Document X1KqLj4RQ9r38vdY0pLJ7rGx

Deoaf'^ent of Co .iunity Heain S-* :ci c' `.V'J C r* Unive'S.t/ ct lCo-s. >? Lou'S. I;e Ken'ucK/-0292 `,502: 563-6^8^ lMVERS"IYof IDUISVILLE October 31, 1989 Mr. Ron Martin B. F. Goodrich Chemical Group P.O. Box 32950 Louisville, Kentucky 40232 RE: Manuscript review Dear Ron: The Agency for Toxic Substances and Disease Registry of Center for Disease Control asked me to review DeLima Associates development of Case Studie in Environmental Medicine on vinyl chloride toxicity due out |in 19 90 . I would appreciate yo ar comments and suggestions, etc. Please feel free to i idicate any changes you might suggest by writing directly on to bhe manuscript or by telephone. Kind regards, CHT/bjd Carlo H. Tamburro, M.D., M.P.H. Professor of Medicine and Community Health Acting Chairman, Department of Community Health Chief, Division of Occupational Health Director, Liver Research Center SPI-01201 DeLIMA ASSOCIATES 4340 Redwood Highway, Suite 222, San Rafael, California 94903 u Z o lb'83 Telephone (415) 499-1065 August 25, 1989 Dr. Carlo Tamburro Health Science Center, Suite 119A School of Medicine University of Louisville Louisville, KY 40292 Dear Dr. Tamburro: Enclosed please find a final draft of the vinyl chloride monograph of which we spoke, You have been very helpful and have contributed significantly to its contents and tone. We would like to add your name as an add` iuonal Guest Editor, if that is your choice also. I look forward to your comment!. Enclosure Sincerely, DeLIMA ASSOCIATES Lois L. Gerchman, Ph.D. Program Manager SPI-01202 TSDR Case Studies in Environmental Medicine VMYL CHLORIDE TOXICITY March 1990 ALERT... Ef Chronic, low-level vi,r yl chloride exposure may cause angiosarcoma of the liver (ASL), an extremely rare form of cancer. Ef ASL is associated wi\ h a minimum exposure period to vinyl chloride of 3 to 8 years, follow*if by a latency period of up to *0 years. Ef No case of hepatic ar giosarcoma has been reported in any worker who has been exposed to vinyl chloride only since allowable workplace air levels were drastically reduced in 1974. This finding, however, may re flect the passage of zn incomplete latency period. This monograph is one in a series of self-un struction publications designed to increase the primary care provider's knowledge of hazardous substances in the environment and to aid in the evaluation of potentially exposed patients. The Centers for Disease Control designate^ this continuing medical education activity for 1 credit heur in Category 7 of the Physician's Recognition Award o the American Medical Association. Each monograph of the series. Case Studi ?s in Environmental Medicine, has been approved by XXXX for 7 hour of Category 1 crecit. Guest Contributors: Robe# Harrison, MD, MPH; Gloria Hathaway, PhD Guest Editor: Laura Welch, MD Peer Reviewers: Chartfs Becker, MD; Jonathan Bcrak, MD; Joseph Cannella, MD; Bern,fad Goldstein, MD; Alan Hall, MD; Richard J. Jackson, MD, MPH; Jonathan Rcdnick, MD; Linda losenstock, MD, MPH; Robert Wheater, MS; Brian Wummer, MD U. S. Dept rtment of Health and Human Services Public Health Service Agency for Toxic Substances and Disease Registry Atlanta, Georgia 30333 SPI-01203 Lttau I UAU,,iy How to use this issue... This issue begins with a hypcthetical Case Study that describes a realistic encounter with a patient. The case is then develop ed throughout the publication by way of the Challenge questions at the end of each section. The answers to the Pretest are incorporated in (11) through (14) of the Challenge ans wers, which begin on page 20. To fully benefit from this monograph, you are urged to ans'wer each Challenge question as it is presented. Objectives fcr this monograph on vinyl chloride tcxicity: Realize why vinyl chloride continues to be a hazard of great concern Understand the known factors contributing to vinyl chloride poisoning Assess a patient's envirpnmenta! or occupational exposure to vinyl chloride Effectively evaluate and manage vinyl chloride-exposed patients Utilize a variety of scurc ss to locate further information on vinyl chloride Contents Case Studr .................................... 1 Fretest ....................................................... 1 Exposure Pathways ....................................2 Who's at Fisk .......................... 3 Eiolcgical Pate .......................................... 4 Physiological Effects .................................. 5 Clinical Evaluation ................................... 8 Management and Treatment ....................13 Standards Information Sources ..................................16 Answers 20 iii SPI-01204 Case Study Vinyl Chloride Toxicity A 5-year-o Id male comes to your office fc r an initial visit. He complains of fatigue, a 20-pcund weight less and anorexia over the past 2 to 3 months. He ha;,s been in good health prior to this, except for a history of hypertension, for which he has been treated with hydroc}iilorothiazide, 50 mg a day, for the past 3 years. He consumes afccut 2-3 beers per week and dees not smoke tbbacco. Questioning reveals that he has been a r salesman for 25 years. He is married, has 3 children, and has lived near an industrial park for the last 18 years, Three_and one-half years ago, he and his family were evacuated from their home for several days after a railroad anker car derailed and ruptured on the nearby railroad tracks. He and his family were treated at a local emergency room for sore throat and cough; acute respiratory ccmpiamts rescived within 2 weeks. He does not recall the nam e of the chemical that was released, but he rememoers it had a sligntly sweet odor, an odorhe has occasionally no1 iced while in the backyard. His youngest daughter, who has just turned 19, presented him with a grandson last we k. The pregnancy was troubled, but the baby is fine. The rest cf his family is in good health. On physical examination, you find a chronically ill-appearing male. Blood pressure is 140/80; pulse is 72 and regular. He is afebrile. Weight is 174 peu ids. There 3re no skin rashes or lesions. Scierae are slightly ictenc; the remainderef the HEENT examination s normal. There is no thyromegaly, and the neck is supple. No lymphadenopathy is felt. Abdominal exam shIC w;s a liver 12 cm in span, with a smooth margin and slightly tencerto palpation. The spleen is net enlarged, a;rd there are no other abccminal masses. Extremities and joints are unremarkable, arid the neurological exanfiination is completely normal. Rectal exam shews a normal-sized prostate; no masses are felt, and the stool is negative for occult blood. The initial laboratory results include hemes Ilobin, PT, PTT, white blood cell count, and urinalysis, all normal. The SGPT is 372 IU/L and SCOT is 293 IU/L The bilirubin, ferritin, alkaline phosphatase, and senjm protein are reported to be within normal limits. PRETEST What should be. included in this patient's problem list? - '' What is the diil\'erential diagnosis for this patient? What tests woi jld you order to confirm or rule out these diagnoses? Case Report Number 2 - August 23,1989 DRAFT - Page 1 SPI-01205 vmyi /uc Vinyl chloride released from point sourc s to the ambient air is degraded in a matter of hours; that releaf;ed to lakes, streams, or rivers will volatilize in several hours to a fev days, depending on the water's temperature and aeration rate. Vin] I chloride may remain in groundwater, however, for months or yeans. Of all potential sources of vinyl chloride exposure to the general pc) 3uiaticn today, contaminated groundwater is the most enduring. Tf e Environmental Protec- , ton Agency (EPA) estimates that less th in 2% of the country's r drinking water supply is contaminated with rinyl chloride at sufficent levels to be of concern. ' . ' -" (1) Additional history to the Case Stud> : After checking with the Iccal fire decartment. you find that vinyl chloride was contained in the overtu Tied tanker car and that there was an airborne release of approximately 10,000 gallons of vinyl ch oride. Furthermore, you learn from the regional office of the EPA that significant leaks in the reactor v ess fIs may have been occurring over the course of several decades, resulting in frequent environmental cor famination. No air monitoring had been dene outside the slant, Following the tanker car accident, the complex permanently closed. What further information will you request in order to evaluate the extent \f your patient's exposure? --- (2) What are the significant sources of rinyl chlcnde exposure for this patient? > Who's at Risk These at greatest risk of vinyl chloride exp osure are the 2.2 million workers concerned with the production, us< , transport, storage, and disposal of this material. The highest heal h risk has been to these workers exposed as a result of the pelym irization process, espe- dally to individuals who were lowered Irectfy into the reactor vessels after polymerization to remove scli< polymer adhering to the inside. During this cleaning process, the exposure levels to vinyl chloride monomer were typically in the rai ge of a hundred ppm or more. 0 Cf the 2.2 million workers exposed to vinyl chloride, autoclave cleaners have the highest health risk. Case Report Number 2 - August 23,1989 DRAFT - Page 3 SPI-01206 Vinyl Chloride Toxicity Vinyl chloride is well adsorbed. Following ibsorption by all routes, it is rapidly distributed via lipids or lipoproteir s in the bloodstream to all tissues. The liver and kidneys receive thu highest concentrations, followed by the brain, lungs, spleen, and small intestine. Experimental evidence suggests that the oxicity of vinyl chloride is related to its transformation by the liver I one or several reactive metabcl'rte(s). Suspected intermediate metabolites, 2-chlcroeth* ylene oxide and 2-chloroacstaldehyde, a n bind to cellular macromolecules such as DNA and proteins, pjresumably causing liver damage. These metabolites can also un< ergo further oxidation to compounds such as 2-chicroacetic acid and thiodigiycolic acid, which are mainly excreted in the urine. Following absorption, vinyl chloride is metabo lized In the liver. The primary metabolites can cause cellular damage or be further metabolized to compounds that are ex creted In the urine. Physiological Effects Acute Exposure The only data regarding acute exposure to vinyl chloride are early repons among occupationally exposed w< rkers. Deaths appeared to be due to narcosis, but no specific exposure levels have been repcned. Presumably, these exposure ppm. Autopsies revealed congestion of t^te liver, spleen, and kid neys. With acuta axposura to vinyl chloride, tha nerv ous system is the primary target. Chronic Exposure Several epidemiological studies have conivlincingly associated chronic vinyl chic ride exposure with liver tumors , both malignant and nonmalignant, and have suggested an increa >ed incidence of cancers in other parts of the bodv.'Subtle nejicciooii;< at affects have also-been noted in some workers chronically expc sed to vinyl chloride at relatively low levels. With subacute or chronic exposure, tha primary : "target organ Is the liver. a SPI-01207 Case Report Number 2 - August 23,1989 DRAFT - Page 5 rare form of cancer were employed as ni actor cleaners; exposure levels then were presumably much great^\r than these seen today. Most of the cases of vinyl chloride-induc id ASl have been associated with chronic exposures on the ortiei o< 100 ppm. There have been no cases of ASL record! nd in individuals who have been occupationally exposed only since al ll<owable workplace air levels were drastically reduced in 1974. However, this may be due to the fact that a sufficient latency period has not yet elapsed for carcinogenic effects to have presented The few cases of ASL reported to be due to environmental cc ntamination are suspect because of the statistically small numbers involved and the fact that this disease can arise spontaneously Increased incidence of several cancers, other than hepatic, have been suggested by various epidemiolcgictlJ studies of vinyl chiorideexposed workers and by animal studies, 3resently, there is insufficient evidence to establish a causal relatlioiship in humans between environmental vinyl chloride exposures 1 hd suggested Increased incidences of cancer of the brainrbre'astT I jng, thyroid, Jymphatic or hematopoietic tissues, and malignant me anoma. ' Increased frequencies of chromosomal iberrations in circulating peripheral lymphocytes, including fragrr^ents. rings, breaks, and gaps, have been reported in vinyl chloride porkers. In general, these aberrations have not been associated wi|h vinyl chloride levels of less ihari o ppm. Strong evidence of genot(: xicity in a number of biological assay systems suggests that the riperted carcinogenicity of vinyl chicride may proceed via genotoxic mechanisms. Vinyl Chloride Toxicity Chdlengt^J^^ y Referring to the Case Study, would> ou examine yourpatient for C.VS damage ? Formalignancies ether than hepatic? Explain. SPI-01208 Case Report Number 2 - August 23,1989 DRAFT - Page 7 Vinyl Chloride Toxicity The physical examination lor vinyl chlor de-exposed persons in- eludes a thorough evaluation of the live and spleen. The renal, nervous, hematopoietic, gastrointestinal dardiovascular, and respiratory systems snculd also be carefully e xamined for abnormalities. The extremities of vinyl chloride worfcen , particularly the hands, should be examined for signs of acroost jolysis, a result of "vinyl chloride disease,* discussed under Signs and Symptoms below. Signs and Symptoms Acute Exposure. Vinyl chloride has little aic ute toxicity, and air levels between 8,000 ppm and 13,000 ppm may :e tolerated for 5 minutes without the development of symptoms. Lo (ger high-level exposures have been associated with headache, didziness, euphoria, ataxia, and narcosis; cardiac, circulatory, and res; iratory irregularities have also been noted. Depressed myocardial contractility and cardiac dysrhythmias have been reported in anim$ s folllowing acute exposure at anesthetic levels. Such exposure niayisensitize the myocardium to catecholamines and may predispjD se to ventricular fibrillation. Exposures to very high levels (probably n the range of 70,000 to 120,000 ppm) have resulted in death, pre: iumatly due to narcosis. Chronic Exposure. Heavy, long-term o tcupaticnal exposure to vinyl chloride may lead to "vinyl chloric e disease,' a condition involving a number of organ systems and issues and resulting in a variety of clinical symptoms. The reported seriod of exposure before the onset of this disease has ranged from 1 month to 3 years. New cases of "vinyl chloride disease* have not been reported since ac ceptable workplace exposure levels were i educed to 1 ppm in 1974. The signs of "vinyl chloride disease* inii'ude a sclercderma-like condition of the connective tissue of the ingers, accompanied by thickening of the dermis. Acrccsteoiysis. a rare bene disease resuit ing in decalcificaticn of the terminal phal, es of the hand, may also be seen. Acrccsteoiysis has frequently been preceded by a Raynaud-type phenomenon in which there is reversible constriction of the arterioles of the fingers leading numbness, pallor, and cyanosis of the fingers. Vascularocdusiora , stenosis, and narrowing of the digital arteries with the development of collateral circulation have been prominent angiographic finding::s. Short-term vinyl chloride exposure at relatively high concentrations may be tolerated without lasting adverse effects. "Vinyl chloride disease" Is a condition affecting a number of organ systems and tissues. The onset of vinyl chloride-induced liver damage Is insidious, with e clinical picture of non specific hepatic injury. SPI-01209 Casa Report Number 2 - August 23,1989 DRAFT - Page 9 Vinyl Chloride Toxicity Direct Indicators. No reliable direct metfriiod exists for monitoring exposure to low levels of vinyl chloride, A1empts have been made to correlate vinyl chloride exposure leve S with urinary output of thiodiglycolic add, a major urinary met abb file that peaks approximately 20 hours after exposure to vinyl clHloride. Because of wide individual variations in excretion patterns, h owever, urinary thiodigly* colic acid is not reliable with exposure to vii.fiyl chloride at cencentrations less than 5 ppm, nor several days post-exposure. Likewise, no correlation has been found between the a nourtt of vinyl chloride in breath or urine samples and the inspired aiir|at air concentrations less than 5 ppm. Biological Effect Indicators. Overt liver injury is a relatively late occurrence in vinyl chloride-reiated hepati : disease, and detection of early chemical injury in asymptomatic i ividuals is difficult. Standard biochemical enzyme studies (alkaiin^ phcsphatase (AP), aspartate aminotransferase (SGOT, AST), anine aminotransferase (SGPT, ALT) and gamma-glutamyl transp|eiptidase (GGTP, GGT)) when used alone are of limited value in kd<ejntrfying the early phases or progression of liver injury. These enzy mes primarily reflect acute disruption in cell membrane integrity rathur than alterations in the uptake, metabolism, storage, or excretion functions of hepatic cells, Furthermore, these enzyme levels may b<i elevated in nonhepatic diseases, or may return to normal after init af elevation in subacute, chronic or end-stage liver disease, thus co nplicating their interpretation. The ratio of SGOT to SGPT has be e|n reported to be of some value in predicting early liver disease A correlation has been noted between sli jhtly to moderately elevated total urinary porphyrins and secondai y urinary ccprc porphyrin elevations in the early stages of toxic liver <fi,isease. Similar findings seem to be common in vinyl chloride-re ated liver disease, and periodic determination of these values m$y' aid in monitoring the progress of a known clinical case. Recent studies have suggested that mea spring clearance rates of substances remcved from the circulation by the liver provides the most sensitive and specific indicator of e arty ichemical liver injury, Indocyanine green (ICG) is a synthetic dye used for this purpose, When expressed as half-time, ICG cleaifiance rates are directly related to the severity of chemical hepatic i ijury. However, the test has certain limitations: it is invasive, invotv es intravenous injection of a synthetic dye, and necessitates drawing multiple blood samples with same-day analysis. There Is no reliable direct Indicator for vinyl chloride at low exposure levels. Except In an ongoing medical surveillance program, standard bio chemical and liver func tion tests alone may be of limited value in evaluating vinyl chloride-induced liver injury. A rise In urinary eoproporphyrin and total url- - - nary porphyrins can .... signal the early stages of hepatocellular disease. Recent studies suggest that fasting serum bile acids, in conjunction with an indocyanine green clearance rate. Is sensi tive and specific for latent chemical liver Injury. Only biopsy Is more de finitive. SPI-01210 Case Report Number 2 - August 23,1989 DRAFT-Page 11 Vinyl Chloride Toxicity Management and Treatment Acuta Exposure Following acute vinyl chloride exposure, the individual should be immediately removed from the source of e ijposure and given oxygen or artificial resuscitation, if indicated. Any persistent effects should be treated symptomatically. Recovery fro n acute effects is usually rapid and complete with supportive then py; there is no specific treatment or antidote for vinyl chloride exposure. There are no specific treatments for patients with acute exposure to vinyl chloride. Chronic Exposure Symptoms associated with "vinyl chloride disease' tend to disappear after 1 or 2 years following removal from exposure. Hepatic angiosarcoma, on the other hand, grows rbpidly and cames a poor prognosis; if untreated, most patients die w thin six to twelve months of diagnosis. Results of radiation therapy and chemotherapy have been disappointing, and only these patient!; who have had the tumor successfully resected have been tong-tem i survivors. Patients with chronic liver injury should avoid exposure o vinyl chloride, ethanol, acetomincphen. INH, and other hepatetexihs. Followup may require treatment for complications such as ascite:; , diabetes, and bleeding varices. Abnormalities due to `vinyl chloride disease' disappear within a few years if the worker is removed from the expo* sura. Unlike "vinyl chloride ~ disease," hepatic angio sarcoma carries a pocr prognosis. CndIi7LL^^^ (10) What can ycu tell ycur patient aba, it hepatic angiosarcoma ? How will you advise him? (11) What is the danger tc other memb', irs of ycur patient's family and the community? What tests could ycu use tc evaluate and mcnitcr i hese individuals? SPI-01211 Case Report Number 2 - August 23,1989 DRAFT - Page 13 Vinyl Chloride Toxicity The American Conference of Governing ntal Industrial Hygienists (ACGiH) recommends an exposure limit 3f 5 ppm for an 8-hour day and a short-term exposure limit of 10 pdm. The National Institute for Occuoational Safety and Health (NIO; 3 H) has concluded that an exposure level for vinyl chloride is ina jpropriate because of its carcinogenicity. Air in the Environment The 1S82 Environmental Protection Age icy (EPA) emission starv dards for chemicals released to the atmo sphere set a limit for vinyl chloride of 10 ppm, measured at the souiC8. The EPA has set an amis sion standard of 10 ppm for vinyl chloride. Water Pursuant to the Safe Drinking Water Aqt the EPA has issued a maximum contaminant level for vinyl ch cride of 2 ^L, effective January 9, 1989. This applies to all cfcmmunity drinking water systems that regularly serve the same !5 persons for at least 8 months of the year, and cone spends to ah estimated cancer risk of 1 additional case in 100,000 persons expj sed to this level fer a life- time. __ .. Food The Food and Drug Administration (FDA) proposed in 1936 that the vinyl chloride monomer content of pcIyrfTeps used in food packaging or processing may range from 5 to 50 pprf Tdepending on the nature of the polymer and its use. . ^ < - Ths maximum contami nant lave! for vinyl chloride in drinking water Is 2 pg/L (2 parts per billion). The FDA limits the con tent of vinyl chloride monomer in PVC that is used for food packaging. ChoTTirigt^r (12) '//here wcutdycu get help in order! j evaluate others living or working in the community near the former vinyl chloride facility, and the workers vho were employed at the plant? Case Report Number 2 - August 23,1989 DRAFT - Page 15 SPI-01212 Vinyl Chloride Toxicity 11. Popper H .Thomas LB. Alterations of Ijver and spleen among workers exposed to vinyl chloride. Ann NY Acad Sci 1975; 246:172-94. /VI - . / J Carcinogenicity. 12. Technical Report No. 31. The mutageniicity and carcinogenicity of vinyl chloride: a historical review and assessment. Brussels, Belgium: Europ! an Chemical Industry Ecology andToxicology Centre; 1988. 13. Bolt HM. Metabolic activation of vinyl chloride, formation of nucleic acid adducts and relevance to carcinogenesis. IARC Sci Publ. 1986;70:26' -8. 14. Guengerich FP, Watanabe PG. Activeition of vinyl chloride to covalently bound metabolites: roles of 2-chlomethylene oxide and 2-chlcroacetald! hyde. Biochemistry 1979;18:5177-32. 15. Hansteen IL, Hillestad L, Thiis-Evensep E, HeldaasSS. Effects of vinyl chloride in man: a cytogenetic follcwup study. Mutat Res 1978;51:271-6. 16. Heath CW, Jr, Fable H, Creech JL, Jt Characteristics of cases of angiosarcoma of the liver among vinyl chloride workers in the United States. Ann NY Acad Sci 1975;246:231-6. 17. IARC (International Agency for Researlc;h on Cancer). Monograph on the Evaluation of the Carcinogenic Risk of Chemicals in Humans. Vinyl Chlorirt e. Lyons, France: WHO, IARC 1979:19: 377-401. Teratologies! Effects 18. Edmonds LD, Anderson CE.FlyntJW, |ames LM. Congenital central nervous system malformations and vinyl chloride monomer exposure: a comrrunity study. Teratology 1978;17:137-42. 19. Theriault G. Hurra H, Gingras S. Evali ation of the association between birth defects and exposure to ambi- ent vinyl chloride. Teratology 1983:2i :359-70. .............. '-- Related Government Documents Agency forToxic Substances and Disease Registry. Tcxicclcgicai Profile for Vinyl Chloride. Atlanta: USDepartmerit of Health and Human Services, Pub ic Health Service, 1939; DHHS document no. XX-XXXX. Environmental Protection Agency. Health Effects Assessment for Vinyl Chloride. Cincinnati: US Environmental Protection Agency, Office of Environments Critenaand Assessment, 1984; EPA report no. EPA 540/1-86-036. Centers for Disease Control. Recommended Standard. Occupational Exposure to Vinyl Chloride. Atlanta: US Department of Health, Education, and We fare, Public Health Service, 1978; document no. (NICSH) XX-XXX. Case Report Number 2 - August 23,1989 DRAFT - Page 17 SPI-01213 TSDR Answers to Challenge Questions These questions begin on page 3. (1) Since the odor of vinyl chloride was detected by your patient, you can conclude that the air concentration must have been high (3C0 to 5000 ppm) and that jfour patient received toxic or near-toxic dcses cn those occasions. You may want to determine if others smell <d the vinyl chloride and obtain the frequency and extent of environmental contamination from plant recordi , if they are obtainable. The drinking water in your patient's home should be tested since groundwater conta;ihination, caused by releases from the plant, is a possibility. (2) In addition to exposure through possible C3.ntamination of the air and water at heme, your patient may be exposed to vinyl chloride at work. As a ca> salesman, he may daily spend time inside new cars where the ambient air can contain significant amounts :f vinyl chloride (1 to 10 ppm) released from plastic and upheistery including the dashboard and seats. To the S eneral population, this and other sources of consumer exposures to the monomer released from polyvinyl chli ride products such as feed packaging, flcoring, etc. are normally of little concern. Your patient is a nonsmcks r, and so does not receive the added insult of the 29 nanegrams of vinyl chloride present in the smcke from each cigarette. (3) These closest to the source of vinyl chloride i.e., the former workers at the plant, are at highest risk. Assuming only air emissions from the plant, your patie it's immediate family, the surrounding community and especially^ these residents immediately downwind haive probably been periodically exposed. Since airborne vinyl chloride normally phetedegrades within a ffew hours, ambient air exposure is likely to be limited in distance from the plant. If the groundwater has been contaminated, on the other hand, the number of persons affected could be far greater and be located at sem > distance from the plant. `(4) Your patient has lived near the vinyl chlcridip plant for 18 years. Depending on the ages of his children, they may have been periodically exposed in the r younger years. Animal data suggest that exposure at an early age may increase the risk of cancer later on. If your patient's daughter spent much time at the residence during v her pregnancy, there is a chance that his gir andson was exposed in utero. This fact may increase the risk of S-1' cancer fer the grandson, even assuming cassation of exposure following the plant shutdown. (5) It wculd be prudent to investigate all petenti; Ity involved organ systems, even though there is limited evidence to suggest that chronic environmental expoi sure to vinyl chloride may result in neurctcxidity or cancers other than hepatic. kwi (6) The patient's problem list includes fatigue, weight less, slightly icteric sclerae, and liver enlargement. (7) The differential diagnosis at this point might consist of: acute hepatitis (viral, alcohol, or chemical- or drug-induced) chronic active hepatitis granulomatous or neoplastic infiltration Clrrhcsis is less likely since transaminases ire high, but it cannot be oiled out. In light of the normal alkaline phosphatase, primary biliary cirrhosis or bi Ie duct obstruction are not considered. Case Report Number 2 - August 23,1989 C RAFT - Page 20 SPI-01214 Vinyl Chloride Toxicity (8) Viral hepatitis should be ruled out witl i the appropriate serologies and a liver-spleen scan performed. An MRI (magnetic resonance imaging) scar and an angiogram might also be helpful. Direct indicators, such as urinary thiodiglycolic acid or vinyl chk ride levels, would only be helpful if significant quantities of vinyl chloride are presently being consumed in the drinking water. However, negative results, in tests using these direct indicators, do not rule out drinking w ater contamination. (9) The differential diagnosis now most ikely includes: cirrhosis malignancy Hepatic angiosarcoma is not normal! y prominent in the differential diagnosis of liver function abnormalities, However, the known exposure to vin> I chloride and the test results thus far make it a probability. In that case, hepatic arteriography would reveal a :haracteristic appearance, with displacement of hepatic arteries, and a blush and "puddling* during the midd e of the arterial phase. Percutaneous liver biopsy is contraindicated in cases of angiosarcoma because of the vascular nature of the tumor and the possibility of complicating thrcmbccytcpenia or significant bleettling; laparoscopic bicpsy would be more appropriate. (10) Hepatic angiosarcoma grows rapidly and carries a poor prognosis. If untreated, most patients die within six to twelve months of diagnosis. The o rly long-term survivors have had the tumor successfully resected. You might assure your patient that there i no evidence that the vinyl chloride exposure at work will influence the evolution of his disease. As a precau: ion you might suggest that he ventilate new cars befere entering them for prolonged periods and drive with 1 he window open to maintain ventilation. Until the drinking water at his heme is tested, the family should use bottled water to avoid any possible exposure there. (11) Since the rest of the family and the r earby community may have had similar exposure to vinyl chloride, all should undergo testing for transamiinases, alkaline phosphatase, and serum bile acids to detect latent chemical injury, tf these tests or an i ndccyanine green clearance rate are positive for hepatic injury, bicpsy may also be helpful. If the drinking water is net contaminated and there is no waste disposal source to contaminate the water in the future, I ie exposure for the family and community has likely terminated. (12) Ycur local, county, or state health dep a:rtment should be contacted and notified of the suspect case. Because hepatic angiosarcoma is an extremel;' rare disease, even one case would alert public health authorities to a potential risk to the community around|this plant. Your report should initiate case-finding investigations among the workers at this plant as well as in tie community. Public health authorities may also want to evaluate the potential for groundwater contaminat on around the plant. SPI-01215 Case Report Number 2 - August 23,1989 DRAFT - Page 21 A Division of The Society of Tht Plastics Industry, Inc. Roy T. Gottesman Executive Director October 10, 1989 Dr. Robert Hinderer BFGoodrich Company 3925 Embassy Parkway Akron, Ohio 44313 Re: Human Carcj noaens - Vinvl Chloride Dear Bob: Dr. Brian Bennett of ICI, who maintains the angiosarcoma registry visited with me in Wayne on October 5th. He kindly provided me with the enclosed paper from Environmental Research 49, 143-151 (1989). The marginal note s on this copy are those of Dr. Bennett who has met with the author Dr. Benjamin Van Duuren at NYU Medical Center. Also, Dr. Bennett advises me that because of some apparent errors in the publication, he p .ans to write a letter to the editor, pointing out the mis-inte rpretations/errors. This is for your information and files. Sincerely yours, RTG/pmb SPI-01216 Wayne Interchange Plaza II 155 Route 46 West Wayne, NJ 07470 (201) 890-9299 1/ //; ENVIRONMENTAL RESEARCH 49, 143-151 (1989) I/m* a REVIEW Comparison of Potency of Humai Carcinogens: Vinyl Chloride, Chloromethylmethyl Ether and Bis(chlorometh whether Benjamin L. Van Di L'REN Laboratory of Organic Chemistry and Carcinogenesis Inst T.ute of Environmental Medicine, Sew York University Medical Center. Sew Y<c rk Sew York 10016 Received November 4, 1)88 The a-chloroether carcinogen chloromethylmethyl eth r (CME) and its impurity bisichloromethyDether (BCME) are direct-acting alkylating age i ts. Vinyl chloride (VC) is an indi rect-acting carcinogen but its accepted carcinogenic in te mediate, chloroethylene oxide, is also an a-chloroether. Both CME-BCME and VC have been in industrial use since about 1950. Hence, they were selected for comparison of ncy as human carcinogens using numerous epidemiologic reports. There were 115 death: due to angiosarcoma of the liver among several hundred thousand VC-exposed workers on the basis of reports from 10 countries during 1955 and 1984. Reports from five cou ntries cited a total of 87 respiratory cancer deaths among only 3024 CME-BCME-exposed w.i rkers. If a recent court settlement in the United States is taken into account, the number respiratory cancer deaths due to CME-BCME rises to 117. On the basis of these number|s of cancer deaths, and the levels and durations of exposure, it is concluded that VC is a v|,eak human carcinogen compared to CME-BCME. C 1989 Academic Press. Inc. INTRODUCTION Thirty-six chemicals or mixtures of chemicals ape now classed as materials for which there is sufficient evidence of human careijiogenicity (1ARC, 1987). They are referred to as Group 1 human carcinogens bj the IARC. In most instances sufficient animal carcinogenicity data are also abailable for these 36 materials, Included in this group are chloromethylmethyl ther (CME), bis(ch!oromethyDether (BCME), and vinyl chloride (VC). The pui P'ose of the present report is to compare the potency of these carcinogens to hun|a;ns based on animal bioassay data and epidemiologic studies. These chemicals came into use in chemical inid|ustry at about the same time, 1950, although VC was used on a small scale prior 1950. The animal and human carcinogenicity data on these chemicals first bee ame known during the years 1968-1973. Since then, extensive studies on their i.nimal carcinogenicity an$l epidemiologic studies on occupational exposure to them have been carried out. Thus, they provide a valuable series in which tc( compare potency as human carcinogens. The animal carcinogenicity results on CME, B CME, and VC preceded publication of the first case reports and epidemiologic s udies by several years. Thus, these human carcinogens are unusual in that the hiitorical sequence of events for 143 0013-9351/89 $3.00 Copvnghi C 1989 by Academic Press. Inc. All nghis of reproduction tn *ny form reserved. SPI-01217 144 BENJAM1X I.. VAN DUUREN most human carcinogens is the rev rse. For most of the 36 chemicals on the current list 'of Group I human carciln ogens. epidemiologic studies provided the stimulus for subsequent laboratory inimal carcinogenesis bioassays and related biochemical studies, as was pointed :>ut in the preamble of the most recent compilation i'IARC, 1987). INDUSTRIAL PRODUCTION CME is used on a small scale in chemical industry as an intermediate in the manufacture of anion-exchange reshs from polystyrene and related polymers (Van Duuren et al.. 1968). The resin made from polystyrene. CME, and trimethylamine. named Amberlite IRA-400, is used in the purification c f household water and on a larger scale for deionization of water used by the electric power and pharmaceutical industries. CME is synthesized from methyl tlcohol. hydrochloric acid (HC1). and form aldehyde (CH:0). The latter two reatents lead to the formation of BCME. Thus. CME as manufactured and used contains varying amounts of BCME. ranging from 1 to 109c, depending upon the exact conditions of manufacture (Van Duuren 1980). BCME was manufactured on a pilot-plant scale when CME first came into full-scale production, but it is not used in chemical industry because of its acute toxicity. Because CME as manufactured and used contains BCME. these two chemicals are referred to as CME-BfME in the discussion on occupational ex posure that follows VC was used in industry from abou: 1930 but did not come into large-scale use until about 1950 for the manufacture of its polymer (PVC) and copolymers, e.g., with vinylidine chloride (Wessling and Edwards, 1971). Production figures for CME-BCME or the anion-exchange resins for which it is used were not given in any of the published epidemiologic studies and could not be ascertained from industry sources, VC on the other hand, is No. 8 on the list of the top 10 organic chemicals manu `actured in the United States (Anonymous Chem. Eng. News, 1988). In 1987, 8.2i billion pounds of VC was manufactured in the United States alone. It was estima ed that in the same year 7.6 billion pounds of PVC was manufactured in the Unit d States (Anonymous Chem. Eng. News, 1987). Because of the relatively limitec use of anion-exchange resins compared to PVC, it can be safely concluded that he amount of CME-BCME manufactured worldwide is minuscule by comparison to the amount of VC produced. It should be noted that both CME and BCME ar : used in laboratory syntheses as alkylating agents in reaction with nucleophiles s.ich as amines, as well as in displacement and addition reactions (Summers, 1953). ANIMAL BIOASSAYS Laboratory-purified CME is a weak carcinogen and an initiating agent in twostage carcinogenesis on mouse skin. It also causes induction of fibrosarcomas by subcutaneous injection in rats. BCME is a mouse skin initiating agent and carcinogen and causes fibrosarcoma by jbcutaneous injection in rats. In all three bioassays BCME was notably more pc tent than CME (Van Duuren et al., 1968. 1969). In further studies subcutaneous injection of CME and BCME in newborn mice resulted in increased induction tf lung adenomas in animals exposed to CARCINOGENICITY OF VC AND CME-BCME 145 BCME but not in those exposed to CME (Gar us et al.. 1969). In several subsequent studies the inhalation exposure of rats tc CME and to BCME was studied, BCME proved to be a potent carcinogen for rats by this route at 0.1 ppm resulting in lung cancer and esthesioneuroepithelioma (Kuschner et al.. 1975). In other inhalation experiments in rats at various doses induction of lung cancer was not observed but nasal tumors were induced (Lec|ng et al., 1981). These bioassays were recently reviewed (Van Duuren and Van Duuren. 1988). On the basis of inhalation bioassays in which rats were exposed to mixtures of hydrochloric acid and formaldehyde (Sellakum; r et al., 1985) and hence to BCME it was subsequently concluded that BCME is m arkedly carcinogenic to rats in the dose range of only 0.1 to 0.4 parts per billion (V;,n Duuren and Van Duuren. 1988). VC was first shown to be carcinogenic by in hblation exposure using Wistar rats at a dose level of 30.000 ppm (Viola et al. 1971). Zymbal gland tumors were observed together with metastases to the skin lung, and bone. Subsequently, a series of large-scale bioassays was undertaken using iinhalation exposure of Wistar and Sprague-Dawley rats, Swiss mice, and gold n hamsters (Maltoni et al.. 1984). Extensive dose-response studies were perform|ed in these bioassays. Lung adenomas, angiosarcoma of the liver (ASL), and idenocarcinoma of the mammary gland in mice were observed. The same type of exposure in rats in the 50- to 10.000-ppm range led to induction of ASL, neph oblastoma. neuroblastoma. Zymbal gland tumors, and miscellaneous tumors at other sites. From the above bioassays it is clear that BC1 E is a much more potent carcinogen by several orders of magnitude than VC in "at inhalation experiments, on the basis of numbers of animals with malignant tun ors and doses used in the inhalation experiments. CME must be classed as a w :ak carcinogen and its carcinogenicity can be ascribed in part to the presence o: 'BCME in industrial grade CME and to the formation of BCME from the hydrolly sis products of CME. Both CME and BCME are highly reactive dirfct-acting alkylating agents which do not need to be metabolized in vivo in order to exert their biological activity, Like other direct-acting carcinogens such as etoxides and p-lactones. they are expected to exert carcinogenic action at the sit : of contact in animal tests (Van Duuren, 1980). This is indeed the case, as show n by induction of nasal and lung tumors by inhalation exposure in rats, skini canc s'r by topical application in mice, and lung cancer by occupational exposure in hi mans. Unlike CME and BCME, VC is an indirect-ac t|ing carcinogen which is activated in vivo to chloroethylene oxide, a highly reactive and unstable epoxide. Extensive studies on metabolism of VC in vitro and in vivo and bioassays of the metabolites point to this epoxide as the activated carcinogei ic intermediate of VC. as originally suggested on the basis of structure-activ ty considerations (Van Duuren, 1975). This subject has been reviewed (Singer ar dG' runberger, 1983). Because of its accepted mode of action. VC is expected to ye a multipotential carcinogen in animals and humans. This is borne out by the animal carcinogenicity data and epidemiologic studies in workers exposed to VC OCCUPATIONAL EXPOSURE CME-BCME Three reports appeared in 1973 describing the occurrence of lung cancer, most frequently oat cell carcinoma, in workers expo sbd to CME-BCME (Figueroa et SPI-01219 146 BENJAMIN .. van duuren al., 1973; Sakabe, 1973; Thiess et at., 1973). On the basis of the animal carcino genicity data available at the time an< these three early reports, both CME and BCME were classed as human carcinogens by the U.S. Department of Labor in 1974 (U.S.D.L., 1974). They were classed as Group 1 human carcinogens by the International Agency for Research on Cancer in 1979 (IARC, 1979a). During the years 1973 and 1987 numerous epidemiologic studies dealing with CME-BCME were published (IARC, 1987). A report involving three worker deaths from lung cancer in a small BCME manufacturin' facility in the United Kingdom appeared recently (Roe, 1985). The number of respiratory cancer d( aths ascribed to occupational exposure to CME-BCME and to BCME alone are summarized in Table 1. These data were culled from the literature up to 1987. ''he five countries reporting epidemiologic studies covered the total period 1948 t trough 1981. Numerous interim epidemiologic studies appeared dealing with the same man ufacturing facility in the United States. The first report concerning respiratory cancer among workers at this facility appeared in 1973 (Figueroa et al., 1973). One of the 1987 reports (Collingwood et a1987) gave findings on six other CME manufacturing facilities which are grotped together in Table 1. Thus the total number of respiratory cancer deaths fiom five countries was 87 out of 3024 ex posed workers. It is of considerable interest to compare the respiratory cancer deaths in one manufacturing facility in the United Sta:es as presented in Table 1 with the classaction settlement reached in 1987 in the Philadelphia Court of Common Pleas in Pennsylvania. According to this settlement 62 workers who died of respiratory cancer were deemed to have been expo; ed to CME-BCME and their estates were awarded monetary benefits. Twenty-fit e of these had oat cell carcinoma of the lung and 37 had other respiratory canoer. This settlement did not exclude the possibility that there were other worker: exposed to CME-BCME who may have developed respiratory cancer. Monetary awards were based on the 62 workers having worked in certain buildings in th; facility at specific times and developed TAE le t Respiratory Cancer Deaths rom Exposure to CME--BCME Country U.S. UK. China Japanf Germ an yc U.S. Period of exposure 1948-1981 1948-1980 1958-1981 1955-1970 1954-1971 1948-1980 Number of workers 737 221 318 32 18 1.698 dumber of leaths8 32 10 12 5 8 20 Duration of exposure* (years) 1-19 1-15 2-18 7-12 6 5-19 Reference Maher, 1987 McCallum, 1983 Hsueh. 1984 Sakabe, 1973 Thiess. 1973 Collingwood, 1987 a Taking the legal settlement into consideration, the total number rises from 87 to 117 (see text), b Years from first exposure to diagnosis of respi atory cancer. f Exposure to BCME only: all others to CME- ACME. SPI-01220 CARCINOGENICITY OF VC AN D CME-BCME 147 respiratory cancer (Krimsky, 1987). It is not; ble that the number of workers compensated for this one manufacturing facility 62, is almost double that given in the recent epidemioiogic reports (Collingwood i 't al., 1987, Maher and DeFonso, 1987). It has been pointed out in some of these reportts that (1) the respiratory cancers were mostly oat cell carcinoma of the lung and. ) in a number of cases there was a remarkably short latent period between beginhi ng of exposure and diagnosis of lung cancer and hence an unusually high incidente of this cancer among younger workers. Smoking histories were examined in some of the studies summarized in Table 1 but were not considered in calculations of ancer risk, on the basis of the conclusion that this confounding factor is diffic|il t to assess quantitatively (Doll. 1984). The levels of exposure to CME-BCME were in earlier years, i.e., up to the early 1970s, rough estimates at best, and moreover, varied not only from one facility to the next, but also frequently within : same facility. It was only after these chemicals were known to be carcinogenic to animals and humans that exposure to them became monitored, regulated and reduced. Before 1970 exposure to CME-BCME at certain stages of use in the manufacture of anion-exchange resins was so high that buildings had to be routin ly evacuated three or four times during one 8-hr shift (Figueroa et al., 1973). During the process of manufacture of anion-iexchange resin, excess CME was destroyed by addition of water to the reaction vessels. This step, referred to as quenching, is a highly exothermic reaction, whi :h results in the release of HC1, CH,0, methyl alcohol, and undoubtedly unreaded CME-BCME, all within the building where the resin was being manufacture^ at times with inadequate ven tilation. Attempts were made in some of these studies to divide worker exposure into low-, medium-, and high-risk levels (Maher and DeFonso, 1987; McCallum etal., 1983). This type of classification is difficult to e /aluate because exposure levels are not available for at least the first 20 years thait these chemicals have been in use. Moreover, the manufacture of CME is by its nature a batch-type operation, The number of batches and the quantities produ c;da: nd used for any given length of time did not emerge from any of the studies reviewed here. It was also impossible to obtain with any degree of certainty the temporal exposure levels for the critical 20-year period, i.e., intense exposure for t rief periods of time compared to long-term exposure to low levels of CME-BCM OCCUPATIONAL EXPOS URE: VC The first full report dealing with the occurren:e of angiosarcoma of the liver (ASL) in VC-PVC workers (Creech and Johnso l , 1974), appeared 3 years after the initial animal carcinogenicity bioassays wen described (Viola et at., 1971). Since then numerous papers have dealt with ASL and cancers in other organs and systems in workers in the VC-PVC industry (IARC 1987). The most recent compilation of worker deaths ascribed to ASL as a result of exposure to VC was reported by the Associate n of Plastics Manufacturers in i*. lr SPI-01221 148 BENJ AMIN L. VAN DUUREN n)} 01*" ir I ^. * n Europe (APME) for the years 1 >55 through 1984. (Forman et al., 1985). A total of 115 deaths from ASL were cuunted for Europe, North America, and Japan. Thirty-five of these cases wer^ from 10 manufacturing facilities in the United States. The largest proportion >f ASL cases occurred between 20 and 29 years from the beginning of exposure. The median latent period was given as 22.6 years, The authors concluded that addi tional cases may be expected after more than 30 years. Close to 11% of the AS1. deaths occurred in autoclave cleaners and production operators where the hig hest levels of exposure to VC were encountered, The total number of workers e> posed to VC was not given in this compilation, During two-and-a-half decadi s, 1950-1975, i.e., before human carcinogenicity was established (IARC, 1979a) the major concerns in manufacturing industries were the narcotic properties of VC and the fact that at sufficiently high levels, 4% by volume (Weast and Astle, 1 S 81), it becomes a fire and explosion hazard. As a result of these concerns some information is available on VC concentrations in components of some manufactu -ing facilities prior to the early 1970s. The highest concentration of VC was found in the polymerization reaction vessels after cornpletion of the process. This has been reported to reach 3000 to 4000 ppm. Other areas in the facility gave mea:s|urements ranging from 1 to 1000 ppm (Barnes, 1976). These levels decreased markedly after the early 1970s (IARC, 1979b; Barnes, 1976; Purchase et al. 1987). Several recent reports present additional epidemiologic findings on cancer incidences in VC-PVC workers (Laplanche et al., 1987; Heldaas et al., 1984; Smulevich et al., 1988). They prese i it data on ASL, lung, stomach, skin, hematopoietic and lymphatic systems. Soi ne of these cancers of organs and systems other than the liver were mentioned earlier reports and reviews (IARC, 1987). Further studies in some of these are is are indicated because of marginal significances in some instances, e.g., malignant melanoma as pointed out by the authors (Heldaas et al., 1984). There a e indications that ASL may occur only at high levels of and/or prolonged expo; ure to VC (Forman et al., 1985; Smulevich et al., 1988). In one study increased d< aths in VC-exposed workers were reported from cancers of the lymphatic, hemati >:poietic, digestive, respiratory systems, including bone, brain, and skin, but no A SL's were observed (Smulevich et al., 1988). i'L 1 ` CONCLUSIONS The number of workers expo<ed to VC during the years 1948-1981 is probably two orders of magnitude higher t lan the number of those exposed to CME-BCME during the same period. In the letter case, and if the legal settlement reached for one manufacturing facility is taki:n into account, there were 117 respiratory cancer deaths reported from five couijtries from 1948-1981 among 3024 workers. By comparison there were 115 ASL deaths among several hundreds of thousands of VC workers from 1955-1984 in t|he APME compilation. The latter is undoubtedly tr. < /t^'At/Jl'much more complete than that given in Table 1 for CME-BCME respiratory - cancer deaths. Exposure levels to VC range from one to 4000 ppm with roughly 11% of ASL deaths occurring in workers exp<Kised to a 3000- to 4000-ppm level. VC is a narcotic gas with a pleasant odor which ads to euphoria, unconsciousness, and sleep. On SPI-01222 CARCINOGENICITY OF VC A VD CME-BCME 149 the other hand CME-BCME is highly irritating and noxious in vapor form. Moreover, in air even at low levels of humidity, CMEl-BCME releases highly noxious fumes of HCI and CH;0. CH;0 causes eye ar d mucous membrane irritation at 0.01 ppm to 2.0 ppm (NRC-NAS. 1981). The odor threshold concentration for HCI is about 0.1 ppm and irritancy becomes prcjnounced in the range of 5-20 ppm (NRC-NAS. 1976). Thus, unlike VC exposure CME-BCME exposure forces a warning on workers to such an extent that they evacuate work areas when unbearable levels of these chemicals and their hydrolysis products appear. It is therefore reasonable to conclude that levels o: exposure to CME-BCME were lower than those to VC by several orders of m ignitude. There is another factor which should be borte in mind. The Group 1 occupational carcinogens (IARC, 1987) are indirect-aic ting agents with the exception of CME-BCME, melphalan, and sulfur mustard, It is expected that the markedly higher human and animal carcinogenicity of (JME-BCME compared to VC is ascribable to their high order of direct-acting; all y lating reactivity; i.e., metabolic activation is not required for CME-BCME. It the case of the indirect-acting carcinogen VC, the delivered level of activated carcinogenic intermediate is undoubtedly substantially lower than the amounts of VC inhaled. A part of the VC inhaled is metabolized to innocuous products and the activated carcinogenic intermediate will also be partially removed by irre evant reactions with glutathione, proteins, and other tissue constituents (Van ren and Van Duuren, 1988). It is possible that additional information will be forthcoming concerning such matters as total number of workers exposed to /C or quantities of CME-BCME manufactured, in order to place the above observ|a:tions and conclusions on a more solid foundation. From the animal bioassays and epidemiologic studies summarized in this report it is clear that CME-BCME represents a much more potent animal and human carcinogen than VC. ACKNOWLEDGMENTS This work was supported by NIH center grants CA 133 4:3 and ES-00260 and American Cancer Society grant No. 00009. This paper constitutes Contributit n No. L235 from the Laboratory of Organic Chemistry and Carcinogenesis. REFERENCES Anonymous (1987) Polyvinyl chloride growth resumes at sic w pace. Chem. Eng. Sews. 47. Anonymous (1988) Top 50 chemical production totaled 567 billion lbs in 1987. Chem Eng. News. 31. Barnes. A. W., (1976). Vinyl chloride and the production of PVC. Proc. R. Soc. Med. 69, 377-310. Collingwood. K. W.. Pasternack. B. 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