Document wD50QDRy5bgkGwOoJXO1kE32D

Risks to the Offspring from Parental Occupational Exposures Joanna F. Haas, MX)., and David Schottenfeld, M.D. Risks to the offspring of workers with occupational chemical exposures may derive from mutagenic, terato genic or carcinogenic effects of industrial agents to which the parents are exposed. Evidence for impaired pregnan cies and hazards to the offspring of working populations with chemical exposures is. hoive'/er, very limited. Perhaps the best documented example is increased spontaneous abortion rates in female operating room personnel who have first trimester exposure to waste anesthetic gases. Evi dence is reviewed for hazards to the offspring resulting from parental occupational exposure to vinyl chloride, benzene, chloroprene, rac/iation and petroleum-derived hydrocarbons. It is essential in investigating the roie of occupational factors that other environmental and behav ioral factors with major effects on pregnancy outcome be accounted for. These include smoking, alcohol, and drug exposures- An approach to surveillance for chromosomal abnormalities in offspring of occupationally exposed parents is outlined. Derived from the Creek word "repae," meaning a mar vel, prodigy or monster, the word "teratogenic" was used by 1857 to mean the "production of monstrous for mations or births."' The term has been refined to refer to the biological science dealing with "the causes, mecha nisms, and manifestations of developmental deviations of either structural or functional nature."4 An agent may act as a teratogen when administered in a number of ways, whether to the male or female before mating, to the female during pregnancy, or to the fetus directly.1 Agents in the environment may produce alterations in the ge nome. mutations, and bv that mechanism lead to abnor malities of development in the offspring Viral, drug or chemical agents acting through common pathways may produce indistinguishable results. TKe outcome of such mutations may theoretically be fetal defects or predis- FiOfn Cnw*>ll Ijimt-miy ,tl Collt'ip* .'Oli I Mti.ift Keltr'intf C**KPT Dux 60 IJ75 S<vl A..' Ni-V. >ork NSliKUl Supported ui |>jr( bv J tontMCl ~ ilb itv- Ami-rrt.in IVlrnli-UT' In'tituM? position to neoplasia. Agents which alter the rate of growth of the fetus or are lethal to the fetus without pro ducing specific anatomic or functional anomalies are bet ter termed developmental toxins than teratogens. Cancer in the offspring of individuals exposed to a car cinogen may theoretically be the result of any of three types of exposure: prezygotic, by alteration of parental germ cells; transplacental, by passage of carcinogenic substances across the placental barrier; or postnatal, by contamination of the environment with carcinogenic sub stances, primarily dirough ingestion [including substances excreted in human breast milk) and through inhalation. Evidence for risks to the offspring of humans occupa tionally exposed to potentially hazardous substances is reviewed in the present work. The term trans-generational carcinogenesis is used to describe the occurrence of cancers In the offspring which can be attributed to paren tal exposures. This term is proposed to encompass not on ly the established process of transplacental carcino genesis. by which a substance administered to the mother during pregnancy results in cancer in the offspring, but also the controversial issue of preconception alterations in genetic matter resulting in increased teratogenic or cancer risk in the offspring. The latter effect could theo retically result from each of three distinct mechanisms: chromosome breakage, point mutation, or abnormalities in gametogenesrs or fertilization. Mutagenic and Teratogenic Characteristics of an Agent and Trans-Cenerational Carcinogenesis Mutagenesis, teratoyenesis and carcinogenesis are re lated phenomena, but the nature of their relationship is complex and occasionally controversial It has been argued that the "same chemical that causes abortion in the early stages nuv produce malformations during organ development and neoplasia when exposed later in preg nancy. Therefore, screening for transplacental hazards should include, whenever possible, the entire range of fetal response, including cancers that may develop some time after birth Teratogenic, mutagenic and carcino genic activities jre all demonstrable for a number of com- Journal ot Occupational Medicme/Voi 21, No. 9/September 1979 607 s AP0bdf64f2 pounds, but transplacental carcinogenic potential has rarely been demonstrated (or known teratogens and mutnyens. Teratogenic effects may reflect a variety of ac tions mvolviny the mother, the placenta or the feto-pla* cental unit These effects can be mdtrec t and may not in volve immediate action of the agent on the taryet fetal tissue.1 Transplacental carcinogens may act directly on the fetal tissues which are inherently more vulnerable be cause of the high rate of cell division, high proportion of undifferentiated cells and immaturity of immunosurveillance mechanisms. To appreciate potential danger from an environmental exposure to offspring of the exposed organism, the out come of all exposed pregnancies should be considered. Early fetal wastage commonly results from abnormal fetal development. At the other extreme, transpiacentaliy-induced tumors hardly ever appear in rodent species until the animal reaches maturity. In the only docu mented example of chemical transplacental carcino genesis in humans, vaginal adenocarcinoma following diethylstilbestrol (DES) exposure, the tumor occurs decades following exposure. Thus, since transplacentally-induced tumors, unlike malformations, are rarely present at birth, one must also observe the offspring into adulthood to see the full spectrum of resulting tumors. Environmental Threats to Pregnancy Outcome Recognized threats to pregnancy outcome are not un commonly encountered in the environment and must be excluded when new problems are suspected. Threats are ' posed by biologic, chemical and physical agents, and may derive from medical therapeutic interventions, drug and substance abuse, and environmental or occupational exposures to chemical agents. A/coho/.--The most widespread documented threats to the fetus come not from the maternal physical environ ment but from the use of tobacco and alcohol during * pregnancy. Only recently has the risk of alcohol ingestion in pregnancy been evaluated and the concept of the fetal alcohol syndrome refined.' Of infants born to recognized chronic alcoholic mothers, 83.3% had birth weights under the tenth percentile, compared with 2.3% in a compara ble non-alcoholic population.1 In addition to intrauterine growth retardation, the infants had retarded post-natal growth and intellectual development. A characteristic facies, with short palpebral fissures, hypoplastic philtrum, thin vermilion line of the upper lip and retrognathia, has also been described. in addition to these features of the fetal alcohol syn drome, congenital malformations of various types occur with excess frequency. Recognition of an associated in crease in the occurrence of congenital malformations ironically reemphasizes ancient observations and ad monitions against alcohol use during pregnancy* The ad verse effects on the fetus of maternal alcohol abuse dur ing pregnancy were further quantified by Ouellette et al,1 who classified women at the first prenatal visit into four categories according to alcohol consumption and in dependently evaluated pregnancy outcome. Compared to those born to abstinent or moderate drinkers, infants born to heavy drinkers had twice the risk of having an ab normality at birth. The frequency of congenital abnormal ities in the offspring of heavy drinkers was extremely high--32% when minor abnormalities were included. 17% if only major anomalies wore considered. Multiple abnormalities wore present in 20% of the offspring of heavy alcohol users. Major, minor and multiple abnor malities occurred significantly less often among abstinent or moderate drinkers. Animal models, including chicks. rats and guinea pigs, have been developed for evaluating the effects of ethanol alone on offspring, and support the view that ethanol itself is a harmful agent, and that its teratogenic potential is common to several species.M Smoking. --Another factor influencing pregnancy out come. maternal smoking habits, should be addressed in efforts to tie environmental exposures of the parents to the survival and integrity of the fetus. Kline et alu suggest that the odds of spontaneous abortion among women who smoke are 1.8 times those of nonsmokers. This association remains statistically significant after maternal age, and number and outcome of previous pregnancies are taken into account. The manner in which smoking affects fetal survival is controversial. Smoking results in lowered birth weight, which may or may not be related to the increased fre quency of spontaneous abortion.1114 Lowered birth weight may result from impaired maternal nutrition or fetal anoxia, neither of which produces an excess of chromosomal abnormalities in the conceptu*. Alternate explanations for an association between smoking and spontaneous abortion have been proposed. Since spon taneous abortion serves as a means of selectively termi nating abnormal conceptions and since 95% of abnormal pregnancies are believed to terminate this way, an associ ation between an environmental factor and increased spontaneous abortion should always evoke suspicion of a teratogenic phenomenon.'* Smoking increases the risk of spontaneous abortions by ? factor of 1.8, yet the percent age of abortuses which are chromosomally abnormal is dose to that expected. The absolute risk of a chromosomally abnormal fetus appears, therefore, to be higher in smoking mothers. The relationship of karyotypic abnormalities in spon taneously aborted products of conception to maternal smoking habits is complicated by variation in the propor tion of chromosomally abnormal fetuses with increasing maternal age and by the fact that a large proportion of smokers are younger women.14 An increase in the rate of chromosomally abnormal conceptions might be masked in a proportionate ratio analysis if there was also an in creased loss of conceptions without demonstrable cyto genetic abnormalities. Evidence for an increase in congenital malformations in children of smoking mothers is limited and conflicting.. In a cohort of births occurring in the first week of March, 1958, in England. Scotland and Wales, Fredrick and col leagues11 identified a 60% increased risk of congenital heart disease among children of women who had smoked at least one cigarette per day after the fourth month of pregnancy (7.3 vs. 4.7 cases per 1000 live births). This ef fect remained statistically significant after adjustment for maternal age, parity and social class. An investigation of congenital defects of all systems registered in South Wales from 1964 to 1966 which took into account mater nal age. parity, social class, area of residence and date of delivery did not associate maternal smoking habits with 608 Risks to Offspring from Parental Occupational Exposures/Haas and Schottenfeld { i i AP000I0413 congenital malformations in any system 11 It is possible that moderate increases in relative risk might have gone undetected Analysis of data from a mailed survey of a large num ber of professional women in medicine identified a rela tive risk of up to 1.7 for spontaneous abortion and a risk of congenital abnormalities of up to 2.3 in heavy smokers after the effects of age, parity and exposure to anesthetic gases were considered. Drug Exposure.--In uteroexposure to diethylstilbestrol (DE51 with the subsequent development of vaginal adenocarcinoma, is the prototype for transplacental on cogenesis in humans Appreciation of the causal role played by in utero exposure to OES followed hard upon the report of seven cases of the hithertofore exceedingly rare tumor, adenocarcinoma Of the vagina, presenting in young individuals, 14 to 22 years of age.**** The syndrome appears to involve not only cases of vaginal adenocar cinoma, but a spectrum of abnormalities of the vagina and cervix. Only when exposure to DES occurred during the first four months of gestation were neoplasms op ab normalities observed. The OES vaginal adenosis-adenocarcinoma relation ship is the only documented example in humans of cancer in the offspring attributable to parental environ mental chemical exposure. The therapeutic agent was given in a high dose, commonly more than 10 grams in the first half of pregnancy. DES, a synthetic nonsteroidal estrogen analogue, was likely to have a direct effect on the development of the target tissue at a crucial point in embryogenesis. Since the risk to the offspring appears limited to exposures which occur during the first four months of gestation, direct exposure of the fetus is likely to be essential to die pathogenic mechanism. The long latent period, with exposure in utero and emergence of clinical sequelae in adolescence, probably reflects the im portance of pubertal endogenous estrogens as promoting factors, and is a reminder of the need for an extended period of observation following suspect trans-generationai carcinogenic exposures. The association between DES and vaginal adenocarcinomas, as important as it is, does not serve as a model for preconception parental oc cupational exposures and trans-generationaI carcinogen esis. Teratogenic effects of a multiplicity of drugs are now documented or suspected and these will not be discussed here further except to reiterate the need to remove the, potentially confounding effects of such agents in investi gations of other possible causes of impaired fetal devel opment*4 C<ven the current status of our understanding it is essential that in the search for exogenous causes of teratogenesis and abnormal pregnancy outcomes, the poten tial confounding impacts of maternal smoking, drinking, and medication intake be taken into account. Radiation. -- If preconception radiation exposure in creases cancer risk in the offspring, it would heighten con cern over other agents which produce chromosomal dam age. Chromosomal aberrations attributed to vinyl chlo ride and benzene exposure, for example, are reminiscent of those produced by radiation. While the genetic consequences of irradiation from the atomic bombings might be expected to produce some lethal mutations in the offspring of survivors, this effect has been difficult to demonstrate. Cohort studios of off spring of survivors classified by radiation exposure level did not show excess mortality in the children of the high exposure group Neither wore excess congenital malfor mations. increased infant mortality, nor impaired survival during the first ten years of life detected, regardless of ex posure level to either parent. Thus, although animal ex perience strongly suggests that such effects should be manifest in offspring of individuals exposed to ionizing ir radiation, studies of Japanese atomic bomb survivors have rot demonstrated measurable effects.*4 No substantial increase in leukemia risk has been de tected among offspring of survivors. Analyses having a 90% chance of detecting a four-fold increase in risk of leukemia among children of heavily exposed survivors were negative. Neither did ^gMt-onset of observed leukemia cases nor type of leukemia in offspring differ by level of parental radiation exposure. Despite the docu mented persistence of chromosomal aberrations in the somatic cells of adults exposed to the atomic bomb, nb measurable impact on mortality, congenital malforma tions or leukemogenesis has been detected in their off spring,** In addition to radiation exposures related to tire atomic bombings, diagnostic and therapeutic medical radiation of the parents has been investigated to assess risks to the offspring. The magnitude of leukemia risk associated with previous radiation was estimated, after adjustment for maternal age and pregnancy history, to be 1.73 times that of mothers who had not been x-rayed. Despite the sugges tion of greater risk in women with higher x-ray exposure, no clear-cut dose-response gradient was demon; rated. The relative risk of leukemia in the child associated with preconception diagnostic radiation of the father (131) was not statistically different from unity. When both mother and father had histories of preconception diag nostic x-rays, the order of magnitude of the relative risk, 1.49, was about the same as that for children whose mothers alone had received radiation." Exposure to medical radiation has been widespread. By the early 1960's, approximately 35% of a group of mothers of healthy children reported having received diagnostic radiation prior to conceiving. Similarly, about 22% of fathers of the same children reported having had some sort of diagnostic radiation at some time prior to the child's conception. Seif-reporting considerably under estimates the extent of x-ray exposures.** The tendency to substantially underreport x-ray exposure points up the dif ficulty of excluding differences in prior radiation expo sure as a basis for observed differences in chromosomal aberrations. Neither is it reasonable to automatically pre sume that medical radiation exposures have been equally present in the study and comparison groups, especially if these groups have not been matched by age or calendar period of observations. Occupational Exposures and Pregnancy Outcome Vinyl Chloride. --Chromosomal abnormalities may oc cur more often than expected in persons exposed to vinyl chloride, especially following intense exposures of long duration. The import of such abnormalities for reproduc tive outcome remains ill-defined. Chromosomal aberrations were reported in 1975 in Journal ot Occupational Medicine/Vol. 21, No. 9/September 1979 609 J APOOOf0414 hmw iSfew ItofcbL Swedish vinyl chloride workers. Abnormalities appeared in cells drawn from seven males with occupational expo sure histories of nine to 29 years (mean 1b byears) at vinyl chloride concentrations which had declined to 20-30 ppm by 1974." The group exposed to vinyl chloride had aber rations in a total of 9.52% of all cells, comparcdtol.94% for cells of three unexposed controls. Differences in the frequency of chromatid and isochromatid breaks ac counted for most of the disparity. Considerable variation was exhibited, with cells considered abnormal ranging from 1.5% to 16% in the exposed workers. There was no apparent relationship between duration of exposure to vinyl chloride and the proportion of cells which were ab normal. Age, radiation exposure or other environmental factors were not evaluated, nor was it clear on what basis individuals had been selected for study. In New York State, chromosomal aberrations were re ported in somatic cells of 11 men who had worked in a polyvinyl chloride polymerization plant and who were be lieved to have experienced intense intermittentexposures to vinyl chloride in concentrations of over 500 ppm, as well as chronic, but unquantitated exposure forfour to 20 years (mean, 15 years). Control samples were drawn from four males in the same factory who were not known to have had vinyl chloride exposure, and from six males from outside the factory. Complex chromosomal aberra tions (rings, dicentrics, fragments) occurred significantly more frequently in the exposed than in the control group, a result which was properly Interpreted with caution. The authors point out the absence of age-matched controls and the substantial age difference between study group and controls. The frequency of chromosome breaks and gaps was unexpectedly high in both control and study groups iU No relationship could be defined between dose or duration of exposure and frequency of chromosomal aberrations. Investigators reporting from the United Kingdom studied 56 men who had had chronic exposure to vinyl chloride monomer in the course of manufacturing poly vinyl chloride and compared them with 24 unexposed in dividuals." Vinyl chloride exposure of men employed in its manufacture could not be easily quantitated. Individ uals with exposures to radiation or with recent viral infec tions or prolonged drug treatment were excluded. Samples were coded and read blindly. A higher propor tion of cells with chromosomal aberrations, the majority of which were breakages, was found in vinyl chloride-ex- posed workers than in controls. Unstable and stable chromosomal aberrations and breaks were all signifi cantly more common in cells from exposed workers. Not all investigators have identified such changes. No differences were found in frequency of chromosomal aberrations between a group of 209 employees of a vinyl chloride plant (occupational exposures averaging 40.3 months) and a group of 295 individuals undergoing pre employment physicals11 No relationship was established between duration of vinyl chloride exposure and degree of chromosomal damage. The absence of blind evalu ation in this study, as well as inclusion of individuals with minimal exposures in the exposed group, makes interpre tation difficult. This difficulty is compounded by the sub stantial difference in mean age of study and control group members. Pregnancy outcome in the wives of men exposed to vinyl chloride monomer (VCM) has been said to be less favorable than th.it experienced by wives of a group of polymerization and polyvinyl chloride (PVC) fabrication workers.11 " One comparison group, the polymerization workers, was believed not to have been exposed to VCM, wheras PVC workers had low VCM exposure. Data on pregnancies and pregnancy outcomes in the wives were derived from interviews and questionnaires administered to male workers. Participation rates for the groups queried ranged from 62% to 77%. Fetal death was de fined as any known conception which did not result in a live birth and rates were adjusted by paternal age. Mater nal age was not known, but was presumed to correlate closely with paternal age. Analysis of, questionnaire re sponses suggested that the number ot fetal deaths per 100 conceptions was higher in the VCM-exposed group than in the comparison group. This difference was reported on ly far the period following vinyl chloride exposure. Ad justments removing women who were chronic aborters eliminated statistically significant differences. While die authors felt that these observations were likely to reflect a real difference in pregnancy outcome not attributable to either interviewer or patient recall bias, thexonclusions were based on indirect sources of information and could not take into account the multiplicity of maternal factors known to affect pregnancy outcome. The study design precluded documenting in even the crudest manner the validity of pregnancy histories. Without such adjustments i and validation, the inferences made by Infante and col-] leagues11 11 cannot be sustained and little light is shed on the possible association of abnormal pregnancy outcome with paternal occupational exposure to VCM. Studies of pregnancy outcome {t.e, spontaneous abor tion, late fetal death (stillbirth), low birth weight, neonatal death) in other settings have shown the profound and sub tle effects of confounding variables such as race, socioeconomic status, maternal age, birth order, parity, smoking and alcohol exposure during pregnancy, mater nal infections, and previous pregnancy outcomes. These effects may readily reverse the direction of toe relation ship between a suspect antecedent factor and the out come of pregnancy.1* Future efforts to document a rela tionship between impaired pregnancy outcome and occu pational exposures of fathers must validate information on pregnancies and take into 'account known con founding factors. Chforoprene. -- Structural similarities between vinyl chloride and chloroprene have raised questions about long-term hazards resulting from chloroprene exposure. Chloroprene is mutagenic In certain systems and possibly carcinogenic. The possibility that it has induced excessive miscarriages in the wives of male workers and led to chromosomal aberrations has been asserted but not well documented.1* Benzene -- Benzene also may cause chromosomal aberrations following heavy occupational exposures. Twenty males working in a factory in which benzene had been used as a solvent were studied for chromosomal aberrations. Members of this group had one to 20 years of benzene exposure; 14 were known to have previously been neutropenic. Chromosomal abnormalities were re ported in 2.5% of all cells from exposed workers, com- 610 Risks to Offspring from Parental Occupational Exposures/Haas and Schottanfeto l f AP00010415 pared to 1 0 to 1 4% for controls. Most of the excess was due to chromosomal aberrations of the unstable types In addition to the excess of abnormal cells in the exposed group, the number of unstable alterations per abnormal ceil was higher in the exposed group than in the controls.17 In a separate investigation, ten workers in an Italian rotogravure plant who had had sequential exposures, first to benzene and later to toluene and xylene, were studied. These workers had been subjected to concentrations of benzene ranging from 125 ppm to 532 ppm or higher. The maximal allowable concentration at the time of these ex posures had been 25 ppm. Another group of 24 workers had primarily toluene exposures except for trace contamination with xylene. These 34 workers were matched with healthy controls of similar age and sex, who had been drawn from the general population and who had no history of benzene or radiation exposure. A signifi cantly higher proportion of abnormal cells was found in the benzene-exposed individuals than in their matched controls, tn the group with toluene exposure, no such ex cess was present. When the benzene and toluene groups were compared to each other, an excess of chromosome changes was present in the benzene group. Most of the excess was attributable to unstable chromosomal altera- tions.,, These studies and others" support the impression that exposure to benzene, particularly exposures intense enough to result in acute toxicity, can be followed by a measurable excess of chromosomal aberrations which may persist for years. If similar effects occur in germ cells of exposed individuals, the consequences in fetal wastage, congenital anomalies and even neoplasms might be manifest in their progeny To date no excess of such abnormalities has been reported in offspring of benzeneexposed individuals. Anesthetic Cases. -- Occupational exposures of female operating room personnel to waste anesthetic gas es have been held responsible for decreased fertility, in creased rate of spontaneous abortion, low birth weight and possibly impaired development in the offspring. An excess of spontaneous abortions in wives of men pro fessionally exposed to anesthetic gases has been suggest ed but not confirmed. Among operating room nurses, 297% of pregnancies terminated with spontaneous abortion, compared to 8.8% among control nurses A similar excess of spon taneous abortion was observed for female physician anesthesiologists compared to female physicians in other specialties.49 Spontaneous abortions occurred two weeks earlier on the average among the operating room ex posure groups than among controls, at an average of eight rather than ten weeks of gestation. Another survey suggested that for female nurse-anesthetists who had worked during pregnancy, the frequency of birth defects in the offspring was 16.4% compared to 5.7% for pregnancies in which the mother had not worked.4' Studies from Finland and the United Kingdom also sug gested a deleterious effect on pregnancy outcome from maternal exposure to operating room environments. An increase in frequency of early spontaneous abortions, as well as low birth weight, has been reported for Finnish fe male operating room staff.4* Among female physicians in England and Wales, greater incidence of congenital de fects. lower birth weights and higher stillbirth rates, but not higher spontaneous abortion rates, were reported from pregnancies of women holding anesthesiology apliomtments than from those of other women physi cians.41 The effects of paternal exposure to anesthetic gases are uncertain. Congenital anomalies were reported to be increased by 25% in the offspring of male anesthesiolo gists compared to offspring of male members of the American Academy of Pediatrics, but no difference was reported for spontaneous abortion rates among wives of male operating room personnel compared to controls44 Questionnaires completed by 5119 married male physi cians in the United Kingdom suggested an increase in minor but not in major congenitaj.anomalies, and no dif ference in frequency of infertilHrT spontaneous abortion or cancer in the offspring of mile anesthesiologists com pared to control physicians/'.7^' Hydrocarbons. --'Two studies offer conflicting evi dence with respect to the risk of cancer in children -of men whose work might lead them to be exposed to petroleum-derived hydrocarbons. Fabia and Thuy4* re viewed death certificates in Quebec during 1965 to 1970 to identify children who had died from malignant disease while under five years of age. For 386 of 402 such children, birth certificates were also found in the Quebec population register. A control group of 772 children [two for each cancer death) was selected using the birth registration record preceding and following that of each case in the official files. This effectively matched for season, calendar period, and province of birth. Occupa tion of the father at the time of birth was taken from the birth certificate. An industrial hygienist independently grouped the fathers into three levels of probable exposure to petroleunvderived hydrocarbons. Occupation of the father was unknown for 30 cases and 56 controls. The dis tribution of occupation of the father at birth differed for cases and controls. Most of this difference was the result of an excess among cases of paternal occupations con sidered to be hydrocarbon-related. The relative odds of .cancer in the children of men holding hydrocarbon-re lated jobs at the time of the child's birth were 3.1, an in crease which was unlikely to have occurred by chance. Most of the excess in exposed occupations was account ed for by motor vehicle mechanics, machinists, miners and painters. When similar analyses were conducted by the type of cancer in the child, the excess of hydrocarbonrelated occupations prevailed for the following group ings: leukemia-lymphoma, nervous system malignancy, other tumors. Fathers of four of five cases of Letterer-Siwe disease were in the hydrocarbon-related work groups. No such excess was present for children with Wilms' tumor. The differences observed could not be attributed to dif ferences in parental age or in geographic residence at the time of birth. The investigation was based on deaths in children under five, and it is possible that social class bias may have been introduced in that fashion. If, of those with a childhood neoplasm, children of more affluent parents are more likely than children of poorer parents to survive beyond age five, they would not be included in the study group. This would lead to a higher proportion of children with parents of lower socioeconomic status in Journal of Occupational Medtcine/Vol. 21 .No. 9/Sepiember 1979 611 i j i i AP000I04I6 the cancer death group and would'bus the distribution of father's occupation. Moreover, it v*m not possibly to con firm that fathers in the socalled "ipo*ed" group did. in fact, have contact with hydrocarbon-derived chemicals. While not ideal, the death certificate probably is a valid source of diagnostic information far cancer deaths in young children. The cancer groupfagF employed in the analysis -- "leukemias and lyroph--nas," "nervous system" and "others" -- were quite broad and included many histopathologic entities. Occupational association was not restricted to specific entities within the broader categories. Because die epidemiologic features of the various histopathologic types of leukemias, lymphomas, and nervous system tumors are tfetinctive. a specific chemical exposure or class of exposures-, if assumed to be of causal significance, would more Ckely be linked with specific histopathologic as well as gsystem effects. A study with a similar design butdeferent findings was conducted in Finland.*7 Children under 15 years of age who developed cancer were identified from the Finnish Cancer Registry, 1959-1968. Of 1409 cancer cases so iden tified, the final series consisted of 652 pairs for whom birth records which included fath9*s occupation were available. Each case was matched wife * child whose birth date immediately preceded dial of the case and who was bom in the same maternity welfare district This procedure matched effectively by calendar period, season and domicile at the time of birth. Father's occupa tion was drawn not from birth registration records but from records of the free, nationwide antenatal care system in operation in Finland. Father's occupation was classified by likelihood of hydrocarbon exposure in a manner which was shown to be comparable with that employed in the study done in Quebec. No excess risk for hyduxarbon-exposed fathers was detected for any class of neoplasms either for children whose cancers occurred under five or under 15 years of age. ' -The two studies differed primarily in the source of in formation on father's occupation. For the Finnish study, that information was drawn from antenatal records com piled for the most part in the first trimester of gestation. This may be a better index of exposure at the time of-conception than information recorded at the time of birth in the birth certificate itself. Although a large number of pairs were discarded in Finland because father's occupa tion was not recorded, these came from a circumscribed calendar period. Since a matched pairs design was main tained throughout the analysts, removal of these cases should not influence the result. The Finnish study used in cident cancer cases and looked at age groups up to 15 years at the time of cancer diagnosis. The Quebec group identified only cancer deaths up to five years of age. Variation in terminology of occupational classification might also contribute to the differences, although efforts were made to establish their comparability. At present, the contradictory findings of the two studies are not readily reconciled. Surveillance of Spontaneous Abortions as a Strategy of Environmental Monitoring The relationship between mutagenic, teratogenic and carcinogenic effects in the offspring of persons exposed to noxious environmental agents is a complex one. Surveillance of spontaneous abortions may have a number of advantages as a prospective means of monitoring for such effects since defective conceptions are aborted selectively. As a result, studies of teratogenesis focusing on spontaneous abortions may be con siderably more efficient than those conducted in new borns. Because the frequency of abnormalities ts higher in spontaneous abortions, the sample size needed to demonstrate a change in risk is much smaller than that re quired for a parallel query addressed to defects recog nized at birth. The magnitude of this difference esn be dramatic, if chromosomal defects diagnosable on the ap pearance of the newborn are considered alone, the sam ple size required may be hundreds of times that required in an investigation examining prevalence of chromosomal anomalies in early abortion.*', In Sedition to sample size considerations, study of spontaneously aborted concep tions offers a lead time of at least six months over studies of live births. The abortion specimen can be studied with care and thoroughness, permitting detection of anomalies lethal to the fetus which might escape detection in studies of live births. The problem of power and sample size is only one of the issues which beleaguer investigators of associations between exposures to parents and outcomes of pregnan cy. Related factors are the timing of the exposure, mater nal or paternal, in relation to conception and/or gestation, and the specific measures of pregnancy outcome.** Pater nal exposures may act in two ways -- by contamination of the maternal environment resulting in secondary maternal exposures, or directly by affecting paternal ger minal tissue. Since spermatogenesis is a continuous pro cess, paternal exposures occurring shortly before concep tion are those requiring the most investigative attention. Cumulative or delayed effects are more likely to be of im portance in maternal exposures. By focusing on early pregnancy wastage, particularly if the frequency of chromosomal abnormalities in the aborted product of conceptions can be determined, the objectives of study are better focused and achieved with reduced sample size, and the confounding effects of the maternal in utero environmental factors are minimized. in conclusion, while the potential clearly exists for teratogenesis and trans-generational carcinogenesis in die off spring of workers exposed to mutagenic and carcinogenic agents, such effects have been difficult to demonstrate conclusively in humans. Future investigations must take into account a variety of environmental and behavioral factors which can affect fetal development H causal associations between occupational exposures and pregnancy outcome are -to be identified. Reference* 1 OED; The Compact Edition of the Oxford English Dictionary, Oxford. Oxford University Press. 1971, cites Oungiison Medical Lex icon, 1*5? 2 Wilson |C. Environment and Birth Defects. New York: Academic Press. 1973. 3 Staples RE. Definition of teratogenesis and teratogen, in Methods for Detection of Environmental Ajjenis that Produce Congenital De fects. T. H Shepard et al {fds.X Proceedings of theCuedaloupe Conterence Amsterdam- North Holland Publishing Company, 1975. 4 haumem IF. it : The susceptibility of the fetus and child to tluNTiKal pollutants Chemicals in human teratouenesis and trans placental carctftOKeneMS Pediatrics 53607-612.1974. 612 Risks to Offspring from Parental Occupational Exposures/Haas and Schottenteld i AP00010417 ma.m t 19 6/6t J9quid|d9S/6 'ON '13 `lOA/aupipsw iwonBdnwQ JO itujnof 9X61 '66C-UCI dojA9<3 ionw Aj -4p 8t)ijdt/jo pur uoi)3npoxli uciunq uo swjjj ;Quwtd jo sairwofl -*a t*3itAqd pur |*3i111943 *2 ums put 'I aui)* `M8 ou*qo4S 5* ZX6l 'OSC-SVt Kil /otuMpjdj / tuy ;tuuoiigom inwuAjojiAuo ui 10*04 :suowoqt snotutiuods jo 93ut)j)Ajns :jt > 'g ouiqojis *2 utMS 'f *ui)x 9* 9X61 *OK-WV O psjy ao$ A9y f J8 suoqednaso p*)*|*>uo<u*:>oipAq u* tjaqicj jo ftupdtjjoatp ui juur^ n odd*i put *i uauo|*s `i u*u*ui|n^H X* >161'00l-96;9t p*W ao$ aAiiy / 4? smMip )uru8!|*ui jo SuiAp uupRip jo ipjiq jo uiq It laqitj jo uoqedrwo qi Anqj. put ( tiqej 9* SX6 1 `608-iOt t JWur? 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'9X61 '09I>9X<) *31 j9jqO l WV *3,uj iu*u*ajd 01 pj>siwujpe )oqoj|t |Aqi9 jo naajj* 3iu8oifm^ g( X3(uorn 'u Libl MS-935 X63 P*W I (8u? N Aourutajd Buunp asnq* foq03[t (pujaitui jo 8u;idijjo uo <139j J9 9<2>Apy -3 J9UI9M pu* `Nd utuuoa `3H soa 'wa auaitano 01 CX61 1001*6663 l*9U*7 A3w*jui Ap* w auroip -uA |oqo3|* |ri#| uqi jo uo>nu7I039a 'MO qiiuis pu* in sauof '6 3X61 '691-X91X61 ?3S PF3VANUU* sjaqiou* 3i)oq03|* jo tuutHjjo aqi N3P"*Hltn 9 9X61 X90K901 863 PW I/UJ N aujOipuAs |ol(03|t |P1( 9i(| MO muS P* MS uau*(3 X 1X61 VW1I * AO/0JPi9J uiuurfn{Mii3jP3jiOiuj.iq3|(>iu.<)rpKuti< inMvAi.tAouv yv| *>8 9 `*>61 ifi it faqftVj q3iy >iqsuonn''i (qiikOd jo A|Jni* y 4iy*u.Ho.iLKj.viv.iu.iVou*Mj j uijo^ pui1 vl oiorjiQ S j R E L f i </ E O v RESEARCH St DEVELOPMENT AUG 2 1977 W. M. SMITH A CR0S5-SECTICNAL EPIDEMIOLOGIC SURVEY OF VINYL CHLORIDE WORKCRS \/ Richard J. Waxweiler, M.S.I.E. Henry Falk, K.D., M.P.H.* Anthony McHichael, H.O., Ph.D'.** Joseph S. Mallov, H.O. A. Scott Grivas, M.D.* William T. Stringer, M.S. * Cancer and Birth Defects Division, Bureau of Epidemiology, Center for Disease Control, Atlanta, Georgia ** Occupational Health Studies Group, University of North Carolina, Chapel Hill, North Carolina DEPARTMENT OF HEALTH, EDUCATION AND WELFARE Public Health Service Center for Disease Control National Institute for Occupational Safety and Health Division of Surveillance, Hazard Evaluations and Field Studies Cincinnati, Ohio April 1977 APOOOf0419 DISCLAIMER Mention of company name or product does not constitute endorsement by the National Institute for Occupational Safety and Health. 11 r APOOOI0420 ABSTRACT A considerable number .of studies have associated occupational vinyl chloride monomer (VCM) exposure wHh a variety of adverse health effects. The extent to which VCM induces these abnormalities in the workforce is not well defined. This cross-sectional medical survey of 433 predominantly white male employees, divided into four VCM exposure groups (never, light, heavy, former), deter mined the prevalence of illnesses and abnormalities based on data gathered by, interview, medical examination, blood and pulmonary function tests, liver scans, and hand and chest x-rays. Age-adjusted analyses Indicated that hepatomegaly, central nervous system symptoms, diastolic hypertension and spouses' fetal wastage (the latter two statistically significant at p <05) were more prevalent among past or present VCM exposed workers than among controls. Although VCM-relatcd respiratory system problems, acroosteolysis. Raynaud's phenomenon, and 'chromosome aberrations have been identified by other investigators, no excessive prevalence of these toxic effects was found in this population compared with industrial worker controls. Itl apooo10421 ZZMMOOOdV r A .......................................................... saaipuaddy 81 .........................................*.......................................................................... 141 gj ................................................. .................................... *,.................... soouajaiaa g .............................................. uotssftssio Z ................................................................................................................... spoman \ .............................................................................. ,------ *................ uoH3nP*J*til ja ..................... siudia&pa|MOinpY HI ...........................................*.................................................................. SIN31NOD I b%* r ACKNOWLEDGEMENT The authors would like to thank Dr. Joseph Wagoner, Ms. Laura Andersen, and Or. Peter Infante from the National Institute for Occupational Safety and Health, Dr. John Gamble and Or. Robert Spirtas, from the Occupational Health Studies Group at the University of North Carolina, and Or. Clark Heath from the Center for Disease Control, all of whom contributed to the planning, execution, and analysis of this project. Ve also acknowledge and wish to express our appreciation for the coopera tion and assistance of Local 336 of the United Rubber, Cork, Linoleum, and Plastics Workers of America and the Firestone Chemical Company. i i AP000I0423 INTRODUCTION The causal relationship between occupational exposure to vinyl chloride monomer (VCM) vapor and`the development of liver angiosarcoma is now well established. Following the first cluster of VCM-induced human cases of liver angiosarcoma discovered by Creech and Johnson (1), there have been a number of corroborative findings including animal bioassay tests (2*3), additional case reports of VCK-induecd liver angiosarcoma (4), and formal epidemiologic studies (5-7). Available evidence also indicates that VCM can induce non-malignant liver alterations (9-15), portal fibrosis in particular, long before the development of clinically manifest liver malignancy. Furtherfore, patho physiologic effects do not appear to be limited to the liver. For example, experimental animal research (2,18), as well as clinical (17) and epidemio logic (5,7,8,16,19) studies of workers exposed to VCM and polyvinyl chloride (PVC) plastic dust, indicate a toxic effect on the respiratory system. Some of these same studies have also found increased risk of hematopoietic and central nervous system tumors. Microbial test system studies (20-22) and cytogenetic studies of VCM-exposed workers (23-26) indicate possible genetic effects. The anesthetic properties of vinyl chloride monomer (14) have been implicated as causing numerous central nervous system symptoms such as head aches, dizziness, and fainting in exposed workers (27). The extent to. which VCM induces clinically detectable abnormalities among workers occupationally exposed has not yet been well defined. Consequently, in order to determine the range of health affects associated with VCM, the National Institute for Occupational Safety and Health (NIOSH) and the Bureau of Epidemiology of the Center for Disease Control (CDC), in collaboration with the Occupational Health Studies Group (OHSG) of the University of North Carolina, conducted a cross-sect'ional medical survey at a chemical plant in Pottstown, Pennsylvania, which has a PVC polymerization operation, a PVC fabrication operation, and a rubber tire production operation. The specific objectives of the survey wore: 1) To compare the prevalence of liver abnor malities and liver disease in VCM-exposed workers and appropriately selected .control workers at the plant; 2) To identify those tests best suited for detection of other illnesses and abnormalities in these groups of workers. 1 i J APOOOI0424 METHODS The plant selected is one of the older PVC polymerization plants in the United States, having operation continuously since 1948. The plant thus provided a faborable research opportunity, since sufficient time had elapsed for the appearance of VCM-induced chronic effects. In addition, the plant provided the unique situation where a PVC polymerization ("chemical'') plant, a PVC fabrication ("plastics") plant, and a non-VCM plant (a rubber tire operation) were located next to each other within one large corporate facility, although the individual plants were physically distinct from one another. Further, selection of non-VCM-exposed controls was facilitated because the University of North Carolina had conducted prior industrial hygiene surveys within these plants as part of an ongoing joint company-union research project. *$ Shown in Table 1 are the four groups of hourly (production) employees who were requested to participate in the study. The first three groups arc ordered by current VCM exposure. The first group consisted of a sample of the 2400, rubber workers in the plant who were not exposed to VCM. These workers were age-frequency matched to the VCM*cxposcd chemical workers, and were chosen from departments 'in the plant identified as having the least exposure to other potentially confounding toxins such as solvents, dusts, and fumes; The second group, the plastics workers, included everyone currently working in the PVC fabrication operation who had never worked in the chemical polymeri zation operation. Since these men were working with solid PVC plastic, their 8 hour time v/eighted average exposure to VCM was probably below 10 ppm prior to this survey. However, for the third group listed, the chemical workers, the VCM exposure before 1974 was considered to be very much higher than in the plastics area. Every employee working In the chemical plant at the time of this survey was included in this group. All former chemical workers working elsewhere In the plant made up the fourth group surveyed. Participa tion rates of those requested to participate varied from a low of S2X in the rubber workers to a high of 772 in the chemical workers. Using these four groups, two etiologic models were designed for classi fying subjects in the analysis of the relationship of health status to VCM exposure. The first, the Acute Exposure Model, reflects the abovementioned sampling design, and is based on the subject's job at the time of participa tion tn this health survey. The former chemical workers were treated as a separate group for this analysis, regardless of their current jobs, since under an assumption of acute exposure etiology, their past VCM exposures, 2 r APOOO10425 however -brief. mpht bo associated wii/i some residual health effects. A second ctloloinc model, a Cumulative Exposure Model, based on each worker** entire work history at the plant, afforded no meaningful comparisons because of the extremely high correlation between aye and dose, which pre cluded any legitimate a9C adjustment. Data presented here are therefore confined to the cross-sectional ("Acute exposure'') comparisons. The health testing program, as outlined in Appendix A, consisted of 0 comprehensive ?10 item questionnaire, including the Rose cardiovascular and British Medical Research Council respiratory symptom (BMRC) questions, administered to participants by trained medical Interviewers, a thorough physical examination performed by HI0SI1 and CDC physicians, pulmonary function tests, chest x-rays, and a series of laboratory tests including a complete blood count, platelet count, urinalysis, liver function, serum protein electrophoresis, hepatitis antigen, and sputum cytology. In addition, all study subjects who had been chemical workers for at least ten years underwent liver-spleen scans with lead markers and hand x-rays performed at a nearby hospital. Cytogenetic studies were carried out on a very small sample of workers (Appendix B) (39). Participants from all three shifts were tested during the shift they worked during the month of October* 1974, All physicians, interviewers, and technicians were blind to the occupational status of each worker; occupation al status was determined independently, by use of the company's personnel records. Individual consent was obtained from each participating worker. Results of testing were released only to the participant himself and to the physiclan(s) designated by each worker. Detailed medical reports on all of the questionnaire and physical examination findings, as well as most of the laboratory findings, were sent to the designated phsyicians within two months of. the examination. Summary letters of these findings were sent to all the workers at the same time. Meetings were held with study partici pants before, during, and after the medical examination to discuss procedures as well as findings. The United Rubber, Cork, Linoleum and Plastics Workers of America and the local union (URW Local #336) Health and Safety Committee at the Pottstown plant provided considerable support in obtaining participation of workers In the study. Almost all examination were performed during working hours, and the plant personnel department and local union safety representatives assisted in the examination scheduling. Similarity of the groups was measured in terms of age, race, sex, alcohol consumption, and cigarette smoking. All of the study subjects were tale except for two plastics workers. Eleven (3K) of the study subjects were black and were distributed farily evenly over the four occupational groups. All sex-race groups were included in the analysis. The age distributions of the current chemical workers and rubber worker controls 3 f1 4 AP00010426 were ^similar since they h.ul been grmjp'-iikUeltrd on <if(e Initially. However, when ell four occupational groups wore considered, the aio distributions were signiflcortLly different (Table ?). Therefore, aye adjustment of all test results was carried out using the direct method with the aye distri bution of the entire 411 persons as the standard. Analysis of daily alcohol consumption based on current drinking habits showed that the four groups were nearly identical; thus no adjustment for alcohol consumption was,deemed necessary (Table 3). Although there were no statistically significant differences in smoking habits, the distribu tions did vary sufficiently for pulmonary function testing and respiratory symptom results to be smoking adjusted. Liver Only one person, a chemical worker, gave a history of cirrhosis. Approximately 32 of those interviewed in each occupational group gave a positive history of gall bladder disease, whereas hepatitis (Table 4) was slightly more prevalent among persons who had been exposed to vinyl chloride. The four liver function tests used - serum glutamic oxaloacetic trans aminase (SGOT), total bilirubin, lactic dehydrogenase (IDH), and alkaline phosphatase - were analyzed by comparison of mean value, and by prevalence and severity of abnormals (Table 4). In the total study population reported herein, 212 had an abnormal SGOT, S% an abnormal total bilirubin, 42 an abnormal LDH, and 132 an abnormal alkaline phosphatase. For the most part, similar abnormality prevalences were found In each of the occupational groups, the major exception being abnormal LDH levels in 11.62 of the former chemical workers. Neither the overall mean values nor distribution of the abnormals by severity differed notably among the occupational groups. Two methods were employed to detect hepatomegaly: physical examination (measured by both palpation and percussion) and livor scan. The liver scan procedure, described in Appendix A, consisted of six pictures with lead markers to aid in liver size determination. However, when the liver size measurements from the scans were tested for inter-reader variation, it was found that reader number one averaged 3 centimeters in height and 2.4 centimeters in width greater than reader number two. These differences were statistically significant ( p < .001) in a matched pairs t-test. Standardi zation of measuring techniques among the readers was therefore deemed insufficient for their use in the analysis of hepatomegaly. Hepatomegaly as measured by palpation or percussion is somewhat subjec tive. To determine whether one physician might have been overzealous in diagnosing hepatomegaly, thus possibly biasing the results, prevalence of palpated hepatomegaly by individual physician was calculated. Ho statis tically significant difference was observed. Of tho two measurements on physical examination, palpation (as defined by palpable liver) appeared to be the more sensitive, diagnosing 112 of the total population as having r 1 hepatomegaly compared with CX by |jerc>iision {> 11 centimeters) (Table 5). The good consistency between the two techniques for detunninimj hepatomegaly ms demonstrated by agreement in over 902 of the cases diagnosed by percussion. One of the more interesting findings in this study was the Relationship Detween Hepatomegaly and VCM exposure.. Current chemical workers had almost twice the age-adjusted prevalence (13.22S) of palpated hepatomegaly as did rubber workers (7.12) and plastics workers (7.32). A gradient in tho same direction from chemical workers to plastics workers and rubber workers also existed \Wien hepatomegaly was diagnosed by percussion alone* (6.22, 5.02, 3.42), and by both percussfon and palpation (4.C2, 3.52, 0.02). However, no differences wore found between current chemical workers in high, medium, and low exposure jobs (not shown). Two of the eleven people with hepatomegaly by percussion and palpation were heavy drinkers and one of these two also had a history of hepatitis. To Investigate the occurrence of liver problems evidenced by combinations of abnormalities, cases wore analyzed that had two or more of the four liver function tests abnormal and hepatomegaly by both percussion and palpation. All four cases that met these criteria had been exposed to VCM. One was a former chemical worker and the other three were current chemical workers. All Of them had an elevated SGOT. Of the 123 liver scans performed on long term VCM-exposed workers (a few salaried and hourly employees not in the four major occupational groups were included in this number), 94 were read as normal by all three nuclear medicine specialists independently. Of the 29 scans read as abnormal, only four were read as abnormal by two reviewers and none were read as'abnormal by all three reviewers. One reviewer read a total of two scans as abnormal, and the other two read 13 and 18 scans, respectively, as abnormal (Table 6). The four cases read as abnormal by two readers included 1) a 33 year old salaried process control engineer (not a member of the four occupational groups) whose LDH was elevated, 2) two chemical workers who worked as polymer reactor cleaners (the job associated with the highest VCM exposure In the chemical plant) aged 44 and 47, both of whom were light drinkers and had no abnormal liver function tests, and 3) a 52 year old former polymer reactor cleaner now working elsewhere in the chemical plant who was a greater-thanmoderate drinker and- had no abnormal liver function tests. Other Abnormalities There were no significant differences between groups for symptoms suggestive of Raynaud's phenomenon (Table 7). In addition, there was no difference between groups for the presence of an abnormal Allen Test (which has been suggested as an indicator for acroosteolysis). TWonty-tw of the 207 hand x-rays taken were read as abnormal for same state of acroosteolysis by. at least one of the two independent radiologists. Most of the abnormal findings reported were from Reader ff2. All but two of the abnormal Hies related to damage to the tufts of the cortex, a less S ) APOOO10428 / severe stotc of ocroosteolysis, ami-many wore possibly related to other causes such ns trauma. Although the otliur two x-rnys showed possibly more severe changes of the shaft, they were only read as positive by one reader. One of the two cases had worked since 190? in the chemical plant, while' the other, a maintenance man since 1964, had worked intermittently in the chemical plant. Central nervous system symptoms elicited during the interview (Table 8) showed that severe persistent headaches were slightly mere prevalent among chemical and plastics workers, compared to rubber and former chemical workers. A history of having ever lost consciousness on the job was less conmon in the rubber workers. On neurologic examination, the four occupational groups were found to be similar, with the exception of slightly diminished reflexes in the chemical group. `Since some of the known effects of VCM on humans (angiosarcoma, acrooste olysis, and Raynaud's phenomenon) involved the circulatory system, there was a specific interest in the results relating to the cardiovascular system. No noticeable differences among the occupational groups were found for prevalence of angina pectoris, as measured by the Rose Questionnaire, but a much higher prevalence of systolic hypertension (>, 140io) In the former chemical workers, and a higher prevalence of diastolic hypertension (>. 90mm) in all three YCMexposed groups compared to rubber workers, were seen (Table 9). Current and former chemical workers also had an increased history of having been told of . hypertension in the past by a physician, and an increased history of having taken either "water pills" or blood pressure medication in the past, compared to rubber workers, furthermore, the age-adjusted (by analysis of .covariance) mean diastolic blood pressures were significantly different among the four groups (p< .05). Tables 10 and 11 present prevalences of Pulmonary Function (PF) impair ment among job groups. In Table 10, smoking, age, and height differences between study subjects were automatically controlled by comparing actual PF value with expected PF value derived from the appropriate smoking cate gory of the total plant population. In Table 11, the actual PF values of study subjects in each job group, and smoking category were compared to expected values derived from the*literature, and the prevalence reported in other VCM workers. FEF$q/FVC and FCF75/FVC Impairment cut-off points have been shown to be effective in distinguishing normal subjects from those with obstructive lung disease (33). There was no difference between job or smoking groups in the prevalence of volume impairment (FVC). Flow impairment was not consistently associated With any job group. For example, the former chemical workers had the highest ?revalence of Impaired FEF25-75* FEV/FVC (non-smokers), FEF50/FVC and FEF75/ VC (smokers) and FEV1 (smokers). Present chemical workers had the lowest Srevalenee of impairment of airflow (FtFgs.ys FEV 1/FVC, FEFsg/FVC), but Ighe&t prevalence for FEVl (overall) and FEV1 (non-smokers). Rates of $ 1 1 APOOOI0429 f airflow rr.tenl > 102 of lowest :$ were observed in non-smoking former rher.iic.il workers M?.') comp.nxxi to hourly chemical workers ['l?.'*) for FCVl/FVC, and smoking former chemical workers (652) compared- to i*ubl>or (502), plastics (562), and hourly chemical (Gif) for rEF/jj/FVC. With regard to FEFyr/FYC, rates of impairment were consistently high for all groups. Hearly Half of the study subjects had small ain/ays obstruction to which this test pertains. Toniicr chemical workers also had the hiyhost provalenco Of CV/YC impairment; and rubber workers the lowest prevalence. The greatest and most consistent effects were those of smoking. Except for FVC, smokers had consistently higher prevalence of impairment by all PF tests. Because of the possibility of more recent, or more subtle, exposure effects among workers in this study population, beforo-and-after shift PF tests were carried out on a sample of 56 of the participating workers (Figure l). Since there was a higher proportion of smokers within the subset of chemicals workers, cornered to the rubber and plastics subsets, results are presented separately for smokers and non-smokers. Smokers overall had statistically significant reductions for all seven PF tests. Non-smokers, however, showed little reduction, with the most obvious being for flow rates at low lung volumes, FIIF50 and FEF75 (measuring small airways performance)# Chemical workers who were smokers had signifi cant reductions for five of the seven tests, predominantly reflecting small airways obstructive change. However, both the plastics and rubber workers who smoked showed reductions of similar magnitude,*although the smaller number of plastics smokers precluded their attaining statistical significance. The other two respiratory system health tests, sputum cytol ogy and chest x-rays showed minor inter-occupational group differences. No sputum cytology findings revealed more than moderate atypia. Mild and moderate atypia age-adjusted prevalence rates were 262, 29.42, 33.32 and 17.92 for the four groups, respectively. When the chest x-rays were read by three radiologists by the UICC/llO criteria for pneumoconiosis, only one definite case was detected; and he was a former silica worker. The health questionnaire incorporated the British Medical Research Council's chronic respiratory system questionnaire (see Appendix A). A comparision of age-smoking-adjusted respiratory symptom prevalence rates in the four occupational categories is presented in Table 12. For three of the four symptoms analyzed, the current hourly chemical workers had symptom rates slightly higher than those of the rubber worker control group. The ' plastics workers, and former chemical workers however, had rates substan tially higher than the rubber workers. Information on the pregnancy outcomes of the workers' wives, gathered as part of the questionnaire, were analyzed by age of father at time of conception, both before and after exposure at the plant. Since the number of pregnancies was so small, all workers In the chemical and former chemical 7 j apoooio43o lfr01000dV a (0 jqpuaddy os^c aas) sa6e dues aqq X'loneujxoadde 40 (auuosjad dqo iuojj umwp'siojiuoo jo ias tetJisnpuj -uou c um 9)84 Si3?:jao.iq 434614 5 ppq quoid 045 1? pa(pnqs sdnojS aajqi aqq >0 qopj -juesijjiiGis ^ueansHeqs 3jom soauajajjip im/id-tuiii* osaqi jo auow 'StlnoaB joqqo ne u&m uofijodojd ofioqpajq joqfnq /TiaqS^s e peq sjs^jom leo^uiaqo ai|) ueqi ajnsodxa \-fih jsmoi poMinsajd 41,1/1 sjo^jom S3|4S?ld am '(tl aiql) sjo^jom joqqiu ueqq aBp^pajq anosouo.up ;o uoiqjodoid jsqBiq Xt)i|6iis c pei{ sjyqjow pasodxo H3A poiwaipu;. suo^jom 041 jo ojduiBsqns 11puis v uo qno paj.jjea snitooqdtiiXi poo(,q (cjoqd^jad jo saipnis D(.uo6oi) (32) s^s-CiPue 041 iuojj popntoxo wc sjaqjoq* ajuo.iqa aq 01 paaopisuoa uatuow jo s.naueufiojd uot| uoab sis.isjod aaunjojjjp 5nil *o.toq possimjp qou ijrlnutnLV '(Stt'8 s/isjoa f.o'GI) iuou>isnfpp o6e JOiji? (Ino.ifj 10.41UOD 0111 uem (50* >U) aqt?j im*op .ipqoj .iai|5iq ^uuudijn1 -Bis /funansn^l* B pcq dn0.16 pt<`>odxa W3A ^.imu-id aqq `ojnsndxo s.puuqsnq aqi 01 quonbosqns 'joaomou "(il'9 s/isjoa ;',0*9) oCv .10, poqsnfpi? uoqM sdnojt) 0/41 oin uooMioq Jtojjip iou inp iaiLM in cop (Pioj o.msodxa-<M<j "Cl oiqpi 01 uoai(> oji* soqcj 41 cap (vioj oijpods -o6e [cu.iirjpti dno.il> (ojhioo c 51? .a^Ctuuc sisn uj pauiqiooo ojom /C041 *`iiaw -Xoidujo jo'ijt} jo ajojoq Jji|iio oliM'`lV4 (Pioj Aq .ujjip qon pip srinojB JOIJIO on oqi ojiiis puc 51I110.1U ojnsodxo i; \ /jcuiud oqi ui popnpuj ojom sdnoj6 j ZEHHOOOdV ; i 6 Itiutuiui q-jiM 6untap uoqM sGutpuij poqjodaj Buiripn'puc^s jo Xqinaujip ai|) jo'asncaoq o$it qnq 'qsoa qGtq put `)uaiudinb3'>o X^ iiqtssooocuj. 'ajnsodxa uontjpca oq) jo osncooq Xiuo ?ou `oGcuitp joai'i X^Jito oiqissod qaaqap oi-iso) Gutuaojas e st ona (.njiqnop jo aq o) sjcodde upas jsau aqi (Of) ojaqwasia paqaodoj uaaq sty 4a6e joj poisnfptun 4ajns -odxa wDA jo uoi)tjnp Xq aDuattAajrf Xio6oiuo)td3q jo iuojpca6 v *)uajpwfl ajnsodxa owes aq) pawonoj Xtt6auJ0)td8q jo aojfiap !q)oq jo *uoissnaj+d `uoptditd Xq pajnseaui uaqw sjo^jom joqqru aq) o) sjo^jom sat)**ld at|) 0) sj9)|jom ieaj,tuaqo aq) iuojj aunsodxo jjDA 0) )uaiptj6 asuodsoj-asop jiiom 9 poMOnoj souoiPAdJd Xip6aiuo)td3H '6upj|.j)s si ajaq uaos s)(nsaj aq) jo Xsua)sisuod am `uopeuiuitxa itDjsXqd Xq Xit6auw)edaq 6uiujuuo)Dp jo uo(S -pajduij. pafipaiMOiup? aq) ondsao 'Xie6aujo)*doq sl sjs^jom pasodxa-HSA^ou put pasodxs-MDA uaaMiaq aouejajjip )sa) aAissajduii Xiitauauinu qsotu aqj. ($)upco)0)tdaq apjM-iueid pajjt) uapiun auios jo eDumsjxe oq) Xq jo uoi)tindod oauajajaj Xjojtjoqei am put suoi)?indod Xpn)s aq) uaoMjoq saouajajjip (o6t -G-a) o^qdtjfiouiap jaq)ja Xq'pauitidxa aq Xjqtssod pinoa Xpn)s s^O ui X)}iPUf-touqc s$e)tqd -soqd au^it^Ls jo aouo^OAOjd qBiq Xeidsjp sdnojp *jom ano.) [|t )*q* )ppj 9qi *uoi)ttndod iwauab aqi ui i^t) js JOddn aq) se Xqntuuouqc joj )uj.od uopaaJttuap aq) qas saj,JO)tJoqti. aq) aims 'astitqdsoqd auntie pa)CAdia q)iM sjd^jom pasodxa i^A jo ot jsao uMoqs aAtq saipnis aajq) i(t icq) Xq)jOMaiou XiJt[nDi)atd sj. )i -XiaA^Dadsaj *sdnoj6 jnoj aq) u\ punoj 8J8M SLtuuouqt %2'L put *tx*9 'Z\`Z *X6`fr tuaiu3_siq) fmsn 'Itiujouqe %9 punoj (Ofr < utq) jsi|)j ituuouqe se pauijep si OS <) 109S `OJ uo|J9)}J9 X)neuuouqt aAinaiJisaj ojoui t 6uisn (oe) `19 qo *sun jno ueq; jaMO( X^t?L)ut)5qns 34e ip^q* jo q)oq sua^joM posodxoun ui put sja^JOM pasodxa ioa ieuuout|t %2 Xio)euii.xoJdde punoj (62) Xpnqs s,))tXM *109S 0) qasdsaj q)^n *so^pn)S jaq)0 om) oq) uy utij) `j5moi XpqGi^s )nq *o) JtUui^s osie dJt sopuwuouqt uiqrujuq (t)0) put *asv)vt|dsoqd aui(C3j(e jo aauaitADjj (-ootid Gui^t) aq Xwi saj.)i[tuuouqe paqtioosso jo suto)du>Xs o) pO)tisJ tojp itauaaqa aq) jo ino'uoj.i'ioios-j [as `lopcui ojuojq) aq) uj. )uoiptJG asuodsoj-asop ou si ajaqi oouj.s put 4mu1 icuuouqt qqiM g9'C X[uo apniDili SJaqjOA (tatiuotp iuajjna oq) asuis `jjaomou) `s.ia^JOM itDimoq) jauuioj aq) ui ssaaxa si,i|) joj aiqisuadsaj Guiaq st )no painj aq ueo a6t `po)snrpe-a6v'oje sitnsaj aq) aauis *Xpni< s^qq uj, sdnojQ )som q)i )ua)sisuoD st ipupi *soi)i[tuiioiiqy i;q) q)iA^ A'iS)nuixojd(lt punoj saGe utow jomoi qitM (OC`62) sjoqjow oa pa.U)oj pui? oahpo'jo suonttndod uo ouop saipnqs jaipo '092 U*M) JO)cojG sanitA suosjad oiuqi Guipnpui sjaqjoM leaimaqa jatuuoj aqq jo %z\ ut inq sdnojp ij.iow aq) jo oo.Hp jo XV-2 Xpo ui punoj O-iom sai)t piiuouqt hq) -uopdaoxa or:o iiiim `soDiinjnjjip dnoaG louoHOdnaao-ja)ui (iupip)s po.Moqs s)sej uoiiduiij' joaj [ oq) jo ouoq wotssnosia T i < I r or early changes. K is possible, i^wcvor, that with continued collabora tion in an ongoing testing program, these problems could be overcome. The divergent liver scan results reported by our throe readers could bo secon dary to a number of factors: a) Center where the scans were performed and the respective institutions of the three reviewers, despite a major effort on our part to standardize techniques before- the study started* b) different standards for the interpretation of normal and abnormal by the three review ers, and c) the possibility that a number of these scans represent truly equivocal findings, i.c., changes that are minimal or borderline and for which agreement or diagnosis would be difficult to attain. The Tatter interpretation is supported by the fact that many of the reported findings were in the possible or probable categories, rather than the definite category. There were only four workers who were judged as having hepatomegaly and who also had two or more abnormal liver function tests (one of which was always the SCOT). In addition, liver scans of four other workers were read as abnormal by two readers. The fact that all eight were exposed to VCM suggests the possibility that such screening tests, separately or jointly are detecting early VCM-induced liver disease. Only by following this, and other, populations prospectively would it be possible to fully assess the predictive value of any of'these tests for detecting VCM-induced disease. Splenomegaly and decreased platelet counts, two findings which have been noted in earlier studies of VCM-exposed workers (30,13), were not seen in this study. The extent to which these VCM-asscciated changes are related to primary disease in the spleen or secondary to portal hypertension is not entirely clear, but this study does suggest that these screening tests may be related to a slightly more advanced stage of the disease than might have existed in this survey. Other previously recognized health effects due to vinyl chloride exposure were not very frequent In this population. Prevalence of symptoms of Raynaud's phenomenon were not increased, and Allen test .abnormalities wore no more common among VCM-exposed than non-exposed workers. Although indica tions of acroosteolysis were seen in over 10% of the hand x-rays, poor Inter-observer reliability among the x-ray readers, the fact that most of the x-ray changes noted were for the earlier stages of acroosteolysis, and the absence of increased symptoms or physical findings suggestive of acroosteolysis Indicate that this disease is not a major problem at the plant now. (A review of serial x-ray taken In prior years would provide a clearer picture for the development of this disease over time.) A history of central nervous system symptoms, expected from the anesthetic effect of vinyl chloride, was found more often in vinyl chloride exposed workers. This is consistent with an earlier study by Splrtas, et al. (27) of the same plant. Because of changing working conditions over time, it is quite possible that many of the central nervous system symptoms reported in the medical history occurred well in the past, and although no neurologic abnormalities were noted during this cross-sectional examination, one should .uimlardi... 10 APOOO10433 r not rule out the possibility that su;abnormalities might have boon present at a time when central nervous system symptoms wore more prevalent. Overall, thor`o is little proof that current. VCM exposures are high enough to induce these VCM-relatcd central nervous system health effects. The substantially lower prevalence in the rubber workers of diastolic hypertension, measured as greater than OOiun llg, is difficult to explain. The excess hypertensives in the other three groups are all in the 90-105mm Hg range. While the anxiety levels nay have been higher in workers currently or formerly exposed to .VCH (since most of them were aware of its carcino genic potential), if such emotions were responsible for the differential prevalence of diastolic hypertension one would expect a concomitant dif ferential prevalence of systolic hypertension - which did not exist except in the former chemical workers. Additionally> pulse rates were similar in the four groups which argues against an anxiety etiology. More chemical and former chemical workers reported previously diagnosed hypertension than rubber workers, and there was also an increased history for having taken water pills or anti-hypertensive medication In the past; however, it was impossible to tell from interview data whether their exposures or hyperten sion came first. The increased prevalence in former chemical workers of systolic hypertension, if due to VCM, would also be expected In the current chemical workers, unless the systolic hypertension temporarily follows a diastolic hypertension-induced selection out of the chemical area. Such a hypothesis, although very tenuous, would be consistent with Table 9. While these cardiovascular findings may be unrelated to VCM exposure, VCM has definite known vascular effects such as angiosarcoma, acroosteolysis, and Raynaud's phenomenon. Therefore, it is plausible, at least by analogy that VCM in some way is responsible for the hypertension. Although there was a random allocation of subjects to the various examining physicians, it Is well known that a single blood pressure reading Is a somewhat unreli able finding in epidemiologic studies, and the relationship noted here between systemic hypertension and VCM exposure warrants more detailed investigation. Experimental studies and case histories suggest that VCM acts a a lung Irritant at high exposure levels (10,13,14). The reported epidemiologic study of VCM-PVC workers tends to support this literature (19). This study suggests no difference in PF on respiratory symptoms related to VCM exposure. Former chemfeal workers tended to have higher rates of impairment, but this could be due to exposure in their non-VCH jobs, or could reflect some selfselective migration away from that work area by individuals most prone to develop symptoms in response to exposure to the chemical plant environment. However, in the absence of information on jobs held subsequent to chemical plant jobs., no conclusions can be made. The environmental factor having the greatest effect on baseline lung function was smoking. Smokers in all job groups had higher rates of flow Impairment when compared to non-smokers. This was a consistent finding, and the impairment was of greater magnitude than any differences observed between job groups. 11 * APOOO10434 StOlOOOdV l. * 21 )insui Aaoqeaidsaj euros ooe^ sdnoj6 qof u* 3*43 eapl 6ui)aoddns 4opn)iuGetu jeiuuj.s jo suo^onpeu paouioaodxo sdnoaG qof ue ui'sja^ouis 'uoiqonpaj a[))n pawoqs saosjouis-uog' *owniOA 6uni moi qe smO[> joj /fisnouqo qsoui `jj u} suoiqonpoa )ueoytu6is peg neaaAO sjo)joujs *oansodxo injiiuog auuos pooquaijii oq) sqsoBGns i/tqs eg) jsao Jd ui uoiqanpoa Auy 'saoqaoM ouios uo qno poujoo aaaw S)$0) qjjgs aaqjt pue-aaoisq `paezeg oansodxa quajano agq jo Aqmqissod ogq ssasse 01 sdnoa8 qof joqqo aqq ueqq sqinsaa joiqaq peg saa^JOM [eoimago ag) sqsoq Jd aqq o ipjoaos jo> poDpuj `sojnsodxo )ueoy].u6is Gupuoiaadxa eq Ann saogaoM sin J llp qeqq sqsofiBns `sdnoaG qof aqi Buoure suroqduiAs aO uoL)aun> Ajoqeaidsoa joqq}.a ui soouaaajjip jo aouosqe eg) pue `quauuiedtuj jd JO oouoieAsad g6}.g sigj. `aaAdMoq `q6ui ooq si quauuieduii auios Apq oq saagaoM dAf^ Ajsao ;o auo qnoqe joj *suoj.qeindod Gui^aon aaqqo q paaeduioo uagM paqbasis aeadde qou saop Apnqs st.qq u). oauaiOACud quouiaieduii molj, squatuaiedui.i (S^j3j 05J3j) aqea moi> oqq uaawqaq oqeipaiuaaqui sen `uoiqounj sApMjfe news jo aoqeaipuf ue osie '3A/A0 peaiodiuj, jo oouateAaud 'poqeniPAa Au.nj uaaq qou seq (3AJ jo a&equoaaad e so passoadxo) Stjaj pue OSjjj aoj sjjoqna aqi jo apueoii.iu6is aqq Aioqcunqaoiufi *A3j 03 aeifuiis sen `uononjqsqo sApmjjp news jo uo^eoipuj. OAjiisuas e osie 1 0Sj3j ps.iieiluji jo aouaieAoad `)uaui -aiediui jo (?,o$<) oouoieAojd gGjq e paeiOAsa `uoiqonaqsqo sAe/u^e news aoj 1 soi 3AHJ.SUSS v `^J3d '(flt-SC) suopeindod posodxs-uou oq oiqeaeduioo set* pue *saagjOM diuag ao (t?E) oipxo^ uo^tod oi paaeduioo uaqn paieAaia 30U sett `uoponansqo sAc/aji? aaGavi jo aoieoipuj. lie 'quauinieduii I A3J Aaofione^ qof oanua 9M3 J0 snnsoa eg; 33*>;j 0) Aiosinun si auon? s.iaqaoM osoin ui quauiaiodw; aumiOA os pue `UtiOaD qof gseo jo jot uegq ssoi osiaduioo Aoq) `joasmoh 'is^P OAd 01 oansodxo asa-)eoa6 ogj OAcq (sDi)seid) saoqraudo Aanqueq pue (sjsqao.M lesiuiagp) saaGGeq ag) Apnjs sni3 U{ `saaquo/i oaj u.i 6un[ oqi 14 saGupip 0Ai)0ia)S0a aqiaasap aanqius)j, 1 og) uj. siaodoa om) iseot 'OM ui uonanpoa fiuipuodsaaaoo ou sett eusqq asueoaq sdcgaod `P'jjpaoio sen Apnqs sun U.1 3uoiu.i}rdui| oaj /IA3J jo osu^ieASJj *cfiu!puu oijnowoanls inuaouqe jo asnepaq poiaaias aaa pauieqqo aaonsaAano ouiniOA-Mou goign tuoa/ ilno.di oq; jo fiv osneaaq Apn^s (61) * 1 w 3 *>M3 1*1 paqeAoio mj Aim 3AJ/^J3J ao^ so)ea juauiajeduii ;uotu,i|Vrtuii DAJ/$*J3i ;o DDusiPAO.ul oiqeaeduioo AigUnoa peg diioaG qof goeo tit saoiwuwiofi `aoiauiejeU jj Aue aoj pue `vdno.ib qof oin ,/o Aue uj qii.Niujedmi jo apun|DAoad isaqfiiq oqq sett sun 'Apins auigi 14 punoj (Q[) 'n* 7,) `a<)iii[-[ sr ooiiDieAaad owes sip pup `stlnoaG qof .iono ogq ur-tn ao|(iiq nfjl-ot P )*> oouaieAO.id (OAJ/SAAJJ) )nomaiPduq mou peg pugnu`j osn> oqtt saogaoM ipppiaip aocuaoj (3AJ ;o 5S/.> IA3.I) 3U0nwjp*`wi ttOU im iPiipiAipuj Aue fiuipnpxo aiog) o) aOA.>ott unp oq Aj'ui sun `Ap'us snn uegi .p?ioi AnqGiis 0JP (DAJ) luoiuaiPiluii JHunioA joj sovm aioif) ' jNOiuaivilui aoj ejai>iiaa aiog) Gujsn *(II iqei) s.ur'i.iott OAd-H)A aoiuao; |iuv luaama jo uon<.'iii'Iod aoq)Oue ui *ip *)o 'anufll J`> Cu{puij og) n; uonriiiitod sjqi jo oj'ioiPAdatt )uoui -JlPduu r.i)eioa iio*:t.ii'-li!wa L?it.ioj:<a uy si:ur!|,*A,o AJOH'.i|lvna ao jj aoi|)ia uo oansodxo ^a jo nojja )uo.ii'MI' mi Cl pm' 01 s>|qi>i uj sdno.ili qof uo.vnoq suosiai'd-'.ioa po)Siifpo Out utirs pm1 iijlijag *oCu liMaaiui. og^ x While the Increased frequency ot ehrouosonwl aherriiLions oniony the different occupational groups, compared with controls from outside the plant, may be due to exposure to VCI1 mul/or other plant-wide chemicals, the results reported in Table 14 might also be due, at least partially, to age or socioeconomic status differences. Adilitioually, It should be noted that although the noyniludc of*the differences between the occupa tional groups studied ot the plant do not support oilier investigations associating VCM exposure with chrumotom.il aberrations (23-26), there arc differences among t.her.0 various studies in the composition of the papulations under study which might mate direct comparison somewhat difficult, and the sample size in this study was small. The significant excess of fetal loss experienced by the wives of workers subsequent to their husband's VCM exposure must be assessed against the weaknesses inherent in a questionnaire survey. These weak nesses have been discussed elsewhere (20) lending credence to the belief that these findings are not spurious. This excess is biologically consis tent with the previously demonstrated mutagenic response to VCM in micro bial test systems (20-22), arid the increased frequencies of chromosomal aberrations in VCN-exposed workers found by other investigators (23-26). This evidence mandates further research into this new adverse health consequence of VCM and additional agents found to be mutagenic in labora tory test systems and which are in broad use in the plastics and rubber industries. Finally, while no cases of hepatic angiosarcoma, far advanced liver disease, or cancer of other sites were detected by the study among those currently employed, this should not be misconstrued v/ith regard to the recent extensive documentation of VCM liver carcinogenicity and toxicity; nor does it preclude the existence of such VCM-related conditions within this study population. In fact, liver angiosarcoma has been found previously at this VCM polymerization period, and with a short period of time elapsing between earliest clinical manifestation and death. Hence, only a small proportion with such silent and difficult-to-dlagnose diseases could be expected to be found in a cross-sectional, medical survey. It should be pointed out that there are differences between plants with respect to work practices, production techniques, working conditions, and composition of workforce, in the presence or absence of various associated toxins, and other factors. This potential diversity of exposure within the PVC Industry cautions'against drawing general conclusions from this single study, about the hazards of VCM exposure, and the usefulness of screening tests in general VCM-exposcd working populations. It is, therefore, necessary to put these into perspective alongside those reported from other plants, both in this country and elsewhere. Nevertheless, there are some tentative conclusions based on our findings which merit further evaluation. 13 t AP000I0436 r Finally, with rogjrd to the currently recommended liven* screening procedures, the apparent low specificity of the liver function tests as A screening procedure taken together with their unknown sensitivity and predictive value, emphasize the generally perceived need for a more specific test inr delecting early liver damage in VCM exposed workers. Simultaneously, the true early screening value of t fiesta standard liver function tests used in this study needs to be determined by a longitudinal medical survei11 a nee program of the workers. APOOOI0437 RirrcitfNCES 1. Creech, J. and Johnson, M.: Anoiosiircoma of l.Ivor in Manufacture of Polyvinyl Chloride, 0. Occ. Med., 1C, ISO-l'ul (1974). 2. Moltonl, C. and Lefcminn, G.: Carcinogenicity "iuassnys of Vinyl Chloride: Current Results, Ann. N.Y. Acad. Sci., 246, 195-218 (1975). 3. Keplinger, M., Goode, J., Gordon, 0., and Calendra, J.: Interim Results of Exposure of Rats, Hamsters, and Mice to Vinyl Chloride, Ann. N.Y. Acad. 'S.Ci., 246, 219-220 (1975). 4. Lloyd, W. Angiosarcoma of the Liver in Vinyl Chloride/Polyvinyl Chloride Workers, J. Occ. Med., 17, 333-334 (1075), 5. Tabersltaw Cooper Associates Inc.: Supplementary Epidemiological Study Of Vinyl Chloride Workers I, Report May 30, 1975. 6. Nicholson, W., Hammond, E., Seidman, H. and Sellkoff, I: Mortality Experience of a Cohort of Vinyl Chloride-Polyvinyl Chloride Workers, Ann. N.Y. Acad. Sci., 246, 225-230 (1975). 7. Waxweiler, R., Stringer, W., Wagoner, J., Jones J., Falk, H. and Carter, C.: Neoplastic Risk Among Workers Exposed to Vinyl Chloride, Ann. N.Y. Acad. Sci., 271, 40-48 (1976) 8. Ott, G., Linger, R. and Holder, B.: Vinyl Chloride Exposure in a Controlled Industrial Environment, Arch. Env. Health, 30, 333-339 (1975). 9. Harsteller, H. and Lclbach, W.: Unusual Splenomegalic Liver Disease as Evidenced by Peritoneoscopy and Guided Liver Biopsy Among Polyvinyl Chloride Production Workers^ Ann, N.Y, Acad. Sci., 246, 95-134 (1975). 10. Lester, D., Greenberg, L. and Adams, W. Effects of Single and Repeated Exposures of Humans and Rats to Vinyl Chloride, Amer. fnd. Hyg. Assoc. 0., 24, 265-275 (1963). 11. Suclu, I., Prodan, L., Ilea, E., Paduraru, A., and Pascu, l,:* Clinical Manifestations in Vinyl Chloride Poisoning, Ann. N.Y. Acad. Sci., 246, 53-69 (1975). 12. Gedlgk* P.. Muller, R., and Bechtelsheimer, H.: Morphology of Liver Damage Among Polyvinyl Chloride Production Workers. A Report of 51 Cases, Ann. N.Y. Acad. Sci,, 246, 278-285 (1975). 15 APOOO10438 13. lamp*, C,, Juhr* S., Stein, G. und VfiHin.ui, G.: Furl her Insults in * Polyvinyl Chloride Production Workers, Ann. N.Y. Acad. Sci.*, 246, 18-20 (1975). 14. Patty. F., Yant, W. and Waite, E.: Acute Response of Guinea Picjs to Vapors Of Sonic New CoiraucrciaV Organic Compounds, Public Healih Reports 45, 1063 (1930). 15. Viola. P.: Pathology of Vinyl Chloride, Med. Lavoro, 61. 174-179 (19/0). '. 16. Wegman, 0.: Discussion, Ann. M.Y. Acad. Sci., 246, 20-32 (1976). 17. Szende, B., Kapis, K., Nemos, A. and Pinter, A.: Pneumoconiosis Caused by Inhalation of PVC Dust, Med. Lavoro, 61, 433-436 (1970). 18. Frongia, N., Spinazzola, A., and Bacardii, A.: Lcsioni Pulmonari Sporimentali da inalazione prolungata di polveri di PVC, Med. Lavoro, 65, 321-342 (1974). 19. Miller, A., Tiorstcin, A., Chuang, M. and Solikoff, I.: Changes in Pulmonary Function in Workers Exposed to Vinyl Chloride and Polyvinyl Chloride, Ann. N.Y. Acad. Sci., 246, 42-52 (1975). 20. Bartsch, H., Malavielle, C. and Montcsano, R.s Human, Rat and Mouse livcr-Mcdiated Mutagenicity of Vinyl Chloride In S. Typhimuriuw Strains, Int. J. Cancer. 15. 429 (1975). 21. loprieno, N., Barale, ft., Baroneelll, S., ct al.: Evaluation of the Genetic Effects by Vinyl Chloride Monomer (VCM) Under Hawaiian Metabolic Activation: Studies in Vitro and In Vivo, Mutation Res., 40, 85 (1976). 22. Rannung, U., Johansson, A., Rami, C. and Wachtnieister, C.A.: The Mutagenicity of Vinyl Chloride After Metabolic Activation, Ambio 3, 194 (1974). 23. Ducatman, A., Hirschhorn, K. and Solikoff, I.J.: Vinyl Chloride Exposure and Human Chromosome Aberrations, Mutation Res., 31, 163 (1975) 24. Funes-Cravloto, F., Lambert, B., Linsten, J. et al.: Chromosome Aberrations In Workers Exposed to Vinyl Chloride, Lancet, i, 459 (1975). 25. Purchase, Richardon, C.R. and Anderson, Chromosomal and Cominant Lethal Effects of Vinyl Chloride, Lancet, ii, 410 (1975). 26. Hansteen, I.L., Hillestad, L. and TMis-Evensen, Chromosome Studies on Workers Exposed to Vinyl Chloride, Mutation Res., 38, 112 (1976). 16 AP00010439 27. Spirtar,, ft., HJliclind, A.J., r,., :<, J.F., and Van Erl, M.D.: Tlie Association of Vinyl CUloricU* Exposures with Morbidity Symptoms, Am. Ind, llyg. 0., 779-/89 (1075). 28. Infante, P., L'atjoner, J., McKiehaol, A., Waxweiler, It., and Falk, H.: Genetic Risks of Vinyl Chloride, lancet, 1, 734*735 (1976). 29. Wyatt, R., Cl at.: An Epidemiologic Study of Blood Screening Tests and Illness Hislorh.'s Among Chemical Workers Involved In the Manufacturo of Polyvinyl Chloride, Ann. N.Y. Acad. Sci,, 246, 30-07 (197'i). 30. tills, R., Anderson, M., Nicholson, W.J., et al.: Prevalence of Disease Among Vinyl Chloride and Polyvinyl Chloride Workers, Arm. N.Y. Acad. Sci., 246, 22 (1975). 31. Morris, J.F., I'.osk, A., and Johnson, L.L.: Spirometric Standards for ' MeaHhy Hon-MiioUing Adults, Am. Rev. Itesp. Dis., 103, 57 (1971). 32. Buist, S.A. and Ross, B.B.: Predicted Values for Closing Volumes Using a Modified Single Breath, Nirtogen Test, Am. Rev, Resp. Dis., 107, 44, (1973). 4 33. Lapp, N.L. and Hyatt, R.C.: Some Factors Affecting the Relationship of Maximum Expiratory Flow to Lung Volume in Health and Disease, Dis Chest,' 51, 475 (1967). 34. Zuskin, E., Wolfson, R.L., and Harpel, 6.: Byssinosis in carding and spinning workers: prevalence in the cotton textile industry, Arch. Env. Kith., 19. 606*673 (1569). 35. Bouhuys, A., et al.: Chronic Respiratory Disease In Hcnip Workers, Am. J. Med., 46, 520-37 (1969). 36. Bouhuys, A.: The Forced expiratory Volume (FEV75) In Healthy Males and In Textile Workers, A.R.R.D., 87, 63-0 (1963), 37. Olson, H.C., and Gilson, J.D.: Respiratory Symptoms, Bronchitis and Ventilatory Capacity in Men': An Anglo-Danish Comparison, with Special Reference to Differences in Smoking Habits, Brit. Med. J., 1, 450-6 (1960). 38. Reid, D.D., ct al.; Cardiorespiratory Disease and Diabetes Among Middle* aged Mala Civil Servants, Lancet 1, 469-73 (1974). 39. Heath, C.W., Jr., Dumont, C., Gamble, J.. et al: Chromosomal Damage in Hen Occupationally Exposed to Vinyl Chloride Monomer and Other Chemicals, fnvlr. Res., In press (1977) 17 AP00010440 YCM Exposure None Lightly Exposed Exposed Past Exposure TABLE 1 Subgroups of Workers Included in Survey Occupational Broun (N) Rubber (2400) Plastics (105) Sawipl e Sought 9* Ml 1 Participants (Participation Rate) 134 (622) 00 (767,) Chemical (164) Former Chemical (101) All All 126 {77%) 71 (707) ;l?A 18 APOOOI0441 r Age 15-29 30-39 40-49 > 50 Total Mean Age TABLE 2 Age Distribution of the Four Occupational Groups Rubber , Plastics Chemical Former Chemical 36 (27%) 19 (24%) 26 (21%) 12 (17%) 23 (17%) 7 ( 9%) 13 (11%) 13 (1U%) 34 (25%) 12 (15%) 47 (36%) 29 (41%) 41 (30%) 42 (51%) 40 (32%) 17 (24%) 134 (100%) 40.3 eo (ioo%) 44.4 126 (100%) 42.3 71 (100%) 42.4 Total '93 (23:0 56 (14%)122 (30S) 140 (35::) 411 (100%) 42.1 chi square 29.03 p 8 .01 19 APOOO10442 f TADLE 3 Alcohol Consumption by Occupational Group Alcohol Score* 0 .01 to .74 .75 to 3.75 >3.75 Total Rubber 31 (232) 35 (262) 58 (432) 10 { 82) 134 (1002) Plastics 13 (162) 24 (302) 37 (462) 6 ( 82) GO (1002) Chemical 26 (212) 36 (292) 58 (462) 6 ( 52) 126 (1002) Former Chemical 14 (202) 18 (252) 35 (492) 4 ( 68) 71 (1002) Total 84 (202) 113 (282) . 188 (46%) 26 ( 62) 411 (1002) * Equivalent ounces of pure alcohol per day X2 2.54 (p >.05) 20 r i AP00010443 ' TAOLE 4 Severity of Liver Function Abnormal1 ties SCOT (>39 Abnormal) Former Rubber Plastics Chan leal Chemica Kean Total Abnormal 40-49 >49 Prevalence* 31.6 22 16 6 17.1* 32.1 19 16 3 22.8* 32.6 25 17 8 19.8* 34.5 19 14 5 26.9* Total Bilirubin (>1 Abnormal) Mean Total Abnormal 1.01-1.40 >1.40 Prevalence* .69 8 6. 2 5.4X .63 5 4 1 5.4* .64 4 4 0 3.5* .63 4 3 1 4.3* IDK (>225 Abnormal) Kean Total Abnormal 226-250 >250 Prevalence* 171 2 1 1 1.8* 174 4. 3 1 4.2* 170 4 2 2 3.6* . 185 `8 5 3 11.8* Alkaline Phosphatase (>85 Abnormal) Mean Total Abnormal 86-115 >115 Prevalence* 67 18 15 3 13.1* 66 10 8 2 11.9* 66 16 15 1 12.5* 69 11 8 3 15.6* History of Hepatitis Humber Prevalence * 3 1.9* 1 .8* 5 3.7* 4 5.6* Directly Age adjusted 22 * '' 9 APOOOJ 0444 TABLE 5 Prevalence of Hepatomegaly Palpation Number Prevalence* , Percussion Number 12-13 cm >13 cm Prevalence* Both Palpation and Percussion Number Prevalence* Rubber 9 7.IX 4 3 1 3.42 1 .82 Plastics 8 ' 7.32 5 4 1 5.0% 3 3.52 Directly Age Adjusted Chemical Former Chemical 17 13.22 10 13.OS 7 4 3 5.22* ` 1 1 -0 .82 6 4.62 1 .82 22 AP0dbTd445 TABLE 6 Liver Scan Results Total number of liver scans performed in study: Mormal to all 3 readers: Abnormal to 1 reader only: Abnormal to 2 readers: Abnormal to all 3 readers: 123 94 25 4 0 Reader fl 12 13 Definitely Abnormal m 2 - -- 2. Probably Abnormal 13 16 2 -- 31 Focal Defect 2 9 2 -- 13 Diffuse Disease 7 13 -- 20 Other 4 - -- 4 23 f * AP00010446 TABLE 7 Prevalence* of Raynaud's Symptoms t Rubber Had attacks of numbness, cold blue coloration in fingers a. Unilateral b. Bilateral c. Such attacks precipitated by cold d. Such attacks precipitated by emotional upset 4.5% 2.4% 4.IX .6% Plastics 2.OX 3.61 1.5% 0% Chemical 4.1% 3.1% 3.8% .6% Former Chemical 5. B% 1.8% 6.9% 2.5% Age Adjusted 24 APOOOl0447 8frHH000dV s. po^snfpv a6v X8*S %fr'9 Ye3TUoq3 -rauuoj XC`9 %rt i iwpuoio XZ'S ii'Zi sauseid Xt*2 qoj* aiji uo Ouuujpj jo ssausnopsuo^ 6ui$oi K9`8 saippppsH ^uais^sja^ sjoass :*o iotsut aoqqny suio}dw*s iuojs^s sncAja^ ipjiuao jo *a3uoieAa.id 8 31flVt TABLE 9 Severity of Hypertension Former Rubber Plastics Chemical Chemical Systolic Number Hypertensive (> 140 mm lig) 140-160 nni Hg 161-180 wit Hg >180 nrn Hg Prevalence* Mean* 40 32 8 0 36.6% 132.4 31 22 6 3 32.5% 135.7 48 41 3 '4 37.52 134.9 31 22 7 2 45.62 137.2 Diastolic Number Hypertensive (> 90 mm Hg)** 90-94 iwu Hg 95-105 mm Hg >105 mm Hg Prevalence* Mean* History of taking water pills or blood pressure medication 31 17 10 4 24.3% 82.0 4.7% 33 14 12 7 39.9% 86.1 11.5% 51 25 21 S 39.4% . 85.7 26 17 5 4 41.02 84.4 9.7% 16.02 Previously told of high blood pressure by a physician* 19.6% 20.5% 25.7% 24.7% Age Adjusted ** Rubber vs xs (Mantel-Haenszel) significant (p <.05) 26 fr s APOOOI0449 t TABLE 10 Prevalence of Pulmonary Function (PF) Impairments* Among Job Groups Adjusted for Ago, Height and Smoking PF FEV1 < 0.80 predicted FVC < 0.B0 predicted FEF < 0.80 predicted 25-75 CV/VC > 1.20 predicted Rubber 9.8 4.5 16.5 17.6 % Impairment Plastics Hourly Chemical 3.8 10.4 6.8 6.4 21.3 26.6 17.6 24.8 Former Chemical 8.5 5.6 25.4 30.0 * Expected values based on total worker population categorized by smoking 27 AP00010450 TABU n Prevalence of Pulmonary function (PC) Impairment Among Occupational Groups by Smoking Category % Impairment PF FEV1/FVC < 0.7b Non-Smokers Smokers All FEV1 < 0.80 Predicted* Non-Smokers Smokers All FVC < 0.80 Predicted Non-Smokers Smokers All FEFso/FVC <0.56 Non-Smokers Smokers All FEF75/FVC < 0.30 Non-Smokers Smokers All CV/VC > 1.20 Predicted** Non-Smokers Smokers All Rubber 31.4 44.4 39.9 t 8.2 13.9 11.3 8.2 6.9 7.5 4.9 18.1 12.0 39.3 50.0 45.1 6.8 25.0 16.8 Plastics 37.8 53.5 46.3 8.1 14.0 11.3 5.4 11.6 8.8 10.8 18.6 15.0 46.0 55.8 51.3 10.8 35.7 24.1 Chemical 22.2 41.3 34.4 11.1 18.8 16.0 6.7 8.8 8.0 2.2 10.0 7.2 42.2 51.3 48.0 15.6 35.0 28,0 Former Chemical 41.9 47.5 45.1 9.7 20.0 15.5 12.9 7.5 9.9* 3.2 20.0 12.7 48.4 65.0 57.8 36.1 38.5 28.6 Miller et ftl. 32 48 45 ... -- 3.9 4.7 4.6 __ -- 44 ' 63 60 __ -- -* Based on regressions from Ref. 31 ** Based on regressions from Ref. 32 * 28 i i AP00010451 Wfrpjpqociv i 2 9 rp.4 wi t> 6 1 & JJ Si ESI l* (! ---*--* t, 'IfilBWJ i i* tj Il!!!!i- lllillllr [ ' 1 's TABLE 12 Age and Smoking Adjusted Prevalence Rates of Respiratory Symptoms Symptom t Cough 1 and 2 Phlegm 1 and 2 Persistent Cough and Phlegm Breathlessness (Grade 2,3,-1) Rubber 10.0* 16.8* 6.8* 19.8** Plastics 21.0 26.5 13.5 20.4 N Age (years) Height (inches) 133 40.31 (12.8)* 69.8 (3.4)* 80 44.4 (13.7) 69.2 (2.4) Chemical 15.7 14.8 Former Chemical 13.7 28.0 7.9. 9.8 22.3 25.7* 126 42.1 (13.2) 69.5 (2.2) 71 42.2 (11.0) 69.6 (2.8) * 1 missing ** 3 missing t Scored according to BMRC criteria 30 i tt AP00010453 t i I Paternal Age Group {Years) TABLE 13 Paternal Aye Distribution for Oul Deaths According to Husband's VC Exposure ii Controls*1 Primary VC Exposure Pregnancies fetal Deaths l[N) ' "W Pregnancies tin-- fetal Deaths N "c*r <20 20-24 25-29 30-34 >35 ALL AGES AGE-ADJU5TED 31 BO 38 6 4 159 Prior to Husband's Exposure 2 .4 4 3 0 11 G.5 5.0 10.5 1G.7 0.0 6.9 6.9 7 44 56 27 14 148 0 2 7 5 115 0.0 4.5 12.5 18.5 . 7.1 10.1 6.1 <20 20-24 . 25-29 30-34 >35 ALL AGES AGE ADJUSTED Subsequent to Husband's Exposure 1 43 87 87 55 273 0 0.0 0 0 ........ 4... ------9.3, ..._____ 22________ ___ 3 3 3.4 48 11 7 8.0 36 3 10 18.2 33 6 24 8.8 139 23 8.8 0.0 13.6 22.9 8.3 18.2 16.5 15.8* Mantel-Hacnzel x2 significant At p <0.05 for the comparison of the trto post exposure groups 31 _r APOOOt 0454 TABLE 14 CYT0GENCT1C STUOIES Exposure Chemical Humber of Subjects 14 Plastics 4 Rubber Controls* 17 A Average Aqe 49.4 (44-65) 52.5 (46-58) 48.5 (31-58) 44.3 (37-51) Average Months Worked Number of Number Metaphases With Scored Brekaqo 291.1 (215-346) 1105 74 315.8 160 14 (261-341) 305.8 (114-357) - 1306 586 77 21 Percent With Brekaae 6.7 7.8 5.9 3.6 CDC male employees not exposed to laboratory chemicals 32 AP00010455 APPCROrX A TEST- PROCEDURES I. Medical Questionnaire* Administered by trained medical interviewers (U.S.P.H.S. Venera! .Dlscosp Representatives)i the questionnaire contained sections on demo graphic information * a past history with complete review of systems and emphasis on prior drug use, a family history with special emphasis on liver diseases, a respiratory symptom questionnaire based on the British Medical Research Council Questionnaire, and a cardiovascular symptom questionnaire (the Rose questionnaire). Specific questions relating to potential VCM induced effects such as Raynaud's phenomenon were included. In addition*, a section related to the occurrence of still- ! births, miscarriages, and birth defects In offspring of workers was Included. II. Physical Examination A general thorough physical examination by CDC physicians Including tests chosen a priority for their relevance to possible vinyl chloride Induced disease, such as the Allen Test, liver examination by both palpation and percussion, a careful neurologic examination, and a gum guaiac stool examination. HI. Hematologic Test 10 ml of blood v/as drawn. A smear was made iiwnediately for a quali tative platelet estimation and the remainder v/as refrigerated and sent to Upjohn Laboratories in King of Prussia, Pennsylvania, where hemoglo bin hematocrit, white blood coll count, and platelet count were performed within four hours of the time the blood was drawn. IV. Serologic Procedures 30 ml of blood was drawn, centrifuged, and the scrum pipetted off and refrigerated immediately at the test site. (Sera for the sorbitol dehydrogenase procedure was immediately frozen in dry ice.) At the end of each eight hour testing session the serum was transported by direct auto courier to National Health Laboratories in Alexandria, Virginia, for a standard SMA-12 run including total bilirubin, alkaline phosphatase, lactic dehydrogenase, scrum cholesterol, serum glutamic oxaloacetic transaminase, total protein, albumin, blood urea nitrogen, glucose, inorganic phosphate, calcium, and uric acid. Addi tionally, serum protein electrophoresis, hepatitis antigen, sorbitol dehydrogenase, and ornithine carbamyl transferase were run. 33 /i i AP000I0456 , / r V. Urinalysis ' Each subject had a routine urinalysis with microscopic examination performed by Upjohn Laboratories in King of Prussia, Pennsylvania. Specimens were transported together with the hematologic specimens. VI. Sputum Cytology Each subject was given a 102 propylene glycol mist and asked to cough into a jar of carbowax solution. At the end of each week the samples were sent to.Dr. Geno Sacconuno's laboratory in Grand Junction, Colorado for analysis. VII. Chest X-Ray For persons who had received a chest x-ray within the last six months, that x-ray was obtained and used for our review. All other people in the study were given 14 x 17 posterior - anterior x-rays on a mobile unit at 70-80 KV by a licensed x-ray technician. Films were developed on site and quickly read by a physician for quality and problems requiring immediate medical attention. Later, all films were sent to three U1CC/IL0 certified radiologists, Dr. Benjamin Felson at the University of Cincinnati, Or. Martin Uonner at Johns Hopkins Hospital, Dr. M. Dennis at the University of Maryland, who read them according to the 1970 UICC/I10 criteria for pneumoconiosis and other chest diseases. VIII. Hand X-Rays For a number of study participants, hand x-rays that had been previously taken by the company within the last six months were used. The rest of the subjects were given routine hand x-rays (45 KV, 90 MAS, with cardboard holders) at Pottstown Memorial Medical Center by their staff. Th.c hand-x-rays were then sent along with the attached forms to Or. Martin Donners and Dr. Walter Whitehouse at the University of Michigan Hospital for reading. IX. Liver Scan Five people had previous recent liver scans done at the request of the plant administration at the Pottstown Memorial Medical Center and these scans were used. The other 110 people were also scanned at the Pottstown Memorial Medical Center using a diverging collinator (gantna camera). One milliliter of Technicium 99 Sulfur Colloid was injected Into patients 10 to 15 minutes before scanning. A lead marker was placed on the right coastal margin to aid in liver size determination. Six pictures including anterior-posterior and lateral views of the spleen and liver were taken. A standard reading form was developed 34 APOOO10457 by Or. Mallov In conjunction with tho three nuclear medicine specialists who later read the films, Or. Edward Silberstein at the University of Cincinnati, Or. Mansfield at the Jefferson Medical Center, and Dr. T.P. Kaynie at the University of Indiana. Pulmonary function Testing All workers performed the pulmonary function tests seated and with a noseclip. At least 5 forced exhalations were obtained. The equipment used was Model 220 waterless spirometer and Model 750 Recorder, made by Cardio Pulmonary Instruments, Houston, Texas. For spirometry and flow volume parameters, the following procedure was followed: 1) several relaxed breaths, 2) Inhale to about 2/3 full capacity, 3) forcibly exhale to RV, a) inhalo to full capacity, 5) forcibly exhale to RV. Three curves for calculations were selected on the following basis: 1) FVC and FEVi n within 102 of each other and 2) appearance of curve - if it were possible to have a choice between curves, they were selected on the basts of a) partial exhalation between 60 and 752 of FVC, b) initial forced expiration done w.ith full force and without hesitation and c) similarity in the shape of the curves. Calculations of flow are expressed as percent of FVC exhaled. At least three single-breath Nitrogen (SBN?) maneuvers were performed, . with inhaled and exhaled Nj differences less than 5S. Exhaled flow from full vital capacity was maintained below 0.4 liters/sec. The criteria for selection of two curves were that VC be within 10- of each other, and exhaled flow rate was not greater than 0.7 liters/sec. for longer than 1/2 second. Individuals having less than two acceptable curves were not recorded. Clsoing volume (CV) was determined by drawing a straight line by eye along the latter part of the alveolar plateau. The volume between the first convincing point of departure from this line and the full VC was recorded as CV. 35 AP00010458 APPENDIX B >4. chromosomal hamacr in hkn occupationally exposkd TO VINYL CHLORIDE MONOMER AND OTHER CHEMICALS Clark W. Heath, Jr., H.D. Cheryl R. Dumont, M.T. (ASCi'J1 John Cambio, I'h.D.2 Richard J. Waxwcilur, M.S.I.E.* ^Cancer and Birth Defects Division, Bureau of Epidemiology, Center for Disease Control, Public Health Service, U.s, Department of Health, Education, and Welfare 1000 Clifton Road, N.E. , Atlanta, Coorgia 30333 ^Occupational Health Studies Croup, University of North Carolina at Chapel Hill ^National Institute for Occupational Safety and .Health, Center Tor Disease Control, Cincinnati, Ohio 45226 36 <* f APOOO10459 09KM000dV ii a CtCOC ciSaono `inucnv `3'N 'PCOH tiojjna 009T 1013UOJ 03l!Otn JOJ 4J5U30 /'.toiojuivip-fcljt ] ncaing uo|fjATC! uuoj.-a Pl5tf jo^aojjg `q,H * *Jf `uinon `fj h-,bI3 J1 sjoojd ptg 0PT^"T'lD T<^`TA Puu xauicsowoji]^ :pe.q 3ujMini>i Z i r Chror*>ynm.' and Vinyl Chloride - Ite.-ilh # 3 Introduction Data from various sources suggest ih.it tho biologic effects rf vinyl chlorido monomur (VCM) include lautagetiiei l y .is well as onco genicity. Pertinent studios include observetiunr; concerning the mutagenic effects of VCM in bacterial test systems (Kannug, et cl, 1974; tarts eh, Mnlaveillo, and Moutrnauo, 1975), mutagenicity of VCM metabolites in rcnminaliau cells (Hubem-m, ltartoch, end Sachs, 1975), and cytogenetic studies of polyvinyl chloride (PVC) polymeriaat ion workers (Uucatman, Ib'.rsclihorn, and Selikoff, 1975; Kunes-Crovioto, et ol, 1975; Kilian, Piccianc-, and Jacobson, 1975; Purchase, Richardson, and Anderson, 1975). Also relevant may be observations suggesting increased fetal loss in families of FVC workers (Infante, et al, 1976). Among 'the several cytogenetic studies reported, 3 have suggested increased chromosomal breakage among polymerization workers (hucatsan, Hirschhorn, and Sciikoff, 1975; Funus-Crnvioto, ec al, 1975; Purchase, Richardson, and Anderson, 1975), and one has not (Kilion, Piceiano, and Jacobson, 1975). This report concerns cytogenetic 'analyses conducted on workers employed at a rubber and plastics plant, some exposed to VCM and others not. . * K" ite rials1 .a..n..d..M...e...th...o..d.s The work described here was.port of a crois-acctionai study - designed to provide multiphasic medical screening data on tho health status of men employed at. a largo rubber and plastics plant. Tho 33. * S APOOOf0461 r I Cliromusouies and Vinyl Chloride licnth 4 overall study was conducted jointly by die Center for Disease Control (CUC) (National Institute for Occupational Safety and Health and Bureau of Epidemiology) and die Occupational Health Studies Croup of the University of North Carolina in cooperation with the Firestone Corporation and the United Rubber Workers. Results of the entire Study, together with a detailed description of the study's design ond Methodology, will be published separately'. Cytogenetic analyses, primarily designed to Pleasure frequencies of chromosomal breakage, were pnrforwud on peripheral blood lympho cytes from 33 men; specimens were obtained frotu 18 men in October 1974 and 19 in January 1975 (2 on both occasions). Subjects were restricted to non primarily or exclusively employed for 10 years or longer, in 3 different employment categories: 14 in FVC polymerization (presumed high exposure to VCM, intermittent or sustained), 4 in PVC 'processing (presumed .low exposure to VCM), and 17 in rubber tire manufacture (industry controls; presumed negligible exposure to VCM). Work his tory details were obtained by interview and confirmed by review o coepany records. Initially, the study was designed to compare breakage frequencies in workers exposed to VCK with frequencies in other workers. How-, ever, when initial analyses showed no significant differences among worker groups, a control group was selected (April 1975) consisting of 4 mole employees at CDC not exposed directly to any laboratory . ' 39 . AP000I0462 r *CliroiMfiowes .uiJ Vinyl Chloride.- Heath elieulcAls. UaLcrl.nl for cytugcuolic analysis was prepared In the name pnrncr with Lite same reagents as Lite earlier material from workers at Lite pique* To assess comparability in microscopic reading of elides bclwv.cn April 1975 and the earlier dates, previously-read slider from Lite high VCM and industry control groups were blindly interspersed autnng Lite C)>C worker slides. Breakage frequency recorded on the second reading of high VCM/industry control slides (0.0a of 150 scored moi.iphaucs) did not differ significantly from the first reading. Cytogenetic material was processed using standard procedures (Moorhead, et ol, 1900). Cells were cultured for 72 hours in the presence of phyLohCBtagglitliniu. Cicinsa staining was used without banding. Rcsults Frequencies of chromosomal breakage in each group are shown in Table 1. Levels of breakagu in all 0 industry groups, whether ex posed to' VCM or not, were significantly increased over the CDC con trol level, the high'VCM group at the p <0.01 level, the low VCM and industry control groups at the p <0.05 level. At the'same time, no significant differences were noted botwoan the 3 industry groups themselves. Croups were comparable in terms of age and number of * month* worked. Breakage frequencies for individual subjects within . groups did not vary significantly one from another. 40 AP00010463 UjV-.fU ' ChtoiunnorK.1!. and Vinyl Chinrldo - Ihvith An clfurt was anih* to rr.-lali! levels of breakage to duration of omployiitcni. and lienee extent of potential toxic exposure (Table 2). While a significant gradient was seen for indusuy controls, inter pretation lo uncertain because of small nurtbcirs and because the u\can ngc of uubjoccH increased with employment duration. No gradient was seen for the high VCM group, whether in terns of total employment , or of employment in contact with VCM. The low VCM exposure group was too small to permit analysis by exposure duration. i Chromatid gaps comprised the r.jjnrity (80%) of aberrations seen (Table 3). Similar types of aberrations were seen with similar frequencies among all 4 groups. Discussion Mien reviewed in terns of comparisons between worker and non*-' worker groups, the present obr-ervatjons are not inconsistent with prior studies suggesting that industrial exposure to VCM is associated with an approximately twofold increase in levels of chroroosope breakage as measured in culture of peripheral blood lymphocytes. In concrasc with at least one prior report (Huberaan, Bartsch, and Sachs, 1975), however, breakage'consisted mostly of simple chromatid gaps rather than more complex forms. . 'The fact thee overall breakage levels were similar In workers exposed heavily, lightly, or negligibly to VCM may imply, in this 41 AROdOt 0464 r Chromosomes and Vinyl Chloride - Heath particular work setting at leant, the presence of agents other than vcm capable of inducing chromosome breaks, Because of the wide range of chemicals to vMch rubber workers at this pl.-mt weve uxpoued (primarily solvents of various kinds),, it was impossible to relate any particular agents to the abnormal effects observed. Ko clear-cut pattern was soon to relate degree of breakage to duration of exposure.' Summary Measurements of chromosomal breakage were made in peripheral blood lymphocytes from workers exposed heavily, lightly, or negl igibly to VCM at a large rubbcv/plnstic* plant. Breakage, levels in all 3 groups wars significantly increased over level* in ncnindustrial controls. Breakage connistud mostly of simple chromatid gaps. The results succecc that ocher agents, in addition to VCM, nay cause cytogenetic damage `in workers employed in the rubbcr/plastics industry. 42 r APOOO10465 99*0I000IV e> V 9auP3sp;vv oajAjiw xvnpcTamfi aoj i{'jjo.nvnon njtaf *jh put .ioij J3 uostprf rjqoq *jj|j ^itvq^.oi qsyA. oft TiTTcui.j;i|>5> two11 y |3i'31t - opT^TM3 T^nTA P'li? snuiouowoatft ( j Chromosome* and Vinyl Chloride - Ueatli References lSartsch, It., Kilavelllc, C., and liontosano, k. (1975). Human, rat. and mouse liver-mcdLaled mutagenicity of vinyl chloride in S. Typhimuvluin strains,. Int J Cancer 15:429-437. Uueatman, A., Hlrschhorn', K., and Sclikoff, J.J, (1975). Vinyl chloride exposure and human chromosome aberrations. tluti Ren 31: 163-168. , 4 Fimet-Cravioto, F., Lambert, B., Llndscen, J., eC al (1975). Letter to editor. Lancet 1:459, Hubcixun, E., Bnrtscli, H., and Sachs, L. (1975). Mutation induction in Chinese hamster V79 cells by two vinyl chloride metabolites, chloroethylcne ox^dc and 2-chloroacetaldohy<la. Int J Cancer 16: 639-646. Infanta, P.F., Wagoner, J.K., McMlchael, A.J., et al (1976). , Ccnecic risks of vinyl chloride. Lancet 1:734-735. Kilian, D.J., Fleclano, D.J., and Jacobson, C.B. (1975). Industrial Vpnitorlng: a cytogenetic approach. Ann NY Acad Scl 269:4-11. Moorhead, P.S., Nowell, P.C., Mailman, U.J., et al (1960). Chromo some preparation of loukocytcs cultured from human peripheral blood. Exp Coll Ulol 20:613-616. ' f .-44 APOOO10467 r , i I Clit'omeeemctf and Vinyl. Chloride * HcatU VurchAstf, I.V.H,, Kiehavdocn, O.K., and Anderson, !>. (1975). loiter to editor.' Lancet 2:410-411. Kannug U., Johansson A., Kamel, C,, and Waeheincis tor, C.A. (1974). Tito autnf.cnIcity of vinyl chlorldo after metabolic activation. Ambio >1194-197. . ` 45 AP00010468 l I Cliroiigaoiacs ami V in y l C H urM -.* rli APOOO10469 Hrt***V i 4 Table 1 REVELS OF CHRQH3S0SUL BREASAGE BY EXPOSURE C30G? i MeCephases Kusiber Average Average Nix&er Xurbet . Percent of Age of Month? Verked " XuTtaer with with Exposure Subleets (Rar.se) (Sense) Scored Breakage Breafce*e* High VCM 14 49.4 291.1 1105 ' 74 6.7 (44-65) (215-3*6) i a v . Low VCM 4 52.5 315.8 (46-53) (261-341) 180 14 7-3 . Industry Controls 17 48.5 (31-53) 303.8 (114-357) 1306 ' 77 5.9 *m C0C Controls *' 44.3 (37-51) - 586 21 3.6 * Levels of statistical significance High VCM vs. CDC Control Low VCM vs. CDC Control' Ir.duatry Control vs. CX Control High VCM vs. Low VCM High VCM vs. Industry Control X2 7.09 X2 4.6* X2 3-95 x2 - O.is X2 * C.31 p * < 0.01 P " < 0.05 ? e.C.05 ? - >-.0.05 p - > 0.05 i i \ \ *\ OZHHOOOdV to a: w ss <? c = s 19V *0-* rt S'2 o OF CHROMOSOMAL BREAKAGE IS RELATION TO EXPOSURE DURATION X U\i6UNIMMAF to VO so sss O?l?M?H to >o VO to,SO to fr !? M o | na XJJ rUr M lF/-l % oI-- I etuio xt X Ok M VO s| S O SO to VI *. CO cr u VwJ oM> wH & U MH in V V WN Ok VI V> IV o VI r t WW O o VI sr> x* V i CTk 1 * >r<> na fcAv O lit > :< o t y * r <n WA M *?> P A M si H VOI mS/l OO Ul s| v l^OO M 5< 2, HI(#1* A*1 O* *!' niu in Kw- :lrlti:' Ul V ii b w'I I*. I>ij n^u - "'I'D j/uj/t pm? oowouottioaiij Duvwyiiycitttf ;nil V Juyl C'liU *ri!i Him I I i APOOOf0471 Table 3 TYPES or CJSKttOSOXAL A3I33ATXCSS 03S2RVSD Cbroaososal Aberration . Chro-etid Ca?s Isochresstid Gaps Chto=atid breaks Isochronjtid Breaks ' /Isochror.3ttd Fragraats"*^ / Exchange Figures ' x Ring Chro~osor.es Total Breakage * Total Cells with Breakage Uypodiplold Cells Kyperdiploid Cells Total Cells 5cored Hlch VCM Nuraber Percent 59 *- 5,3 7 0.6 2 0.2 5 0.5 3 0.3 . 1 0.1 1 0.1 70 7.1 74 6.7 121 2. 11.0 0.2 1105 - Low vex Kursb c r Percent 12 6.7 00 00 2 1.1 00 00 00 14 7.S 14 7-8 33 18.3 00 180 - Industry Controls. Xtfsber ?erccnt 74 5.7 6 0.5 1 0.2 9 0.7 00 00 00 91 7.0 77 5.9- 155 11-9 3 0.3 1306 CDC Controls Kyrier Parran. 18 3.1 C.Z 2 0.3 1 G.2 00 00 22 3.8 21 3.6 61 10.4 1 0.2 366 - i BRTP.K MEDICAL JOURNAL 3A flffg L979 ^ 'y , Angijsarcoma of liver associated with phenelzine Angiosarcoma of the liver ia extremely rare.1 It hat been associated with thorium dioxide, organic arsenic, and vinyl chloride monomer.* Phenelzine (pbeneEhylhydnztoc; Nardil), a monoamine oxidase inhibitor, cause* angiosarcoma of the liver in mice.* We describe a woman who developed angiosarcoma while taking phenelzine. Case report A 64-year-old woman admitted for investigation ef anaemia gave e four* month history of malaise, bruising tendency, and cough productive of small blood dot*. She had been **amy pheaelslne for at lean six years. The initial dose wis 45 mg daily, which was reduced 15 mg daily after three yean. Diezepsm 5 or 10 mg occasionally was the only other regular medica tion. There wa* no history of exposure to thorium dioxide, artenie, or vinyl chloride. Examination showed pallor, generalised wpsoag, and several large bruises. The liver was enlarged and palpable. Full blood count showed haemoglobin concentration 7-8 g.dl, white cell count 7' 10M (7000.am*), platelet count 155 > 10*n (155 000 sun*), and reticulocytes 6*3 Blood film showed fragmentation of red cells. Prothrombin time, thrombin dotting time, and activated partial thromboplastin time were all prolonged. Con centration of fibrin degradation products (FDP) was 160 mg'T. Moderate haematuria was prestnt. Urea and electrolyte concentrations, Inidsl liver function tests, serum i-fctoproteia value, and bone marrow appearance* wereaortniL The hacmatological finding* suggested mild chronic disseminated intra vascular eoagolation (DIG). The baematuria and haemoptysis were ascribed to this process after exclusion of the* causes. Subsequent platelet counts ringed between 20 and 100 . 10* 1, and the raised tltrc of POP persisted. Isotope liver scan showed multiple areas of decreased uptake, and com puterised axial tomography of the liver confirmed arras of abnormal texture. Ia the lateral cpicondylc of the right humerus there was an oncolytic area suggestive of metastatic disease. Results of barium meal and excretion urography were normal. Laparoscopy of the liver surface showed multiple umbilicated nodules up to 2 cm diameter, unlike cirrhosis or metastatic carcinoma. Laparoscopic needle biopsies disclosed normal liver tissue with focal areas of bile-duct proliferation with large pleomorphic edit suggestive of malignancy. At laparotomy numerous haemorrhagic nodules were seen on the liver and parietal peritoneum overtying the right lobe. These wore sampled for biopsy. Histologically the liver showed distorted sinusoids lined by malignant cells aj|*ceat 10 the focal areas of bile-duct proliferation (see figure;. There was no evidence of cirrhosis. The peritoneal nodules comprised blood-filled spaces lined by malignant endothelial cells with pleomorphic nuclei. These changes were considered to be diagnostic of angiosarcoma. .'Ilf* ** * . * i ' F* VJf * . T - t*. * #1 >q Liver biopsy specimen showing distorted sinusoids lined by malignant cells. H and E v 840 (original magnification). r \C n 1679 in our patient may have been related to phenelzine. Ahhough such an association in a patient has not been recorded before, this may represent failure in documenting drug history. The presenting features of this cue were probably manifestations of chronic DIC, which is associated with liver angiosarcoma.* This process may havt contributed to the bloodstained udus. Naked-eye appearances of the liver were not diagnostic at laparoteopy or laparotomy. Primary liver tumour was diagnosed by multiple biopsy at laparotomy. Wt cannot be certain whether the peritoneal aagio- sarcomatous lesions and the lesion ia dm right humerus were metanates from a primary liver rumour or represented tumour growth, which Is true in experiments! animals.'4 We suggest that inquiry about hydrazine compounds---for example, phenelzine, Isonsazid, and procarbazine--should be made ia future cases of angiosarcoma of the Uver. W thank Professor P J Scheuer, Royal Free Hospital Medial School, for reviewing the histology; and Dr H McNulty, Regional Drug Information Service, Bristol Royal Infirmary. 1 Baxter, P J, it al, British Midica!Journal, 1978,2,919. 1 Ishak, K G, in Mtpoiocilhtlar Cardncm*, ed K Okuda and R L Peters*## p 247. New York, Wiley, 197*. . , J 9-J Toth, B, Conor Jhuartk, 1976, SI, 917. /) , / * Toth, B, Conor Rtuarth, 1975,35, M93. yL)jr (Acitpud 2 May Iff9) Bristol Royal Infirmary, Bristol BS2 8HW T K DANF^HMF?cn. mi, chb, senior house officer fat haematology fl L SCOTT) mo, rxer, consultant haematolofist j^tr n BB inpiEi-r^ phd, mkcpatk, consultant senior lecturer ia hiito- pathology Multiple lipomas in pregnancy Lipomas are bcnV tumours of adult fax cells. We report a ease in which multiple lipi its first appeared during pregnane)'. Case report Tht patient, aged 51, wee ih her second pregnancy. Her first pregnaaey, in 1975, bad ended in spontaneous abortion at 12 weeks. She had stopped taking a combined oral contraceptive In 1974 after two years' use. Her periods had remained irregular ever since. She was seen first at the antenatal clinic when 20 weeks pregnant. She was of normal build, with weight 532 kg ecd height 156 cm. Physical eaafniaarion showed no abnormality and ths pregnancy was continuing normally, the uterine size being as exported from the duration of amen* orrhoea. At her next visit at 2B weeks (ore being shared with her general practitioner; the mentioned isolated, sofkl'toaiafui subcutaneous swelling* on both forearms. These were about 2 cm diatneter and had been present for three weeks. Later, a funher six swellings ok the anterior aspects of her thighs became palpable. The swellings eomiauuLto enlarge slowly through out the rest of her pregnane)*, the largest, on her left forearm, teaching 3 ea diameter. Biopsy of a swelling on her right forearm showed the histo logical features of a simple lipoma. There was no vascular proliferation to suggest angiolipoma. The pregnancy wts otherwise normal: the gtined 10 She was delivered at 42 weeks by forceps of a healthy boy weighing 3400 gMa the immediate puerperiura the lipomas became tat end at tbc poitniuTcheck six weeks later all but a swelling 0*5 cm diameter on her left forearm ud disappeared. No lumps on her thighs could be seen or felt. She was breeW-fceding and had begun an oral contracaptive containing only progesterone So far as she knew none of her relatives had multiple lipomas. The patient recovered from laparotomy and the haenumria and haemopty,is lessened. Grots bloodstained ascites developed, however, which required drainage. She died at home five months after presentation. Comment In animals substituted hydrazine derivative* induce a variety of tumours, including tumours of blood vessels.' Phenelzine given to female Swiss mice significantly increased the incidence of angio sarcoma at various sites, including the liver.* Hence the angiosarcoma Comment \ Lipomas ste slow-growing, benign tumours of adipose tissue. Multiple tender lesions, especially if there is family history, at*, characteristic of angiolipcmas.1^ Though her lipomas were tender, \ she had no family history, and histopathologic*! findings were noc \ consistent with angtoiipomas. Lipomas are common, but this is apparently the first report of multiple lipomas appearing in pregnancy and regressing in the puerperiura. Possible explanations include; (a; that the hormonal AP00010472