Document 5DrQ1ao7rz5KboXd6Kv1rYLd0

% ' I * * /-X edck &*u C%^ucat- - -CHEMICALS GROUP --Executive Matt, Swadeslord Road, Wayne, Pa. 19087 PLASTICS DIVISION October 30, 1975 A. R. Adams, Genera) Manager -Teh (215) 687-6150 Twxi ,3Ir. -John Oakes, Editor -The Kftv York Tines Company 229 Vest 43rd Street flew-York, Mew York 10036 . J>ear--Kr. Oakes: j0o Saturday, October 25, the yew "York Tines -published a news story -from Los Angeles wider the caption 4!U.S. Official Links polyvinyl Xhlorlde to Birth Defects." It Is regretful that' a newspaper such -as the Ucw York Times, which enjoys -a reputation for publishing news `that is "fit to print", continues to malign polyvinyl chloride; let -alone check the correctness of a highly technical report- Perhaps m -'the utterance, of. a .federal official such -as Dr- -Kagoner makes the report credible. Tn the first place, there Is sot one -scintilla of evidence that links polyvinyl chloride (a plastic) -with birth defects- Secondly, Dr. Vagoner does not provide the basis-for his assertion that "birth defects are up to three times higher than normal among babies bora in three Ohio towns where polyvinyl chloride, a cancer causing ^chemical, is taanufectured.*1 1 most-assume that-this assertion is 'derived from an ill-conceived ntudy byDr- Peter Infante. After careful research, the Center for Disease Control (CDC), reference 3tol- 24, No. 29, Veek Ending-July 19, 1975, reports that "it could not --establish any association between cases -and vinyl chloride exposure." 'Shat earthly purpose this news release baa accomplished I do not know, mother than to burden the lay public with morbid conclusions irresponsibly "derived and, once given credence by the press, never to be removed .from public opinion. 7sspry -truly. ^fo AAsemm 'iMBJjdl Enclosures: " -- '; :1 Sew York Times Article ' DC -Report VI. 24, Ho. 29 , i v AP00007404 1098 THF t .ASCII, NOVI MRI K 29. 1975" ANtHcrrKM.es Aftovriaa airios in twin vmti and iv pmskvii i t HOSHTAt.,111110 Anenccphilut Spina bifida Painaavllla Suit Paiaamllr Milt No. of No- of Year IUC Raw* am >970 0 1971 1972 197} 2 1974 1 _9 m 26 >0 J U 15 6 31 24 9 I? CO .22 No of No >J Rote ciki Rale Cl^s SO 3 It 2 5X 7 3 3 JO* 44 4 3 0 0-0 47 3-4 3 24 * 4A 45 1 t>-l 2* Hair 111 A7 9A 2 AO 19701974 14 1 144 3-7 9 21-2 224 .y Per 10 MO (Mil wfeitr births. the discrimination of vector of meant can be tested for signifi cance. A high dbcriminaiioo between the malformation group and its matched controls appeared within the first 10 of the 24 variables (ace accompanying figure). Even with S variables a significant discrimination of both groups at 1*7 level was found. The discrimination of both groups was also possible without the two factors "abortioni/siillbinhs in mothers family" and "hours ofdaily work". So eves bt a ample sntb factors each not discriminating significantly between both groups, the linear discriminance analysis makes it possible to discriminate between the malfor mation group and the matehed controls. This might mean that the malformations in our sample can be explained as caused by the combination of many minor factors (extrinsic and intrin sic). lmaianiktunuiildrlrti|Me4iswnak. nn08flB<ui< Men]RtpufebcofGmwt. J-KiracnwcHT K.-H. DrOKSHAUM CONGENITAL MALFORMATIONS AND VINYL CHLORIDE Sin,--In March, 1975, a significantly increased rate of eetvtral-nervouMystem (c.s.i.) malformations was reported in 3 Ohio communities where polyvinylchloride (p.v.c.) polymeris ation plants are located;1 the increase was not uniform and appeared more prominent in the Painesville area. There are two P.vx. plants in Painesville. one of which began operation in 1949 and the ocher in 1967. The birth-defect rates were cofipind from btnb-cenifime data tor 1970-75 and were compared with similar data for the entire State of Ohio. This study suggested a relationship between the higher rales of c.m.s. malformations and the increased risk of exposure to vinyl chloride in them communities. By analysing data collected through the Center for Disease ' Control's hospital-based bulb defeat monitoring programme <*JS.MX-V we examined this sdatkmship. Two hospitals parti cipating in the i.DJK.r. are located ia cities with polymerisa tion plants: one is in ftaroylvansa, the other In Painesville, Ohio. c.M.s.-walforaiuiioa talcs for white infants bom in these two hospitals in 1970-74 were compared with the rales for white infants in each State. No increase was seen in the Penn sylvania hospital, but an increase, primarily in anenerphaly and spina bifida, was noted in the Painesville hospital for the total time 1970-74 (tee table). t. laf--t. P. A Pramimmaf tbc Coolirtaw aa Uccutuinut Cararofmoi, MthlHf* fork AnIf ofSnrace, 2t Marvh. IVS So- V.rt m iIkpw>. Z Ctmrr for Dfmit Central. Congmiltl MKFormatnm SirvrtlUiKc Annual bawasiy 1974. Adaaia. 197}. The r.P.m.p. hospital data for Painesville were compared with birth-certificate data foam the Ohio department of health, and 1 additional case not included in the r.d.m.p. report was added, bringing the total to 15. 30 controls, the first normal white infant bom before and after each case, were selected from the hospital birth registry. Medical reeords for cases and controls were reviewed to confirm the diagnosis and to nbtam. among other data, the parents* occupation and residence at the lime of the infant's birth. In addition, parents of 14 of the affected children were interviewed about previous occupations and residences. The study revealed that none of the interviewed parents of affected infants had ever worked at either of the two r.v.c.-polymerisation plants in Painesville (1 set of parents could not be located, but records show that they did not work at these plants at the time of their infant** births 2 nf <hr fathers of controls had worked at one of the pisnt* t the time of their infants' births. None of the parents in either group lived within 2 miles of the two plants. The chi-square test of significance was used in comparing the distances from residence and work-place of mothers and fathers to the p.v.c. plants tor eases and controls. Comparisons were made at disiancai of 1 to 10 miles, in 1-mile increments. A significanily larger proportion of control mothers than case mothers worked (including housewives) within a 10-mile radius of the p.v.t:. plant, at the 95*7 confidence level. This is probably a chance occurrence among multiple comparisons. Vinyl chloride is a known carcinogen.*4 5*and concern has arisen over its possible teratogenic effeas. This concern stems from recent studies which have shown tai an increase in muta genicity in baeterial assay ystemt* and (bi increased breakage in chromosomes of r.v,c.-poiymerisation workers/ The Ohio Department of Health study1 is the only report that has sug gested that vinyl chloride causes birth defeat in man. Although the follow-up study reported here confirmed a moderate increase in c.N*.s. malformations in Painesville, Ohio, no association was found with vinyl-chloride exposure. Cancer and Binb IMiteu Divtuon. Bureau ef Kpidcmiolefy, Canter far itueaee Coairot. Atlaata. tieerpt I0JJJ.V.S-A. Laary D. Edmonds, Henry Falk Jack E. Nissim LATE COMPLICATIONS OP TUBAL LIGATION Six,--Unlike Mr Darwisb and Dr Saafan (Nov, IS. p. 975', we art uncertain as to the artiology of the late sequels of female sterilisation, which they refer to as menstrual irregu larity, but in our study it will be noted wc looked specifically at menorrhagia and dysmenorrhea. It seems unlikely that a psy chosomatic cause could be present when two different ted J.Camtr for llnaaw CarilM. Morbid,,r and Mortality U'nkh Hcpirt, J-vh 9,1*74, p. 49. 4. Roam*, t\, Jahaauaa, A., RiimL C,, U'achaici'tar. C. A. Amtu. 19*4. J, 194. 5. PuaavCfavmo, K. l-amben. R.. Liadttcn. J. Ltni, 197}, i, 4}9. AP00007405 received, RESEARCH i DCYCLOP ' JAN W. M. SMrt TOE EFFECTS OF MATERNALLY INHALED VINYL CHLORIDE ON EMBRYONAL AND FETAL DEVELOPMENT IN MICE, RATS AND RABBITS I BY* J.A. John, B.A. Schwetz, B.K.J. Leong, F.A. Smith K.D. Nitsehke, H.D. Haberstroh, F.J. Murray H.F. Balmer and P.J. Gehring REVIEWED BY: P. J. Gehring December 19, 1975 Toxicology Research Laboratory Health and Environmental Research Dow Chemical U,S.A, Midland, Michigan 46640 This study was funded by the companies supporting the vinyl chloride projects being administered by the Manufacturing Chemists Association, Washington, D,C. AP00007406 14- rabbits at a significantly different incidence'from controls. Among litters of rabbits exposed to 500 ppm vinyl chloride, the incidence of delayed ossification of the 5th sternebra was increased whereas that of the 6th sternebra was decreased. Delayed ossification of sternebrae did not occur at a higher incidence than control among litters of rabbits exposed to 2,500 ppm vinyl chloride alone or in combination with 15% ethanol in the drinking water. .... ...... DISCUSSION She results of these studies indicate that exposure of pregnant mice, rats or rabbits to vinyl chloride by inhalation at concentrations sufficiently high to cause maternal toxicity . vas not teratogenic in any of the three species. The responses of mice, rats and rabbits are summarized in Table 11. Less maternal toxicity was observed among rats and rabbits than mice during exposure or at the tine of cesarean section. Among rats one maternal death and an increase in liver weight was observed at 2,500 ppm while only a slight decrease in maternal weight gain was observed at 500 ppm. Among rabbits, one maternal death was observed at 2,500 ppm and there was a decrease in food consumption at 500 ppm. In comparison, 500 ppm was quite maternally toxic to mice as evidenced by the significantly decreased weight gain and > food consumption and by the occurrence of a number of maternal deaths ,, f AP00007407 / -15- Exposure to vinyl chloride was not consistently embryotoxic in the three species studied. A significant increase in the percent resorptions was observed among mice exposed to 500 ppm vinyl chloride, but not among rats or rabbits exposed to 500 ppm or 2500 ppm vinyl chloride. Some decreases in .fetal body weight and crown-rump length were observed in rats and mice but not rabbits. A teratogenic response to maternally inhaled vinyl chloride was not observed in mice, rats or rabbits. With the exception of unilateral and bilateral dilated ureter among litters of rats exposed to 2500 ppm vinyl chloride, no external or soft tissue anomalies were observed at an incidence significantly higher than control in any of the three species. Examination of the skeletons revealed only minor skeletal variants; no skeletal malformations were found at an incidence significantly greater than in the control groups. Ingestion of 15% ethanol in the drinking water enhanced some # of the effects of inhaled vinyl chloride. In each of the ' three species tested, maternal weight gain and food consumption was lower than among animals exposed to vinyl chloride alone. The percent resorptions was slightly increased among mice and significantly increased among rabbits exposed to vinyl chloride in combination with 15% ethanol in the drinking > water. Fetal body measurements were lower among litters of AP66607408 4I mice and rats which received ethanol and vinyl chloride compared to vinyl chloride alone* Certain malformations were observed among litters of mice, rats and rabbits which also received ethanol but their incidence was not statistically different than control litters. The effect of simultaneous Ingestion of ethanol on the disposition of vinyl chloride in these animals seemed to enhance maternal toxicity to an extent greater than embryotoxicity. In summary, the results of these studies indicate that exposure of pregnant mice, rats and rabbits to vinyl chloride w by inhalation was not teratogenic at the concentrations tested. Kice were more susceptible to the toxic effects of vinyl chloride than either of the other two species. Simul taneous exposure to vinyl chloride by inhalation and 15% ethanol in the drinking water resulted in toxic effects greater than those associated with exposure to vinyl chloride alone*in the three species. Neither exposure to vinyl chloride alone or in combination with 15% ethanol in the drinking water caused a significant teratogenic response in mice, rats or rabbits. ( AP00007409 SEP 23r 1PB0 t,2>C> SEP 23 r 1 PB0 , FrLE NUMBER . 311 AUTHOR<S> * feiprnARF> j.F.M^/ptrnAPnprM.r.p tAKmcper.M.n iPAnnic.fi.M l ADAMS*W.G.F. TITLE * CHROMOSOMAL, ANALYSES IN VINYL CHLORIDE-EXP.OSED-WORKERS PUBLICATION SOURCE * MUTAT RES 57*325-334*1978 LANGUAGE * ENG * ----------- - COUNTRY I GR BR EE X R'E RIMENTAL DESIGN PERIPHERAL BLOOD LYMPHOCYTES WERE COLLECTED FROM 57 VC/PVC WORKERS* 19 ON-SITE CONTROLS AND 5 OFF-S2TE CONTROLS* AND 48 OR 72 HR. CULTURES WERE PREPARED AND SCORED FOR CHROMOSOMAL ABERRATIONS <CLASSIFIED ACCORDING TO BUCKTON AND PIKEi Bt Cu* Cs CELLS). FIFTY CELLS FROM EACH CULTURE/INDIVIDUAL WERE SCORED BLINDLY. SUBJECTS WITH RECENT HISTORY OF EXPOSURE TO X-RAYSi PROLONGED DRUG TREATMENT OR RECENT VIRAL INFECTIONS WERE EXCLUDED FROM THE STUDY. EXPERIENCE OF VC ODOR DETECTION AND THE DESCRIPTION OF VC EMPLOYMENT WERE RECORDED. THE VC/PVC WORKERS WERE CLASSIFIED INTO 6 GROUPS* GROUP 1* 17 PVC AUTOCLAVE WORK ERS* GROUP 2* 10 PACKERS AND DRYERS OF PVC POWDER? GROUP 3* 7 VC PRODUCTION WORKERS? GROUPS 4 AND 5* CONSISTED OF ENGINEERING MAINTENANCE MEN FOR PVC <11 MEN) AND VC <7 MEN) EQUIPMENT AND PLANT? GROUP 6* 5 MEN WITH OCCUPATIONS OTHER THAN PROCESS OPERATORS IN THE VC/PVC PLANT. THERE WAS NO SIGNIFICANT DIFFERENCE FOUND BETWEEN ON-AND OFF-SITE CONTROLS* THEREFORE THE 24 MEN WERE COMBINED INTO ONE CON TROL GROUP. THE AUTOCLAVE WORKERS ARE CONSIDERED TO HAVE THE HIGHEST EXPOSURE TO VC AND THE HISTORIC AVERAGE EXPOSURE LEVELS ARE GIVEN* 1945 - 1955 APPROXIMATELY 1000 ppmi 1935 - 1960 APPROXIMATELY 400 - 500 PPM* 1960-1970 APPROXIMATELY 300-400 ppm* MID 1973 APPROXIMATELY 15 ppm AND 1975 APPROXIMATELY 5 PPm. THE SMOKING HISTORY ON THESE INDIVIDUALS WAS COLLECTED IB MONTHS AFTER THE BLOOD SAMPLES WERE TAKEN. LIVER FUNCTION TESTS INCLUDING BILIRUBIN* ALANINE TRANSAMINASE* ASPARTATE TRANSAMINASE* ALKALINE PHOSPHATASE* GAMMA-GLUTAMYL TRANSPEPTIDASE AND PLATELET COUNTS WERE PERFORMED ON VC EXPOSED WORKERS AND ON-SITE CONTROLS. THE AVERAGE DURATION OF EXPOSURE IN EXPOSED GROUPS AND AVERAGE AGE OF ALL GROUPS WERE GIVEN* GROUP 1 - 10.7 YEARS EXPOSURE AND 41 YEARSOF AGE? GROUP 2 - 12.7 YEARS EXPOSURE AND 42 YEARSOF AGE! GROUP 3 - 6.3 YEARS EXPOSURE AND 44 YEARS OF AGE? GROUP 4 - 15.5 YEARS EXPOSURE AND 47 YEARS OF AGE? GROUP 3-6.1 YEARS EXPOSURE AND 36 YEARS OF AGE? GROUP 6-8.6 YEARS EXPOSURE AND 40 YEARS OF AGE? CONTROLS - 44 YEARS OF AGE. ** KEYWORDS **** VINYL CHLORIDE? HUMAN STUDY? OCCUPATIONAL EXPOSURE? VC WORKERS? PVC WORKERS? CHROMOSOME ABERRATIONS? DURATION OF EXPOSURE? SMOKING HISTORY? BILIRUBIN? PLATELETS? ALKALINE 157.' AP00007410 PHOSPHATASE\ ALANINE TRANSAMINASE? ASPARATE TRANSAMINASE* EXCURSION LEVELS! PERIPHERAL BLOOD LYMPHOCYTES* B CELLS* C Cf-LLS* JOB CLASSIFICATION* AUTOCLAVE OPERATORS* DRYING* PACKING* PVC POWDER* VC PRODUCTION? MAINTENANCE* Cs* Cu? RINGS! DICENTRICS? FRAGMENTS* CHROMATID BREAKS* CHROMATID GAPS* CHROMOSOME BREAK* CHROMOSOME GAPS* INVERSIONS* TRANSLOCATIONS* MUTAGENICITY. **** ABSTRACTS M'-K'-M'-N- IN THE ANALYSES OF CHROMOSOMAL DAMAGE IN VC/PVC WORKERS THE DATA FROM 4B AND 72 HOUR CULTURES HAVE BEEN POOLED. THE NUMBER AND PERCENTAGE OF CHROMOSOMAL ABERRATIONS ARE HIGHER IN THE EXPOSED GROUPS COMPARED TO CONTROLS* EXCEPT FOR CHROMOSOME GAPS* WHERE THE CONTROL VALUE IS RELATIVELY HIGH* AND FOR FRAGMENTS. WHERE THE CONTROL VALUE IS HIGHER THAN THE VALUE OF GROUP 6 <0.0O). THE AUTOCLAVE WORKERS (GROUP 1) HAVE THE HIGHEST SIGNIFICANT INCREASE<P<0.01> OF TOTAL B TOTAL Cu AND TOTAL C CELLS* COMPARED TO THE CONTROL POPULATION. VC MAINTENANCE WORKERS (GROUP 5) HAVE THE NEXT HIGHEST VALUES* AND PVC LABORATORY WORKERS AND MANAGERS (GROUP 6) HAD THE LOWEST WITH CHROMATID GAPS OCCURRING SIGNIFICANTLY MORE FREQUENT THAN IN THE CONTROLS (P<0.05>. GROUPS 2* 3* AND 4 HAVE VALUES BETWEEN GROUPS 5 AND 6. HISTORY <1973-1974) OF RECENT EXPOSURE CORRELATED WITH A HIGHER PERCENTAGE OF ABNORMAL CELLS (CHROMATID GAPS* TOTAL C CELLS* AND FRAGMENTS). CHROMATID GAPS* TOTAL C CELLS AND FRAGMENTS ARE CONSIDERED THE MOST SUGGESTIVE INDICATOR OF CHROMOSOMAL ABNORMALITIES. SINCE THEY HAVE THE HIGHEST CORRELATION BETWEEN LENGTH OF EMPLOYMENT <AT A 1% SIGNIFI CANCE). LIVER FUNCTION TESTS WERE SHOWN TO HAVE A NEGATIVE CORRELATION WITH CHROMOSOMAL ABERRATIONS (AT EITHER 5% OR 10% SIGNIFICANCE LEVEL.) THERE WAS FOUND A POSITIVE SIG NIFICANT CORRELATION BETWEEN PRESENT SMOKERS AND TOTAL C CELLO (P-0.0239 AND WITH TOTAL Cu CELLS <P*0.05>. PRESENT SMOKERS* LENGTH OF EMPLOYMENT AND EXPERIENCE OF HIGHER SHORT TERM EXPOSURE CORRELATED WITH THE PERCENTAGE OF C CELL ABNORMALITIES. THESE RESULTS INDICATE 4 FACTORS INFLUENCE THE INCREASE OF CHROMOSOMAL ABERRATIONS IN VC/PVC WORKERS* THE JOB CATE GORY* THE LENGTH OF EMPLOYMENT AND RECENT EXPOSURE TO SHORT-TERM EXCURSION LEVELS OF VC AND SMOKING HABITS. THE DIFFERENCE SEEN IN CHROMOSOMAL ABNORMALITIES IN GROUP 1 4THE HIGHEST) AND GROUP 6 (THE LOWEST) IMPLIES THAT THE OVERALL EXPOSURE LEVEL TO VC HAS AN INFLUENCE ON CLASTOGENIC EFFECT. THE AUTHORS SUGGEST USING THE VALUE OF TOTAL C CELL ABNORMALITIES AS AN INDICATOR OF CHROMOSOMAL ABER- ' RATIONS IN FUTURE STUDIES. AP00007411 KoHce: This material may be rTMQCt? by copyright'law (Tltfe 17 U,$,*Code) Rw lived 65/ JAN l4REC*0rattAWC,,# PHIL 3,1971 v.c.m. pol)Aie3stt.SAftd*3$8 rubber and P.v.c. fabri Occasional Survey GENETIC RISKS OF VINYL CHLORIDE J*ETEX F. INFANTE JOSEPH K. WAGONER Anthony J. McMichael Richard J. Waxweilbr Henry Falk Division ofSurveillance, Jiatard Evaluations and Field Studies, national Institutefor Occupational Safety and Health, and Bureau of Epidemiology, Centerfor Disease Control; and School of Public Health, University ofNorth Carolina Summary A study of pregnancy outcome among wives of workers exposed to vinyl<hlor* ide monomer (v.c.M.) indicated tbit, in comparison with controls, there was a significant excess fetal loss in the group whose husbands had a primary exposure to v.c.M., whereas no differences between the groups were observed before the husbands* exposures. The difference in fetal death-rates for the post-exposure comparisons was a reflection of a greater fetal loss associated with the wives younger-aged husbands. The significant excess did not seem to be the result of bias from interviewers, re spondents, nor from women who had experienced chronic abortions weighting the results. These findings, in conjunction with the demonstration of a mutagenic response via microbial test systems and with observa tions of significant excesses of chromosomal aberrations among workers exposed to v.c.M., raise scientific and public-health concern for the possible genetic risks of v.c.M. 10 man. In the past year, several reports have indicated that vinyl-chloride monomer (v.c.M.) is mutagenic in micro bial test systems.'-1 v.c.M. metabolites also have in duced mutations in mammalian cells.4 Likewise, reports from four countries have shown an excess of chromoso mal aberrations in lymphocytes of workers exposed to v.c.M. compared with controls.1"1 However, Purchase et al.' have stated (though no animal data were presented), that the mutagenic effects of v.c.m. expressed as chro mosomal aberrations in lymphocytes in humans do not occur in germ cells in mice; they concluded that the potential danger of mutagenic effects on the fetus via sperm seemed unlikely to exist. In a study without con trols, Selikoff observed fetal death-rates among wives of v.c.m. workers that ranged from 7 to 14 per 100 preg nancies.4 These rates appear to have been higher than expected.*0 To develop further data on this question, pregnancy outcome has been studied among the wives of workers exposed to v,c.m. All current v.c.m. polymerisation and polyvinyl-chloride (p.v.c.) fabrication workers were in cluded for study together with a similar number of cur rent rubber workers (8% of all such workers) selected from work areas relatively free from known toxic materials and matched as a group to the v.c.m. workers by age. Group-participation rates ranged from 62 to 77%. Data for the wives of v,c.M. polymerisation .workers (primary v.c.M. group) were contrasted with data for the wives of p.v.c. fabrication and rubber workers ("controls''), who were known to have had very low or no v.c.M. exposure, respectively. A total of 95 cation workers wen interviewed. Paternal age, preg nancy outcome, and estimates for the time of conception of all pregnancies were ascertained by interview in Oct ober, 1974, from males employed at a rubber manufac turing, p.v.c. fabricating, and v.c.M. polymerising facil ity. As part of a larger survey of worker health, date of first employment in the job categories was determined from company records. Mean paternal age, total number of conceptions, total number of fetal deaths (defined as any product of conception not born alive), and fetal deaths per 100 conceptions were then computed for each group prior to and subsequent to the worker's date of employment. No interviews were conducted with workers' wives and no data were obtained concerning maternal age, except indirectly through paternal age. Since fetal loss is known to increase with ascending parental age, the fetal death-rates for the primary v.c.m. exposure group were age-adjusted to the control group. Table t shows the age-adjusted fetal death-rates for wives of the primary v.c.m. exposure group versus the control group, both prior to and subsequent to each group's respective exposures. Among pregnan cies occurring prior to exposure, fetal death-rates were 6-9% for the controls versus 6-1% (age-adjusted) for the primary v.c.m. exposure group. These rates were not significantly different by Mamel-Haeimel Chi-square testing.13 Among pregnancies occurring subsequent to the husband's exposure, the difference in frequency of fetal deaths between groups was significant at p<0 05 (y,=A-00idf=I).li Although the underlying dis tributions differed, mean paternal ages were virtually the same--30-4 versus 30-2 years. The significant dif ference between the groups subsequent to exposure was a reflection of a relatively greater fetal mortality-rate as sociated; with younger-aged husbands in the primary v.c.m. exposure group. Among pregnancies occurring subsequent to exposure, the fetal mortality-rates associ ated with husbands 30 yean of age and older for the pri mary v.c.m. exposure and control groups were 9/69 (13-0%) and 17/142 (12-0%), respectively} whereas, for TAILI I--MEAR PATERNAL AOE, NUMBfK OP FttOMAMCIES, AMD tlTAl DEATH-RATES ACCOR01NO TO HUSBAND'! VC. IXPQSURE -- Primary "Commit"* etpeauret Pritir lo k*thaitd't trposvrt: Number of fimiliM Men pBtunit gg n conception (yr.) Hember of fuel death* motif wivea Number of pngsandet Afc*aJjutted fetal ifcth/l00 preft Siibsoineot to MitskinB"s exposure: Number of familie, Mcanpateraal age at conception (yr.) Number of fetal Deal h* among wivea Number of prrgiunelet Age-adiutted fetal Jewht'lOOpregg *J 2X0 tl IS* 4S 11} 30 4 24 173 f't TO 2d-4 141 A-! S2 30'2 23 13* ISIJ `Rubber and r.v*. fabrication worticn. fv. polymcnmion worker,. Run age.adjtuied to "control" grasp paternal age dji'ributton. ISubtcquaat te InubanJ*, cipeMirt, the frequency of fatal daatba amenf *** wia Sgnlfleamly treettr In the primary v.c.m. cifwture group than in ibc "cow Iroll" (r<0-05) or in the nudy froup prior to buafaaadH exposure b, age adjuttedAhi-tqiiaftleHing.'1 r TUB Lih TAILS ,1 DEATH - Prior to ku Meaicnopnj Number death Number prejn Agc-mdi' death daitryatv' Mean p. It OKI Number death' Number prepi Ag-aJ|u death- -Rubber a< tv-e. poi)ir JRxtO 1/T husbam.' 14/70 < compar (these d Furth increase exposur mbsequ also wa compan 8-8%, it To d experier favour t group si women inated f lated to tained. families" made were di data in Prior tf and pri 3-1% 0 sure, th sequent! women abortion each tinfor coni was obsi exposur To di have be ing the lerviewi each it> among ' control) Furilval betv loss mi) AP00007412 . 197o fabri- pregption - Octufac- fadl- >te of lined mber >cd as fetal each ite of with ming e. Tding } * roup. rate* 'troup luent ^nanwere tr the c not (uare nt to icy of -t at g dis mally t difi! was ite asmary tiring ssoci*e pri- 9/69 foe KTAL % ulUKT. A A l 29 wivn s "o' 02? by \ T1IE LANCET, APRIL 3, 1976 fmi II--MIA* TATIANAt. AOS, NUMSIA or rKEONANCIKi AND VITAL MATH'MTEI ACCOADINO TO HUSBAND1! .C. tXrOIVM SICLVDtNO MEQNAHCIZS OF WOMAN WITH * 1 VITAL MATHS -- Pnairra itptturt: Alcan paternal age 1 conception (yr.) NombctoffaiR dralhi amongiva Numberr prtfntncia Aj(MJ|USlCd fetal licaihi/IOOpref J SMfic^Ncnt i Auihentf** ttpeturt: Mean paternal afe 1 conception ijt.) Nun*ur oFfatal Jcaihi smoniwiva Number of prepnancin Asc-aJiutioi fetal dc,lh|/100pf.t Fnnuy "Control,*** V.CJ4, cipe*urct UI II 139 49 JO-7 It 263 <-t 21) 9 141 M JO-I 14 120 10-1 ,`lnbbe aid r.r.e- hbricuioa worken. Nt. pdyMntttien worked. (Rita a|MdruM<610 "eontral" paternal iftdutrtbLiiiOfl. husbands less than 30 years of age, fetal mortality was U/70 (20-0%) for the primary v.c.m. exposure group compared with 7/131 (5-3%) for the control group (these data are not shown in tables.) Furthermore, intragroup comparisons indicated an increase in age-adjusted rates for the primary v.c.m. exposure group from 6*1% before exposure to 15-8% subsequent to the husband's exposure. This difference also was significant, p<0*02 (yJ=5*51, df=l).11 Similar comparison for rates in the control group, 6*9% versus 8-8%, indicated no significant difference. To determine whether women who had chronically experienced abortions might have weighted the results in favour of a higher fetal death-rate in the primary v.c.M. group subsequent to husband's exposure, pregnancies of women who had more than two abortions were elim inated from the analyses and the data were recalcu lated to determine whether or not the trend was main tained. The decision to exclude all pregnancies among families associated with more than two abortions was made without prior knowledge of how these families were distributed among the exposure categories. The data in table n show that the trend was maintained. Prior to exposure, the fetal death-rates in the control and primary v.c.m. exposure groups were 6*9% and 3-1% (age-adjusted), respectively, whereas, after expo sure, the rates were 6*8% and 10-8%, respectively. Sub sequently, data were eliminated for pregnancies of women who had experienced, firstly, more than one bortion, and, secondly, more than three abortions, and each time the trend was maintained. No changes in rates for controls were observed, whereas a 2--3-fold increase was observed in the primary v.c.m. group subsequent to exposure. To determine whether differences in fetal loss might have been the result of one or two interviewers weight ing the results, the data were analysed by individual in terviewer. The results demonstrated a general trend for each interviewer to report a higher ascertainment among v.c.m. polymerisation worken than among the control group. Further, the possibility was entertained that the inter val between the date of interview md the date of fetal loss might have influenced the results through dif 733 - ferences in recall. The interval, however, was estimated to have been about two years less for controls, suggest ing that, if a bias did exist, it would have been towards greater ascertainment in the control group. In some cases, the worker failed to indicate the agea of his children and in other cases he was unable to recall the approximate time of his wife's abortion; therefore, the data were analysed 10 determine the distribution of fetal death-rates among the respondents in each ocatpauonal group who did not complete the interview properly. The difference in fend death-rates between groups was very slight. Finally, the worken ny have been sriyrt to bias resulting from prior knowledge of known hazards of vinyl chloride. However, the workers themselves did not always know into which of our employment categories they were being allocated. For example, several P.v.c.1 fabrication worken who were included in the control group thought that they had a primary v.c-M. exposure at a fabrication worker. In the questions regarding pregnancy outoome snr mnrainctf in a much larger imerview-questio&ntke, flie vaults of which demonstrated very few significant differences with no consistent bias for the parameters ascertained between the workers with a primary v.cac. exposure, and the other groups. This observation as well as several others presented above tend to support the validity of the study. In summary, a significant excess of fetal loss was observed among wives of worken following exposure to v.c.m. The excess did not appear in be the remit ofbias from interviewersor n jiuiNfc;iiii, orfiw women who experienced chronic ahortinai warning the results. Several mechanisms by arihsdh each fetal k may arise are suggested. Eitbre fetal or norecad aandity nr perm- cell mutagenesis in the another through indirect v.C-M. exposure from the father might be considered, although these mechanisms seem highly unlikely in view of die highly volatile nature of v.c.m.'1 When the findings of the present study are taken in conjunction with the prior demonstration of it mutagenic response via microbial test systems and observations of cig&iScaat noom of chromosomal aberrations among workers exposed to v.c.m., the leading possibility ia gamed in the father through direct v.c.m. exposure. The increased fetal mortality among wives of worken subsequent to v.c.m. exposure now raises serious scientific and publichealth concern for the possible genetic risks of vinyl chloride to man. Request! fcjftyrinuihiMldteittusiaPJi,nUt.tH,hN Office Building, Roan 515.Ci imiri.Qhia45MB,CUA I. Ilanacti, It., Mirfa^gJtC., MootHino, 0_/.J. Cover. I97J, IS, 42V. 2- 1-npricno, N-, llariAirfcVsroncclli, S, R a!. Huuricm Btx. (an (he proit ^tflflOS.U.JohanLTCS'fUnMl. CL, Wochnouar, C. A. Arrtw. IS74.I, 1*4. 4. Huhrnu. E . Btmck.'i, Sack,, L.tni.J. Caiutr. 197J, 16.639. $. Dnciirnsn, An HirtcMtoSkK., SctitoJT, 1. ), Munm ft**. 1971, SI, !. 6. FmcrCnvww, P., UirIlS, Lim&tm, J_ Ekakny, 1_ Itautiiw A. T-, OitcnNUHGolkar. Sywr.WTl.Lllf. 7. PurchiM, I. F' fl^Ridtar4*0(vAnfcWR.01 M- I97J,ii,Aia. 5. Hillcsttd, L-, Tfalls-EvMMn. E. OfentWuM- 9. Sdikoff, I, J-, NJ.E.H-S. Confer* Public Ht*kh tmplieemwefCeaTV- powntt of PUttiea Manufsetun, Bochum, North Csreiina, Jtdj, 1974. 10- Infante, P. P.Arh. iVV.<4e*tf. Sci. (intnsrcfl). II. Shapiro, S-, Joimv E. X'.,Dtn*en, P. M.XLAenA Q. 1941,40,7. 12. Monte!, N., Haanuet W,J. Utin.CfKtr 719. 13. United Sum Eanroamenia! Ptvweuon tdtet t*ie tubuuKn. mk nt vtnjl Jan. 20.1976. tn^ Wiljnii of GENETIC RISKS OF VINYL CHLORIDE By Peter F. Infante * Joseph K. Wagoner Anthony J. McMichael* Richard J. Waxweiler Henry Falk0 Division of Surveillance,'Hazard Evaluations and Field Studies National Institute for Occupational Safety and Health, 0Bureau of Epidemiology, Center for Disease Control, and +Schoo1 of Public Health, University of N. Carolina Mailing Address: NIOSH, Post Office Building, Room 515 Cincinnati, Ohio 45202 USA AP00007414 In the past year, several reports have indicated that vinyl chloride monomer (VCM) is mutagenic In microbial test systems.VCM metabolites also have induced mutations In mammalian cells.4 Likewise, reports from four countries have shown an excess of chromosomal aberrations In lymphocytes of workers exposed to VCM as compared to controls. "* However, Pur chase et al.,^ have stated recently, though no animal data were presented, that the mutagenic effects of VCM expressed as chromosomal aberrations in lymphocytes in humans do not occur in germ cells in micej they concluded that the potential for mutagenic effects on the fetus via sperm seemed unlikely. In a study without controls, Selikoff observed fetal death rates 0 among wives of VCM workers that ranged from 7-14 per 100.pregnancies. These rates appear to have been higher than expected.^ To develop further data on this question, a study of pregnancy out come was made`among the wives of workers exposed to VCM. All current VCM polymerization and polyvinyl chloride (PVC) fabrication.workers were in~ eluded for study together with a similar number of current rubber workers (8 of all such workers) selected from work areas relatively free from known toxic materials and matched as a group to the VCM workers by age. Group participation rates ranged from 62-77 percent. Data for the wives of VCM polymerization workers (primary VCM exposure group) were contrasted with data for the wives of PVC fabrication and rubber workers ("controls"), who were known to have had very low or no VCM exposure, respectively. A total of 95 VCM polymerization and 158 rubber and PVC fabrication workers were interviewed. Paternal age, pregnancy outcome and estimates for the time * of conception of all pregnancies were ascertained by interview in October, 1974, from males employed at a rubber manufacturing, PVC fabricating and VCM polymerizing facility. As part of a larger survey of worker health, / date of first employment In the job categories was determined from company records. Mean paternal age, total, number of conceptions, total number of fetal deaths, defined as any product of conception not born alive, and fetal deaths per 100 conceptions were then computed for each group prior to and subsequent to the worker's date of employment. No interviews were conducted with workers' wives and no data were obtained concerning maternal age* except indirectly through paternal age. Since fetal loss is known to increase with ascending parental age, the fetal death rates for the primary VCM exposure group were age-adjusted to the control group. Table I shows the crude and age-adjusted fetal death rates for the wives of the primary VCM exposure group versus the control group, both prior to and subsequent to each group's respective exposures. Among pregnancies occurring prior to exposure, fetal death rates were 6.9% for the controls versus 6.It (age-adjusted) for the primary VCM exposure group; These rates were not significantly different by Mantel-Haenszel ' Chi-square testing. 12 Among pregnancies occurring subsequent to the hus band's exposure, the difference in frequency of fetal deaths between groups was significant at P<0.0G(x^=4.OO,df=l).^ Although the underlying distri butions differed, mean paternal ages were virtually the same, 30.4 versus . 30.2 years. The significant difference between the groups subsequent to exposure was a reflection of a relatively greater fetal mortality rate associa ted with younger-aged husbands in the primary VCM exposure group. Among preg nancies occurring subsequent to exposure, the fetal mortality rates associated with husbands 30 years of age and older for the primary VCM exposure and control groups were 9/G9 (13.0%) and 17/142 (12.0*), respectively; whereas. AP00007416 for husbands less than 30 years of age, fetal mortality was 14/70 (20.OX) for the primary VCM exposure group as compared to 7/131 (5.3%) for the con trol group. (These data are not shown In Tables). Furthermore, intragroup comparisons indicated an Increase in ageadjusted rates for the primary VCM exposure group from 6.1% before exposure to 15.8% subsequent to the husband's exposure. This difference also was significant, P<0.02(x *5,51,df*l). Similar comparison for rates in the control group, 6.9% versus 8.8%, indicated no significant difference. To determine if women who had chronically experienced abortions may have weighted the results in favor of a higher fetal death rate in the pri mary VCM group subsequent to husband's exposure, pregnancies of women who had more than two abortions were eliminated from the analyses and the data were recalculated to determine whether or not the trend was maintained. The decision to exclude all pregnancies among families associated with more than two abortions was made without prior knowledge of how these families were distributed among the exposure categories. The data in Table II show that the trend was maintained. Prior to exposure, the fetal death rates in the' control and primary VCM exposure groups were 619% and 3.1% (age-adjusted), respectively, whereas, after exposure, the rates were 6.8% and 10.8%, re spectively. Subsequently, data were eliminated for pregnancies of women who had experienced, firstly, more than one abortion, and, secondly, more than three abortions, and each time the trend v/as maintained. No changes in rates for controls were observed, whereas, a 2-3 fold tncroase was observed in the primary VCM group subsequent to exposure. To determine whether differences in fetal loss may have been the result of one or two interviewers weighting the results, the data were analyzed by Individual interviewer. The results demonstrated a general trend for each interviewer to report a higher ascertainment among VCM polymerization workers as compared to the control group. Further, the possibility was entertained that the time Interval between / the date of interview and the date of fetal loss might have influenced the results through differences in recall. The time interval, however, was es timated to have been about two years less for controls, suggesting that if a bias did exist, it.would have been toward a greater ascertainment in the control group. ' In some cases, the worker failed to indicate the ages of his children and in other cases he was unable to recall the approximate time of his wife's abortion; therefore, the data were analyzed to determine the dis tribution of fetal death rates among the respondents in each occupational group, who did not complete the interview properly. The difference in fetal death rates between groups was minimal. Finally, the workers may have been subject to bias resulting from prior knowledge of known hazards of vinyl chloride. However, the workers them selves did not always know into which of our employment categories they were being allocated. For example, several PVC fabrication workers who were in cluded in the control group thought that they had a primary VCM exposure as s a fabrication worker. In addition, the questions regarding pregnancy out come were contained in a much larger interview-questionnaire, the results of which demonstrated very few significant differences with no consistent bias for the parameters ascertained between the workers with a primary VCM exposure , as compared to the other groups. This observation as well as several others presented above tend to support the validity of the study. In summary, a significant excess of fetal loss was observed among wives of workers following exposure to VCM. The excess did not appear to be the result of bias from Interviewers, respondents, nor from women who experienced chronic abortions weighting the results. Several mechanisms by which such fetal loss may arise are suggested. Either fetal or maternal toxicity or germ cell mutagenesis in the mother through indirect VCM exposure from the father might be considered, although these mechanisms seem highly unlikely in view of the highly volatile characteristic of VCM.^ When the findings of the present study are taken in conjunction with the prior demonstration of a mutagenic response via microbial test systems and observations of sig nificant excesses of chromosomal aberrations among workers exposed to VCM* the leading possibility is germ cell damage in the father through direct VCM exposure. The increased occurrence of fetal mortality among wives of workers subsequent to VCM exposure now raises serious scientific and public health concern for the possible genetic risks of vinyl chloride to humans. APb0007419 REFERENCES 1. Bartsch, H., Malavielle, C. and Montesano, R. Human, rat and mouse Hver-mediated mutagenicity of vinyl chloride in S. Typhimurium strains, Int. J. Cancer, 1975, 15, 429, 2. Loprleno, N., Barale, R., Varoncelli, S., et al. Evaluation of the genetic effects by vinyl chloride monomer (VCM) under the influence of liver microsomes. Mutation Res, In press. 3. Rannug, U., Johansson, A., Ramel, C. and Wachtmeister, C. A. The mutagenicity of vinyl chloride after metabolic activation, Ambio 1974, 3, 194. 4. Huberman, E., Bartsch, H. and Sachs, L. Mutation induction in Chinese hamster V79 cells by two vinyl chloride metabolites, chloroethylene oxide and 2-chloroacetaldehyde; Int. J. Cancer,- 1975, 16, 639`. 5. Ducatman, A., Hirschhorn, K. and Selikoff, I. J. Vinyl chloride exposure and human chromosome aberrations. Mutation Res, 1975, 31, 163. 6. Funes-Cravioto, F., Lambert, 8., tindsten, J. et al. Chromosome aberrations in workers exposed to vinyl chloride, Lancet 1975, i, 459. AP00007420 -/* -.7, Purchase, I.F.H., Richardson, C.R. and Anderson, 0. Chromosomal and dominant lethal effects of vinyl chloride, Lancet 1975, ii, 410. B. Hillestad, L. $nd Thiis-Evensen, E. Preliminary report on the medical examination of 288 employees at the PVC plant, Norsk Hydro a. s., Porsgrunn Fabrikker. Unpublished manuscript. 9.NIEHS Conference on Public Health Implications of Components of Plastics Manufacture, Pinehurst, North Carolina, July* 1974. Selikoff, I.J. Statement during discussion. 10. Infante, P.F, Oncogenic and mutagenic risks in communities with poly vinyl chloride production facilities, Ann. N.Y. Acad. Sci, In press. 11. Shapiro, $., Jones, E.W. and Densen, P.M. A life table of pregnancy terminations and correlates of fetal loss, Millbank Quarterly, 1962, 40, 7. ]2. Mantel, N. and Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease, J. Natl. Cancer Inst, 22: 719-748, 1959. 13. United States Environmental Protection Agency, Sampling and analysis of select toxic substances, Task III, Vinyl Chloride. Contract No. 60-01-2646, January 20, 1976. TABLE I MEAN PATERNAL AGE, NUMBER OF PREGNANCIES AND FETAL DEATH RATES ACCORDING TO HUSBAND'S VC EXPOSURE "CONTROL$"+ PRIMARY VCM EXPOSURE1 PRIOR TO HUSBAND'S EXPOSURE NUMBER OF FAMILIES MEAN PATERNAL AGE AT CONCEPTION (YEARS) NUMBER OF FETAL DEATHS AMONG WIVES NUMBER OF PREGNANCIES AGE-ADJUSTED FETAL DEATHS/100 PREG.0 95 23.0 11 159 6.9 . . 70 26.4 15 , 148 6.1 - SUBSEQUENT TO HUSBAND'S EXPOSURE NUMBER OF FAMILIES MEAN PATERNAL AGE AT CONCEPTION (YEARS) -NUMBER OF FETAL DEATHS AMONG WIVES NUMBER OF PREGNANCIES AGE-ADJUSTED FETAL DEATHS/100 PREG.0 113 30.4 24 273 8.8 62 30.2 23 139 15.8* _-+ RUBBER AND PVC FABRICATION WORKERS. 1 VC POLYMERIZATION WORKERS. 0 RATES AGE-ADJUSTED TO "CONTROL" GROUP PATERNAL AGE DISTRIBUTION. * SUBSEQUENT TO HUSBAND'S EXPOSURE, THE FREQUENCY OF FETAL DEATHS AMONG WIVES WAS ' SIGNIFICANTLY GREATER IN THE PRIMARY VCM EXPOSURE GROUP AS COMPARED TO THE "CON TROLS" (PcO.05) OR TO THE FREQUENCY IN THE STUDY GROUP PRIOR TO HUSBAND'S EXPOSURE (P<0.02) BY AGE-ADJUSTED CIII-SQUARE TESTING.12 AP0bb07422 TABLE I! MEAN PATERNAL AGE, NUMBER OF PREGNANCIES AND FETAL DEATH RATES ACCORDING TO HUSBAND'S VC EXPOSURE EXCLUDING PREGNANCIES OF WOMEN WITH > 3 FETAL DEATHS MCONTROLS'l+ PRIMARY VCM EXPOSURE11 PRIOR TO HUSBAND'S EXPOSURE MEAN PATERNAL AGE AT CONCEPTION (YEARS) NUMBER OF FETAL DEATHS AMONG WIVES NUMBER OF PREGNANCIES AGE-ADJUSTED FETAL DEATHS/100 PREG.0 23.0 26.3 , 11 9 159 141 6,9 SUBSEQUENT TO HUSBAND'S EXPOSURE 3.1 MEAN PATERNAL AGE AT CONCEPTION (YEARS) HUMBER OF FETAL DEATHS AMONG WIVES NUMBER OF PREGNANCIES AGE-ADJUSTED FETAL DEATHS/100 PREG.0 30.2 18 265 6.8 30.8 14 120 10.8 * RUBBER AND PVC FABRICATION WORKERS. 1 VC POLYMERIZATION WORKERS. 0 RATES AGE-ADJUSTED TO "CONTROL" PATERNAL AGE DISTRIBUTION. AP00007423 1. The original "fetal wastage" data which resulted from the Pottstown NIOSH/URW/UNC/FPC quadripartite agreement was first disclosed in a May, 1975 meeting in Akron. 2. The "data" was not considered at that time to be statistically significant. Therefore, did not become an issue. 3. The basic data itself was developed via the initial "personnel questionnaire" which was administered to all our clockcard employees in October, 1974. 4. Dr. Infante Joined NIOSH In August of 1975 and felt he was poorly "briefed" as to the quadripartite relationship. 5. Dr. Infante felt, and still does obviously, that the "fetal wastage" data while not conclusive definitely does require publication if in fact the proper disclaimers were present-that is, the limitations of this information. 6. Nobody could disagree that the information was significant enough to be reported in Lancet as long as again the limitations of the validity of the data were identified. Conclusion Further publicity dealing with the Pottstown study should involve the total quadripartite group and the "fetal wascage" data while being published will clearly identify the limitations and statistical reliability inherent in the data. The net conclusion should be that further studies Including greater numbers of workers is justified, but until this is accomplished the "fetal wastage" data from Pottstown cannot be considered absolute. AP00007424 / AP00007425