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VINYL CHLORIDE Geary Olsen October 30,1989 R&S `>03g? OUTLINE OF DISCUSSION I. VINYL CHLORIDE A. Introduction B. Known Cases Worldwide of ASL Associated with VCM C. CMA/EHA Study D. Dow Study E. The Sir Richard Doll Review F. Calculation of Risk G. Various Authors' Conclusions H. Miscarriages and Birth Defects I. Neuropathy II. THE ST. GABRIEL MISCARRIAGE STUDY R&S 040398 JUNE, 1989 Quote from local audience member 'The chemical that they make more of here than anywhere else In the country is vinyl chloride and it causes that in the wives, it causes cancer and it causes rare liver disease and it is proven and they make it intentionally and it is immoral and criminal to produce a chemical that is known to kill." R&S 040399 H CHRONOLOGY OF PVC PRODUCTION AND HEALTH RISKS 1942 1949 1966-7 1960's 1971 1972-3 1974 Start of commerical PVC production in U.S. Earliest references to AOL and hepatic effects Detailed description of AOL Reports of hepatomegaly First report of experimental carcinogenicity Detailed description of hepatotoxicity First cluster of HAS LIVER LOBULE (PANORAMIC VIEW) Bile duet 3 Kicrnan'i insure 4 Branch of the hepatic 5 portal vein Branch of (he hepatic artery 6 Bile duct 7 Portal area, interlobular space, or Kiertun'i space 8 Bile duct 0 Branch of me hepatic nonai veto 10 Central vein 11 L(laivmerinpal)ate 12 Branch of the hepatic artery 13 Branch of the hepauc portal van 14 Portal area 1$ Bile duct R&S 040400 Bile in. canaliculus f lowi on toward 33 </> O -ft. -Ob o o lobule. Fie. 25-7. Drawing (at high-power magnification) to show how blood from the portal vein and the hepatic artery (left) Hows into sinusoids, lined by reticuloendothelium. that lie between liver cords, and empties into the central vein I rifht). The way that bile travels in the opposite direction in canaliculi to empty into bile ducts in portal areas is also shown. liver limiting plate sinusoids CS3oo7 o ob Mo central vein, in. here sinusoid sheets of: spaces liver cells app e ar as cords branch, of portal vein inhere i' mi1 -i.tml;iiil lot 111\ I i 111 >ri<I -. >.iilit ;i |vIiIimI ,1\I'l'.lUr ;"i .ill **\ | ia i.--11 uni In I'M'ri'it .ill h|im 11-1" III--I I. \rru-ii-|('n|\ sis \rrn-nslenlv sis i mislsls nl Ineall/ei I areas nl Imiie neernsls iml alism pimii. lliese lesions are nmilei li |er am I are mil a-sneialed villi a periosteal icactimi. llie Ii.iikI- ami lingers an* imi.-l miinniiiv IIIV III V ell. Ill a lliaiuritv nl eases. aero-ns(enlv sis Is assoi'l.: -iI auli liaynamls plieiiuiiieHnu and -i iemilennalnii- -km Imusc-. FIG 64--1. A worker entering a PVC reactor vessel to clean out caked polymer adhering to the inner surfaces. During the polymerization reaction, sludge from the slurry has a tendency to form a crust on the im peller mechanism as well as the tank inner surfaces. The caked polymer is periodically hand-chipped by workers inside the tank, and this is the operation that subjected workers to the highest con centrations of vinyl chloride. Current practice requires that flexible ducts be used for purging with clean air before the worker enters. In addition, workers in this operation must be provided with positivepressure air-supplied respirators, preferably the hood type. De mand-type respirators have been used, but may not offer the same protection as the continuous-flow type of hood respirator. (Courtesy of Maurice N. Johnson, M.D.. B.F. Goodrich Company, Akron. Ohio. Photographer-H. Groskinski.) in Iwn wn|ki-l>. Ill llw .n`l l`\(. vvmki-1- lit, llll- |li,ll > iliMlliTs. Ittii i ,i-i`> ui-ri- li li-lil i llri I ll.MldS'"' d| tfll'SC Ulilkl'l-. Till1 llTMMM.li llll.ll. julrllii. .mil (In* |ili;il;im.!i*- ill llii- lii*l uiuiitkiTs, .il.'ii .mliii l.nc i 11*;11n f~-, ili inim-ii 'ilini.uni'll |i\ I!,iv n.iml - 11in-1u11111'111'11. \\ lIsuM 'Imlii-il .il i.i.-i-' ill iM i`11[i;11 11K IkhiiIs ui winkers eiur;meil in vmvi i Mm Musi n| tlir-r wmkfi- Mid imrkei a.ills .iml ntlier <- 11111H;h i11 m |In- |ni|vim-r : Mv.-i- w;ls lne;lll/eil In till- <|i-l;d |ili;il.illi:i`.- i A.is ;|'SIH|;I|C(I will) K.IVIlmiil -V ltl|>lii|II.-. illsnnliT ri-siillcil Irnm .i i mnliiimiimi n| ph in.-ull. mid persmuil iilnis\iht;i.-v. mill urii vv;i.- rcpmleil in I,, -imiliir work. .mil n |>iK iiht nr mmitiim |l)U vvnrkiT,- luilnlleil llie Im prneesmsl || illln |i|;i.-lic |mn|llrl.- illil llnl il .iern-i islenK s|s. Ill I'lTI) mill I'JTI. Dilllmill III llie Ills! .mil 11 k 11 is. I ri; 11 11111111 ;il llie I m\ersil\ nl ' i nlllprelieltsH e slllilv ill ;ti Tn-ii'li'ii|v'I' III v i mtipntituliiie vmvl .mil l'\<`.. llie epiilciim leselileil mine lli;m .>.000 wmkeis III 52 pi. were ilisenvereil, nl vvllirll J.i llml .1 ilelmiliUi 'iispielnlis iluimm.-i'- nf mn i-< i-ln i| V-i- , ll.lllil i le.mitlLI nl llie |mlvInerixers. DimI.mim ilelermineil llml uink pr;ieli s|ieei)ie ;ig(,lll n|- enlllliimilimi nl .infills, .ipp neeiirreme nl llie disease, lie llimudll die ilis rallier lltan Ini ali/.ed in nalnre. Iml was mi.n Injjir auenl nr pnrtal nl eiiiry, -imgr-lun' .-mi -ilizalinn nl siiseepllliililv. " \n imliislrial li epideminlmzie inveslisraliini re\ealeil \invl e| in llie reactor lielnre v i-iililaling In lie alnnit .i alinii nl' (lie eimlaim-rs. llie vinyl ehlnride em real tors iliirinj; serapins: was Immd In lie uml. :i 11 v amuitd 50 ppm. Il was linmd dial .-crapii (MiUmerized vinvl i lilmiile so dial levels n| (ill Immd rinse to llie (lands during lliese nper pntentialK high wnrker respiralnrv iiilialalimi. -lituenls of llie scrapings nl llie reaelnr vessel polymerized resins, unreaeted ealalv.-ls. addli die [mlvmerized vinvl clilnride. No serious diported in any of die aliove-nienlioned eases lieen partially disabled Iteeaiise nl liund sore -Iriction in manual activity. Willi proper p and careful hygienic measures, all these ea i Kie 01--21. \ ellman el al."' reported lindim'- in 70 vtncluves and centrifuses. durins drv ins and sii JO to to ob o o-fe FIG 64-2. The solid, caked polymer must be removed by chisels, hammers, and handpicks. Neither workers nor management may be aware of the hazard involved when a spark is generated by steel on steei. It is not uncommon to open a pocket of the cake lining the vessel. The pocket may contain liquid vinyl chloride monomer. It is very possible that the lower explosive limit for vinyl chloride monomer (33,000 ppm) can be reached during the chipping with steel on steel. Reactor vessels have exploded, leaving nothing but a crater in the ground where the plant once stood. Reactor chipping or cleaning tools should be of the nonsparking type. To minimize worker entry, some companies use high-pressure water guns to re move the caked polymer. These water guns may operate from 9,000 to 13,000 pounds of pressure per square inch. This in itself may produce a serious safety hazard. Some attempts in the United States to remove the caked slurry have utilized closed solvent cleaning systems in which solvents such as tetrahydrofuran are used. To date, such solvent cleaning systems have been relatively unsuccessful. Recently completed production systems using 30,000-gallon reactor vessels have been utilizing automatic highpressure water cleaning guns and solvent systems to minimize or eliminate the need for worker entry into reactor vessels. Older re actor vessels, which contain cooling vanes of heat exchangers, complicate the cleaning process and high-pressure water guns and solvent systems cannot be used in these tanxs. (Courtesy of Maur ice N. Johnson. M.D., B. F. Goodrich Company, Akron, Ohio. Photographer-H. Groskinski.) peopie in a ^roup mI 2(). unikci' in Ichloride polymerization plant, t -igns ol abnormal peripheral eirc murli more frequently In those u -ure. Findings included ntimbne- lo cold. pain. wanosis. iiivoiveit -vndrume. An abnormal Allen le ers. p.-eudoclubbiiii.' in . ehumres in (>. Vc. I be specific elleel ol \l,M culminates in neural, dermai. am: been in doubt. I lie siiporlieiai re-- -elerosis iselerodermai lias prompt a report ol 22 l*\(. workers In I')i0. (t workers bad prodromal .- non. 10 bad typical K.nnaud s -y 'clerodeiina-like ebani'cs in the in y.-is ol (lie distal phalanges and -yndruine yvas described a.- -ympi esiliesia in the lingers willi inerea- digital arteries. < irvuglnhuliuemia immunoglobulin.- l22. 70) were b plasma proteins. I hose with tm mole likely lo have mimuuoloi:ic in A ol 22 and li:M in I ol 23. In be eley ated in l>~r,'r. ' ( .rvoglolllllillS were also see Ward cl ul." Ibese workers \ye patients will) yiml chloride di-ea- ical Findings riicompus-iil" abm blood, nervous system, linn's, a- possible \ (ID: and 33 y inv I cbloi i "globulins were seen in lit)CU. I !' louud in ~)oc/t. 27r/i. and 0rr. II IizO. (73. and librinogen. Klieiun patients when measured In the lal posiliye in low liter In hemagglic definite \ CD and 22.. r'< o| those oresceut evamination ol -kin ami i with definite \ CD showed the peer wilhin the lumen ol .-mall blood > cular endothelium. I lie-e authors \ t.M binds to lyC-prodtioing ay: immune complexes during cold e stimulate complement activation and the conversion ol fibrinogen t* ies and small blood vessels. layer A hepatitis-like ellect has be* posure. In a study ol /() workers CAUSES OF ASL VCM Inorganic arsenic Thorotrast Androgenic - anabolic steroids Fl&S 40406 TOXICOLOGY 1. HAS is linked to the amount of VCM metabolized rather than to VCM concentration. 2. Reactive intermediates, particularly the epoxide (chloroethylene oxide) found by oxidative metabolism of carbon/carbon double bond, are most likely the carcinogenic agents. 3. Short-lived metabolites are formed in the hepatocyte but are carcinogenic in the adjacent cells to which they migrate presumably because their cells have less detoxification potential. Reactive metabolites covalently bond to macromolecules such as DNA. R&S 040407 VCM-INDUCED VS. CLASSIC HEPATOTOXICITY VCM-induced hepatotoxicity: relatively silent progression not detected early by standard liver function tests effective screening tests lacking least common of all causes of hepatotoxicity various parts of spectrum seen with VCM, Thorotrast, arsenic, and steroids (androgenic-anabolic) Classic hepatotoxicity: clincial signs and symptoms appear early hepatic effects noted by enzyme changes, and other readily available laboratory tests many clinical screening tests are used wide array of hepatotoxins have been identified R&S 040408 RETROSPECTIVE ESTIMATES OF TYPICAL TWA 8-HOUR PERSONAL EXPOSURES Estimate 1000 400-500 300-400 150 5 Year 1945-1955 1955-1960 1960-1970 Mid 1973 1975 R&S 040409 VINYL CHLORIDE ILLNESS 1. Enlargement of liver and spleen with a specific histologic appearance 2. Patchy infiltration of the skin resembling scleoderma. 3. Many changes in the tips of the fingers described as acroosteolysis. 4. Peripheral circulatory changes identical with the classical picture of Raynaud's syndrome. ASSOCIATION OF PLASTICS MANUFACTURERS IN EUROPE WORLDWIDE REGISTRY OF ASL RESULTING FROM EXPOSURE TO VCM R&S 040410 Begun in 1974 Cases must be histologically confirmed Mean age at diagnoses = 52 years Incidence of ASL reaches a peak of 20-29 years after exposure 43% of affected individuals were autoclave cleaners R&S 040411 NUMBERS OF VINYL CHLORIDE RELATED CASES OF ANGIOSARCOMA OF THE LIVER BY DATE OF DEATH Period 1955-59 1960-64 1965-69 1970-74 1975-79 1980-84 Total Number of Deaths 2 4 9 23 46 34 118 R&S 040412 ASL REGISTRY UPDATE THROUGH 1987 1985 1986 1987 Cases 5 3 4 Of 50 cases in North America, 42 have occurred at 4 factories. Louisville (15) Shawinigan (12) S. Charleston (10) Niagara Falls (5) R&S 040413 DISTRIBUTION OF CASES BY COUNTRY Country United States West Germany France Canada United Kingdom Sweden Italy Yugoslavia Czechoslovakia Japan Belgium Norway Total Number of Cases 35 26 18 10 9 5 4 4 2 2 2 1 118 Number of Factories Reporting Cases 10 6 5 1 2 1 4 1 1 1 1 1 34 R&S 040414 EHA UPDATE COHORT DEFINITION* 9,370 men who had worked at least one year in jobs involving exposure to vinyl chloride prior to January 1,1973. 32 U.S. plants Observed through December 31,1982 R&S 040415 EHA STUDY OBSERVED AND EXPECTED DEATHS BY CAUSE, SMRS AND 95% CONFIDENCE LIMITS Cause OBS EXP SMR All Causes All Cancers Liver and Biliary Tract* Lung Brain and CNS Lymphatic and Hematopoietic System Nonmaiignant Respiratory Disease Emphysema, inclding COPD 1536 359 37 111 23 37 70 41 1705.3 341.7 5.8 115.9 12.8 36.3 87.6 22.8 90 105 641 96 180 102 80 180 *7 Biliary tract cancers versus 2.7 expected (SMR = 256; 95% CL = 245-511). 95% CL 86-95 94-117 450-884 76-116 114-271 72-141 62-101 129-244 I 04416 EHA STUDY SUMMARY OF CANCER OF LIVER AND BILIARY TRACT Duration of Expsoure <10 Years GBSSMH 6 182 10-19.9 Years OBS 20 SMB 1235* 20+ Years OBS SMR 11 1284* Years.Sinee. First Exposure <20 Years 20-29.9 Years OBS SMB 10 386* OSS 11 SMB 590* 30+ Years OBS SMR 16 1218* <1950 OBS SMR 27 780* Year.-Pf First.Expsoure 1960-1959 1960+ BS SMB 7 440* OBS SMB 3 419 Iyp.e_QJLRlarit YCM EY OBS SMB 1 326 OBS smb 31 693* R&S 040417 EHA STUDY SUMMARY OF ALL CANCER EXCLUDING LIVER AND BILIARY TRACT Pvration of Expsoure <10 Years OBS SMR 174 92 10-19.9 Years qbs 94 sm 102 20+ Years OBS SMR 54 100 <2Q_Ye.ars OBS SMR 120 87 Years Since First Exposure 20-29.9 Years qss 122 sm 105 30+ Years OBS SMR 80 96 <1950 QBSSMH 166 93 Year of First Expsoure 1950-1959 196Q BS SMH 107 105 OBS SMR 49 90 Type of Plant YCM EYC OBS SMR 23 110 Q3S SMR 241 94 R&S 040418 EHA STUDY SUMMARY OF CANCER OF THE LUNG PuratlQiLof-ExpsQure <1Q Years OBS SMB 59 93 10-19.9 Years OBS SMB 37 114 20+ Years OBS SMR 15 75 <20 Years OBS SMR 44 104 Years Since First Exposure 20-29.9 Years . OBS SMB 45 105 30+ Years OBSSMR 22 72 <1950 OBS SMB 54 90 Year of First Expsoure 1950-1959 19SQ OBS SMR 39 106 OSS SMB 18 96 Type of Plant VCM PVC oss SMB 1 QBSSMB 29 R&S 040419 EHS STUDY SUMMARY OF CANCER OF BRAIN AND CNS Duration of Expsoure <10 Years OBS SMS 13 165 Ifel9,9-Yeais OBS 4 SMB 121 20+ Years OBS SMR 6 386 <20 Years QMS SMS 13 184 Years Since First Exposure 20-29.9 Years OBS 6 SMB 158 30+ Years OBS SMR 4 210 <1950 OBS SMB 9 156 Year of First Expsoure 1950-1959 1S6Q OBS SMB 7 164 OBS SMB 7 256 Type of Plant YCM mi OBS SMB OBS SMB R&S 040420 EHA STUDY SUMMARY OF LYMPHATIC AND HEMATOPOIETIC CANCER <10 Years Duration of Expsoure 10-19.9 Years QBS SMB 20 91 QBS 12 SMB 128 Years Since First Exposure <20 Years 2fr29,9Jlfear.g QBS SMB QBS SMB 20+ Years QBS SMB 5 104 3Qt_Yeara QBS SMS 16 88 14 130 7 97 Type-oLP!ant YCM EC QBS EXE QBS EXE 0- 31 114 Year ot First Expsoure <1950 1 950-1959 QBS SMB 19 107 QBS SMB 13 114 196Q QBS SMB 5 71 R&S 040421 EHA STUDY SUMMARY OF EMPHYSEMA MORTALITY Duration of Expsoure <10 Years OBS SMB 25 209* 10-19.9 Years OBS 11 SMB 167 20+ Years OBS SMR 5 117 <2Q_Years OBS SMB 11 158* Years Since First Exposure 20-29.9 Years OBS SMB 17 198* 30+ Years OBS SMR 13 179 <1350 OBS SMR 24 174* YeflLfllBIrsLSxpsoure 1950-1959 OBS SMR 12 189 Type of Plant YM PVC I960* OSS SMB 5 187 R&S 040422 DOW CHEMICAL VINYL CHLORIDE MORTALITY STUDY Michigan Division 593 employees who were potentially exposed to vinyl chloride monomer 1942-1982 17,114 person-years 28.9 person-years average per person OBSERVED AND EXPECTED DEATHS FOR SELECTED CAUSES EXCLUDING EMPLOYEES WITH PRIOR EXPOSURE TO ARSENIC INSECTICIDES, 1942-1982 Cause of Death (ICD-8) Obs Exp SMRt 95% Cle AM causes 130 151.9 All cancers (140-209) 27 31.7 Digestive system cancer (150-159) 9 8.5 Liver cancer (155,156) 1 0.6 Respiratory system cancer (160-163) 10 11.3 Brain cancer (191,192) 2 1.1 Ail circulatory diseases (390-458) 65 75.4 All nonmalignant respiratory diseases (460-519) 9 8.6 All accidents (E800-E949) 8 10.9 86 85 106 - 89 86 104 74 72-102 56-124 48-201 4-899 42-163 23-682 67-110 48-198 32-144 4 Expected numbers are based on calendar time and age-specific mortality rates of U.S. white men. t Standardized mortality ratio; observed divided by expected number of deaths X 100. Cl, confidence Interval of Obs/Exp. Not calculated when expected number of deaths fewer than 5. Liver cancer was an Introkepatlc bile duct carcinoma. R&S 040424 Undetermined Less than 25 ppm 25-200 ppm TWA 200+ ppm TWA Based on highest rated job assignment for at least 1 month Men with at least 5 years of exposure above 200 ppm (7 observed versus 2.8 expected). No predominant tumor site or unique histologic type. 04042s A VCM REVIEW BY SIR RICHARD DOLL 1988 F?&S 040426 OBSERVED AND EXPECTED NUMBER OF DEATHS FROM DIFFERENT H CANCERS REPORTS IN THE FOUR PRINCIPAL STUDIES (0 = OBSERVED NUMBER OF DEATHS, E = NUMBER OF DEATHS) United States United Kingdom Canada Type of Class of Cancer Oa E OE OE Buccal cavity and pharynx Stomach Large intestine Liver Liver and gallbladder Pancreas Lung Melanoma Testis Bladder Kidney Other and unspecified urinary Brain Eye and central nervous system Thyroid Lympho- and retlculosarcoma Hodgkin's disease Leukemia Multiple myeloma * Other lymphatic / i Other ^Lah cancers 13 11 21 39 17 118 5 12 25 12 3 14 11 46 383 11.55 16.01 28.79 5.77 18.40 115.87 8.46 9.06 12.76 7.98 5.45 13.94 8.37 40.50 341.73 4 26 9 11 7 81 2 2 14 3 3 4 2 4 3 7 2 18 235 3.58 23.91 13.94 0 - - 1.94 8 -- 9.88 - 92.12 2 1.74 - 1.38 % 8.00 1 4.10 I i 4.29 I 6.18 ? } 0 0.43 2.35 ^ | 2.50 yI5.16 | 2.35 1Jf i 8.12 2 228.60 20 0.64 - 0.14 - 5.78 - 1.33 0.60 - 1.67 0.95 16.37 My OE 1 0.8 3 3.0 0 1.2 1 0.6 -0 0.7 12 6.1 0 0.2 -- 1 0.7 - 0 0.4 0 0.7 --9 4.5 ______ -j 30 a Observed deaths multiplied by 1.0674 and rounded off to the nearest Integer to allow for deaths without discovered cause. R&S 040427 NUMBERS OF DEATHS FROM NONMAL1GNANT AND ALL CAUSES REPORTED IN THE FOUR PRINCIPAL STUDIES (0 = OBSERVED NUMBER OF DEATHS, E = NUMBER OF DEATHS) Type of Class of Cancer Ischemic heart disease Other circulatory disease Bronchitis b Pneumonia Other respiratory disease Cirrhosis of the liver Other digestive disease Other diseases All nonmalignant causes All causes United States Oa E 521 597.73 157 123.55 44 22.83 16 31.94 15 32.84 j 37 56.06 27 39.52 67 115.68 .United Kingdom 0E 276 288 105 141 36 44 40 61 J 5 5 - -a 43 76 1153 1536 1363.54 1705.27 545 894 665 894 Canada OE Italy OE 25 31.67 19 27.4 1 6 3.21 , 3 5.0 4 c 3.85 2 d 5.40 4 5.2 3 2.7 2 7.0 36 54.76 36 56.4 59 71.07 6 77.5 aObserved deaths multiplied by 1.0674 and rounded off to the nearest integer to allow for deaths without discovered cause. ''Emphysema in data from the United States. 'includes two cases certified as cirrhosis of the liver which proved to be angiosarcoma of the liver, 'includes one case with cause unknown. H MORTALITY FROM VARIOUS CANCERS AMONG VINYL CHLORIDE WORKERS IN 49 PLANTS IN THE FOUR PRINCIPAL STUDIES COMBINED '?4S 040428 (0 = OBSERVED NUMBER OF DEATHS, E = NUMBER OF DEATHS, SMR = STANDARDIZED MORTALITY RATIO)) Type or Class of Cancer 0 E SMR Mouth and pharynx Digestive system (other than liver) Respiratory system Lung Genitourinary system Melanoma Brain Thyroid Lymphatic and hematopoietic system Other All other than of the liver 18 125 223 211 70 2 29 2 57 83 609 16.57 154.59 229.36 214.09 62.81 1.94 19.54 0.43 50.87 63.24 599.35 109 81 97 99 111 - 148 - 112 131 102 R&S 040429 MORTALITY FROM LUNG CANCER IN THE SERIES FROM THE UNITED STATES (US) AND THE UNITED KINGDOM (UK) BY CHARACTERISTICS RELEVANT TO AN OCCUPATIONAL HAZARD (0 = OBSERVED NUMBER OF DEATHS, E = NUMBER OF DEATHS, SMR = STANDARDIZED MORTALITY RATIO)) Data a Characteristic Category 1 h OE SMR Category 2 . O E SMR Observed 20 years or more after first employment (1), others (2) 114 113.96 100 85 93.83 91 Employed 10 years or more in the US (1), others In the US (2) 55 52.45 105 63 63.44 99 Employed before 1956 In the UK (1), others in the UK (2) Ever employed as autoclave worker in the UK (1), others Inth UK (2) 52 51.39 16 17.08 101 29 40.50 72 94 65 74.82 87 a The numbers in parentheses designate the category. b Expected numbers are based on calendar time and age-specific mortality rates of U.S. white men. R&S 040430 MORTALITY FROM CHRONIC OBSTRUCTIVE LUNG DISEASE^ THE H SERIES FROM THE UNITED STATES AND THE UNITED KINGDOM BY CHARACTERISTICS RELEVANT TO AN OCCUPATIONAL HAZARD (0 = OBSERVED NUMBER OF DEATHS, E = NUMBER OF DEATHS, SMR = STANDARDIZED MORTALITY RATIO)) Data b Characteristic Category 1 O E SMR gateqoiy.2 OE SMR Observed 20 years or more after first employment (1), others (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 autoclave worker In the UK (1), others in the UK (2) c 30 15.8 16 10.9 26 30.17 3 6.55 - 190 11 7.0 157 147 25 12.0 208 86 10 13.60 74 46 33 37.22 89 y 'O 09 Described as emphysema in the US study and as bronchitis in the United Kingdom study. The numbers in parentheses designate the category. c Men ever employed as a bagger or drier, occupations which would have caused the greatest occupational exposure to polyvj^|chloride dust, experienced one death from broncN^ against 4.98 expected. R&S 040431 R&S 040432 CALCULATION OF RISK Studies of the quantitative aspect of VCM metabolism have shown that there is a dose dependency in the rate of metabolism. As the dose of VCM increases, the proportion exhaled increases and that excreted in the urine and feces decreases. R&S 040433 extensively. The highly reactive intermediate in the metabolic process, chloroethylene oxide, reacts with cellular macromolecules, including DNA to produce the actural lesions leading to mutations/induction of cancer. R&S 040434 CALCULATION OF RISK Estimation of the exposure levels likely to cause a lifetime risk of -6 -7 ASL of 10 on laboratory date may range as low as 3.9 x 10 ppb (Multi-hit) or as high as 1400 ppb (log-probit). Reasons for this variability include: 1) rate of VCM conversion is limited at high levels of exposures giving inaccurate estimates of the slope of the dose response-relationships; 2) has not been able to estimate the rate of conversion in man; 3) variability of subsets of experimental data used on mathematical models; 4) various differences in assumptions of mathematical models and ^^^S^ssumption^Jse^i^pplyin^h^Tiodels^^^^^^^^^^^ CALCULATION OF RISK R&S ^40435 Although there was considerable variability in the dose-response relationship in the different experiments reported, in all cases a total metabolized dose equivalent to an inhalation of 200 ppm was required to produce an elevation in ASL incidence. 40436 r\ HOW MANY MORE ASL CASES ARE EXPECTED TO DEVELOP WORLDWIDE DUE TO VCM EXPOSURE IN NEXT 30 YEARS? Forman et al Purchase et al Nicholson Estimated New Cases 200-250 150-350 1500 R&S 040437 There has not been a reported death of angiosarcoma of the liver for any Dow employee or employee of a Louisiana chemical plant. R&S 040438 VCM OCCUPATIONAL STUDY CONCLUSIONS VCM caused angiosarcoma of the liver in occupations which had high exposures prior to 1974. Cancer Sir Richard Doll (1988), 'There is too little evidence to confirm or refute the suggestion that vinyl chloride might cause melanoma or cancers of the thyroid, brain, and lymphatic and hematopoietic systems. None of the small excesses that have been recorded point specifically to an occupational hazard ... and most are likely to be the sort of chance effect that is certain to be observed when many types of cancers are examined in many different studies. R&S 040439 VCM OCCUPATIONAL STUDY CONCLUSIONS Sir Richard Doll (1988, continued), '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 likely 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." / R&S 040440 VINYL CHLORIDE COMMUNITY HEALTH CONCLUSIONS Sir Richard Doll (1988), "A very small risk of angiosarcoma may have occurred as a result of vinyl chloride escaping into the environment around plants handling vinyl chloride in the past, but the evidence indicates that the current risk to the general public (if any) must be negligible." VCM OCCUPATIONAL STUDY CONCLUSIONS R&S 040441 K Jones et al (British study, 1988), 'This study does not offer any anecdotal or statistical evidence for an association between brain cancer and VCM exposure." Jones et a) (1988), 'The results of the study do not demonstrate any association between VCM and lung cancer deaths." Wu et ai (NIOSH, 1989), "Our data do not support the hypothesis the excess risk of lung cancer and brain cancer which had been observed at this plant is associated with exposure to either VCM or PVC dust. The lack of significant findings in the cohort analyses for these two cancers was further supported by the lack of a dose response in the case-control studies for exposure to either VCM or PVC dust. R&S 040442 VCM OCCUPATIONAL STUDY CONCLUSIONS Purchase et al (1987), "For brain cancer the association between exposure to VCM and an increased incidence was less clear because of the lower relative risk. Neoplasms of the respiratory tract, digestive system, lymphatic and hematopoietic system, buccal cavity and pharynx, cardiovascular system and colon/stomach were reported to show an increased incidence in one or more studies, but to show no increase, or in some cases a decrease, in incidence in other studies." R&S 040443 VCM I--^ HOCCUPATIONAL STUDY CONCLUSIONS________I Wong et al (1987), "Contrary to our observation on liver cancer, a higher brain cancer mortality risk was found among those who were exposed after age 35 and who were exposed in or after 1960 than those who were exposed before 1960 and at a younger age. Based on the limited exposure information available in this mortality study, the implication of this difference in risk profile is not clear at this point." "For the entire cohort, 115 deaths were due to cancer of the respiratory system, compar d to 122.25 expected. The corresponding SMR was 94.5. Our study, at the 0.05 significance level, has 80% statistical power to detect an SMR for cancer of the respiratory system as small as 124. Therefore, we can conclude that our study has clearly demonstrated that there is no relationship between occupational exposure to vinyl chloride and cancer of the respiratory system." R&S 040444 VCM OCCUPATIONAL STUDY CONCLUSIONS Wong et al (1987), "In our study, 37 deaths were due to lymphatic and hematopoietic cancer, compared to 36.28 expected. The corresponding SMR was 102.0. Our study, at the 0.05 significance level, has 80% power to detect an SMR for lymphatic and hematopoietic cancer as small as 145. Therefore, our study has adequate power to detect an increased risk in lymphatic and hematopoietic cancer as small as 45%. Since we did not see any excess in the cohort as a whole or in any other specific analysis by length of exposure or latency, we conclude that there is no relationship between occupational exposure to vinyl chloride and an increased risk of lymphatic and hematopoietic cancer. 040445 MISCARRIAGES AND BIRTH DEFECTS R&S 040446 INFANTE ET AL1976 STUDY MEAN PATERNAL AGE, NUMBER OF PREGNANCIES, AND FETAL DEATH-RATES ACCORDING TO HUSBAND'S V.C. EXPOSURE Controls Prior to husband's exposure: Number of families Mean paternal age at conception (yr.) Number of fetal deaths among wives Number of pregnancies Age-adjusted fetal deaths/100 pregnancies Subsequent to husband's exposure: Number of families Mean paternal age at conception (yr.) Number of fetal deaths among wives Number of pregnancies Age-adjusted fetal deaths/100 pregnancies 95 23.0 11 159 6.9 113 30.4 24 273 8.8 Primary VCM Exposure 70 26.4 15 148 6.1 62 30.2 23 139 15.8 R&S 040447 INFANTE ET AL 1976 STUDY MEAN PATERNAL AGE, NUMBER OF PREGNANCIES, AND FETAL DEATH-RATES ACCORDING TO HUSBAND'S V.C. EXPOSURE EXCLUDING PREGNANCIES OF WOMEN WITH >3 FETAL DEATHS Controls Prior to husband's exposure: Mean paternal age at conception (yr.) Number of fetal deaths among wives Number of pregnancies Age-adjusted fetal deaths/100 pregnancies Subsequent to husband's exposure: Mean paternal age at conception (yr.) Number of fetal deaths among wives Number of pregnancies Age-adjusted fetal deaths/100 pregnancies 23.0 11 159 6.9 30.2 18 265 6.8 Primary VCM Exposure 26.3 9 141 3.1 30.8 14 120 10.8 R&S 040448 INFANTE ET AL 1976 STUDY PATERNAL AGE DISTRIBUTION FOR FETAL DEATHS ACCORDING TO HUSBAND'S V.C. EXPOSURE Controls Paternal age (yr) Pregnancies Fetal deaths Before exposure: <20 20-24 25-29 30-34 >35 All ages, crude rate Mean paternal age at conception Age-adjusted rate* After exposure: <20 20-24 25-29 30-34 >35 All ages, crude rate Mean paternal age at conception Age-adjusted rate* 31 80 38 6 4 159 23.0 yr. - 1 43 87 87 55 273 30.4 yr. - 2 (6.5%) 4 (5.0%) 4 (10.5%) 1 0 11 (6.9%) - 0 4 (9.3%) 3 (3.4%) 7 (8.0%) 10 (18.2%) 24 (8.8%) - - (8.8%) Primary exposure Pregnancies Fetal deaths 7 44 56 27 14 148 26.4 yr. 0) 2 (4.5/) 7 (12.5/) 5 (18.5/) 1 15 (10.1%) - (6.1%) 0 22 48 36 33 139 30.2 yr. - 3 (13.6/) 11 (22.9%) 3 (8.3%) 6 (18.2/o) 23 (16.5%) - m (15.8^) * Fetal mortality-rates for primary V.C. exposure group are direct age adjusted to the paternal age distribution of the pregnancies in the control group. o''CffrrO o Fig. I. Fetal deaths according to paternal age for men exposed and not exposed to vinyl chloride monomer [adapted from Ref. (6)]. VCM REPRODUCTIVE TOXICOLOGY Animal studies have shown that exposure to high levels of VCM during pregnancy resulted more often in high rates of fetal loss and miscarriage than in birth defects. R&S 040451 COMMENTS REGARDING THE INFANTE ET AL (NIOSH) STUDY K (late) Reuel Stillones (Dean - Public Health - Univ. of Texas) "The problem may be viewed in different ways, but no matter how it is viewed, that analyses is wrong, for it implies that the hazard affects the entire age span, and it intentionally dilutes the strong association in persons ages 25-29 with the zero associations in the other age groups." R&S 040452 COMMENTS REGARDING THE INFANTE ET AL (NIOSH) STUDY K David Schottenfeld (Dept. Chair - Epidemiology, Univ. of Mich.) "While the authors felt that these observations were likely to reflect a real difference in pregnancy outcome not attributable to either interviewer or patient recall bias, the conclusions were based on indirect sources of information and could not take into account the multiplicity of material factors known to affect pregnancy outcome. The study design precluded documenting in even the crudest manner the validity of pregnancy histories. Without such adjustments and validation, the inferences made by Infante and colleagues cannot be sustained and little light is shed on the possible association of abnormal pregnancy outcome with paternal occupational exposure to VCM." R&S 040453 THERIAULT ET AL 1983 STUDY BIRTH DEFECT STUDY SHAW1NIGAN. CANADA___ FOUR OBJECTIVES 1. Document birth-defect rate previously observed 2. Correlate monthly and seasonal variations of length defects with VCM in the environment 3. Correlate geographic variations in birth-defect rates with estimates of VCM in the air 4. Compare a group of parents who gave birth to malformed infants with a control group with respect to residential and occupational histories. 't in 'of o CoO3 DC HAL FORM 0 CHILDREN PER 1 0 0 L IV E BIR TH S `04SS THERIAULT ET AL 1983 STUDY COMPARISON OF TOTAL BIRTH DEFECTS AND CNS BIRTH DEFECTS BETWEEN SCHOOL DISTRICTS WITH HIGH AND LOW ATMOSPHERIC VINYL CHLORIDE CONCENTRATION Births with defects Births without defects Births with CNS defects Births without CNS defects Total births School Districts With High VCM Levels School Districts With Low VCM Levels 87 2,285 16 2,356 2,372 70 2,125 13 2,182 2,195 Total 157 4,410 29 4,538 4,567 R&S 040456 THERIAULT ET AL 1983 STUDY DISTRIBUTION OF CASES AND CONTROLS BY DISEASES OF THE MOTHERS DURING PREGNANCY Before During Before During Mother's Occupation Pregnancy Pregnancy Pregnancy Pregnancy Work outside home without exposure to chemicals Work in VCM industry Work outside home with exposure to 1 chemicals 1 Stay at home 41 o 2 25 22 0 1 45 42 20 00 21 24 47 l Total 68 68 68 68 R&S 040457 THERIAULT ET AL 1983 STUDY DISTRIBUTION OF CASES AND CONTROLS BY FATHER'S OCCUPATION Father's Occupation % Ever worked in vinyl chloride industry Ever worked in industries with exposure to chemicals Never worked in industries with exposure to chemicals Unknown Total Cases 0 20 43 5 68 Controls 0 25 39 4 68 R&S 040458 THERIAULT ET AL CONCLUSION "We were unable to substantiate the presence of an association between VCM in the air and birth defects in the exposed community. In view of the high numbers of angiosarcoma of the liver observed among production workers and the possible large emissions of VCM, It can mean that such an association does not exist. It can also be the result of a small number of observations. The probability of finding an excess of birth defects in the highly exposed districts twice as high as in the poorly exposed ones was 80%. The probability would have been 99% had the excess been three times as high." POLYNEUROPATHY Vinyl chloride has not undergone scrutiny as a neurotoxic chemical. However, lifetime animal toxicology studies have not reported, on an incidental basis, polyneuropathy.