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m of Occupati nal Medicine August 1974 Vol. 16 No. 8 Mortality Study of Workers in the Manufacture of Vinyl Chloride and its Polymers* Irving R. Tabershaw, M.D. and William R. Gaffey, Ph.D. Animal studies have shown that inhalation of vinyl chloride produces in rats angiosarcoma of the liver as well as cancers of the lung, kidney, skin and other sites. Although workers in occupations involving exposure to vinyl chloride have been found to have an increased risk of hemangiosarcoma, no excess of other cancers has so far been reported. This historical prospective mortality study of 8384 men who had at least one year of occupational ex posure to vinyl chloride before December 31, 1972, demonstrated that cancers of the digestive system (primarily angiosarcoma), respiratory system, brain, and cancers of unknown site, as well as lym phomas, occurred more often than expected in those members of the study population with the greatest estimated exposure. The mortality from other cancers was lower than that of the general male population, with the exception of cancers of the buccal cavity and pharynx. There was an excess of these cancers, which however was inversely related to estimated exposure. The explanation for the latter finding is not apparent. The other major findings of the study are: (1) The overall mortality of the study population was ap proximately 75% of what would be expected in a comparable population of U.S. males; (2) No cause of death showed a statistically significant excess over what would be expected in a comparable U.S. male population; and, (3) No deaths identified as angiosarcoma of the liver were found other than those previously identified. This is the first epidemiological study which suggests that in humans vinyl chloride may also be associated with cancer of multiple sites. Drs Tabershaw and Caffey are from Tabershaw-Cooper Associates. Inc.. Sutle 308, 6000 Executive Blvd., Rockville, MO 208S2. 'The research on which this report is based was supported by a group of companies engaged in the syn thesis and/or the polymencanon of vinyl chlonde, and administered in their behalf by the Manufacturing Chemists Association. Journal of Occupational Medicine/Vol. 16, No. 8/August 1974 CMA 013179 509 Vinyl chloride in its manufacture and polymerization has been identified as a narcotizing agent,1 as a liver toxtn,2 3 and as a vasospastic agent producing a specific occupational disease, acroosteolysis,4 Recently, vinyl chteride has been incriminated as a carcinogen producing in a group of workers engaged in the manufacture of polyvinyl chloride a rare fatal liver tumor, hemangiosarcoma.5 Large doses of the chemical in rats reportedly produced cancer of the skin, lung and other organs,4 Unpublished but public in formation7 indicates that inhalation ex periments with rats in doses easily reached in manufacturing operations produces in addition to angiosarcoma of the liver, skin, kidney and other malignant lesions. The present study, however, was not restricted to the conditions and sites suggested by the above investigations, but concerned itself with the entire spec trum of causes of death, to the extent permitted by the size of the study group. The obiectives of the study were: (1) To compare the mortality of individuals who have worked in vinyl chloride plants with that of the general population; (2) To compare mortality patterns within the population of vinyl chloride workers, based upon estimated occupational exposure; and (3) To com pare mortality among vinyl chloride workers with the mortality of other oc cupational groups. The study population consisted of in dividuals from 33 plants who had worked for at least one year in a job in volving exposure to vinyl chloride before December 31, 1972, and included retired and terminated as well as active workers. For each such worker the date of birth and an employment history were obtained, and the vital status of the worker as of December 31, 1972, was ascertained. For those found to have died, those death certificates that were available were obtained and the cause of death determined. The observed mor tality was compared with that of the United States male population. particularly those producing the monomer, this determination could be made on the basis of |ob titles. Usually, however, exposure was a function of both job title and the location of the |ob in the plant, so that the assessment of ex posure had lo be made on a case-bycase basis by plant officials. Data were collected for as far back in time as complete records were kept. In most cases this covered the entire history of the plant. In others, records were kept for a fixed period such as a decade. In a few, records were kept for different periods, depending on whether the worker had died on the job or had left employment. In most plants it was impossible to quantify exposure. However, industrial hygiene and safety personnel in each plant were able to identify certain jobs and locations as involving the highest exposures in the plant, and to classify other exposures as medium or low relative to the "high" represented by the jobs with the greatest exposure. Con sequently, each exposed job in a worker's history was scored 1, 2, or 3 to indicate low, medium or high estimated exposure. This gross classification has two maior failings, as a result of the subjective nature of the estimates. The first is that the scores represent estimated relative exposure within a given plant. It is therefore possible that, in obiective terms, a "high" score in one plant corresponds to a "medium" or even "low" score in another. The second is that the scores usually do not take into account changes in exposure over time. A worker with long service may therefore have had jobs in the remote past which involved "low" exposure relative to other |obs at that time, but which might be "high" in comparison with current exposures in the same job. This subjective classification is therefore of questionable validity in characterizing the exposure of a given worker. For epidemiological purposes, however, those who have high scores can reasonably be expected, on the average. to have had the greatest exposure, while those with low scores will have had the least, even though the true exposure in each group may vary considerably from person to person. The estimated exposure history of each worker was summarized by calculating an Exposure Index (El) This was done by multiplying the number of months on each |ob by the exposure score, totalling these overall exposed jobs, and dividing by the total number of months of ex posure. Follow-up of Study Population A follow-up procedure was instituted for those who had left employment and whose vital status could not be deter mined at the local plant, using direct mail follow-up and retail credit bureau investigations. Table 1 shows the vital status of the population as of December 31, 1972. Follow-up is 85% complete. Those who were not found were bom (and began their exposure) about ten years before the group on which follow up was complete, and had about half the duration of employment in exposedjobs with a slightly higher El. Although there appears to be nothing very unusual"about this group in terms of work history and exposure, it is nevertheless true that their exposures took place further back in time than that of the group suc cessfully traced. It is therefore possible that their mortality, after a substantial latent period, might show a somewhat different pattern from that of the traced group. All of the subsequent analysis is con cerned with the 7128 workers on whom follow-up was complete. Table 2 shows their distribution by duration of exposed employment and the year in which that employment began. Although almost half the study group first entered ex posed employment in 1960 or later, there are nevertheless 854 workers with 20 years or more exposure, and 1640 with 15 years or more. Table 3 shows the relationship between duration of ex posure and El. There does not appear to be a close relationship between the El Data Collection In each plant, data were collected for each worker stated by the plant management to have been employed for at least one year in a |ob involving ex posure to vinyl chloride. In some plants, 510 Numbsi PlICMt Tiblt 1. -- fottaum# Status at I3M tflaif CMtrM* Worksrt. TtUI Alva DM4 IMm* 1314 6776 3S2 100.0 Ml 4.2 1254 15,0 Owtk CsrUHotM lei Mac Use'S. 321 24 921 7.3 Mortality Study of Workers in Manufacture of Vinyl Chloride/Tabershaw, Gaftey and the duration of exposure, that is workers with a higher El do not differ substantially in duration of exposure from those with a lower El. One im plication is that in assessing the relation ship between mortality and Exposure, both duration and level of exposure can be examined separately, as well as m combination. Calculation of Risk of Death The risk of death is expressed as a Standardized Mortality Ratio (SMR), which is the ratio of the number of observed deaths in the study population to the number of deaths to be expected in a comparable population of U.5. males SMR's were calculated for overall mortality and for 33 major cause groups. Table 4 shows observed and expected deaths, and the SMR, for each of these causes for the total study group. In calculating the SMR's for specific causes, the 24 deaths for which no certificates were found were assumed to have the same cause distribution as those for which certificates were available. In the standard population, each SMR would be equal to 100. Therefore, the statistical significance of the deviation of each 5MR in the study population from the expected value of 100 was tested.8 A single dagger indicates those SMR's which differed significantly from 100 at the 5% level, that is, which had a probability of 05 or less of occurring by chance. A double dagger indicates those which were significant at the 1% level. SMR's based on fewer than five ob served cases were not tested for significance. Table 5 shows the same SMR's for workers with an Exposure Index below 1,5 versus those at 1.5 or above. The dividing point of 1 5 represents a level halfway between "low" and "medium." Table 6 shows similar results for workers with less than- five years ex Tobta 2. -- DiotriMtan of Norths Ht Ei*m*9 Emptayiaort by Yoor in NMdi Eipoouro Botox tar 7121 Vinyl Cktartat Norton witt Conptat* Fdtav^y. 1m IsoStart* 1930-39 194049 1950-59 1960-09 197071 Total Total 39 1049 1962 3369 715 7121 <10 2 139 399 1714 715 2995 10119 4 93 257 1442 120179 1 119 393 195 MMttl if tlplfft 110-239 240-299 300-399 4 6 13 151 277 237 131 292 360419 5 34 1796 690 796 S6S 250 39 ItaaoKo 2 20 17 39 posure versus those with five years or more. In order to examine the possible in teraction between duration and level of exposure, the study population was divided into four groups on the basis of both El (low vs high) and duration of ex posure (short vs long) using the same dichotomization as Tables 5 and 6. Table 7 shows the results for short ver sus long exposure in the low El group, and Table 8 shows the same comparison in the high El group. In each of the above tables, deaths for which certificates had not been received were assumed to be distributed as a uniform percentage of all causes. The cause specific SMR's were therefore adlusted upward by a percentage which varied in each subgroup. Results of Analysis The overall mortality of the study population is statistically significantly lower than that of the U.S. male population. There were 352 observed deaths compared with 467 expected, for an SMR of 75. Table 4 shows that no specific cause of death was statistically significantly greater than expected. Several, par ticularly heart disease, accidents and "other diseases" not detailed in the tables, were significantly below their ex pected values. When the study population is divided according to intensity and duration of exposure (Tables 5 and 6) and com binations of these measurements (Tables 7 and 8) three major patterns emerge For malignant neoplasms as a whole, the 5MR increases with increasing ex posure, whether measured by level, duration, or both. In the high exposure group with 5 years or more exposure (Table 8) there are 36 observed cases and 26.11 expected. For cardiovascular -- renal diseases as a group! there are also increases in the 5MR with increasing exposure, but the numbers of observed cases remain less than expected, the differences being statistically significant in all groups ex cept the high exposure, long duration group in Table 8. For all other causes, there are no con sistent relationships with exposure. Within the malignant neoplasms, the largest (although not statistically) significant SMR is in cancers of the buc cal cavity and pharynx, with five ob served, 2.84 expected, and an SMR of 189. However, Tables 5 to 8 show that all these cases have Exposure Indexes below 1.5 and four out of the five have less than five years exposure. Table 10 is a listing of these deaths with age at death, duration of exposure, and cause as stated on the death certificate. Cancer of the digestive system shows Eiponiro InOts 1.0-1.4 1 5+ Unknown Total Ttbta 3. -- No. oirt % of 7121 Yioyl CMorMo Norton by Months of Espoo* Emptaymoot h4 Espoowo Max. Mootto W tootaoi rotif Nl % 4032 (100) 3057 (100) 39 7129 (100) <90 Ita ( 1715 (43) 1240 (41) 60111 Ita. t 1125 (29) 671 (22) 120179 Ita. 5 402 (10) 295 (10) 110123 Ita. % 406 (10) 390 (12) 240-299 Hi % 247 (7) 291 (10) 30035* Ita. % 92 (2) 159 (5) 360419 Ita IS (0) 21 (1) 2155 (41) 1796 (25) 517 (10) 790 (11) 5*5 (1) 251 (4) 39 (1) Unkoiwo 39 19 (1) journal of Occupational Medicine/Vol. 16, No. 8/August 1974 CMA 013181 511 1 i Tablt 4. -- Obsantd DuttoEiptetri Dtatta and Standardiitd Mortality litits in lwyl Chloriba Worktra. Cmm * not11 LCD. NumPer II cann Tuberculous (001-019) Tuberculous of rssotrstory system (001-008) Milifnmt neoplasms (110.205) Milifnint neoplasms. buccal cavity liX ptaryiii (140141) Milipint neoplasms. dipstive oriens anJ"'peritoneum (150159) Milipenl neoplasms, respiratory system (160-164) Milipint neoplasms, renital orpns (170-179) MilipMt neoplasms. unnsry or|Mii (190-111) Milipint neooleims. other ifld unspecified Slttl (190 199) leukemia inp ileukemn (204) Lymphomas (200 203. 205) Onhetes mellitus (250) Maim cardiovascular and ransl diseases (330 334. 400-466, 592 594) Vascular lesions affecting CHS (330-334) Rheumatic fenr 6 chronic rheumatic hiart dis. (400-402, 4)0416) Arteriosclerotic heart disuse (420) Nonrheumatic endocarditis (421. 422) Hypertpsne heart disease (440443) Other hypertensive disease (444447) Chronic 6 unspecified nedhritis 6 renal sclerosis (592-594) Influents and pneumonia (410493) OfisXip 151/467.21 1/5.71 1(5.34 79/77.16 5(2.84 19(21.67 25(23.93 3/3.55 1(3.60 17/11.75 3/3.77 6(6.06 7/6.31 155(207.46 13/24.48 5(6.87 121/137.33 1(6.58 3,5.33 3/2.60 0/427 Sfl.96 Ulcer of stomach and duodenum (540. 541) 2/3.83 ) AppendwtiS (550-553) Hania and intestinal obstruction (560. 561, 570) ... .. . 0(0.66 i/1.51 . Gastritis, duodenitis, enteritis and colitis (543. 571. 572) Cirrhosis of livtr (581) Hyparplisil of prostata (610) Symptoms, senility snd id-defined conditions (760-795) 1/U1 3/15.80 041.39 1/7.34 All other diseases (residual) 21/45.71 Motor vehicle accidents (810-635) Other accidents (800-602. 640-962) 17/32.70 18/30.64 Suicide (953. 970 979) 16/16.13 Hdmiade (964. 980-985) No, f workers Pirson-yurs 1/11.98 7121 77140 SMI* 75 * is 20 no 169 94 112 91 30 155 85 106 120 80 * 57 * 78 95 16 35 124 0 54 7 56 0 71 62 21 01 15 49 r 56 * 63 * 102 9 4 SMR's idiustrt for deth* with tiutt unknown. tSijnifieint at 51 level - Significant at 1% level no excess in the study population as a whole. However, in those workers with an El of 1 5 or higher, there are 12 ob served cases where 9.14 are expected (Table 5) In the subgroup of the above workers with five years or more ex posure, there are 11 observed cases and 7 47 expected Respiratory cancer shows a slight ex cess in Ihe total group, and a similar pat tern for different exposure categories, with 13 observed versus 10 28 expected when the Exposure Index is 1.5 or higher, and 12 observed versus 8.50 ex pected when, in addition, the duration of exposure is five years or more. 512 Malignant neoplasms of other and un specified sites show an excess in the total group, and an increase with both level and duration of exposure (Tables 5 and 6). The relationship with exposure is more pronounced, since those with ex posures of less than five years have fewer cases than expected. The lymphomas, although occurring at about the expected rate when the whole group is considered, are concentrated almost entirely in the high exposure, long duration group. In that category there are four cases observed and 1.84 expected. Cancers of the genital and urinary organs, and leukemia, have fewer cases than expected. The number of cases is too small to examine any trends. Discussion The favorable overall mortality of the study population is a phenomenon com monly observed in working populations. Standardized Mortality Ratios in the low 80's and below have been found.' 10 Even in occupations with well defined hazards which cause an increased risk from a specific cause, the overall mor tality may still be favorable because of the low risk from other ma|or causes of death, frequently in the cardiovascular -- renal category." Mortality Study of Workers in Manufacture of Vinyl Chloride/Tabershaw, Gaffey CMA 013182 Table 5. -- OOsenind OeathJ/Tipncted Deaths and Standardiitd Uortatity Katins in Vinyl Chloride Wwteri, by Estimatnd leunl of Eipotare. Can* tl Owth until LC.D. Ha, ObvExp El < U sm* Obtj El -11.5 suit- Ut Censes ----- in/270.33 70 * 157/195.6* 10 * Tuberculosis (001019) ^ Tuberculosis of respiratory system (00M08) 0/3.38 0/3.16 0 0/2.33 0 0/2.1* 0 0 Milifnint neoplasms (140 209) Malignant neoplasms, buccal cavity and pharyna (140-148) Malignant neoplisms. digesltve pm ind peritoneum < 150-159) Malignant neoplasms, respiratory system U60-1M) Malignant neoplasms, genital organs (170-179) Mihinint neoplasms, urinary orpns (180-181) Milignint neoplasms, oilier end unspecified sites (190-199) Leukemia and aleukemia (204) Lymphomas (200-203, 205) 37/44.26 5/t,62 7/12.50 11/13.56 2/2.30 1/2.07 9/6.57 1/2.16 1/3.46 90 330 60 f 86 93 51 146 49 31 41/32 67 0/1.2! 12/9.14 13/10.2* 1/1.43 0A.52 8/4.52 2/1.57 5/2.54 134 0 141 135 75 0 190 136 212 Diabetes methtus (260) 5/3.65 146 2/2.65 81 Miior cardiovascular and renal disuses (330-334, 400468, 592 594) Vascular lesions ittecting CNS (330-334) Rheumatic fever & chronic rheumatic heart dis. (400402, 410416) Arteriosclerotic heart disease (420) Nonrheumatic endocarditis (421, 422) Hypertensive tuart disease (440-443) Other hypertensive disease (444447) Chronic 4 unspecified nephritis 4 renal sderana (552-594) 84/120.11 7/14.42 373.98 66/71.54 0/4.20 1/5.4* 1/1.52 0,2.50 75 * 52 80 92 0 19 70 0 69/86.95 6/10.06 2/2.15 51/58.05 1/2.19 2/3.66 2/1.07 0/1.77 *5 * 64 75 95 3* 56 201 0 Influenia and pneumonia (480493) 5,5.60 92 0/4.13 0 Ulcer <H stomach and duodenum (540. 541) 1/2.21 4* 1/1.60 68 Appendicitis (550 553) 0/0.35 0 04U7 0 Hernia and intestinal obstruction (550. 561. 570) 041.61 9 14)63 171 - Gastritis, duodenitis, enteritis and colitis (543, 571. 572) 0/0.76 0 14)55 196 Cirrhosis of liver (581) 2/6.50 23 1/6.64 16 Hyperplasia ol prostate (610) 0/0.25 0 0/0.14 0 Symptoms, senility and ill-defined conditions (780-795) 0/4.22 0 1/3.09 34 All other diseases (residual) Motor vehicle accidents (810-835) Other accidents (800-802, 840-962) 14/21.50 8/15.0* 11/17*3 6* + 45 * 66 * 6/15.89 9/13.46 6/12.67 41 * 72 50 * Suicide (963, 970-979) 5/5.73 9* 7/7.02 107 Homicide (964 . 960 965) 0/6.51 0 1/4.94 21 No. of fvln tvsm-ywi 4032 45354 3057 32106 * SMS'! jdtusred for deaths with cause unkmnvn r-Significant at b% level ^Significant it 1% level In view oi these facts, SMR's which are higher than expected may be worthy of attention even if they are not statistically significant. This is especially true in the present study since the num ber ot deaths from many causes is quite small, and even a relatively high SMR may not reach statistical significance. If, in addition, a particular cause shows a consistent pattern of increase with exposure or estimated exposure, the findings are particularly interesting. By these criteria, mortality from digestive cancer, respiratory cancer, can cer of other and unspecified sites, and lymphomas, appear to be related to ex posure as defined in this study. In view of the association between vinyl chloride exposure and angiosar coma of the liver, the digestive cancers were examined further to see what con tribution angiosarcoma made to the ob served mortality pattern. Of the 19 digestive cancers, seven were liver cancers, of which two were angiosarcomas according to the death certificate. However, among angiosar coma deaths in vinyl chloride workers identified by other investigators, there were six which occurred in the present study population during the study period They were all found in the course of the study. Table 11 shows these cases with the cause of death as given on the death certificate. Note that one case was certified as cirrhosis, and was so considered throughout this study, since the validity of comparisons with population data required that cause of death be determined only from in formation on the death certificate The other five were correctly classified as Journal of Occupational Wedicine/Vol. 16, No. 8/August 1974 CM* 013183 513 Table 6. -- Observed Deaths/Eipedad Deaths tnd Standardized Mortality Ratios in Vinyl Chloride Workers by Duration of Eipostd Employment Cause et Death with LC-D. Mo. Ohtlsp ' 64 months SMO* L 60 months Ofas/Eip SUIT *11 uusns 94/144.63 67 * 251/329.30 76 Tuberculosis (001-019) Tuberculosis of respiratory (001 008) 0/2.23 0/2.07 0 0/3.55 0 0/3.33 0 0 Milrgnsnt neoplasms (1*0-205) Malignant neoplums, buctsl curly ind cbltyni (140-148) Malignant necplisms. digestive organs inp peritoneum (150-159) Malignant neoplasms. respiratory system (160-184) Malignant neoplisms. yenitsl ornns (170-178) Militiunt nebplitms. urinsty organs (180-181) Mslifnint neoplisms, otlrer nut untpectfiep situ (190-189) Leukemia tnd aleukemia (704) Lympbpmu (200-203. 208) 13/19.96 4/0.70 2/6.26 3/5,62 0/0.99 0/083 2/3.40 1/1.25 1/2.01 71 65/57.61 688 1/2.16 46 17/16.66 66 21/18.51 0 3/2.76 0 1/2.79 71 15/8.23 96 2/2.53 60 5/4.07 116 47 106 116 112 37 167 81 126 Dubetn mellitut (260) 2/1.80 134 5/4.64 113 Major cardiovascular tnd ttnel disuse (330-334, 400468, 692-684) Visculir lesions affecting CHS (330-334) Rheumatic few 6 chrome rbeumttic burl dr*. (400402. 414418) Afterrostlerotic hurt disuse (420) Nonrheumetic endcurditis (421. 422) Hypertensive bent disnsn (440443) Other hypertensrvn driust (444447) Chronic 1 unspeahed nephritis 8 renil sclerosis (692-694) 28/61.45 4/5.97 2/2.39 21/32.54 0/1.79 1/2.42 0/0.79 0/1.55 65 * 125/157.39 - 81 ... .... 9/18,71 ij. 101 78 * 3/4.53 98/106.39 0 1/5.35 49 2/7.01 0 3A .82 0 0/2.76 81 * 49* 68 96 20 30 170 _ 0 Inhuenu ind pneumonn (480493) 3/2.93 123 2/7.09 29 Ulcer of stomich ind duodenum (640. 641) 1/1.07 112 1/2.78 37 Appendicitis (660 663) 0/0.24 0 0/0.43 0 Hernia and intestinal obstruction (560. 561. 570) 0/0.42 0 1/1.10 93 Gastritis. duPdemtis. enteritis end colitis (643. 671. 672) 1/040 301 0/0.92 0 Cirrhosis of liver (581) 1/4.49 26 2A1.18 18 Hyperplasia of prostate (610) 0/0.07 0 0/0.33 0 Symptoms, senility and ril-deftned conditions (780*795) 1/2.29 53 0/5.09 0 All other disuses (resrdpil) 4/11.97 40 16/26 34 63 * Motor vehicle accidents (810-835) Other iccidents (800-802. 840-962) 107)6.14 7/12.94 75 65 + 7A6.65 10/17 82 43* 58 + Suicide (963. 970-979) 66.34 114 10AQ.28 100 Homicide (964 . 980 986) 1/5.80 20 0/6.20 0 No. of Workers Rarsan-yura 2995 34201 4114 41240 SMR's adjusted tor deaths with cause unknown. ^Significant at 5% level Significant at \% level 514 Mortality Study of Workers in Manufacture of Vinyl Chloride/Tabershaw, Gaffey CMA 013184 Tibi* 7. -- Obumd D*iths/Eipct*d Dditln tixl Stendardiud Mortality Ritist i Vinyl CMorido Workers aith Esposure Indices Bale* l.S, by Duration of EipottO Employment Cause at Oaatk nth LC.D. No All Causes Tuberculosis (001019) Tuberculosa of respiratory system (001-008) Maliynant necplBsms (140-205) Maliinant neoplasms, buccal caxty and pbaryni <140-148) Malipiant neoplasms. diftatiw oriina and peritoneum (ISO-159) Mall(nant neoplasms. 'aspirator? system (160*164) Malijnanl neoplasms. jenrtal orfins (170-179) Miliynint neoplasms. uniury orjans (180181) Malitnant iwoptssms. otlset and unspecified sitas (190-199) Leukemia and ifeukamta (204) Lymphomis (700-203, 70S) Oradetes mellrtus (260) Maior cardiovaseglir and renal diseases (330-334. 4004(3. 592 594) Vistula! lesions aHectiny CNS (330-334) Rheumatic few 4 chronic rheumatic heart dt$. (400402. 410416) Arteriosclerotic hesrt Slant (420) feonrheumattc endocarditis (421.422) Hypertensiyt Peart disease (440443) Ollier hypertensive disuse (444447) Chronic 3 unspecified nephritis 3 renal sclerosis (592-594) Irtflueiwa and pneumonia (480493) Ulcer of stomach and duodenum (540. 541) Appendicitis (550 553) Hernia and intestinal obstruction (560. 561. 570) Gastritis, duodenitis, enteritis and colitis (543, 571, 572) Cirrhosrs of liver (581) Hyperplasia ol prostate (610) Symptoms, senility and ill-defined conditions (710-795) All other diseases (residual) Motor vehicle accidents (810-83S) Other accidents (800 802. 840-9(2) Suicide (983. 970 979) Homicide (9(4 . 980-985) Fto, ot Workers PersM-years < (t Mantbs Enaafr Ohs/Esp 3W 56/19.23 0/1.41 0/1.31 8/12.86 44)45 1/343 2/3.51 010.(3 0/0.55 110.97 0/0.79 0/1.26 2/1.15 21/33.33 2/3.93 2/1.50 16/21.14 0/1.13 1/1.53 0/0.50 0/0.97 i 3/1.86 0/0.63 0/0.15 0/0.27 0/0.26 1/2.80 0/0.05 0/1.43 4/745 3/9.87 3/7.98 3/403 0/3.55 (It 0 0 73 1036 34 (5 0 0 120 0 0 203 73 59 155 33 0 74 0 0 188 0 0 0 0 42 0 0 (3 35 44 36 0 1715 21413 .160 Months Capdsart Obtflt SMN* I32/IIUI 0/1.97 0/1.85 29/31.46 l/l 17 6/9.08 9/10.00 2/1.62 1/1.53 8/4.43 1/140 1/223 3/2.50 63/36.32 5/10.51 1/249 -52/57.87 0/3.02 0/3.90 1/1.02 0/1.53 2/3.95 1/1.53 0/0.24 0/0.61 0/0.51 1/6.09 0/0.20 0/2.79 10/12.92 5/9,22 6/9.85 6/5.66 0/3.43 73* 0 0 95 88 68 93 127 67 187 73 46 124 75 * 49 f 41 93 0 0 101 0 53 67 0 0' 0 16 0 0 79 56 83 109 0 2317 23920 ' SMR's adjusted lor deaths with cause unknown 'Srgruficjrtt at 5% level 'Significant at 1* level Journal of Occupational Medicme/Vol. 16, No. 8/August 1974 CNA 013185 515 Tsblt 1. -- Obstnmd OoathitjpKtbd Deaths ind Stindirdittd Mortality Ratios in Vinyl Chloride Workers with Exposure Indico* o1 1.5 or Grutor, by Ouratiom ol Eiposod Employment Cwim ol Dead wits ICO. he HI Causa Tuberculous (001-013) Tuberculosis o( respiratory system (001-008) Malifnant neoplasms (140-205) Malifnant neoplasms, buccal canity and pbaryos (140-141) Malifnant neoplnms. diftstnn ortans and peritOMvm (150159) Malifnant neoplums, tupirstpry system < 160-164) Mailifnsnl neoplssms. pnital otpris (170-179) Malifnant neeplasms, urinary orfMS (110-111) Malifnant neoplasms, other and unspecified sues (190-199) Leukemts wd Uevkemii (204) |. Lymphemu (200-203. 205) Diabetn mellitus (260) Major cardinascular and renal diseases (330-334. 400-461. 592-594) Vascular lesions affectmf CNS (330-334) Rheumatic fever 1 chronic rheumatic heart dis. (400-402, 410416) Arteriosclerotic heart disease (420) Nontheumstic endocarditis (421, 422) Hypertensive heart disease (440443) Other hypertensive disease (444447) Chronic 4 unspecified nephritis 6 renal sclerosis (592594) InftiMMi md pntumonit (480493) Ulcer o( stwruch tnd duodenum (540. Ml) Appendicitis (550-553) Hernia tnd mtwtmsl obstruction ($60. 561. 570) Gastritis, duodenitis, enteritis and colitis (543. 571, 572) Cirrhosis of liver ($81) Hypcrplisii o( prostate (610) Symptoms, senility and ill-dtRned conditions (780795) All other diseasa (residue!) Motor vehicle accidents (610-935) Other accidents (800-602, 840-962) Suidde (963. 970 979) Homicide (964. 980-965) he, ol Norton haraoft-Yaerl 160 Months Exposure ObtXsp SMR* 38/47.93 79 08)76 0/0,71 0 0 5X.57 0/0.23 1/1,67 1/1.79 0/029 0/0.26 1/1.13 1/0.44 1/0.71 96 0 76 71 0 0 107 288 178 0/0.61 7/16.54 2/1.87 0/0.82 5/10.41 0/0.57 0/0.76 0/0.27 0/0.54 0 54 * 135 0 61 f 0 0 0 0 0/099 0 1/0.35 362 0/008 0 081.14 0 1/0.14 904 0/156 0 0/0.01 0 1/0.80 158 0/4.02 0 7/6.05 146 4/4,73 107 3/2,40 158 1/2.11 58 1240 12821 2. 60 Months Etposurs Ohs/Esp SMR* 119/147.81 81 ' 0/1.57 0/1.48 0 0 36/26.11 083.99 11/7.47 12/8.50 1/1.41 0/1.26 7/3.51 1/1.13 4/1.84 141 0 151 144 73 0 204 90 222 2/2.04 100 62/70.46 4/8.19 2/2.04 46/47.65 1/2.32 2/3.10 2/0.81 0/1.23 90 50 100 98 44 66 253 0 0/3.13 0 0/1.25 0 081.19 0 1/049 709 081.41 0 1/5 08 20 0/0.13 0 0/2.30 6/11.88 0 51* 2/7.43 28 2/7.96 26 4/4 62 88 0/2.76 0 1817 11305 ' SMR's idiusted tor desths with oust unknown. `Signitiant at S% level - Significant at 1% level. CMA 013186 516 Mortality Study of Workers in Manufacture of Vinyl Chloride/Tabershaw, Gaffey Table 1 -- Othw MHIimmIm (190-19, LC.D.) la VDM EpidaatMto Study PayolaUa. , - SMy to Ufa at Daatb Hm. Elttui Cmm o OImi Aatapiy 2744 - 31 3700 45 2090 57 3940 43 4433 4000 54 11 727S 7300 7371 7300 5769 5240 2150 57 44 51 53 , 52 57 54 4771 54 47M 5703 7301 51 59 55 111 WMatpraad mMutalk atdaaama (1 it.) Maiipiaat maiaaana at MM m` 50 villi viinprMi .m mitattHO 59 Brail tamer (cardaaaM) (1 am.) 14 Muiailiii Md pMNMUtii ($ wIl) m Epmdymama, taartb yaatridabnia (2 ataa. poat-aa cmtony) .cf -- 11 Astrocytoma. nalipaaMalt carabni hamiipbara (1 yr.) jac 51 Carciaama a< tM brad. ..... ' M Artarioadaraaia ---- - 1L-. 'i' ' PaaaMaia 1m to daHc eaaoaaOaa 271 Braia tat, fldiliitwe aMawa : (11 an) ' TM 211 Bran tamer, naUfuaat (2 aw.) '** 1 aa --- 249 Snia taaar, madgiaat _ . ] 211 TIjTiM cvcImm with MlutMi > - ' (VI 239 Catenowalaaia CtpciMMt ivt^nl * ' -"`i 201 lipasataoiaa arith aaataataH (3 we.) 4 ' jM .1 113 Catciaomatoiit. primary tafa* Mi ...... r fl (fnt tostary, itmiM arttritta, firpo-c- ra*M- nmrcMii ` a-:. t 300 Cardiac erred (1 br.) - Rawratary anaat aad carabrd ' bypeaii <2 daya) Nidnyivd mrtMttte onjMi (2 mat.) " - r - ` -i 311 GwiiM MvtMtttit wMf' tatiM <7 mot) Sqomwvi mU cvtiaoMMa pfisvy vt uaMaroM m * `J 150 Mtistabc cvdmmi tl ibiMMa Critical tita aadataradaad (Pulmonary aaipkyaaata) 133 Caronoaatna (4 ms.) Primary site uadatataaaad m Journal of Occupational Medicine/Vol. 16, No. 8/August 1974 CMA 013187 517 liver cancer, but only two were specified as angiosarcoma If there had been no angiosarcomas, the number of deaths classified as cirrhosis in this study would have decreased by one, and the number classified as digestive cancer would Rave decreased by five. The pattern^ of duration and intensity of exposure-in these five cases was such that if they had not been present there would have been no relationship between exposure and digestive cancer The mortality pattern in this cause group is therefore attributable to angiosarcomas of the liver. The other cause group worth further investigation is cancer of other and un specified sites, both because it is a heterogeneous category and because it seems, unlike the other cancers, to be more related to duration than to level of exposures. Table 9 shows a list of the specific causes included in this category, which is essentially brain cancer and generalized cancer with primary site unknown. About 40% of the observed deaths were due to brain cancer. In the general male population, about 22% of this category is due to brain cancer, so that not only is the mortality from cancer of other and unspecified sites excessive, but brain cancer is overrepresented within the category The possibility exists based on the lack of specificity of some of the listed causes that some of the brain cancers were not primary, but metastases from another unidentified site such as the lung. The cancers of the buccal cavity and pharynx are difficult to explain because of their occurrence in the low exposure, short exposure group. It is possible that this is a chance occurrence, that ex posures to other substances were in volved, or that the mouth and pharynx may be peculiarly susceptible because of the gaseous nature of the chemical. Possible Biases in the Calculation of Risk There are two major potential sources of bias in the study. The first is that the follow-up rate is lower than is desirable. The second is that observations of workers with long exposures followed by a long latent period are not adequately represented, so that the power of the study to detect causes of death associated with long exposure and long latency is impaired Populations with such characteristics exist and Tibti 10. -- MilifRMt Haopiawu of Bvcal Cavity and Pkaryu (140-141, LCD.) in KM EpMnmMoa Study Population. Study fl4 4|i <t Doatk Ma. EiHMi Como * Snm kntapiy 3003 3431 3001 7365 31 H 57 54 3354 63 49 Carcinoma of lip With IMtlttlSIS to tunc ""I naek (5 ire) 30 Pulmonary adoma (50 mm.) Pulmonary matattaiaa (Cardnoau. apidarmoMl, tonyiM m4 mandibla) 71 Mctwtttie lOuamous call Cl. primary tawn palatt 40 AlcbetasJ dua to matutaui to modiastmom (4 m.) Hultipt# malifnant matastasas to brain, bwr 6 madiasttmim (1 yr.) Adanecanmcma ot natal pharynx (2 yrt.) 26 Uittnt htmorrhapa into trachaolrn Statot pod larynffrphpryntactomy, latt mdial pack dutnchai WoH-diflarontiatnd karatiamai souamons all caranonta of Ml pyrrtarm smut (mot.) A0 A0 yes y m i Table 11. -- ItaifMiKiM 0*4tte in KM EpMtmMpfy study PopatattofL Stady He 4250 4255 576$ 7303 7376 7365 kpt at Datk 54 60 4$ 36 62 43 Mv Eipuod Cans* aa Sinn 203 Cirrhosis al lim (tat. naaks) 261 Btaadias bom Inpmama (3 days) (Laannaci ankpad) 167 Anponircorns it lobs af km (10 mat.) 174 Lhnr failura (1 mo.) Cancat of Ibar, primary (15 moo.) 23S Cordite tompoiitdt tod mount Ml hemothoru (mins.) Widely mettttotk in|ioiarCQini o( iryor (4 moo.) 214 Hapatic taiharn Primary CJronoms km fkrtapny ) ym r yts should be investigated. References 1. Lester D Greenberg LA, Adams WR: Ef fects of single and repealed exposures of humans and rats lo vinyl chloride. Am Ind Hyg Auric / 24.265-75. 1963 2. Marsieller H|, Lelbach WK, Muller R. el al |Chronic toxic liver lesions in the PVC (polyvinyl chloride) -- producing workers ! Dlsch Med Wnchenschr 98,2111-14, 1973, 1 Kramer CG. Mutchler IE: The correlation of clinical and environmental measurements for workers exposed to vinyl chloride Am Ind Hyg Assoc / 33 19-30, 1972. 4 Dodson VN, Dinman BD, Whilehouse WM, el al Occupational acroosieolysis III A clinical study Arch Environ Hllh 22.83-91, 1971 5 Creech IL. lohnson MM Angiosarcoma of liver in the manufarlurc of tmlyvinyl chloride I Occup Med 16 150-51, 1974 6 Viola PL, Bigolti A, Cupulo A: Onceogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 31.516-22, 1971. 7. Occupational Safety and Health Ad ministration. Occupational Safety and Health Standards. Emergency Temporary Standard for Exposure lo Vinyl Chloride. Federal Register 39 (67) 12342-44, April 5, 1974. 8, Chiang CL. Standard error of the ageadiusied death rate. Vital Statistics Special Reports. 47 (1961) pp 275-285 9 Lloyd IW, Ciocco A Long-term mortality sludy of steelworkers; I. Methodology. / Oc cup Med 11.229-310, 1969 10, Tabershaw/Cooper Associates, Inc., un published 11 Redmond CK, Ciocco A, Lloyd IW, Rush HW Long-term morlalily sludy of sleelworkers IV Mortality from malignant neoplasms among coke oven workers / Oc cup Med 14:621-629, 1972 518 Mortality Study of Workers in Manufacture of Vinyl Chloride/Tabershaw, Gaffey CMA 013188 cumstance is SMR values ^^par:s or more jd metarlier, for ;han for men are levels are employed for US, and for jm the angiolan for other >r very small, tion, and the higher in the is more like>f groups is 1 urces is given vas observed, allowance is unidentified ning 103). In for the men lore than for periods (111 , four of the t occupations ' against 1.82 nd the Swedrs of deaths year towards numbers of eresiimated 'derestimated been rising might cause on et al (36) <peered. The irovide some f Monson et workers and >tal reported 1); therefore roportion of esis the data - subtracted ion was noi do not coi owever, the i subtracted aths remain i difference >ne-iailed= 3 / [ J as the origin 8.94 expected Additional information from two other sources is given in table 5. The_small excess reported provides little further evidence of an occupational hazard, as one of the two deaths-observed in the Swedish study oc, .irred in a young man who had been employed for less than a year when the diagnosis was made, while the excess death rate for brain cancer observed in the German study was less than that observe^ among chemical workers not exposed to vinyl chloride (2.9 deaths after allowance for deaths from unknown causes against 1.6 expected) and among workers in the PVC fabrication industry (5.9 deaths after allowance for deaths from unknown causes against 1.1 expected). Cancers of lymphatic and hematopoietic tissues. The idea that vinyl chloride might cause cancer of the lym phatic and hematopoietic tissues -- more specifically the lymphatic tissue -- was suggested by Tabershaw & Gaffey (45) and by Waxweiler et al (50) in two cohort studies, when they found, respectively, five deaths from lymphomas in the most heavily exposed workers aeamst 2.54 expected and four deaths from cancers of U: lymphatic and hematopoietic tissues against 2.5 ex pected. These small excesses might have been ignored if the laboratory findings had not been interpreted as suggesting that lymphomas were produced experimen tally in animals exposed to vinyl chloride by inhala tion (29). The idea that similar exposure might also cause lymphomas in humans, therefore, merits seri ous consideration. The data from the four principal studies that are summarized in table 4 provide little --pport for the hypothesis when all cancers of the lymphatic and hematopoietic tissues are considered to gether (57 deaths against 50.87 expected, SMR 112) and very little more is obtained from the separate data for cancers of the lymphatic system (Tabershaw & Gaffey's definition of ICD list numbers, eighth revision, 200--203 and 205 being used) that are shown in table 1 (35 deaths against 29.40 expected). The position is, i, 'ireover, hardly altered if the data in Tabershaw & Ujffev's initial report are subtracted (29 deaths against 23.36 expected, SMR 124). Little additional information is provided by the results of the German study (49). (See table 5.) This study obtained an SMR of 214 for exposed workers (based on 15 observed deaths, increased to 16.5 when allowance is made for the number of deaths from un known causes) against SMR values of 77 and 34 for -`>u unexposed group of chemical workers and a group cl PVC fabricators. It showed that the excess of the exposed workers was present only for men who had been exposed for more than one year and that this ex cess was most marked for men who had been exposed for five years or more (10.7 deaths after allowance for the number of deaths from unknown causes against 4.0 expected, SMR 268, P one-tailed <0.01). 3 <elanoma. An excess of melanoma was reported for Norwegian workers by Heldaas et al (22), who raised the possibility that vinyl chloride might have produced the disease. Four cases were observed when 0.79 were expected, and three of the four were in men whose oc cupations involved the highest exposures (against 0.51 expected). At the time of the writing of their report, one further case had been detected with onset three years after the closure of the study. Subsequent studies in other countries have, so far, reported only two deaths against 2.0 expected. (See tables 1 and 5.) Thyroid cancer. An excess of thyroid cancer was also reported in the Norwegian study (22), in which two cases were observed against 0,16 expected. The inves tigators were not aware of any other studies indicating an excess of this type of cancer, and they drew no con clusion from their observation. Two of the three major studies that have been reported since the Norwegian observation was made gave no data for thyroid can cer; the third reported two deaths against 0.43 ex pected. (See table 1.) One death from thyroid cancer, it may be noted, was reported in the US by Monson et al (36), Cancers of the digestive tract. Suggestions that vinyl chloride might cause cancers of the digestive tract in general have sometimes been made, but they have not taken adequate account of the contribution of cancers of the liver to the total number of cancers of the digestive system, particularly when it is borne in mind that some liver cancers are likely to be misdiagnosed as cancers of other organs. The combined data from the four principal studies shown in table 4 weigh heavily against the idea that any such effect has been produced. Other cancers. One of the remaining types, or classes, of cancer listed in table 4 shows a statistically signifi cant excess, namely, the heterogeneous group of ``other cancers" (83 observed deaths against 65,24 ex pected, P two-sided < 0.05). This excess is only mar ginally significant and may be a chance observation. The most likely explanation is, however, that a few angiosarcomas of the liver were not recognized and were diagnosed as secondary liver cancer or carci nomatosis, site unknown, the number of deaths in this category therefore being increased. Hazards of nonmaiignant disease No previous study has suggested that any nonmaiig nant cause of death other than cirrhosis of the liver would be likely to be increased as a result of exposure to vinyl chloride, and cirrhosis of the liver is presumed to be increased only because of the liver changes that were observed as pan of the "vinyl chloride illness" (24, 31, 33). Two other possibilities have, however, been raised, namely, the production of nonmaiignant respiratory disease, because of the changes in lung function and radiographic appearances that have been Table 7. Mortality 'ram selected nonmalignant causes and all causes in the four principal studies combined. (0 = observed number of deaths, E = expected number of deaths, SMR = standardlzed-mortality ratio) Type of disease 0 E SMR Source of information* Bronchitis, emphysema" 80 66.83 120 1. 2 Other respiratory disease 71 125.78 56 1, 2 All respiratory disease Ischemic heart disease Other circulatory disease* All circulatory disease* Cirrhosis of the liver Other disease 160 797 252 1 103 46 238 200.82 885.73 264.55 1 209.35 66.26 368.07 All nonmalignant disease All external causes 1 547 1 844.50 226 295.15 All nonmalignant causas All causes 1 773 2 139.65 2 441 2 747.85 80 1. 2, 3. 4 90 1,2 95 1,2 91 1. 2. 3. 4 69 1. 2, 4 65 1, 2. 3, 4 84 1. 2. 3. 4 77 1, 2, 3, 4 85 1, 2, 3, 4 69 1, 2. 3. 4 i = United States study (14), 2 = United Kingdom study (25). 3 - Canadian study (46), and 4 = Italian study (4). 0 Bronchitis in the United Kingdom study, emphysema in the United States study. * Includes cerebrovascular disease in the United Kingdom and Italian studies. Table 5. Mortality from chronic obstructive lung disease* in the series from the United States (US) (14) and the United King dom (UK) (25) by charactenstics relevant to an occupational hazard (O = observed number of deaths, 6 = expected number of deaths. SMR = standardized mortality ratio) Data characteristic * Category 1 O E SMR Category 2 O E SMR Observed 20 years or more after first employment in the US (1), others in the US (2) Employed 10 years or more in the US (1), others in the US (2) Employed before 1956 in the UK (1). others in the UK (2) Ever employed as an autoclave worker in the UK (1), others in the UK (2)* 30 16 26 3 15.8 190 10.9 147 30.17 86 6.55 46 11 7.0 157 25 12.0 208 10 1360 74 33 37.22 89 * Described as emphysema in the US study and as bronchitis in the United Kingdom study. 0 The numbers in parentheses designate the category. * Men ever employed as a bagger or drier, occupations which would have caused the greatest occupational exposure to polyvinyl chloride dust, expenenced one death from bron chitis against 4.98 expected- recorded for men exposed to PVC dust (2, 26, 27,44)i and acute cardiac death, from analogy with the effect of other halogenated hydrocarbons (25) and the ob servation of an increased mortality from myocardial infarction in the few years following the cessation of exposure in the Swedish PVC processing industry (35). Relevant figures for the numbers of deaths from inese and other nonmalignant causes that are obtainable from the four principal studies were given in table 2, and they have been summarized in table 7. Cirrhosis of the liver. Three of the four principal studies gave separate figures for cirrhosis of the liver, none of which showed an increased mortality (tabfc 2); in combination they gave an SMR of 69 based on 46 deaths- The fourth study, which did not give sepa rate data for cirrhosis of the liver, reported four deaths from all diseases of the digestive system combined against 3.85 expected and noted that the four included two that were certified as due to cirrhosis of the liver, but actually due to angiosarcoma (46). in the two sup plementary studies in which data were given for this disease, the SMR was 82 in one, based on 15.1 deaths after allowance for the number with unknown causes (49), and 133 in the other, based on seven deaths (37). . Nonmalignant respiratory disease. The data for non malignant respiratory disease are confusing in that the total SMR from the combined data for the four prin cipal studies is 80 and is the sort of figure that is com monly found in healthy industrial populations, yet the US study recorded a substantially increased mortality from emphysema (41 deaths and an SMR of 180 be fore any allowance was made for deaths from un- F known causes). No such excess was found in the UK, where 36 deaths from bronchitis gave an SMR of 82. International comparisons of chronic nonmalignant respiratory disease are complicated by the usage of dif ferent terms to describe what it is now agreed is best called chronic obstructive lung (or pulmonary) disease, but which in the past tended to be called emphysema in the US and chronic bronchitis in the United King dom. It must, therefore, be presumed that the two categories of "emphysema" and "bronchitis" used re- , spcctively in the two large national studies were meant to describe the same thing. One must assume, there fore, that the experiences in the two countries were \ ery different, despite the fact that both related to cohorts that had very similar experiences of angiosarcoma of the liver and so, presumably, fairly similar exposures to vinyl chloride. Separate figures are shown in table 8, where avail able, for the mortality observed among men with dif ferent durations and intensities of exposure. Unlike the data for cancer of the lung that were shown in table 6, they provide no consistent evidence of a greater risk in the groups in which an occupational hazard would be expected it vironmental 1 to give any t from emphyr h.-' My be due mv ..erall ex> however, thai by deficiencie respiratory di other respira the question could be a Health Assoc th they wet m toe out-of the coding oi "other respir included emi emphysema t be classified to 502, and t of the emphi: 'me catej number 527. for both the grossly defic respiratory No excess and asthma' 44 with 6.3 number of > Cardiovasci sclerotic) he elude the vt to acute cai big nationa an increase! "roup of di .->e record of the SMR and there is in the subsii studies. In creased mo ployment i deaths, SM dave work A slight ity was rec man study 1 The death eases and this seclic mental Hi io accour cause. To and SMR 72 2, 26, 27, 44), kith the effect and the obti myocardial i cessation of industry (3_). hs from these -e obtainable en in table 2, le 7. our principal s of the liver, trtaliry (table ' 69 based on lot give sepad four deaths :m combined four included s of the liver, i the two stmtiven for this n 15.1 deaihs .nown causes i deaths (37). lata for non,ng in thal the : four pi i* ^that iscoin- tions, yet the sed mortality R of 180 be lts from un,d in the UK, . SMR of 82. onmahgnant usage of difigreed is best tary) disease, : emphysema United Kingthat the two .ms" used res were meant sume, thei cnes were very ed to cohorts osarcoma of ar exposures i where availnen with dife. Unlike the own in tabi.` a greater risk iazard would be expected to be concentrated. The authors of the En vironmental Health Associates report (14) were unable to give any explanation for the increased mortality fr^m emphysema, and they point out that it could ,lly be due to excess cigarette smoking, as there was no overall excess for cancer of the lung. It is striking, however, that the excess is more than compensated for by deficiencies in the other categories of nonmaiignant respiratory disease (pneumonia 15 deaths,5 SMR 47,0; other respiratory disease 14 deaths, SMR 42.6), and the question arises whether the emphysema excess could be a classificatory artifact. Environmental H-rtlth Associates (14) list all the 41 deaths which show th,.i they were coded under ICD number 527 which, in the out-of-date seventh revision that was used for the coding of all deaths in the study, was the code for "other respiratory disease not otherwise classified" and included emphysema. Under that revision, however, emphysema that was associated with bronchitis should be classified with bronchitis under ICD numbers 500 to 502, and the possibility may be considered that some of 'he emphysema deaths should have been classified u: ome category of respiratory disease other than ICD number 527. If this were the situation, it could account for both the excess mortality from emphysema and the grossly deficient mortality from other nonmaiignant respiratory diseases. No excess mortality from "bronchitis, emphysema, and asthma" was observed in the German study (SMR 44 with 6.3 deaths observed after allowance for the mber of deaths from an unknown cause) (49). Cardiovascular disease. Data for ischemic (or arterio sclerotic) heart disease (which may be presumed to in clude the vast majority of all deaths certified as due to acute cardiac disease) were given only by the two big national studies, and they provide no evidence of an increased mortality. The SMR values of 90 for this up of diseases and of 91 for all cardiovascular dis ease recorded in the four principal studies are typical of the SMR values of healthy industrial populations, and there is no suggestion of any occupational hazard in the subsidiary analyses provided by the two national studies. In particular, there is no evidence of an in creased mortality within one month of leaving em ployment in the UK study either for all workers (52 deaths, SMR 61) or for the most heavily exposed amo ve workers (9 deaths, SMR 42). A slight increase in ischemic heart disease mortal ity was recorded for the exposed workers in the Ger man study (49), but it was less than that recorded for The deaths attributed to different groups of respiratory dis eases and the corresponding SMR values that are cued in this section for the US study are as given by the Environ mental Health Associates (14) and have not been adjusted 1o account for the number of deaths from an unknown Juse. To take account of these deaths, the observed deaths and SMR values can both be multiplied by 1.0674. the unexposed chemical workers and the PVC fabri cators (SMR values of 127,131, and 158 based on 97.2, 126.7, and 109.7 deaths, respectively, after allowance for the number of deaths from unknown causes). Discussion The information that has now been obtained about the long-term health of men occupationally exposed to vinyl chloride is massive and compares favorably with that available for any other occupational group. Two facts are outstanding. First, the men have experienced a specific hazard of a type of cancer that is normally extremely rare, namely, angiosarcoma of the liver. The rarity of this disease under other conditions made the detection of the hazard easy; but the long latency period before the disease appears after first exposure (almost always more than 10 years and usually more than 15 years) meant that a large number of men had been exposed before the hazard was detected and that it will still be many years before the extent of the pro tection provided by the reduction in exposure in the 1960s and that of the further reduction that followed the recognition of the hazard in 1974 are known. There is, unfortunately, no effective treatment for the dis ease, and the number of cases is reflected in the num ber of deaths. Some 50 deaths have occurred among the 16 740 men who were followed in the four prin cipal studies that have been reviewed in this report, so that approximately 1 in 335 men have been affected, 2 7o of the deaths having been due to this one cause. Eventually many more men must be expected to de velop the disease. One estimate (38) suggests that the total may be increased 10 times, but a more realistic estimate is two to three times (19). The second outstanding observation is that the mor tality of the exposed men, other than that due to angiosarcoma of the liver, is typical of the normally healthy industrial worker -- that is not to say that no other hazard exists, but that the effect of any other hazard is small. The massive data that are now available provide no reason for thinking that any hazard other than one of cancer has been overlooked. It is, however, still dif ficult to decide whether vinyl chloride produces a risk of developing cancer other than angiosarcoma of the liver which might be small compared to the risks produced by nonoccupational causes, but yet abso lutely almost as large as the risk of developing the nor mally very rare angiosarcoma. One of the many hazards suggested can be dismissed, as there is no evidence to support it, namely, that of vinyl chloride as a cause of any cancer of the diges tive tract other than angiosarcoma of the liver. Two hazards (of melanoma and cancer of the thyroid) have been suggested only very recently, and few of the avail able studies have provided information about them. There is no good theoretical reason or laboratory evi dence to suggest that either should be produced by CrtA 013191 73 vinyl chloride, and, in light of present evidence, the simplest explanation is that the reported excesses are the chance effartt that must be expected when many different types of cancer are studied in several different populations. Strfar as melanoma is concerned, it has to be remembered that the disease has become much more common in recent years in Scandinavia (where the excess was reported) due, it is believed, to the popularity of sunbathing and the increased oppor tunities for Scandinavians to travel to the warmer parts of Southern Europe and North Africa. The extent to which this change may have affected the observation in Norway needs to be examined. Two other hazards (of lymphoma and brain cancer) were suggested by the early results of some of the US studies. That vinyl chloride might produce a hazard of lymphoma was initially supported by the prelimi nary results of animal studies, but the complete results of the many investigations that have been undertaken (see reference 29) do not suggest that lymphoma or any other cancer of the hematopoietic system is liable to be produced. There is, however, some evidence that brain tumors can be produced in rats (29). The hypoth eses that lymphomas and brain cancers might be produced by vinyl chloride have been supported by the observation that both these types of cancer have caused death more often than might be expected from national mortality rates, but the excesses observed in the com bined data from the four principal studies in this re view are small and not statistically significant, and the hypotheses remain unproved. The small excess of brain cancer is particularly difficult to evaluate, as mortal ity rates from this disease have changed rapidly over time as methods of diagnosis have improved and the suspicion of an occupational hazard (which was raised in 1975) could have influenced the findings. What ex cess has occurred has been limited to the US and Ger many, and the German findings carry little weight, as the excess was found in each of the three occupational groups studied, irrespective of the chemicals to which they were exposed. The supplementary data from the German study showing an increased mortality from lymphatic and hematopoietic cancers are more impres sive, particularly as the excess was the most marked for men who had been employed for at least five years. In these circumstances, judgment must still be sus pended untit the data for each study are analyzed for each specific type of cancer, by intensity and duration of exposure, and by time since exposure began. There remains the suggestion that vinyl chloride might cause lung cancer. At first sight, this possibil ity is ruled out by the SMR of 97 for the combined data for respiratory cancer for the four principal studies. Lung cancer is, however, normally so com mon (accounting for about 8 % of the expected deaths) that an increase in mortality that was half as impor tant (numerically) as the increase in mortality from angiosarcoma of the liver might easily be overlooked (95 % confidence limits of the SMR 85--112). The in cidence of the disease varies moreover within a couq. try, and there must be doubts as to whether the n*. tional experience provides a suitable reference for mtj employed in plants that are not evenly distributed about the country. In these circumstances one cannot exclude an occupational hazard unless it can be shown that the mortality of the exposed men is independent of the factors that might be expected to influence it if some of it were occupational in origin, namely, the intensity and duration of exposure and the time since exposure began. It is not possible to examine these relationships in detail, as the reports do not provide all the necessary information. Such information as they do provide, which was summarized in table 6, supports the idea that exposure to vinyl chloride involves a small hazard of lung cancer. Taken in conjunction with the knowledge that lung tumors have been produced in sev eral species of animals exposed to vinyl chloride by in. halation (29), it would seem that a small hazard of lung cancer probably did occur. The evidence is not, how ever, strong enough to conclude that it definitely did. If it did, the hazard was evident only for men who had been employed for many years at a time when expo sures of several hundred parts per million or more were common, and any persisting risk can be only minute and incapable of detection. The questions that have been left unanswered by this discussion might well be answered definitely if (i) all ' the exposed men could be followed to (say) the end of 1984, (ii) the investigators could present their data in comparable ways, taking account of duration of employment and time since first employment and presenting data separately for men first employed be- , fore (say) 1965 and between 1965 and 1974, and (iii) I estimates could be made of the effect of correcting the I results for each group of employees for the locality in | which they lived and worked. Hazards to tho general population As vinyl chloride has been proved to cause cancer in man and is a mutagen in laboratory experiments, it must be presumed that even the minute doses that escaped into the general environment from production plants or (in the early days of manufacture) from PVC materials will have caused some risk of cancer to the general public. These risks must, however, have been very small, as air concentrations of vinyl chloride, e\en within a kilometer of plants handling vinyl chloride, used to be (in or around 1975) of the order of 10 to 40 ppb (1,3,15), and this level is about one-ten thou sandth of the concentration that has caused an occu pational hazard. It is obvious, therefore, that it would be impossible to detect the risk of any cancer that might be produced by vinyl chloride other than a risk of angiosarcoma of the liver, as it has proved so diffi cult to detect any other risk among men who were ex posed occupationally. The position with regard to an ' giosarcoma t mally so ran to one of tb dioxide, and animal incid In these circ in a man livi ride was use controlled n of the effect Severalsu whether any and Elindet viemity of pl and Sweden al (11) faun to thorotras with vinyl d tion of the (3) found I* 12-year peri lived half a plant, and, i Brady et al tributed to a pie living w using vinyl c last two stin rence of as dose to mai his colleagu* ;..-ms with r the referents six neighbo New York S pollution w oped the dit eight years, and this pci latency. Th u.icr 15 or i covery of tl of the envirc or PVC ma eral public. Current c chloride art previously Agency. Re lew hundrei age values for three of being 20 pp 88 ppb (ju higher valu ciated with 11 The figure have been 74 CMA 013193 over within a counto whether the naJe reference for men evenly distributed Tstances one cannot less it can be shown men is independent cted to influence it origin, namely, the and the time since e to examine these >rts do not provide information as they in table 6, supports ode involves a small injunction with the ien produced in sevinyl chloride by in mall hazard of lung idence is not, howlat it definitely did. ly for men who had a time when expotillion or more w ere .an be only minute unanswered by this definitely if (i) all .d to (say) the end 1 present their data tnt of duration of employment and prst employed be"and 1974, and (iii) a of correcting the i for the locality in tion to cause cancer in ry experiments, it minute doses that it from production acture) from PVC k of cancer to the jwever, have been inyl chloride, even ng vinyl chloride, the order of 10 to >out one-ten thouis caused an occufore, that it would : cancer that might er than a risk of s proved so diffimen who were exwith regard to an giosarcoma of the liver is different. This disease is nor mally so rare that, in the absence of specific exposure to one of the known causes (vinyl chloride, thorium dioxide, and arsenic in pesticides and medicines), the annual incidence* on the order of 1--2 10~7 (5, 8).6 In these circumstances the discovery of even one case in a man living close to a factory in which vinyl chlo ride was used in the days before exposure was tightly controlled may be regarded as presumptive evidence of the effect of environmental pollution. Several surveys have been undertaken to determine whether any such cases have occurred. Saric et at (43) and Elinder & Pershagen (13) sought for cases in the vicinity of plants handling vinyl chloride in Yugoslavia and Sweden and found none. In Holland Dalderup et al (11) found eight confirmed cases not attributable to thorotrast or arsenic and could trace "no contact with vinyl chloride," but they made no specific men tion of the patient's place of residence. Baxter et al (3) found 14 confirmed cases in Great Britain over a 12-year period, one of which was in a man who had lived half a kilometer from a PVC manufacturing plant, and, in New York State over an 18-year period, B. udy et al (3) found 19 cases that could not be at tributed to any known cause, five of which were in peo ple living within a mile of plants manufacturing or using vinyl chloride. The overall incidence rates in these last two studies were not unduly high, but the occur rence of as many as six cases among people living so close to manufacturing plants is surprising. Brady and his colleagues, moreover, compared their series of pa tients with matched referents and found that none of tnc referents lived equally close to a plant. Two of these six neighborhood cases (one in England and one in New York State) cannot be attributed to environmental pollution with vinyl chloride, as the men who devel oped the disease had lived near the plants for six and eight years, respectively, before developing the disease, and this period is too short to allow for the necessary latency. The other four cases, however, all occurred al ter 15 or more years of local residence, and the dis- ery of these cases strongly suggests that pollution of the environment around plants manufacturing VCM or PVC may have caused a minute hazard to the gen eral public. Current concentrations around plants handling vinyl chloride are certainly much lower than those reported previously by the US Environmental Protection Agency. Recent British measurements made within a few hundred meters of the VCM areas have given aver-^e values below the daily limit of detection (5 ppb) for three of five plants, the readings at the two others being 20 ppb (100 m outside the boundary fence) and 88 ppb (just inside it) (47), although substantially higher values were recorded on two occasions asso ciated with putting one plant into operation and with The figure of 1.4 I0-* cited by Heath et al (21) seems to have been a misprint for 1.4 10-'. an accident at the other. According to any reasonable criterion the hazard to the general public (if there is any at all) must be negligible (42). No other hazard to the general population, other than a hazard of cancer, can reasonably be postulated. Summary This paper reviews (i) the possible effects of vinyl chloride on the personal health of men exposed by virtue of their occupation (other than the early effects of the very high concentrations to which men were ex posed when the industry was first developed -- uncon sciousness, cardiac arrhythmia, and the characteristic "vinyl chloride illness") and (ii) the carcinogenic effects that might conceivably be observed in the gen eral population as a result of the widespread distribu tion of vinyl chloride as a pollutant. The possibility that vinyl chloride might actasa teratogen or might cause mutations in the germ cells has not been exam ined, as the little evidence that has been adduced relating to such possible effects has been reviewed else where and the conclusion was reached that no such ef fects have been demonstrated. Many groups of workers exposed to vinyl chloride in the manufacture of VCM or PVC have been studied since the carcinogenic potential of vinyl chloride was first recognized. Some results have shown that occu pational exposure can cause angiosarcoma of the liver, and others have suggested that it may cause several other types of cancer as well. The actual situation can be determined only in an examination of all the evi dence, especially the combined results of those studies that include a substantial proportion of observations on men more than 25 years after their first exposure and cover a long enough period for more than 10 % of the employees to have been expected to die. The results of four studies can be usefully combined for this purpose. They are two national studies, one from the US and the other from the UK, and two studies of employees in one plant in Canada and two plants in Italy. The results of other studies from the Federal Republic of Germany, Norway, Sweden, Italy, France, and Japan can be used only to provide sup plementary information. The many earlier reports of exposed workers in the US and the UK concern men covered more completely in the two recent national studies, and their results serve only as sources of hy potheses. Minor criticisms can be made of three of the four most useful studies. They do not seriously affect the value of the results, except that allowance has to be made for the failure to determine the cause of 6.3 7o of the deaths recorded in the US study. Three of the studies use national rates to estimate the numbers of deaths that might have been expected to occur in the absence of any special occupational hazard, and the fourth (Canadian) uses rates for the province in which 75 CMA 013193 the plant was situated. It must, therefore, be kept in mind that the rates used may not have been wholly ap propriate for the localities in which the plants were situated. This circumstance is potentially important for the US study,-which covered workers in 37 plants, 22 of which wefF situated in the southern part of the country. The other less informative studies arc. for the most part, open to more serious criticism, and the value of each set of results needs to be assessed separately in relation to each disease. The combined results of the four principal studies show that the SMR values, reflecting the ratios between the numbers of deaths observed and those expected in the absence of an occupational hazard multiplied by 100, have been (i) 77 for accidents and other violence, (ii) 84 for diseases other than cancer, and (iii) 102 for cancers other than cancer of the liver. All these results are what might be anticipated for an industry devoid of any specific occupational hazard. The low ratio for diseases other than cancer reflects the "healthy worker effect," which results from the selection process that inevitably excludes some of the less healthy members of the population from industrial employment and is compatible with a higher ratio for cancer, as the mor tality from cancer is not normally subject to such an effect, apart from the first two or three years imme diately following the start of employment. The mortality from cancer of the liver was nearly seven times that expected. Most of the 51 excess deaths were known to be due to angiosarcoma, even though this diagnosis was not recorded on the death certifi cate. The excess corresponds closely with the 49 deaths due to angiosarcoma reported to the International Register of Angiosarcoma Cases as occurring in em ployees of the plants concerned during the periods under observation. All the men who developed the dis ease were likely to have been exposed to concentrations of vinyl chloride of several hundred parts per million or more. Three other types of cancer which have been sug gested to occur as a result of exposure to vinyl chlo ride are cancers of the lung, brain, and lymphatic and hematopoietic systems. The combined data for the mortality from respiratory cancer fail, at first sight, to support the hypothesis regarding lung cancer (SMR 97). Higher ratios for lung cancer have, however, been observed consistently in the subgroups in which the effect of an occupational hazard would be most like ly to be seen (that is, men employed for more than 10 years, exposed to higher than average concentrations, or observed more than 20 years after first exposure). In two of the supplementary studies it was also noted that the mortality from lung cancer was specifically increased among the most heavily exposed workers. The combined data show small excesses in the mor tality from cancers of the brain and of the lymphatic and hematopoietic systems. The excesses are, however, not statistically significant, and there is nothing to sug gest that they are occupational in origin. An excep tion is the observation of an increased mortality from cancers of the lymphatic and hematopoietic systems in the supplementary study from the Federal Republic of Germany. Two types of cancer were reported to be in excess in the Norwegian study, namely, thyroid cancer and melanoma. The significance of this finding is difficult to assess because very little information about these cancers has been provided by other studies. Suggestions that vinyl chloride might cause cancers of the digestive tract have failed to account for the contribution of angiosarcoma of the liver. When this disease is excluded, the mortality from digestive tract cancer decreases to below the average (SMR 82 for the four principal studies). A small excess mortality from the heterogeneous group of "other cancers" in the combined results of the four principal studies was statistically marginally significant (83 deaths against 65.23 expected, P<0.05). Some of the excess was likely to have been due to the misclassification of angiosarcomas as secondary can cers of the liver or carcinomatosis, site unknown. The following three nonmalignant causes of death have required special examination: cirrhosis of the liver because of damage to the liver in "vinyl chloride ill ness, " myocardial infarction (from analogy with the effect of other halogenated hydrocarbons and because of some observations from Swedish PVC fabricators), and nonmalignant respiratory disease because of changes in lung function and the radiographic appear ance of the lungs observed in men exposed to PVC dust. Far from being raised, the mortality from cir rhosis of the liver was less than expected in the three principal studies and in one of the two supplementary studies which gave separate figures for the disease (SMR values of 69. based on 46 deaths, and 82, based on 15 deaths), while in the other supplementary study the increase was trivial. Data for myocardial infarction have not been re ported separately. But myocardial infarction accounts for most of the deaths attributed to ischemic heart dis ease, and there is no evidence that either ischemic heart disease or cardiovascular disease as a whole was un duly common (SMR values of 90 and 92, respective ly) or related to occupational exposure. The data for the third category of nonmalignant dis ease (nonmalignant respiratory disease) are confusing, because the two large national studies give conflicting results. The combined data for the four principal studies show the low mortality that is commonly found in healthy industrial populations (SMR 80). This fig ure hides, however, an increased mortality from chronic obstructive lung disease (SMR 120), which in cludes emphysema and is due to a grossly increased mortality attributed to emphysema in the US study (SMR 193). The corresponding mortality in the British study, which was preferentially described as due to bronchitis, was less than expected (SMR 82), as was the mortality from pneumonia (SMR 50) and other res 76 CMA 013194 piratory dise no consisten physema or and it seems US cudy wa ties w ith the Review of long-term ht vinyl chlorid men have exf extremely ra mately 1 in: studied died the observed of time the i be expected the mortalir. of that of no hazard has The data i ard other thu is, however, rids produce due to nono< liver, and, it cause almost liver. There is to the suggestu noma or can and hematof ti.,.i have be pational haz cers of the ly German stu< sort of chanc many types > studies. The lack < ccr in the co icviewed do have been a the disease, of the disea national rat deaths. The would be m< than other { li.tve existed c-Msience of Clearer ar been posed various gro results in m As vinyl c ments and i doses that h pollutant p.irably min 2 * .mortality from Jfietic systems eral Republic to be in excess oid cancer ,.nd ding is difficult on about these tudies. ,t cause cancers ccount for the ver. When this i digestive tract SMR82forthe heterogeneous <ined results of illy marginally cted, P < 0.05). )een due to the econdary canre unknown, auses of death osis of the liver iyl chloride illalogv with the ns and because C fabricators), 1Ce bl ecause of iphic appear- ;ed to P VC Tty from us ed in the three upplementary ir the disease and 82, based memary study : not been re gion accounts emic heart disischemic heart vhole was un>2, respective- malignant disire confusing, ve conflicting our principal nmoniv found 80). This figirtality from 20), which in-sly increased the US study I I in the British ied as due to R 82), as was and other res- 1 1 piratory diseases (SMR 46) in the US study. There is no consistent evidence that the mortality from em physema or bronchitisovas specifically occupational, and it seems possible flat the reported excess in the US study was an artifact due to nosological difficul ties with the use of the seventh revision of the 1CD. Review of the massive data now available on the long-term health of men occupationally exposed to vinyl chloride leads to two clear conclusions. First the men have experienced a specific hazard of the normally extremely rare angiosarcoma of the liver. Approxi mately 1 in 335 of the men exposed in the 49 plants studied died of the disease, and approximately 2 % of the observed deaths were attributed to it. In the course of time the numbers of cases of angiosarcoma must be expected to increase two to three times. Second, the mortality from all other causes has been typical of that of normally healthy industrial workers. If any hazard has existed, its effect has been small. The data provide no reason to think that any haz ard other than one of cancer has been overlooked. It is, however, still difficult to decide whether vinyl chlo ride produces small risks of cancer, compared to those due to nonoccupational causes, at sites other than the liver, and, if so, whether, in total, these risks might cause almost as many deaths as angiosarcoma of the liver. There is too little evidence either to confirm or refute the suggestion that vinyl chloride might cause mela noma or cancers of the thyroid, brain, and lymphatic i' J hematopoietic systems. None of the small excesses that have been recorded point specifically to an occu pational hazard, apart from that attributable to can cers of the lymphatic and hematopoietic systems in the German study reviewed, and most are likely to be the sort of chance effect that is certain to be observed when many types of cancer are examined in many different studies. The lack of any increased mortality from lung canccr in the combined results of the four principal studies reviewed does not exclude the possibility that there may have been a small occupational hazard of developing the disease, as geographic variations in the incidence of the disease throw doubt on the validity of using national rates for estimating the expected numbers of deaths. The greater mortality in groups of workers who would be more likely to show an occupational hazard than other group* suggests that a small hazard may h ive existed. The evidence is, however, weak, and the existence of a hazard has not been proved. Clearer answers to some of the questions that have been posed in this review might be obtained if the various groups of investigators could present their results in more appropriate and comparable ways. As vinyl chloride is a mutagen in laboratory experi ments and a proved human carcinogen, the minute doses that have escaped into the general environment 3' pollutants must be presumed to have caused com parably minute risks to the general public. No such 2 risk could possibly be detected, other than one of angiosarcoma of the liver which is normally an ex tremely rare disease. Several surveys have sought evi dence of the existence of such an effect, and sugges tive evidence that such an effect may have occurred at a time when environmental pollution was much greater than it is now has been found in one. References 1. Air Products and Chemicals. Inc. Comments on the pro posed standard for vinyl chloride. Letter to DR Goodwin. Environmental Protection Agency, Washing ton, DC 23 September 1976. (Cited in an unpublished report by Barr to Air Products and Chemicals, Inc, in 1981). 2. Baser ME, Tockman MS, Kennedy TP. Pulmonary function and respiratory symptoms in polyvinyl chlo ride fabrication workers. Am Rev Respir Dis 131 (1985) 203-208. 3. Baxter PJ, Anthony PP, MacSween NM, Scheuer PJ. Angiosarcoma of the liver in Great Britain, 1963--73. Br Med J 2 (1977) 919--921. 4. Belli S, Bcrtazzi PA, Comba P, Foa V, Maltonj C, Masina A, Pirastu R, Regianni A, Vigotti MA. Indagine sulla mortalita dei produtiori di PVC in Italia: Disegno dello studio e primi risultoti. Cancer Lett (in press). 5. Brady J, Liberator* F, Harper P, C-reenwald P, Bur nett W, Davies TN, Bishop M, Polan A, Vianna N. Angiosarcoma of the liver: An epidemiologic survey. J Nail Cancer Inst 59 (1977) 1383--1385. 6. Buffler PA, Wood S, Eifier C, Suarez L, Kiliane DJ. Mortality experience of workers in a vinyl chloride monomer production plant. J Occup Med 21 (1979) 195--203. 7. Byren D, Engholm G, Englund A, Westerholm P. Mor tality and cancer morbidity in a group of Swedish VCM and PVC production workers. 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Received for publication; 16 February 1988 I 78 013196 CMft ORIGlNAi Scand J R Assoc exhai Results by Jack Ron Dew K A large p study was cupationa; About 20 For each p r>nst expo: i.iialyticst at a time t< remarkabl This rep cancers in bustion pr classes. Ft bustion e ilcpendin; jot fuel, o from the substance without c lamp oil), profile of j is consider a propane tipidemio Institute Canada. ' Departme versity, V 1 Departme University Reprint req cn epidemic 1 rappier. S'. 1 mada. H'