Document GQ1g0jw2QjGB7VvDabGY8257

J)f?A f r- *v 1990 fa CtfaicOu R&S 000292 BIOLOGICAL THRESHOLD FOR VINYL CHLORIDE EXPOSURE-INDUCED HEPATIC ANGIOSARCOMA IN HUMANS Introduction Ct'vv Chemical Confident^! Malarial Produced Pursuant To Protective Order v._C.i.nc,;qJns., Case ?Jo. SO-4337 Ceioesiae Parish, LA Smith v. Tha Dow Chemical Company Case No. 84-CV-0393 S(H) Western District of New York In most epidemiological studies, it has not been possible to determine the dose of the agents to which humans have been exposed. Occasionally, crude retrospective dost-response curves have been developed. A summary was made by the Meselson Committee regarding the dose levels of several known human carcinogens which appear to be carcinogenic in certain human populations.1 The characteristics of exposure and the spectrum of effect comes together in a correlated relationship customarily referred to as a dose-response relationship. This relationship is a fundamental and pervasive concept in toxicology. Indeed, an understanding of this relationship and its facile use is the essence of the study of toxic materials. Although a full understanding of the intricacies of both dose and response entails many complexities, only a few assumptions form the skeleton of the relationship. The first is that an implicity assumption of causality is made. To arrive at a quantitative and precise statement of the relationship between a toxic material and an observation effect or response, one must known with reasonable certainty that the relationship is indeed a causal one. This is true for vinyl chloride and angiosarcoma. In many epidemiological studies, results show an association between a response and the disease, and one or more impinging variables. Not infrequently the data are amenable to Biological Threshold. . continued . - Tonlic : ;:vj"'d2r i ... :i:ant r 'n:,,Cas8ftlo. C-,J.7 - , LA L: "l>1"1 ^Hgmlca! Company Case f^c7 34-CV-03S3 S(H) Western District of New York --""" 2 presentation in terms similar to those employed in experimental use of dose response in pharmacology and toxicology. In strict usage, the dose-response relationship is firmly based on the knowledge or a reasonable presumption that the effect is a result of the toxic agent. The second assumption is simply and obviously that the response is, in fact, *.0 til/3 dose. The simplicity of this assumption is often a source of misunderstanding. This assumption is really a composite of three others that will recur frequently: R&S 000293 A. There is a molecular or receptor site with which the chemicals interact to produce the response; B. The production of response and the degree of response are related to the concentration of the agent at reactive sites; C. The concentration at the site is, in turn, related to the administered dose. Thus, the numerical and graphic dimensions of a dose-response relationship can include the assumptions that: (1) the response is a function of concentration at the site; (2) the concentration at the site is a function of the dose; and (3) the response and dose are causally related.2, 3 In toxicology, when assessing the safety of a substance, it is necessary to have both a quantifiable method of measurement and a variety of criteria in points of toxicity that can be used. The ideal criteria should be closely associated with the molecular events resulting from exposure to the toxic agent. This idea is usually considered unapproachable in clinical Biological Threshold. . ., continued To Protect 0rfe rr0aUC8(, Pursuant fel Conocojnr., Cm y.0. 90-4837 C:,'J3'isy Parish, j.:, Comoanv Cc3i Ho. 94-CV-Q333 S(hT Western District of New York settings, especially with regard to effects with great latency, such as malignancy. Vinyl chloride-induced hepatic angiosarcome among plastic workers represents such a clinical setting. The selection of a toxic end-point for measurement is also not always so straightforward. In vinyl chloride exposure, other end points (non-malignant) have been quantitatively demonstrated to be precise indicators of the acute and chronic phases of hepatotoxicity.4,5' 6 In addition, prospective clinical data has been accumulated and developed over the past ten years through extensive screening and medical surveillance of vinyl monomer-exposed workers which fulfill most of the above criteria. This paper provides the clinical and epidemiological evidence for both a dose-response and biological threshold response to an occupational hazard.7 R&S 000294 Materials and Methods Vinyl chloride-associated hepatic angiosarcoma (HAS) was studied in two populations. One consisted of 1,200 vinyl chloride polymerization workers from the index plant, i.e., where the original human vinyl chloride-associated HAS observations were made. This index plant also is the single largest contributor of VC-related HAS cases worldwide. This cohort has been followed respectively fromJL74"to the present via a medical surveillance program. The medical surveillance program consisted of annual medical examinations, clinical laboratory screening on an annual/semi-annual basis which included over 50 biochemical studies of blood and urine, x-ray examinations of the chest, abdomen and hands, Biological Threshold. . ., continued p... rr-;-| Cc"':1en.' *! fv''' Crde. 'nc,, ii*<j. -v ... .A njiw Chemical Company 0393 S(H) Wwien.wan-ici of New York . '-3r:i 4 radioisotopic studies of the liver, spleen and brain, and angiographic-hemodynamic examinations of the portosplenic system. Detailed follow-up clinical investigations were performed on all biochemical, radiological, or clinical abnormalities. Approximately 110 cases of hepatic disease constitute a sub-cohort of this population, 15% of whom have vinyl chloride-associated non-malignant liver injury.8, 9 The second population of cases consisted of all VC-associated HAS cases reported to the Angiosarcoma of the Liver Registry of the Imperial Chemical Industries Corporation in England.10 This Registry contains all histologically-documented VC-associated HAS cases reported in the scientific literature, by government agencies and/or chemical industries, from North America, Europe, South America and Asia.11*23 All cases have been histologically confirmed as liver angiosarcomas. Each case has a date of birth, company or factory of employment, date of clinical diagnosis, age at diagnosis, date of first exposure, years of exposure (i.e., years worked in a vinyl chloride polymerization manufacturing plant), years from first exposure to time of diagnosis (latency), date of death, estimated exposure levels, occupational (job) activities, and some information with regards to prior occupation, nationality or country of origin. R&S 000295 From these two cohorts, 108 histologically-confirmed cases of angiosarcoma constitute this study population group. Each case spent from three to 37 years working in vinyl chloride polymerization production plants in 12 different countries from 1938 through 1984. Forty-three (43) cases of HAS are from North America, 2 from Japan, 6 from Biological Threshold. . *, continued To S ^"aJ Ro" ^M?% h PofiSil, l:] if Wsstern District of Hew York P^ducBd Pursuant 30 0 U) o o o 5 to (O o> Eastern Europe, and the remaining 57 from Western Europe and the United Kingdom. All cases have been histologically confirmed as liver angiosarcomas. All histological identifications were made or confirmed by internationally-recognized and experienced pathologists before this analysis and independent of this study's author. No histologically- confirmed case has been excluded. Forty (40) cases were retrospectively identified or identified before the beginning of this study in 1975. The remaining 68 cases developed during the 10-year follow-up interval since the beginning of this study. Data and Results Worldwide HAS case occurrences demonstrate a poisson-like distribution with the peak occurring about 1976 (Figure 1). The earliest cases identified in North America occurred in 1962 with a peak and median occurrence between 1974-1975. The open circles identify the North American cases, including the index plant first identified in 1967, with the median in 1976 and peak in 1978. The eight remaining cases were identified between 196578 with the median and peak occurring in 1973. The annual incidence of HAS by date of diagnosis and geographic location for four leading countries is shown in Figure 2. The distribution by year of first exposure for the entire cohort begins in 1940 and finishes in 1968 (Figure 3). The initial 38 cases (triangle-based circles) retrospectively identified (between 1955-1974), began their vinyl chloride exposure before 1968. Since 1974, all 68 prospectively identified cases (closed circles) also began their year of first exposure prior to 1968. Figure 4 illustrates the age at which diagnosis was first made among Biological Threshold. . ., continued tecuve . Cone co, Inc., C.. Parish, LA s v The Dow O'- r1 t'j.r.ijsny ..w.i: uisirictofWew Yorit 6 the VC-associated HAS. The frequency of HAS latency periods has a skewed distribution, peaking at approximately 20 years (Figure 5). The range of the latency periods is from 9-38 years. The mean latency period for each five-year interval, starting with 1940-44, demonstrates a progressive shortening from 35 to 14.6 years with an overall average latency of 22.6 years 1 * uv1u ^J R&S 000297 The latency periods point out a discrepancy between the reduction in occupational exposure levels and the sudden decrease in HAS occurrence. On initial observation, the reduction of exposure levels in 1974 appears to have produced a rapid and profound reduction in the incidence of angiosarcoma (Figure 1). Had the reduction in exposure levels instituted in 1974 been a major factor in reducing the occurrence of HAS, its effect would not be expected for at least nine years, i.e., shortest latency. In fact, study of the latency period in other cancers in which the carcinogen, its dose and duration are known, have shown a prolongation of the latency period which a decrease in dosage or duration of exposure. A review of the index plant cases (13 cases) illustrates a reversed exposure-latency relationship between the total (or first year of) exposure and the onset of disease. This relationship holds for all the North American (United States and Canada) cases and the various European countries (western Germany, Fiance, United Kingdom, Sweden and Yugoslavia). In contrast, these HAS cases' latency periods decrease with shorter duration of exposure (Figures 6 and 7). To Pr,i'C'C.V " CskT" ' . Sr ; , UCed^ Biological Threshold. . ., continued 8 Utilizing this data, each year of exposure was weighted on the basis of the estimated level of exposure. Each case's total exposure was redetermined based on the exact year of exposure. Replotting of the latency versus total cumulative exposure (weighted exposure) continues to demonstrate the same linear relationship in an even more highly correlated manner. This is seen in index plant cases (Figure 11), USA cases (Figure 12), the Canadian cases (Figure 13), and holds true for the European and world-wide cases. It is most dramatically shown in the short-exposure group (Figure 14). R&S 000298 Discussion These data provide, for the first time, clinical (human) evidence for a biological threshold for VC toxicity including carcinogenicity. The retrospective and prospective demonstration that all cases of VC-associated HAS began their first exposure before 1968 in plants which began operation before 1967 (majority before 1960), indicate that a common pattern of environmental working conditions were present during the induction and subsequent promoting periods. Vinyl chloride's carcinogenic effect is related to a particular time and environment. This pattern is confirmed in seven countries around the world. If, as traditionally understood, the risk of developing VC-associated HAS is related to the different levels of environmental exposure during the earlier years of employment, then the gradual reduction in exposure levels should be reflected in the changing incidence rates zmong those workers exposed at different times and durations.25 Exposure during eariy Biological Threshold. . ., continued Chemical ConiiccntiSi 'ctive Order Conoco, Inc., Case :su Parish, IA Ths Da1.*: C^n-.ip-.j Ci "ipsny ~^V-G333 S|hT~~ Western District of New York 7 The total years of exposure for each of the cases is shown in Figure 8. Ninety-three cases (93%) had 10-43 years of exposure (median 20 years); seven cases (7%) had only Vh6 years of exposure (median 5 years). Continued exposure during the latency period could affect the length of latency. Therefore, the relationship between total years of exposure and latency was studied among those with concomitant exposure and latency periods versus the smaller groups with limited short total exposures. This latter group is not significantly affected by continued exposure which might of itself act as a promoter. These eight individuals (short-exposure group [SEG]) had left the chemical industry for other occupations with no or very limited exposure to other known carcinogens. Figure 9 correlates the year of first exposure with latency in SEG. In regards to total years of exposure, the same reverse relationship was found .,, CcovvkxuWU cixei aen in the long cases aommuifcMit exposure ga&p. (M The Effect of Weighted Exposures A review of the literature and industrial records indicates a progressive linear decrease in exposure levels from 1940 (1-3 ppms) to 1974 (50-250 ppms). Data reported in the literature and extrapolated from the various industrial data were used to construct estimated exposure levels.7, 24 Two exposure curves were plotted from these reported exposure levels covering the 1940-74 years (Figure 10). R&S 000299 R&S 000300 Biological Threshold. . continued n.... comical Confidential Materia! Prrdir.ad Pursuant . :ve Order .^Crauco. 'n . jsie'j Parish, lh v. The Dow C'; "Ja. 94-CV-C3S-"- i, C^trict oi Pievu York 9 years (1940-1950) was at a higher intensity. The cytotoxic effect of VC was shown by the severity of the hepatocellular injury seen among workers exposed during those years. In these early workers, far more pamechymal injury, hepatocellular necrosis, fibrosis, and portal hypertension were found, concurrent with clinical development of HAS.26, 27 It is highly probable that in these situations the liver and endothelial cells were unable to undergo cancer transformation between the VC cytotoxic injury did not allow the cells to survive. Therefore, fewer total induced cells were available for further transformation by the action of promoters or repeated exposure.28 Those individuals whose exposure occurred in later years (1951-60) were exposed to lower vinyl chloride levels. Although these levels were less cytotoxic, they were still able to induce the carcinogenic effect. Therefore, a larger proportion of surviving cells were initiated and available for the promoting effect of either continuing exposure or other environmental agents. This group had the more rapid induction (shorter latency) of HAS development. As the environmental levels were further decreased (after 1968), the liver was able to maintain adequate detoxification to prevent both the cytotoxic effect and the carcinogenic induction or initiating phase. This level of exposure appears not to be affected by other promoting agents or continued low-level VC exposure. In support of this hypothesis are the findings in later exposed workers (1960-1975), and evidence of histological hepatocellular adaptation, e.g., focal hepatocellular hyperplasia and mild increase in sinusoidal fibrosis.6 Biological Threshold. . ., continued }t \ *r ^- nJ- 94-CV-w- Western District of Nsw York J_ J Pursuant 10 These findings reflect the hepatocyte's adaptation and very mild cytotoxic injury to endothelial cells, which in turn stimulates collagen forming cells. The latter scenario is further supported by the fact that after five to ten years of follow-up, these histological lesions (which are highly correlated with the individual's total exposure to vinyl chloride) have shown no evidence of progression even with continued low-level VC exposure (< lOppm).20 In addition, all biochemical abnormalities initially seen have regressed and the histological picture on subsequent biopsies has been stable and unchanging.28,30 R&S 000301 Therefore, these data support the concept that high leves (> 750ppm) of vinyl chloride produce severe liver cell (hepatic and sinusoidal) injury and reduce or significantly delay the malignant expression or transformation of initiated endothelial cells. At lower levels (or range of levels) which appear to be somewhere between 250-700 ppm, there is a maximal carcinogenic effect with less cytotoxic injury. Whether this latter phase can be totally accounted for by the VC level of exposure and not contributed to by confounding or enacting secondary agents, requires further study. Finally, low levels (1-50 ppm) appear to be within a biological threshold. Neither significant cytotoxic nor carcinogenic effects occur at these exposure levels. In addition, this level also does not appear to act as a promoter nor cause progression of already existing hepatocellular lesions. The data also suggests that there may be a co-factor or interaction of other chemicals occurring which may play a role in the shorter latency periods and reverse dose-response with regards to malignant transformation. Biological Threshold. . ., continued Dow Chemical Confidential Material Produced Pursued To Protective Order Rr.ss v. Conocojx^ Case No. 90-4837 Calcasieu Pr/isr, L4 Smith v. The Co .v Chemical Company Case No. S4X7C393 SiH) Western District of New York 11 Greenberg and Tamburro,31,32 utilizing a rank-order method for estimating chemical exposure, illustrated this method's ability to identify the causal relationship between VC and other chemicals with the development of HAS. Their study suggests that catalysts which biochemically inhibit the liver's major detoxifying mechanism responsible for the removal of active vinyl chloride metabolite might be a confounding or interacting factor. Industrial plants performing different operations might have environments which provided dual exposures. One, like vinyl chloride, which is hepatotoxic and carcinogenic, and another, like diethyl maliete, which might decrease or impede the liver's detoxifying capabilities, thus allowing for a more rapid induction of carcinogenesis -- hence, a shorter latency. In contrast, those plants not utilizing these detoxifying inhibitors may account for the usual and more prolonged course of cancer induction, i.e., increased exposure, decreased latency. R&S 000302 This hypothesis is supported by review of HAS cases in the various countries and their plants' start-up dates. As shown in Figure 15, all HAS cases developed in PCB plants whose start-up began before 1967 -- in eastern Europe before 1953, in Canada before 1941, in the United States before 1953, and in western Europe all but three plants before 1954. This indicates a high probability that either the level of exposure and/or type of exposure during these periods play an important role in type of injury seen and the way in which the tumor developed. These clinicqal data provide a clear demonstration of a biological threshold for a known carcinogenic non-radiation agent in a human population. It demonstrates a uniquely- Biological Threshold. . continued Dow Chemical Confidential Material Produced Puiynf> To Protactivs Order Ross v. Ccttneo, Inc., Case No. 90-4837 Calcasieu Parish, LA Smith v. The Dow Chemical Company Casa No. 94-CV-0393 S(H) Western District of New York jC 12 different pattern of latency in chemically-induced cancer, even though its distribution characteristics are mathematically the same as reported by Doll and Hill33 and fit the concepts of latency initially illustrated by Sartwell34 and later expanded by Armenian and Lilienfeld.35 The reverse dose-response to latency relationship, however, is quite different from that reviewed by Polednak, Cobb and others, and reflects a different mechanism or model for chemical carcinogenesis.36 This study provides carefully-observed human experience data, prospectively acquired, which can be used to guide the development of future environmental policy with regards to vinyl chloride environmental exposure. 30 99 C/> o ooCO oto R&S 000304 Biological Threshold. . ., continued C!WC3I Confidante Katoriai Prodi-csd PLW` i f ^ ^ -^fr. 'a:cc-;`y`,23 `jrdsr J0,`* h -'-'(f-i-lfi Csss No. 90-4337 Cass No. 94-CV-0J93 S(H> Western Cistrict of New York 13 J REFERENCES 1. Contemporary Pest Control Practices and Prospective. Reported of the Executive Committee, Vol. I. National Academy of Sciences. Washington DC, 1975, P' 75. 2. Albert A (1965). Fundamental aspects of selective toxicity. Annals of New York Academy of Science 123, pp. 5-18. 3. Loomis TA (1978). Essentials of Toxicology, 3rd Edition. Lea & Febiger, Philadelphia. 4. Popper H, Thomas LB (1975). Alterations of liver and spleen among workers exposed to vinyl chloride. Annals of New York Academy of Sciences 246, pp. 172-194. 5. Thomas LB, Popper H, Burke P, et al. (1975). Vinyl chloride induced liver disease; from idiopathic portal hypertension (band syndrome) to angiosarcoma. New Engl J of Medicine 292, pp. 17-22. Biological Threshold. . ., continued To '.V.j.-r Bcssi.C=; Catessiet; ; ,, Czsc f.'o. 90-4337 -.A STiith y, Ths Day; Chemical Company Case No. S4-CV-03S3 S(H) Western District of Maw Yerk 14 6. Tamburro CH, Makk L, Popper H (1984). Early hepatic histological alterations among chemical (vinyl monomer) workers. Hepatology 4, pp. 413-418. R&S 000305 7. Tamburro CH, Greenberg RA (1982). Safe carcinogenic and toxic exposure levels in vinyl chloride induced hepatic angiosarcoma. Clinical Research 30, p. 307a. 8. Greenberg RA, Tamburro CH, Kupchella CE (1978). Prospective medical surveillance program for detection and prevention of industrially-related cancer, fn Prevention and Detection of Cancer, Niebeurgs H, Ed. New York: Marcel Dekker Inc., Part 13(2), pp. 1921-1928. 9. Dannaher CL, Tamburro CH, Yam LT (1981). Occupational carcinogenesis: the Louisville experience with vinyl chloride associated hepatic angiosarcoma. American J of Medicine 70, pp. 279-287. 10. Bennett B (1983). Angiosarcoma registry. Works Medical Officer, ICI Hill House Works, Cleveleys, Blackpool, Lancastershire, England. 11. Marsteller HJ, Ledback WK, Muller R, Juhe S, Lange CE, Rohnerf HG, Veltman G (1973). Chronisch-Toxische Leberschaedenbe, Arbeitem in der PVC Produktion. Deutsch Med Worchenschr 98, pp. 2311-2314. Biological Threshold. . continued 12. Delorme F, Theriault G (1978). Ten cases of angiosarcoma of the liver in Shawinigan, Quebec. J of Occupational Med 20, pp. 338-340. 15 13. Spirtas R, Kaminski R (1978). Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers: 1977 update. J of Occupational Med 20, pp. 427-429. 14. Bonneton G, Champetier J, Foumet J, Guidicelli H, Legrand J, Dupre A, Hostein M, Marty F, and Pahn M (1977). Angiosarcome hepatique et fibrose portale chez les travailleurs due chlorure de vinyl. Deux observations, ha Nouvelle Presse Medicate 6, pp. 735-742. 15. Pilichowski P, Faurd-C, Aubert M, Pahn M, Latreille R, and Barrie J (1977). Angiosarcome costal lie a une intoxication au chlorure de polyvinyl. La 33 C/3 o o Nouvelle Presse Medicale 8, pp. 2485-2486. 16. Falk H, Heath CW Jr, Carter CD, Wagoner JK, Waxweiler RJ, and Stringer WT (1974). Mortality among vinyl chloride workers. Lancet 2, pp. 784-785. 17. Lee Fi, and Harry DS (1974). Angiosarcoma of the liver in a vinyl chloride worker. Lancet 2, pp. 1316-1318. Biological Threshold. . ., continued To Protsctivs Order ' ' dussjjtepcca, kig,, Casg fjo. 90-4837 Csfcasieu Parish, LA Comosny Case Mo. S4-CV-03S3 SIHJ JVestm District chXew YrA ysn* 18, Block JB (1974). Angiosarcoma of the liver following vinyl chloride exposure. J Amer Med Assoc 229, pp. 53-54. 19. Dannaher CL, Tamburro CH, and Yam LT (1981). Occupational carcinogenesis: The Louisville experience with vinyl chloride associated hepatic angiosarcoma. Amer J Med 70, pp. 279-287. 20. Creech JL and Johnson MN (1974). Angiosarcoma of the liver in the manufacture of polyvinyl chloride. J of Occupational Med 16, p. 150. 21. Saric M, Ulcar Z, Zorica J and Gelic I (1976). Malignant tumors of the liver and lungs in an area with a PVC industry. Environmental Health Perspectives 17, pp. 189-192. 22. Monson RR, Peters JM, and Johnson MN (1974). Proportional mortality among vinyl chloride workers. Lancet 2, pp. 397-398. U 23. Heath CW Jr, Falk H, and Creech JL Jr. (1975). Characteristics of cases in Ji => angiosarcoma of the liver among vinyl chloride workers in the United States. oo 3 4 Annals New York Academy of Sciences 246, pp. 231-236. 3000 ESTIMATED VINYL LORIDE EXPOSURE X EXPOSURE PPM 1000 - 500 200 100 50 25 a BINNS TAMBURRO X X 800000 S'Sd --I------------- :--------------- 1---------------------------- L_ 40 50 '60 YE^S X I WEIGHTED ESTIMATE OF TOTAL EXPOSURE Dow Chornies! Cmhdsnlid Material Produced Pursuarif To Protective Order ggssv,C_n^gn, ;;A, Casa No. 90-4837 C.C:j :>ju LA CXiLCELL`2 L^Tical Company Css: lie. S4-CV-0333 S(H> Wsstarn District of iVaw Yotk IIOO 900 700 500 300 - 100 . VINYL CHLORIDE ASSOCIATED ANGIOSACOMA USA CASES R&s 000310 10 20 latency (first exposure to diagnosis) CYRS.) 30 AO FIGURE 12 *-J-eooo ssu CANADA CASES WEIGHTED CUMULATIVE EXPOSURE LATENCY (YRS.) L ^ '41lim.lCal Confidentisf Material Produced Pursuant ! 3 Protective Order Pf--Case No. S04C37 ~JH\i!]lCj'i Ccrcsnv Use ?Jo.4 7-0303 SiH) Vaster*; District of New York VINYL CHLORIDE ASSOCIATED ANGIOSARCOMA (Short Exposure Cases) 30 </ OO oco to LATENCY (first exposure to diagnosis) POLYVINYL CHLORIDE PRODUCTION PLA NTS TRY - NO. PLANTS R&S 000313 SjJOA MEN JO 13UJSIQ UJSJS3M (H)S eSfO-Aim '0;i 2^3 AUcdiuo^ pi'a:?',3 ivgq v, r.;, 'g ir'vc:. , ` " `J figure if YEAR EXPOSURE BEGAN R&S 000315 v. 'hiL'n.y O-^sriv Cas2f^.:-'!-Cv-C303 5ii;j y/ssfsm District of Mow York Biological Threshold. , ., continued ' 17 24. Binns CHB (1979)- Vinyl chloride: a review. J of Society Occupational Med 29, pp. 134-141. 25. Tamburro CH and Creech JL (1983). The identification of hepatic injury and hepatic angiosarcoma among vinyl chloride workers: The epidemiological approach. / of Occupational and Environmental Health 5, pp. 37-48. 26. Makk L, Delmore F, Creech JL, et al. (1976). Clinical and morphological features of hepatic angiosarcoma in vinyl chloride workers. Cancer 37, pp. 149-163. 27. Berk PD, Martin JF,1 Young RS, et al (1976). Vinyl chloride associated liver disease - NIH Conference. Annals oflnt Med 84, pp. 717-731. 28. Tamburro CH (1979). Chemical hepatitis, pathogenesis, detection and management.a Med Clinics of North America 63, pp. 545-566. 29. Tamburro CH (1984). Relationship of vinyl monomers and liver cancers: angiosarcoma and hepatocellular carcinoma. Seminars in Liver Disease 4, pp. 159-169. - ---V i . 'smt R&S 000316 Biological Threshold. . ., continued IS 30. Tamburro CH and Greenberg RA (1980). Identification of human toxicity and carcinogenicity by ethylene derivatives. In Mechanisms of Toxicology and Hazard Evaluation, Holmstedt B, et al., Eds, New York:Elsevier/North Holland Biomedical Press, pp. 319-334. 31. Greenberg RA and Tamburro CH (1981). Monitoring exposure to hazardous chemicals in an industrial setting: a method of demonstrated utility. In System Sciences in Health Care, Tilquin C, Ed. Torontoi'Pcrgamon Press Ltd., pp. 1143-1151. 32. Greenberg RA and Tamburro CH (1981). Exposure indices for epidemiological surveillance of carcinogenic agents in an industrial environment. J of Occupational Med 23, pp. 353-358. 33. Doll R and Hill AB (1956). Lung cancer and other causes of death related to smoking: A second report on motality of British doctors. British Med J 2, pp. 1017-1081. 34. Sartwell PE (1950). The distribution of incubation periods of infectious diseases. Amer J ofHygiene 51, pp. 310-318. Biological Threshold. . ,, continued .. , Sn:;ih fits jjj.-v *>.:. Ctsysny Cass Ns. S4-CV-03C3 S{H) Wsstarn District of Msw York 19 35. Armenian HK and Lilienfeld AN (1974). The distribution of incubation periods of neoplastic diseases. Am J of Epidemiology 99, pp. 92-100. 36. Polednak AP (1974). Latency periods in neoplastic disease. Amer J of Epidemiology 100, pp. 354-356. R&S 000317 Biological Threshold. . continued 1 ,v"' v,'; Proceed Ficsuam [ ? jy .. -Xi kT93-4337 i ' .'' >i\ i \ .! V. Ccfr.lsnv 'f- NT S4-CV-S3D3 g;hj Wjstom District of Now York 20 LIST OF FIGURES 33 B C/> o o o 03 00 Figure 1: Worldwide HAS case occurrences, with the peak occurring about 1976. Figure 2: The annual incidence of HAS by date of diagnosis and geographic location for four leading countries. Figure 3: The distribution by year of first exposure for the entire cohort (1940-68). Figure 4: Illustrates the age at which diagnosis was first made among the VC-associated HAS. Figure 5: The frequency of HAS latency periods (skewed distribution), peaking at approximately 20 years. Figure 6: I. HAS cases' latency periods decrease with shorter duration of exposure. Figure 7: II. HAS cases' latency periods decrease with shorter duration of exposure. A Figure 8: The total years of exposure for each case. Figure 9: Correlates the year of first exposure with latency in the short exposure group. Biological Threshold. . continued r C '.''2 27 C'1'" C. . i <i_ Cose ij. <-Cv'-OJ03 SiHJ Western District of ftevv Vcrfe .A 21 Figure 10: Two exposure curves illustrating reported exposure levels covering the 1940-74 years. Figure 11: Latency vs.total cumulative exposure (weighted exposure) in index plant cases. Figure 12: Latency vs,total cumulative exposure (weighted exposure) in USA cases. Figure 13: Latency vs.total cumulative exposure (weighted exposure) in Canadian cases. R&S 000319 Figure 14: Latency vs.total cumulative exposure (weighted exposure) in the short exposure group. Figure 15: All HAS cases developed in PCB plants whose start-up began before 1967 (in eastern Europe before 1953, in Canada before 1941, in the United States before 1953, and in western Europe all but three plants before 1954). Biological Threshold. . ., continued " ' v: .So-:;.. jiCfii l-rju'ucsd Pursuant f . r;c.C:'337 LA f,i; v. 7r,? ro-.v Cfismic^! Ccnysny UiSEKo."4-'cyjj303 SiHI Western District of Mew York 1 LIST OF TABLES /6 The range of the latency periods is from 9-38 years. The mean latency period for each five-year interval, starting with 1940-44, demonstrates a progressive shortening from 35 to 14.6 years with an overall average latency of 22.6 years. 30 0 cn o o o co ro o i-zeooo ssu VINYL CHLORIDE ANGIOSARCOMA CASES WORLD-WIDE Ci- K\~ a ^ 3 ? C CP C/2 | - ^ -v'im /l o SO. g<C aO k'J2;U1 J -rC oO " Cl' ?- V- I- -4 -- " to 'o, 'j' ;> o S' CCDJ iCo*3i t'J_ -o i-(a2o- W. YEAR OF DIAGNOSIS 4o W oM VINYL CHLORIDE ASSOCIATED ANGIOSARCOMA IN VARIOUS COUNTRIES CANADA '41 U.S.A. 139-46 ## I NUMBER OF CASES 5 [ FRANCE '41-'57 3- 5 [ GERMANY '52-60 3- ___ !_______ I_______ I- I I 1952 '56 `60 zseooo ssu 53 fTi J CO n, :/y CO Ir'j !c CD J o$ ^ f!L*> I -5 Pr * c8hKs ru Ior0I?Tx> L2- "O '64 '68 '72 '76 80 YEAR op eseooo ssa VINYL CHLORIDE ANGIOSARCOMA YEAR EXPOSURE BEGAN ^ ppm 2000 2000 l\ 9r * P*1 200-500 500 1 4- * 50-200 1 o 7 00 LU 00 < (J , o1 A O oLl *? DC LU CD 3 ff ** 3 ?*? * 8 I o <<1974 J l974 C?\rp n|^ -h 0 cj |r CO CuCCO>OD S= CO ii n COCO Cj> 4!j's, rj CO ^ ccf*:j4. a 1940 i. ... t... 1-.1.... L 45 1-1 1___11 50 I '55 wYEAR J__L _j___ i___I___ i i i i i 60 65 70 itf? VINYL CHLORIDE ANGIOSARCOMA AGE AT TIME OF DIAGNOSIS 9* NUMBER OF CASES uagcjn,} psanpOJH 'aieiMle.iunp-.iR * 7 f ' f i 4 *? 44 Hi 44 4 4 4 % 4 4 `i < * t 4 ' 4 4 *4 H . - #' P *# '# *^ A 4f* ' > / H 44 4'4 *' <JJ-fir f rro! tr> ocu L r cj i rt_-i U: L-/< r *ju -*- ^3 CJ CD* nO. L4-. c*!o_ Y Yu" L S' 4J iL rj A A2. v r' r- Tj` 5. o ^C'i "M ^S? &3 r> ;3 ro ra cj t<oV-- J c& Li- ^ s^ ^o. ro: t-cOx: IVV? 4 4 4 4 ft * t f 44 * 44 44 44 y ; / XX 4 4 4 4 4 4 4* 4 444 4 44X444.4 : 4 4 i i i 1 i i i _J___ !___ 1___ !___ 1___ 1___ 1___ L i i i i i 1 ! ! 1 1 1 1 1 l I f f 1 1 1 / 35 40 45 50 55 60 65 70 AGE frseooo ssh TOTAL NUMBER OF CASES I sseooo s$y VINYL CHLORIDE ANGIOSARCOMA TIME FROM FIRST EXPOSURE TO DIAGNOSIS 9r 7- # o 3 i l I I I l 1 I l I I l l l I I___ 1___!___ I___ !___ I___ I___ I I I I l 10 15 20 25 30 YEARS 35 j RELATIONSHIP OF#<POSURE TO LATENCY IN VINYL CHLORIDE ASSOCIATED ANGIOSARCOMA (In North America ) I960 r LlI or ~ SOOppm USA tn o 1955 Ol A CANADA XA UJ Ll o 1950 o:` < LJ X ~ 2000ppm A AA 1-- 1945 -- CO cn A A A Ll A 1940 ___________ li_____ it i1 iii 5 10 15 20 25 30 LATENCY IN YEARS (first exposure to diagnosis ) gzeooo r FIGURE 6 FIRST YEAR OF EXPOSURE zseooo ssa RELATIONSHIP OF EXPOSURE TO LATENCY IN VINYL CHLORIDE ASSOCIATED ANGIOSARCOMA 1965 ( In Europe ) ~ 250ppm I960 A^ AA FRANCE A GERMANY ~ 500ppm 1955- A A 1950 A A AA AA A A 2000 ppm 1945 - 5 10 _______I____________ 1_____________ !______ 15 20 ' 25 LATENCY IN YEARS (first exposure to diagnosis ) 30 (1941) ___ 9 # TOTAL YEARS OF EXPOSURE IN CASES OF HEPATIC ANGIOSARCOMA IN VINYL chloride workers 9 1 *.ftft .. ft -- 00 7LU -- in < o U_ O 5 __ Qd UJ CD - 3 2 3 1L V . /i ft ^<0* ft f ' ft. t t 'ft .ft - ftft ,Y 1 ft ' . 1 ftft M ft ft '*ft > ft ft ft ft ft ft ft ft-ft ft ft ft ft ft ft ' * '* , Jr , r * 1 ~ r-, I'O [" 1 iiN IJl 1' I y oli o 5% . r-J L-i-! F, 1 i `Fi a- V < Jji > [ 31 ^ l l'J l r? o i-- o. r-i 73 3 1 1 l!J- -2 |r L" 73a. y~ C- J ^ rLi o yi ^ 5-J. i -D. rj Si' ' ' L; ft ft.ft ft ft * i ft ft * i / , 9 .4-4 // tEf -- * JC-O- ~--J CrJ " **4 5'2 c` ^ * ft ft ft ft ft ft ft ft ft* ft ft ft .* ' - jrf ti f'i0 c C, < r: j ft ft ft ft ft ft ft ft ftft ft ft4 ftft ft .ft ft ft '> / J_J___ I I i I i i I i ! 0 5 10 15 20 25 30 -Y 07'. a * ^IT YEARS 8ZE000 FIGURE 8 YEAR OF FIRST EXPOSURE 63000 SVU VINYL CHLORIDE ASSOCIATED ANGIOSARCOMA (Short Exposure Cases) 965 r 3.5 250ppm I960 500ppm 1955 NJ INDEX CASE AND ^ NUMBER OF YEAR EXPOSURE 1950 ~2000ppm 1945 5 j_ 10 15 LATENCY (first exposure to diagnosis ) 30