in chromosomal no specific data on drug JVSfi* ^ breakage frequencies ^ use. smoking.or alcohol . g "^>v V*-A. ,/ ' ' % 1 -' \ - Varying :.......... ! Em&V.**3'*.>*A'*nd*enjo,n~era/,1` *. 2l; Inexact 24 Significant increase in ' chromosomal > abnormalities; ' ' J significant correlation ' between smoking and wui Cecils . , laatct txpouut 4.U-, aSSSS *boui IS moiitli gsp blUetdwelietn!"b*l*o*o*d'--wmL`pk'"v` $;Cfe 4*" , w. .... Tendency to a decrease 'Inexact exposure data; - in chromosomal small sample size abenatioos,compared *** ' u> prior sampUngs C'/'V`1, r; . .n. 'W'w'vwi Ho significant '^'V' ^'Inexact exposnre dataf mutagenic effed - , ' .*> + -T,si R&S 024849 1>|| * 1 ' t&f'ir-..* -k - ry-** #" _ - / . Ki-'is? HUMAN MALE EXPOSURE TO VINYL CHLORIDE 523 , initially, the return to norma! levels may take quite 'sometime. Table I summarizes major data findings and infor mation from the foregoing studies on chromosomal aberrations. ` Sister chromatid exchanges 'v.'In addition to examination of gross chromosome aberrations, the investigation of sister chromaiid exchanges (SCEs) may provide a promising means of biological monitoring in instances of exposure to vinyl chloride, or other known or suspected mutagens. SCEs reflect intrachromosomal rearrangements of , the DNA helices." Crossing over between the sister Chromatids of a single chromosome is a phenomenon ... that was recognized after the development of a special . technique."' Cultured cells are permitted to replicate twice in bromodcoxyuridine (BUdR), allowing incorporation of BUdR into newly synthesized DNA in place of thymine. BUdR affects the staining proper- ,. ties ofchromatids. Ifa SCE has occurred, this may be , . recognized by the fluorescence patterns along the ^-chromatids. -.The molecular mechanism of SCE induction is not comprised o1 21 male workers and 6 controls. The eases and controls represented a second sampling from a group of vinyl chloride exposed workers and controls first examined IS months earlier and described in the 1978 study by Purchase era/.1*Sample members were examined for the presence of chromosomal aberrations or SCEs. in their peripheral lymphocytes. In all exposed groups significant increases were reported for most types of chromosomal abnormalities. The number of SCEs per cell w as slightly increased in the exposed groups, with the highest value in the 10 cases who were autoclave workers. However, the increases wore not statistically significant. The investigators postulated possible mechanisms for the data results. It was hypothesized that the exposure levels of vinyl chloride which the work force were exposed to were not high enough to induce SCEs. Anderson el at. concluded that the analysis of SCEs may be of limited value after very low chronic chemical exposure or if some lime has elapsed after acute exposure. However, analysis of SCEs may be of value during high chronic chemical exposure and during the first few days immediately following acute exposure. Some investigators have reported significantly increased levels of SCEs in workers occupationally.; r..; I -.;>( !| * v- ; m cnromosomcs may persist lor several years whereas occupationally exposed to vinyl chloride monomer. y)";3'V- lt-l,"jr'yiiiv'^&'y`:^fthe''SCE-frcqucr>cy in lymphocytes may remain at a In the third blood sample series, the investigators''. ' ,r ' , ' for 4 to 16 weeks following exposure." The also used the SCE technique and compared the ,' , "v r^vSt! | .''timf- lair between exnosure and analvsis. a?; well as frequency of observed chromosomal aberrations with V the number of SCEs in each sample. Blood samples' ` \ from 8 healthy persons were used as controls. The sex' { ''Vv monitoring. ,'.v -v.-tV-.1` distribution on eases and controls is not stated. The 4(1 . , investigators reported an increase in the frequency of *' -'ufi.'ll'-''- .J- . a' Data are available from several studies pertaining chromosomal aberrations and the numberiof SCEs per * V3 I ^9' / :T;-'"vl S toSCEsin industrial populations exposed to vinyl cell in 7 blood samples in cases compared to controls.' ^St ,'Wt_ ''''chloride 'Anderson er 'at?* in 1981, reported data The level ofsignificance for the frequency of SCEs in y;S> 'A designed to assess whether the SCE cases compared to controls was P< 0.001, according m x '^gjiV^gltech'nique may offer'adyantages over conventional ., to the r-test. It was the opinion of the investigators^.'* 'l^chrqmospmal analysisjin monitoring human popula- i; that evaluation of the frequency of chromosomal *; -'`j^P^^^^j^tiorw^expose^to ,'mutagens/Thc sample population j aberrations and the number of SCEs may be equally 'p: ,a i exchanges in human males exposed to vinyl chloride Dose of , exposure (dvgppm) Of T controls Majorfindings ?- Study limitations. * ' #$1 ' -f: I ``x ' , y :y? _ Increased frequency 'of chromosomal - aberrations and SCEs . .. Significant mutagenic ncuct exposure data" hi effect; 'shgbdy increased* # - SCEs m/ 4h m mm- - '.r.l-* M'U' K?/- t-?'t r, & ,/ i'-.'i-iblSgS I tMO"., * v ``4T-f'* ,/'r*'.<-..<r,,***' . - *- . v^.v;,;,' ..;71- ~5cS'. ^4:*'Si..' :.., _ *4 m ',<t*kvy-*- *V..- *. - , , , f , v ,, w 514 L. UZYCH suitable methods for testing high-dose vinyl chloride The investigators reported initially high, albeit mutagenicity in vivo. declining, rates of CNS defects. Defect rates for The relatively small size of the sample population in 1970-1972, particularly rates for ancnccphaly, were the Kuccrova ei at. study (9 cases, and ii controls) 1.5-2 times higher than those recorded for white affects the statistical significance of the study. The 9 births in surveillance systems using similar data sources cases had been exposed to "relatively high" mean in Flurida, Nebraska and Georgia. However, the rate annual doses of vinyl chloride monomer, estimated of total CNS defects declined from 1970 to 1974. In to be about 20--150 ppm of air. The controls were 1970. 14 cases of CNS 'defects were confirmed reportedly not exposed to `known' (not specified) (including 9 eases of ancnccphaly. 4 cases of spina mutagens, during the 3 months before the time of bifida, and 1 `other* CNS defect). However, in 1974, blood collection. Duration of exposure for the 9 eases only 1 case (of spina bifida) was confirmed. The ranged from 10 to 27 years. Controls were matched investigators stated that the decrease was not unique for age and sex. Several of the cases and controls to Kanawha County insofar as a similar, though less were smokers and/or used alcohol. Six of the eases marked, trend was evident in available data for other used 1 or more drugs. Precise data for these variables parts of the country. arc not presented. However, the investigators stated The Edmonds ei a!, data do not provide a clear that the smoking and other habits of workers appeared basis for evaluating the possible relationship between to have no effect on the frequency of any chromo parental exposure to vinyl chloride and other possible somal changes. atmospheric pollutants and the rate of various con A summary of information concerning human male genital CNS defects. Edmonds a at. reported no exposure to vinyl chloride and SCEs is presented in differences between cases and controls concerning Table 2. parents' possible exposure to vinyl chloride at the time of. or for 5 years before, their child's conception, cither by direct occupational exposure or by location Effects on pregnancy of work place with respect to the PVC polymerization plant in Kanawha County. The investigators therefore The exposure of human males to vinyl chloride may concluded that, on that basis, there was no evidence be associated with various adverse pregnancy out that the observed higher CNS defect rates could be comes. Published data on this subject arc inconclusive. related to parental exposure to vinyl chloride at the Some of the difficulties potentially involved in reaching place of occupation. definitive conclusions in this area are mentioned in a If there is an association between community review piece by Clcmmescn,1'' exposure to atmospheric vinyl chloride and observed ' In 1978, Edmonds el at?1 reported data from an rates of CNS birth defects, a decrease in atmospheric 1t epidemiologic investigation undertaken in Kanawha vinyl chloride levels might reasonably be followed, County (Charleston). West Virginia. The i.tvcstiga- after an approximate 9 month time lag. by a corres lion was:undertaken because of concern ihct high ponding decline in rates for CNS malformations. rates of congenital central nervous system (CNS) However, Edmonds ei at. reported that the greatest defects observed in Kanawha County might be decrease in rates occurred in 1973, and preceded the , associated with environmental exposure to vinyl decline in levels of vinyl chloride emissions. Data on chloride monomer. vinyl chloride emissions from the Kanawha County . During the pertinent time period, 1/1/70-31/12/74, PVC plant showed that the annual mean vinyl chloride HI ' 47,residents of Kanawha County at lime of birth had ifj.ijSK".'.-confirmed CNS defects. Att cases were white. For I'(' ' each confirmed case, 2 controls were selected from I i ' *' ' birth certificate records. The controls were live born d' infants,whose parents lived in Kanawha County and emissions (Ib/h) decreased from 265 in 1973 to 180 in 1974 and 76 in 1975. Edmonds era/, further indicated that there arc seven major chemical plants and several smaller ones'in the Kanawha River Valley. Thus, to conclude that vinyl chloride alone may be associated' iv. ' whose' birth certificates immediately preceded and with high rates of CNS malformations disregards `:RA - - followed that of an infant with a CNS defect and gave over ICO other compounds emitted from Kanawha : -'no indication of congenital malformation. The families Valley area plants. :-.f '.'of affected infants and matched controls were inter- Studies pursued in communities containing chemical" V:-- - - viewed by telephone. The investigators reported that industrial facilities, producing or using multiple known -1,-- ``dose'/case control matching was achieved for the orsuspected toxins, in genrral may be confounded by v 1 following variables: paternal education, maternal age. difficulties in determining whether one or more ofthe ', -'and Hollingshead Index. Edmondseraf. furthersuted substances, either independently or in an additive or ; ' that cases and controls were `comparable' with respect i synergistic manner, may be associated with observed To maternal education, proportion of previous fetal ' levels of abnormalities.' ,, On?- other children wid^ congenital anomalies. /- Some investigators have reported a significant ' i * >f-r V- - -'Vi n. `'^ v >" " , 1 4 R&S 024851 HUMAN MALE EXPOSURE TO VINYL CHLORIDE SIS excess of fetal loss among wives of workers following indirect vinyl chloride exposure from the father might exposure to vim) chloride. In 1976. In/amc et at. be considered. However, in their view, these mechan reported data front a sludy of pregnancy outcome isms seemed unlikely because of the highly volatile among the wives of workers exposed to vinyl chloride nature of vinyl chloride. Based on the study findings, monomer. Data for the wives of vinyl chloride poly taken in conjunction w ith the prior demonstration of merization workers were contrasted with data for the a mutagenic response in microbial systems and the wives of PVC fabrication workers and rubber workers. observations of significant excesses of chromosomal A total of 95 vinyl chloride polymerization workers aberrations in workers exposed to vinyl chloride, it and 158 rubber and PVC fabrication workers were was the authors'opinion that the leading possibility is interviewed. germ cell damage in the father through direct vinyl Because fetal loss is known to increase with chloride exposure. increasing parental age, the fetal death rates for the Several variables affect the analysis of the data of vinyl chloride polymerization workers were age Infante etal. The investigators do not provide precise adjusted to the control group. Infante et al. found data on the level of exposure to vinyl chloride. The that mong pregnancies occurring prior to exposure, rubber workers were selected from work areas fetal death rates were 6.9% for controls versus 6.1% described as being 'relatively free' from known (age adjusted) for the vinyl Chloride polymerization (unspecified) toxic materials. Data on duration of workers. These rates were not significantly different exposure were not provided. Significant risk factors by Mantcl-Hacnszel chi square testing. However, for spontaneous abortion may include a maternal among pregnancies occurring subsequent to the age of 30 years of more, excessive cigarette smoking husband's exposure, the difference in the frequency and alcohol use during pregnancy. Infante et at. did of fetal deaths between cases and controls was signifi not obtain data concerning maternal age, except cant, at P <.0.05. The investigators stated that the indirectly through paternal age. Data concerning the ' significant difference subsequent to exposure reflected smoking habits, alcohol use, drug use, radiation the relatively greater fetal mortality rate associated exposure, or infections in cases and controls arc not with younger aged husbands in the group of poly presented. Although some investigators suspect that merization workers. For pregnancies occurring after women may be more accurate reporters of repro exposure, the fetal mortality rates associated with ductive history than their mates, Infante et al. did not husbands 30 and older were 13.0% for the polymeriz conduct any interviews with workers' wives.7 ation workers and 12% for the control group. The study by Infante cl al. has been critically However, for husbands less than 30. fetal mortality examined in the literature. In a letter published in the'1 , rates were 20.0% for the polymerization workers but Lancet, Paddle'9 stated that the assertion by Infante only 5.3% for the control group.,' etal. of a significant excess of fetal loss among wives of Since one spontaneous abortion may be associated workers following exposure should be supported by a , 'with a 66% increase in the risk of a subsequent specification of the methods of data collection and a abortion,'it is. possible that part of an observed tabulation of the raw data before analysis. It was / increased loss occurring in the wives of men exposed Paddle's view that the use of a questionnaire, and the to vinyl. chloride may be`associated'with a high ensuing low response rates, where the subject is percentage of spouses with a history of previous spontaneous abortion, must detract from the study's ' abortions.7 To determine whether women who had accuracy. It is further observed that the Infante et al. chronically experienced abortions might have weighted data arc presented after an age adjustment procedure ' the results in the current study, in favour of a higher which behaves `very misleadingly'. For instance, a fetal death rate in the group of polymerization workers crude percentage of 10.1 for a sample whose average subsequent to the.husband's exposure, the invest!-', age is 26.4 was adjusted down to 6.1, while a figure of ' gators stated that pregnancies ofwomen who had more 16.5 for a sample of average age 30.2 was reduced ` than two abortions were eliminated from analysis. ; only marginally, to 15.8. Infante et at. reported that with this adjustment the In a responding letter, subsequently published in trend was maintained.. Prior to exposure, the fetal the Lancet Infante et at. stated that the questions death rates for controls and polymerization workers about pregnancy outcome were contained in a were 6.9 and 3.1% (age adjusted), respectively. After.; questionnaire which was part of a cross-sectional health exposure, the rates were 6.8 and 10.8% respectively. survey.-10 The results of the survey reportedly showed ; Infante et at. concluded that fetal loss was signifi- no consistent bias towards a higher prevalence for the candy more among wives'1, of .workers following indices measured in the study or control group. With exposure to vinyl chloride,' Several possible mechan- , regard to age adjustment, they explained that the . isms for the observed fetal Joss were suggested. It was study group rate became 6.1% after direct age adjust ^hypothesized that either fetal or maternal toxicity or ' ment, as a result of a younger paternal age for ------ -fl mutagenesis in the mother associated with ' 'v . t f ,, pregnancies in the control group. Additionally, with ,, '. <. 1 < '"V-'.A 4 ' ^ ^ ' a.vVij f;f 'm M'm i;- -'ll A: *fj-.{;w.h &,(*< wir/ 4^ 526 L. UZYCH i4<% J <&&*, |& w. direct age adjustment, the 16.5% figure was reduced to 15.8%. They stated that age adjustment for the :''' subsequent to exposure comparisons resulted in little - change in the rates because the age distributions for pregnancies in both the study and control groups after exposure were similar. : 1 It is difficult to determine precisely the causes of observed adverse reproductive outcomes. Spon taneous abortions may result from the cmbryotoxic effects of various environmental agents and from various other factors, including maternal endocrine disturbances, abnormalities of the placenta, faultyembryo development, intrauterine infections, and severe maternal trauma.31 Congenital malformations may be associated with various toxic chemical agents. A number of toxins may be associated with impaired '' fertility in men. Future studies intended to document a possible relationship between impaired pregnancy outcome and paternal exposure to vinyl chloride must carefully validate information on pregnancies and take into account various confounding variables. Spermatic alterations ' . A 19S0study by Sanotsky e/o/.3- raises the possibility , that human male exposure to vinyl chloride may be associated with spermatic alterations. The paper was not published in English. However, an English . language abstract states that reproductive functioning was studied in men occupationally exposed to either chloroprcnc, vinyl chloride or antimonite ore dust with reproductive functioning assessment being based on 'indirect' evidence and from analyses of ejaculates. The abstract states further that 'pathologic changes' were detected in the ejaculates. This study is the only published literature known to the author pertaining to human malc'cxposurc to vinyl chloride and possible resultant adverse effects on sperm. A salient research need may thus exist for extended investigation of this aspect of paternal vinyl chloride exposure, including study of possible effects on sperm count, motility and morphology. Conclusion On the basis of selected, available data, the exposure of human males to vinyl chloride may be associated with various chromosomal aberrations in lymphocytes as well as increased levels of sister chromatid ex changes. Paternal exposure to vinyl chloride may further be associated w ith adverse reproductive out comes. The possibility of adverse effects on sperm associated with human male exposure to vinyl chloridemust also be considered. Data pertaining to the possible biological effects associated with paternal vinyl chloride exposure arc relatively sparse, conflict ing and inconclusive. The mechanisms for the possible reproductive related risks posed by paternal exposure to vinyl chloride are not certain. Extensive, carefully designed studies should be undertaken to further elucidate the biological effects, and associated mechanisms, possibly associated with .paternal exposure to vinyl chloride. B&Jry. Refcrences 1 1 Binns CHB. Vinyl chloride; a review. Journal of the ' Kilian DJ & Picciano DJ. Industrial monitoring: a cyto- ' ' -;y: Society of Occupational Medicine 1979:29; 134-MI. genetic approach. Annals of the New York Academy of s. Messite J 4 Bond MB. Reproductive toxicology and Sciences 1975:249; 4-11, ., " occupational exposure. In: Developments in Occupational 10 Picciano DJ, Flake RE, Gay PC, et at. Vinyl chloride .' Medicine, ed. C. Zenz, pp. 59-129. Chicago: Year Book cytogenetics. Journal ofOccupational Medicine 1977; 19; - V Medical Publishers, 1980. 527-30. ~ ;V 3 Party FA, Yam WP St Waite CP. Acute response of 11 Ducatman A. Hirschhorn K 4 Selikoff li. Vinyl chloride ' 'guinea pigs to vapors of some new commercial organic " .compounds. Public Health Reports 1930; 45:1963-71, exposure and human chromosome aberrations. Mutation Research 1975; 31: 163-8. ft? - 4 Doerr v. B.F. Goodrich, 484 F, Supp. 320 (N.D. Ohio 12 Funes-Cravioto F, Lambert B, Lindsten J. et a!. ; . V; 1979). > Chromosome aberrations in workers exposed to vinyl / ? Complaint filed in Doerr v. B.F. Goodrich, C81-174J chloride. Lancet 1975:1:459. -J ' (N.D. Ohio. Aug. 24,1981). 13 Purchase tFH. Richardson CR St Anderson D. Chromo * Fleig I Sc Thiess AM, Mutagenicity of vinyl chloride. somal and dominant lethal effects of vinyl chloride. Lancet ' * ; . 'i Journal of Occupational Medicine 1978; 20:557-61. 1975; li; 410-1, . . A Hatch M, Kline J 4 Stein Z. Power considerations in 14 Szemesi I. Homyak E, Ungvary G. et al. High rate of1 .'A studiesof reproductive effects of vinyl chloride and some chromosomal aberrations in PVC workers. Mutation -- V structural analogs. Environmental Health Perspectives Research 1976; 37: 313-6. 1981;41:195-201. Purchase IFH, Richardson C 4 Anderson D. Chromo- - 'T' ' _ %* Rossner P, Sram RJ, Novikova J, et al. Cytogenetic somal effects in peripheral lymphocytes. Proceedings of .`vjtKL. a i-vl ; analysis in workers occupationally exposed to vinyl the Royal Society ofMedicine 1976:49:290-1. -5. ., j-'-'WfUs " chloride. Mutation Research 1980; 73:425-7, , . " Heath CW, Dumont C, Gamble J, et al. Chromosomal A ^ ! ci -,v /" p ' ' , - -a-r` J.C-V J .-A tiPIS! v.: m _______ ' ~ .li./. -j iimM'/rrTOlW t* V-t,' Vf%r\ . -'''*' * . 'i /V V,* ,?: /;v..r^- HUMAN MALE EXPOSURE TO VINYL CHLORIDE 527 dim*gc in men occupationally exposed to vinyl chloride monomer and other chemicals, Environmental Research N77; 1-1:68-72. ,. Kili:n DJ & Picciano D. Cytogenetic surveillance of industrial populations. In: Chemical Mutagens: Principles and Methods for Their Detection, volume 4, ed. A Hollacnder pp. 321-39. New York: Plenum Press. 1976, Purchase IFH. Richardson CR, Anderson D, et al. Chromosomal analyses in vinyl chloride-exposed workers. Mutation Research 1978; 57: 325-34, ** Anderson D. Richardson CR, Weight TM, et al. Chromo somal analyses in vinyl chloride exposed workers results from analysis 18 and 42 months after an initial sampling. Mutation Research 1980; 79: 151-62. ** Harutecn IL, Hillestad L, Thiis-Evensen E, et al. Effects of vinyl chloride in man a cytogenetic follow-up study. Mutation Research 1978; 51: 271-8. ,:i Kucerova M. Chromosomal aberrations induced in occu pationally exposed persons. In: Mutagenicity: New Horizons in Genetic Toxicology, ed. JA Hcddlc pp, 241~ 60. New York: Academic Press. 1982. 22 Vainio H. Sorsa M, Rantanen J. et al. Biological moni toring in the identification of the cancer risk of individuals exposed to chemical carcinogens. Scandinavian Journal of Work and Environmental Health 1981; 7: 241-51. ** Thompson JS & Thompson MW, Genetics in Medicine. p. 18. Philadelphia: WB Saunders, 1980, f4 Anderson D. Richardson CR, Purchase IFH, et al. Chromosomal analysis in vinyl chloride exposed workers: comparison of the standard technique with the sister* chromatid technique. Mutation Research 1981; 83: 137-- 44. Kucerova M. Polivkusj Z & Batura J. Comparative evaluation of the frequency of chromosomal aberrations and the see numbers in peripheral lymphocytes of workers occupationally exposed to vinyl chloride monomer. Mutation Research 1979; 67: 97-100. 26 Clcmmcnscn J. Mutagenicity and teratogenicity of vinyl chloride monomer (vcm) cnidcmiological evidence. Mutation Research 1982: 98: 97-100. 27 Edmonds LD, Anderson CE, Flynt JW, ctal. Congenital central nervous system malformations and vinyl chloride monomer exposure: a community study. Teratology 1978: 17: 137-12. 241 Infante PF, McMichacI AJ. Wagoner J, et al. Genetic risks of vinyl chloride. Lancet 1976: i: 734-5. ^ Paddle GM. Genetic risks of vinyl chloride. Lancet 1976: 1: 1079. 20 Infante PF, Wagoner JK. McMichacI A. etal. Genetic risks of vinyl chloride. Lancet 1976: i: 1289-90. 31 Bang KM, Lockey JE & Keye \V.`Reproductive hazards in the work place. Family and Community Health 1983; 6: 44-56. 32 Sanotsky IV, Davttan RM & Glushchcnko VI. Study of the reproductive function in men exposed to chemicals. Cigiena Trudai Professionalnye Zabotevanha (Moskva) .. 1980; 5: 28-32. (Received 28 Maren i9SS; accepted IS June 1988) 'Vtf' .1 -.-.'. .'j ras...-..':.: "s* `w..' ' &$' ft#r. >- :;v 1- 1 "-V- ' .3.1f *< -s : 1... , iI Yl,.\ - ti , , 'V ,,,> ? iSt m