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VINYL CHLORIDE Geary Olsen October 30,1989 R&S 027694 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 027695 OPRAH WINFREY SHOW JUNE, 1989 Ht'ifu, Qubte from locell 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 027696 THREE PHASES IN PVC PRODUCTION VCM production 27697 CHRONOLOGY OF PVC PRODUCTION AND HEALTH RISKS 1942 Start of commerical PVC production in U.S. 1949 Earliest references to AOL and hepatic effects 1966-7 1960's j' 1971 1972-3 * Detailed description of AOL *i,v Reports of hepatomegaly First report of experimental carcinogenicity Detailed description of hepatotoxicity 1974 First cluster ofHAS LIVER LOBULE (PANORAMIC VIEW) t Hepauc lobule 2 Bile duet 3 Kiernant nuurc 4 Branch of the hepatic portal vein $ Branch of the hepauc artery 6 Bile duct ? Portal area, int^iobuiar ipace, or Kicrnan'a pace 14 liver piataa (laminae) 17 8 Bile duct 9 Branch of tne hepatic Portal vein 10 Central vet* 11 L(liuvmerinpalal te 12 Branch of the hepaue artery 12 Branch of the hepauc portal voe 14 Portal area 15 BUc duct R&S 027698 R&S 027699 SUe in. carn.cxlieu.lu* flo%v> on toward hila duet* iA -flow* -toward.* canAval vain. of lobuAe. Fig. 25-7. Drawing (at hizh-power magnification i to show how blood from the portal vein and the hepatic artery ileft) riows into sinusoids, lined by reticuloendothelium. that lie between liver cords, and empties into the central vein i riqhn. The way that bile travels in the opposite direction in canaliculi to empty into bile ducts in portal areas is also shown. R&S 027700 liver 2 arench^ma limiting plate sinusoids central vein, in. here sinusoid sheets of spaces liver cells appear as cords branch, of portal vein, in here iIn- 'lahilnnl Ini \m\i hlnniii-. .will .1 I nnr-u i-i'.'hlri I ,nit.i'-'c . i I f k t`f ^ :m .ill I`Mhim 11 (' lint In >11 ninil I I' ill < 1 l-- I I, Oi lilt* u|*\l A.MKt-f- hi Ini' (il.it 1 i.Ur 1 \s1 f uiwt- nh rihhrO \mi-ult'<il\ sis ftttlTMlfc-ot these vvnrkei'. [In- nnmuai niiae | >; 11 * * 11 it. .lllil I lit* | ili.il.uii'i*- <>l tin- I'-i'l m \r ro-i >'|enl\>|' i nllslsl' 11I ini all/ril areas nl linin' lli'iTii'l' lllil til isl il'| it li >11. ril.*s,. Ii'slnll'. .111' tlniilrnilrr mill me tint a':-nr|,ili'i| Milt 11 periosteal reaction. I lie li.imi- and Iiiihits are nm-l 1 mn- rmil|v |||\IIIVI'll. Ill ;| m,limits nl I at in'ii'lenls'l' I' a;--nri- ,ii-ii mill ll.mimiil s plienninenmi hmi"rs. mil ~i lernilermnlnii' 'km milker'. .il.'ii . 11111 ii -1.1 \ 1 1 iraiiriili-miiii'ii mnp.nneil 1 iv l!,i\ 11.1111I - iilietiumenmt. \\ dsnn -liulii'il .il 1 .i-i-' iI in 1 mi.it lilt- (l.linl> nl maker' eiez.med m \lli\l 1 him 1 Mii'-t ni 1 i 11 "i' wink 1' 1 - fi.nl i\*i(ki`' mills .mil other 11)n 11ii;n i 11 in the pniwm-r 11 \ -1 - w.t- IiiimIi/i'iI in tin' ili'i.il 11I1.1 l.mm- mis a--meialcd unit li.ivn.iiiii *. v it) | l 1 >111 --. disorder re-ailled Imm .1 iniim.ilinii nl pii instill, mill |n'f.-'inuil idio-v nera-v. .mil urn i-ilir i-aitM"'. I'ri'vali'iu vv,r> npnrirri in In i'tn|ilnvi'i-s |ii-rl 1 trnn 11 ^ 'mnlar work, .mil n workmen proee--mil' llie |n)\irnt hi manni.n ms. More titan IOO worker* liainlli'il the tin [ifi 11 'ts^i*iI ll min jilaslx |in 11 Iln`1 ^ 1I11I nut 1! IllO-nstrolv 'I'.. fio3J Ill I*>70 ami 1071. Ilniman '-a tin- ln-i V> ami liiilnsinal lli-allli al Iln- I niwwii ni ' Oro comprehensive 'link nt arrii-ii*li`n|\-i> in e mmpnimrimi: \in\l .mil l'\ ( I ln- i'|inli-mi< o rrsi'iili'il Minn' ill.ill 5.000 workers in .12 pi were discovrird. nl lilt'll 2.) Ii.nl a rirlimlr U -nspictoiis dimmo'C* nl .h hmi.ii'uIi.i, i liaml rlcaninn nl llic puls rni'i i/et*. Itmlsnn ' determined ilia! mirk piarh 'peri lie aurnt nr i nmliiiiahiiti nl .uienls. app oernrrrnre nl till- disease. Ill' lllnliixlll tin- ill' rather llum localized m naUin-. lull ua. nnai InsiK' ajlt-nt nr pnrlal nl nitrv. -lieges! mu 'mi 'ili/alinn nl siisrrptilnlitv. \n industrial Ii epidemiologic invn'liiralinn ri'M-ali'il vinvl rl m the reactor lietore wnlilalnn: in lie almnt ' .ition nl llu- containers. tin- v m\ I rhlnride rm reactors durinji scrapnii! was Immil In |>r- mul' FIG 64-1. A worker entering a PVC reactor vessel to clean out caked polymer adhenng 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 ot hood respirator. (Courtesy of Maurice N. Johnson. M.D.. 8.F. Goodrich Company, Akron. Ohio. Photographer-H. Groskinski.) ally around 50 ppm. It was Iniiml dial 'i rapn polymerized vinyl chloride 'o that level?. nl ill* Immil close In the liallils dimin' ihr'e npct poteniiallv Itisrii worker rrspiratorv mlialalmn. '(intents nl tin.' 'I'rapimrs nl iln- rr.u-lor v 1 --1 polymerized resins. nnrenrled eatalv't.*. aililit the polymerized vinyl riiloriili'. \n .rnmb diported in any nl the above-mentioned rases been partially ilisahlnl lit-rau.-r nl hand >nie 'trirtion in manual activity. With proper p and careful hvgiemc measure', all thc-e 1 .1 iKijt 04--2k ^ \ eltman el al. " irpniied tmdmus in 70 v Inclaves and cenlrilnires. diirma drvma and -n lJhi\liiizrrs. i iti\i (.iilnriiit'. I \ >1 \ 11 n \ i *. 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 steel. 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 tanKs. (Courtesy of Maur ice N. Johnson. M.D., B. F. Goodrich Company, Akron, Ohio. Photographer-H. Groskinski.) people 111 .1 ni'Oltp III 2(), woikeln\(chloride polvmenzatiou plant. 1 -inns ill .ilmormal petipheiui mm much mint* IretpienlU in liio-e -lire, iindinns included nnmiiuetii ciilil, pam. cxanosis. imoiwu -\ndromr. Vn Liiinuiin.il Vilen u-` is. p-eudoeluhhinn in i i. 7. ihannes in t>. !' r. I lie .-|irciiic cllecl >i \ I \] iilmiluile- in iienr.il. ilt'iiniii. .iii*. Iieen in ilmiht. I lie -ii|icilici.u trsclerosis iM-lenxlenn.il iia- i>n>mt>> .1 report III 22 I'Vt. nulkri- !,\ I'>i6. (> milkers hail iiinilrnmal null. 10 hail typical Kavn.md-elerodrrma-like rhaline- ill llic ni \-is ni (lie ilislal phalanne- an<i -vniiruine was ilcscnheil it- ~\ itipi eslhesi.i in I he tinners with mcna dinital arteries. Crxonlohiiliiiemia iininuniinlnlinliiis |22.7%I were t* plasma proteins. i hose with m* more likely In have imimmnlnnie in .'> ni 22 ami InM in I *>l 22. In lie elevated in ti7%. 1 I .IAOi;lohlllins well* also ~ec Ward H al.' I hese workers we patients with vim I chloride diseas K.il Iindinns i-iicoiiipa--inn aim* lilood. nervous svslem. limns. .1possilile \(,L): and -i."> nml elilon iniohulms were seen in t><(7r. 1)' found in .">3%, 27%. and 0%. 11 InG. (>. and lihrmonen. Klieum patients when measured hv die l.ii positive in low titer hv iiemannlu definite Vt.D and 22.7% ot those orescent examination ot -km and i with detinue VCD showed the prewithin the lumen ol -ni.ill lilood i ular endothelium. Ilie-e authoiV CM Ilinds to InU-prodiicine am immune complexes dunnn cold e stimulate complement activation and tile conversion ol lihrmonen t< ies and small blood ve-~el~. Liver V hepatitis-like etleet has he* posure. In a studv ol 70 worker- R&S 027703 CAUSES OF ASL VCM Inorganic arsenic Thorotrast Androgenic - anabolic steroids R&S 027704 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. 4. Reactive metabolites covalently bond to macromolecules such as DNA. R&S 027705 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, Tnorotrast, 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 R&S 027706 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 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 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 027709 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 027710 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) 02771 DISTRIBUTION OF CASES BY COUNTRY Country United States West Germany France Canada United Kingdom Sweden Italy Yugoslavia Czechoslovakia Japan Belgium Norway \Jotal 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 J34 EHA UPDATE COHORT DEFINITION* R&S 027712 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 027713 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 Nonmallgnant 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 R&S 027714 R&S 027715 EHA STUDY SUMMARY OF ALL CANCER EXCLUDING LIVER AND BILIARY TRACT Duration of Expsoure <10 Years obs smb 174 92 10-19.9 Years OBS SMB 94 102 20t Years OBSSMR 54 100 <20 Years OBS SMB 120 87 Years Since First Exposure 20-29.9 Years OBS SMB 122 105 30t Years OBS SMB 80 96 siaso OBS SMB 166 93 Year of First Expsoure 1950-1959 OBS SMB 107 105 OBS SMR 49 90 Typo of Plant YOM PVC OBS SMB 23 110 OBS SMB 241 94 EHA STUDY SUMMARY OF CANCER OF THE LUNG Duration of Exosoure <10 Years OBS SMR 59 93 10-19.9 Years OBS SMB 37 114 20+ Years OBS SMR 15 75 <20 Years OBS SMR 44 104 Yeare Since First Exposure 20-29.9 Years OBS SMB 45 105 30+ Years OBS SMR 22 72 <1950 OBS SMR 54 90 Year of First Exosoure 1950-1959 1960+ OBS SMB 39 106 OBS SMR 18 96 Type of Plant YCM EYC OBS SMB OBS SMR R&S 027717 EHS STUDY SUMMARY OF CANCER OF BRAIN AND CNS Duration of Exosoure sIQYeats OBS SMB 13 165 1Q-.19.9_Yfiflr3 OBS SMB 4 121 20+ Years OBS SMB 6 386 <20 Years OBS SMB 13 184 Years-SInce First Exposure 20-29.9 Years OBS SMB 6 158 SOOfeara OBS SMR 4 210 <1950 QB3SMB 9 156 Year of First Exosoure 1950-1959 1960+ PBS SMB 7 164 PBS SMB 7 256 Tvoe of Plant YCM EYC PBS SMB PBS SMB R&S 027718 R&S 027719 EHA STUDY HSUMMARY OF EMPHYSEMA MORTALITY Duration of Expsoure <10 Years 10-19.9 Years 20+ Yeats 0SSMB 25 209* 05 SMB 11 167 OBSSMR 5 117 <20 Years 05 SMB 11 158* <1950 05 SMB 24 174* Years Since First Exposure 20-29.9 Years 30t.-Ygata 05 SMB 17 198* Year of First Expsoure 19504859 OBS SMR 13 *179 4 ! I960* 05 SMB 12 189 05 SMB 5 *187 Type of Plant M EXC 0SSMB 0S SMB R&S 027720 DOW CHEMICAL VINYL CHLORfDE 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 R&S 027721 OBSERVED AND EXPECTED DEATHS FOR SELECTED CAUSES EXCLUDING EMPLOYEES WITH PRIOR EXPOSURE TO ARSENIC INSECTICIDES, 1942-1982 Cause of Death (ICD-8) Obs Exp SMRf 95% Cl All 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 All 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 * 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 X100. Cl, confidence Interval of Obs/Exp. 5 Not calculated when expected number of deaths fewer than 5. Liver cancer was an introkepatic bile duct carcinoma. y R&S 027722 DOSE-RESPONSE RELATIONSHIP 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. R&S 027723 VCM REVIEW BY SIR RICHARD DOLL 1988 R&S 027724 OBSERVED AND EXPECTED NUMBER OF DEATHS FROM DIFFERENT CANCERS REPORTS IN THE FOUR PRINCIPAL STUDIES (0 = OBSERVED NUMBER OF DEATHS, E = NUMBER OF DEATHS) Type of Class of Cancer 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 J Other All cancers United States Oa E 13 11.55 11 16.01 21 28.79 aa 39 5.77 17 18.40 118 `115.87 -a -a 5 8.46 12 9.06 -a 25 12.76 a. 12 7.98 3 5.45 14 13.94 ii 8.37 46 40.50 383 341.73 United Kingdom OE Canada Italy OEOE 4 3.58 26 23.91 9 13.94 11 1.94 0 0.64 1 0.8 3 3.0 0 1.2 8 0.14 1 0.6 -a 7 9.88 0 0.7 81 92.12 2 5.78 12 6.1 2 1.74 0 0.2 2 1.38 14 8.00 1 0.7 }3 4.10 3 4.29 4 6.18 1 1.33 a 2 0.43 } 0 0.60 4 2.35 3 2.50 7 5.16 0 0.4 }2 2.35 am 18 8.12 1 1.67 0 0.7 0.95 9 4.5 235 228.60 : :20 16.37 30 21. Observed deaths multiplied by 1.0674 and rounded off to the nearest integer to allow for deaths without discovered cause. NUMBERS OF DEATHS FROM NONMALIGNANT 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 United Kingdom 0E 521 597.73 276 157 123.55 105 44 22.83 36 16 15 31.94 32.84 i j |, 40 37 56.06 5 27 39.52 - 67 115.68 43 288 141 44 ' 61 . ' 5, " 76 1153 1363.54 545 665 1536 1705.27 894 894 Canada OE Italy OE 25 31.67 19 27.4 I 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 ^Observed 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. R&S 027726 MORTALITY FROM VARIOUS CANCERS AMONG VINYL CHLORIDE WORKERS IN 49 PLANTS IN THE FOUR PRINCIPAL STUDIES COMBINED (0 = OBSERVED NUMBER OF DEATHS, E = NUMBER OF DEATHS, SMR = STANDARDIZED MORTALITY RATIO)) Type or Class of Cancer 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 0 18 125 223 211 70 2 29 2 57 83 609 E 16.57 154.59 229.36 214.09 62.81 1.94 19.54 0.43 50.87 63.24 599.35 SMR 109 81 97 99 111 - 148 - 112 131 102 R&S 027727 H MORTALITY FROM CANCER OF THE LIVER AND OTHER CAUSES AMONG VINYL CHLORIDE WORKERS IN 49 PLANTS IN THE FOUR (0 = OBSERVEDPNRUINMCBIEPRALOSFTDUEDAIETHSSC,OEM=BNINUEMDBER OF DEATHS, SMR = STANDARDIZED MORTALITY RATIO)) Cause of death Cancer of the liver8 Cancer of other sites Other diseases Accidents, poisonings, and violence All causes 0 59 609 1547 226 2441 E 8.45 599.35 1844.89 295.15 2747.84 SMR 698 102 84 77 89 a Including cancers of the gallbladder In the series from the United States. R&S 027728 MORTALITY FROM SELECTED NONMALIGNANT CAUSES AND ALL CAUSES IN THE FOUR PRINCIPAL STUDIES COMBINED (0 = OBSERVED NUMBER OF DEATHS, E = NUMBER OF DEATHS, SMR = STANDARDIZED MORTALITY RATIO)) Type of Disease 0 E SMR Source of Information Bronchitis, emphysema Other respiratory disease All respiratory disease Ischemic heart disease Other circulatory disease All circulatory disease Cirrhosis of the liver Other disease All nonmallgnant disease All external causes All nonmallgnant causes ^ All causes 80 71 160 797 252 1103 46 238 1547 226 1773 2441 66.83 125.78 200.82 885.73 264.55 1209.35 66.26 368.07 1844.50 295.15 2139.65 2747.85 120 56 80 90 95 91 69 65 84 77 85 89 1,2 1,2 1,2,3,4, 1,2 1,2 1,2,3,4 1,2,4 1.2,3,4 1,2,3,4 1,2,3,4 1,2,3,4 1.2,3,4 J 1 = United States study, 2 = United Kingdom study, 3 = Canadian study, and 4 = Italian study. D Bronchitis in the United Kingdom study, emphysema In the United States study. c Includes cerebrovascular disease in the United Kingdom and Italian studies. MORTALITY FROM LUNG CANCER IN THE SERIES FROM THE UNITED STATES (US) AND THE UNITED KINGDOM (UK) BY CHARACTERISTICS RELEVANT TO AN OCCUPATIONAL HAZARD R&S 027729 K (0 = OBSERVED NUMBER OF DEATHS, E = NUMBER OF DEATHS, SMR = STANDARDIZED MORTALITY RATIO)) Data a Characteristic Category 1 Ob E SMR Category 2 ob E 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) 114 113.96 55 52.45 52 51.39 16 17.08 100 85 93.83 91 105 63 63.44 99 101 29 40.50 72 94 65 74.82 87 age-specific mortality rates of U.S. white men* R&S 027730 MORTALITY FROM CHRONIC OBSTRUCTIVE LUNG DISEASE^ THE 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 Category 2 O E 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 0- 09 Described as emphysema in the US study and as bronchitis in the United Kingdom study. 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 polyvvi^n^yil chloride dust, experienced one death from bronchitis against 4.98 expected. R&S 027731 CALCULATION OF RISK Calculations based on the amount of material metabolized on human data have produced -6 exposure values of about 1 ppm for a 10 lifetime risk. __________ ) R&S 027732 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 027733 CALCULATION OF RISK In rats, VCM has been shown to be metabolized 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 027734 CALCULATION OF RISK Estimation of the exposure levels likely to cause a lifetime risk of -6 -7 ASLoflO on laboratory date may range as low as 3.9x10 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 5) assumptions used in applying the models. CALCULATION OF RISK A; s4 ** 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. R&S 027736 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 y R&S 027737 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 027738 VCM HOCCUPATIONAL STUDY CONCLUSIONS U-v | 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 027739 VCM U-^ HOCCUPATIONAL STUDY CONCLUSIONS | Sir Richard Doll (1988, continued), 'The combined data for the mortality from respiratory cancer fall, 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." 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." R&S 027741 vcm HOCCUPATIONAL STUDY CONCLUSIONS | 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 al (1988), 'The results of the study do not demonstrate any association between VCM and King cancer deaths." Wu et al (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 bf 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 027742 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 027743 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, compared 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 027744 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. MISCARRIAGES AND ii BIRTH DEFECTS R&S 027746 INFANTE ET AL 1976 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 v-------------------------------------------------------------------------------------------------------------- Primary VCM Exposure 70 26.4 15 148 6.1 62 30.2 23 139 J15.8 R&S 027747 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 027748 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. m 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%) m - (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%) 23 (16.5%) m (15.8^d * 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. R&S 027749 Fig. 1. Fetal deaths according to paternal age for men exposed and not exposed to vinyl chloride monomer (adapted from Ref. (6)1. R&S 027750 r\I 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. COMMENTS REGARDING THE INFANTE ET AL (NIOSH) STUDY R&S 027751 (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 027752 COMMENTS REGARDING THE INFANTE ET AL (NIOSH) STUDY 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 027753 THERIAULT ET AL 1983 STUDY BIRTH DEFECT STUDY SHAWINIGAN. 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. R&S 027755 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 027756 THERIAULT ET AL1983 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 chemicals Stay at home 41 0 2 25 22 0 1 45 42 20 00 21 24 47 Total 68 68 68 68 R&S 027757 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 027758 "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 R&S 027759 K Vinyl chloride has not undergone scrutiny as a neurotoxic chemical. However, lifetime animal toxicology studies have not reported, on an incidental basis, polyneuropathy.