Document KJmQkpGLqEEKojzbZ6xbxDY6x

" OCCUPATIONAL CANCER: CLINICAL INTERPRETATION AND APPLICATION OF SCIENTIFIC EVIDENCE Linda Rosenstock, M.D., M.P.H. Departments of Medicine and Environmental Health University of Washington S e a t t l e , Washington 98105 ABSTRACT H a i n t a i n i n g a n awareness t h a t workplace f a c t o r s may c o n t r i b u t e to o c c u p a t i o n a l cancer i s one of t h e most formidable o b s t a c l e s in early clinical recognition. This early recognition provides an o p p o r t u n i t y f o r a p r a c t i c i n g p h y s i c i a n t o make a n i m p o r t a n t c o n t r i b u t i o n t o new knowledge i n t h e f i e l d . Another i m p o r t a n t reason f o r t h e p h y s i c i a n t o have a h i g h index of s u s p i c i o n of cancers being r e l a t e d t o workplace exposures has t o do w i t h compensation b e n e f i t s which may a c c r u e t o t h e i n j u r e d worker. The p h y s i c i a n ' s r o l e i n t h e compensation system is c r i t i c a l b o t h i n p r o v i d i n g m e d i c a l o p i n i o n , which is m a t e r i a l t o t h e f i n a l d e c i s i o n , and because i n many states i t is t h e p h y s i c i a n who s t a r t s t h e t i m e c l o c k f o r t h e s t a t u t e of l i m i t a t i o n s . Three case examples are used t o i l l u s t r a t e the importance of c l i n i c a l r e c o g n i t i o n by a n a l e r t p h y s i c i a n : 1) mesothelioma and l a b o r ; 2) l u n g c a n c e r i n a plumber who smokes and one who does n o t smoke; 3) leukemia i n a r u b b e r i n d u s t r y worker. Given t h e i n h e r e n t p r e v e n t a b l e n a t u r e of o c c u p a t i o n a l c a n c e r s , i t is hoped that society w i l l assist i n searching for these important links. INTRODUCTION Despite t h e accumulation of knowledge about and t o o l s t o a s s e s s known and suspected o c c u p a t i o n a l carcinogens, t h e t a s k remains a d i f f i c u l t one f o r t h e p h y s i c i a n f a c e d w i t h d e t e r m i n i n g t h e workrelatedness of cancer i n any individual p a t i e n t . Perhaps t h e 261 Copyright 0 1984 by Marcel Dekker, Inc. 0731-3810/84/2203-0261$3.50/0 1 262 i 1 ROSENSTOCK CLIN ! most formidable o b s t a c l e i n t h i s d e t e r m i n a t i o n is t h e f i r s t s t e p which t h e p h y s i c i a n must t a k e i n e v a l u a t i n g any p a t i e n t who may is a And 1 1 have an occupational disease, namely, maintaining awareness that shou i)..,aj workplace f a c t o r s may be of importance. Only t h e n can t h e o t h e r tic important steps follow o f diagnosing, t r e a t i n g , and n o t i f y i n g is t r i;$ t h e a p p r o p r i a t e p a r t i e s of t h e p r e s e n c e o f a known o r s u s p e c t e d Perhi occupational disease. That the physician usually f a i l s t o obtain much E.' even t h e most rudimentary i n f o r m a t i o n necessary t o i n i t i a t e t h i s sequence h a s by now been commented upon by many ( 1 , 2 ) . conti the F ' Alice Hamilton's comments of o v e r 50 y e a r s a g o , f o l l o w i n g s i m i l a r t o h: I comments by Ramazzini of 200 y e a r s earlier, are, u n f o r t u n a t e l y , s t i l l t o o a p t . She s a i d , " I f t h e r e c o r d i n g i n t e r n e would o n l y --.-. t r e a t t h e p o i s o n from which t h e man i s s u f f e r i n g w i t h as much i n t e r e s t as h e g i v e s t o t h e c o f f e e t h e p a t i e n t has drunk and t h e tobacco he has smoked, i f he would a s k as c a r e f u l l y about t h e l e n g t h of t i m e he was exposed t o t h e p o i s o n a s about t h e a g e a t I which h e had measles, t h e t a s t e of t h e s e a r c h e r f o r t h e t r u t h a b o u t i n d u s t r i a l poisons would b e made so v e r y much e a s i e r (3):` There a r e many p o t e n t i a l b e n e f i t s t h a t d e r i v e from t h e c l i n i c i a n ` s c o n s i d e r a t i o n of t h e work- relatedness of cancer. The f i r s t is t o h e l p a r r i v e a t t h e c o r r e c t d i a g n o s i s and in t u r n d e s i g n a p p r o p r i a t e t r e a t m e n t . A new p l e u r a l e f f u s i o n I n a n asbestos- exposed worker should call f o r placing mesothelioma h i g h e r on t h e l i s t of d i f f e r e n t i a l diagnoses than i t o t h e r w i s e I i: ! would be. Primary lung carcinoma, p a r t i c u l a r l y i f t h a t worker 263 is a l s o a smoker, is, of course, a l s o a s t r o n g consideration. And knowing of t h e a s b e s t o s e x p o s u r e and i t s many s e q u e l a e should add a n o t h e r e n t i t y t o t h e l i s t , t h a t of a benign asbestot i c effusion. The second reason t o consider workplace f a c t o r s i s t o f i n d new a s s o c i a t i o n s between h a z a r d s and d i s e a s e . Perhaps i n no o t h e r a r e a than occupational h e a l t h is t h e r e a s much o p p o r t u n i t y f o r t h e p r a c t i c i n g p h y s i c i a n t o make i m p o r t a n t c o n t r i b u t i o n s t o new knowledge. The i n s t a n c e s a r e m u l t i p l e of the p h y s i c i a n who, sometimes a f t e r t h e problem i s f i r s t b r o u g h t t o h i s o r h e r a t t e n t i o n by workers, e s t a b l i s h e d a new l i n k between a n e x p o s u r e and a n a d v e r s e h e a l t h outcome. T h i s was the case when o n l y a few y e a r s ago D r . Keogh i d e n t i f i e d t h e neurotoxic p r o p e r t i e s of dimethylaminopropionitrile, a chemical used i n p l a s t i c s m a n u f a c t u r i n g ( 4 ) . The h i s t o r y of i d e n t i f i c a t i o n by p h y s i c i a n s of o c c u p a t i o n a l c a r c i n o g e n s i s a l o n g one, s t a r t i n g w i t h P e r c i v a l P o t t who i n 1 7 7 5 r e p o r t e d s c r o t a l c a r c i noma among London chimney sweeps ( 5 ) . That t h i s same class of . substances, coal combustion by- products, which caused t h e rare s c r o t a l tumor c o n t i n u e s t o cause lung cancer i n coke-oven workers is a clear and sorry statement t h a t i d e n t i f i c a t i o n alone is not enough. A more recent example of i d e n t i f i c a t i o n of a human c a r c i n o g e n by a p h y s i c i a n , i n t h i s case a p a r t - t i m e p l a n t physician, i s t h e r e p o r t i n 1974 by D r . Creech of t h r e e cases of h e p a t i c angiosarcoma among workers i n a s i n g l e p o l y v i n y l chloride manufacturing f a c i l i t y ( 6 ) . I n t h i s i n s t a n c e , t h e car- by earlier animal studies ( 7 ) . Other reasons for considering workplace factors in clinical practice include being better able to educate and counsel workers. The role of smoking cessation, which is a primary, but a l s o a secondary preventive intervention, insofar as it relates to asbestos-related lung cancer risk, is but one example. Consideration of exposure to occupational carcinogens is an important component of designing effective Screening or surveillance programs for individuals or groups of workers. One important factor in this regard is the appreciation of the effect of population prevalence of the abnormality, or the pretest risk of the disease in any individual, on the diagnostic efficacy of the screening test. This aspect of Bayes's theorum has received increased attention, in general, in the clinical literature, for example, as noted in the marked variation in the ability of ST segment depression in exercise treadmill testing to predict the presence of coronary artery disease (8). For example, assuming a sensitivity and specificity of 90% of the chest x-ray to detect a lung abnormality such as cancer, then 90% of those with the abnormality will have an abnormal chest x-ray and 90% of those without abnormalities w i l l have a normal chest x-ray. If one then evaluates patients from a population where the lung abnormality has a prevalence of 1 in 100, the positive predictive value of the chest x-ray, that is how many with the abnormal CLIN IChL INTERPRETATION 265 chest x-ray are going t o have t h e abnormality, is q u i t e low a t roughly 8%. This i s c o n t r a s t e d w i t h t h e u s e of t h e c h e s t x- ray to screen p a t i e n t s with a higher prevalence of the abnormality, 1 i n 10, where t h e test c h a r a c t e r i s t i c s of 90% s e n s i t i v i t y and specificity have not changed, but the positive predictive value of an abnormal c h e s t x-ray has increased t o 50%. It is important, formally o r informally, t o incorporate t h i s concept of pretest p r o b a b i l i t i e s i n t o c l i n i c a l p r a c t i c e when s c r e e n i n g f o r health problems among t h o s e o c c u p a t i o n a l l y exposed. Chest x- rays have n o t been shown t o be c o s t - e f f e c t i v e a s r o u t i n e s c r e e n i n g teats in p a r t because of t h i s e f f e c t of population prevalence. I n a d d i t i o n , if e a r l y d e t e c t i o n does n o t a l t e r s i g n i f i c a n t l y the course of i d e n t i f i e d a b n o r m a l i t i e s , then one of t h e main p r i n c i p l e s of u s e f u l n e s s of s c r e e n i n g tests i s v i o l a t e d . This appear6 t o be t h e c a s e with screening chest x- rays. For t h i s reason, t h e o r e t i c a l c a l c u l a t i o n s of the cost- effectiveness of screening f o r l u n g c a n c e r among a s b e s t o s workers do n o t s u p p o r t its use, despite the profoundly increased risk for lung cancer among this p o p u l a t i o n ( 9 ) . These same c a l c u l a t i o n s , n o t s u r prisingly, support t h e cost- effectiveness of screening f o r colon c a n c e r among asbestos- exposed i n d i v i d u a l s because of their increased r i s k f o r these cancers a t about 1 1/2 t o 3-fold and because e a r l y d e t e c t i o n c a n a l t e r t h e n a t u r a l h i s t o r y of these tumors. F u r t h e r work c l e a r l y needs t o be done i n t h i s a r e a , however, g i v e n t h e p o t e n t i a l t h a t among t h i s e x c e p t i o n a l l y high- risk g r o u p , o t h e r s u r v e i l l a n c e s t r a t e g i e s may t u r n o u t t o benefits, even independent from litigation under third party product liability, may be significant and can be established in the setting of definite occupational exposure and a pathologic diagnosis. A third reason is that mesothelioma is a signal neoplasm of asbestos exposure so that monitoring the incidence of this tumor provides one means to evaluate the overall burden of asbestos-induced disease. The Physician and Workers' Compensation The physician's role in the workers' compensation system is critical, both in providing the medical opinion which is mterial to the final decision, and because in many states it 26 7 l i m i t a t i o n s . I n t h e S t a t e of Washington, f o r example, t h e worker has o n l y one y e a r t o f i l e from t h e t i m e f i r s t n o t i f i e d by a physician of the presence of a work- related problem. It has been i n t e r p r e t e d t h a t t h i s same n o t i f i c a t i o n w i l l s t a r t a t h r e e year s t a t u t e of l i m i t a t i o n s on l i t i g a t i o n under t h i r d p a r t y product l i a b i l i t y . The p h y s i c i a n i s a l s o l e g a l l y bound t o inform t h e worker of h i s o r h e r r i g h t s under t h e compensation e y a t e m , i n c l u d i n g t h e r i g h t t o be r e p r e s e n t e d by a n a t t o r n e y and t o pursue t h i r d party l i a b i l i t y (12). The judgment by t h e p h y s i c i a n of t h e p r o b a b i l i t y of t h e work- relatedness of t h e medical condition is key in compensation and r e l a t e d s i t u a t i o n s . The workers' compensation forms i n moat states demand t h a t t h e p h y s i c i a n i n d i c a t e t h e d e g r e e of c e r t a i n t y of work- relatedness. The workers' compensation form i n the S t a t e of Washington is t h e same f o r a c c i d e n t s and d i eeases. The p h y s i c i a n must r e p l y t o t h e q u e s t i o n , "is t h e c o n d i t i o n diagnosed t h e r e s u l t of t h e i n c i d e n t d e s c r i b e d ? " by narking one of f o u r c a t e g o r i e s : d e f i n i t e l y , probably, p o s s i b l y , 00. D e s p i t e t h e y e a r n i n g t o t r e a t t h i s as a L i k e r t s c a l e , xplacing a l a r g e somewhere between p o s s i b l y and p r o b a b l y , t h e physician must e f f e c t i v e l y make, with important i m p l i c a t i o n s , what i s u l t i m a t e l y a y e s o r no answer. "Yes", by a n s w e r i n g d e f i n i t e l y o r p r o b a b l y , and "No" by answering p o s s i b l y o r no. If t h e d e c i s i o n i s no, t h e p a t i e n t w i l l a l m o s t never r e c e i v e cornpensation and i f i t i s yes, the p a t i e n t w i l l sometimes CLINICAL INTERPRETATION 269 of causation. These a r e : mesothelioma i n a l a b o r e r ; lung cancer i n a plumber who smokes and i n one who does n o t smoke, and leukemia i n a r u b b e r i n d u s t r y worker. Case Number 1 The p a t i e n t i s a 60- year- old man w i t h a t h i r t y - f i v e y e a r history of unprotected asbestos exposure while employed doing general l a b o r and d e m o l i t i o n work i n t h e c o s t r u c t i o n t r a d e s . He had s e v e r a l months of m a l a i s e , a 10 pound weight l o s s and constant, d u l l , right- sided c h e s t pain. Chest x- rays showed a right- sided p l e u r a l - b a s e d mass w i t h f r e e l y - l a y e r i n g f l u i d . P l e u r a l p l a q u e s were p r e s e n t i n t h e l e f t hemithorax. A d i a g n o s i s of mesothelioma was made from b i o p s y m a t e r i a l o b t a i n e d a t limited open thoractomy. The r e l a t i o n s h i p of t h e diagnosis of mesothelioma t o t h i s p a t i e n t ' s o c c u p a t i o n a l a s b e s t o s expsure, would probably be unquestioned even by t h e most s k e p t i c a l . T h i s i s a s i t u a t i o n where most who a r e informed would n o t h e s t i t a t e a t r e s p o n d i n g even w i t h a ' d e f i n i r e ' t o t h e q u e s t i o n of t h e p r o b a b i l i t y of the work- relatedness of t h i s p a t i e n t ' s tumor. I n t h e c a s e of mesothelioma, t h e smoking s t a t u s of the p a t i e n t appears t o have no r e l a t i o n t o r i s k such t h a t an i n d i v i d u a l ' s smoking s t a t u s i s not r e l e v a n t t o t h e d e t e r m i n a t i o n of cause. Evidence f o r t h e relationship between mesothelioma and asbestos exposure is derived from a n i m a l s t u d i e s but more i m p o r t a n t l y from epiderniologic studies. Mesothelioma has been i d e n t i f i e d a s a s i g n a l neoplasm of a s b e s t o s exposure, with a h i s t o r y of a s b e s t o s e x p o s u r e found i n anywhere from 50% t o n e a r l y 100%o f t h o s e w i t h mesothelioma. While a s b e s t o s may n o t be t h e o n l y c a u s e , i t is c e r t a i n l y t h e most s i g n i f i c a n t one i n r i s k for mesothelioma, such t h a t r e l a t i v e r i s k has v i r t u a l l y no meaning, a s t h e r e are no expected c a s e s i n t h e absence of exposure. Absol u t e r i s k is used t o develop dose- response relationships. Before examining t h e evidence about t h e dose- response relat i o n s h i p between a s b e s t o s and mesothelioma, i t is worth reviewing some o f t h e r e a s o n s why t h e p r a c t i c i n g p h y s i c i a n s h o u l d be concerned w i t h s u c h r e l a t i o n s h i p s . Few would q u e s t i o n t h e importance of recognizing a p l a s t i c anemia a s an i d i o s y n c r a t i c response t o chloramphenicol, d i s t i n c t from t h a t drug's predict a b l e m y e l o s u p p r e s s i v e a c t i v i t y . I n t h e same way, u n d e r s t a n d i n g dose- response relationships i n occupationally- related diseases a l l o w s t h e p h y s i c i a n t o u n d e r s t a n d b e t t e r why and t o what d e g r e e t h e i n d i v i d u a l p a t i e n t is a t r i s k f o r a n a d v e r s e outcome and t o a n t i c i p a t e , and i f possible prevent, t h i s outcome i n t h e i n d i v i d u a l o r o t h e r exposed workers. It also may be h e l p f u l i n d e t e r m i n i n g p r o g n o s i s and t r e a t m e n t (13). Although mesothelioma may r e s u l t from b r i e f and sometimes casual asbestos exposure, there is convincing evidence that the o c c u r r e n c e of mesothelioma has a c o n s i s t e n t r e l a t i o n s h i p t o i n c r e a s i n g d o s e , a l t h o u g h n o t a l i n e a r one ( 1 4 ) . Risk does n o t appear t o be r e l a t e d t o age a t f i r s t exposure, but t i m e from f i r s t exposure, with a dramatic increase i n r i s k with t i m e . T h i s r e l a t i o n s h i p of r i s k i s as a f u n c t i o n of t h e 4 t h o r 5 t h CLINICAL INTERPRETATION 27 1 power of time from f i r s t exposure ( 1 5 ) . T h i s phenomenon r a i s e s concerns about even low-dose childhood exposures, a s these confer the g r e a t e s t r i s k of developing mesotheliomna a t an age when t h e r e a r e fewer o t h e r competing c a u s e s of d e a t h . But, c l e a r l y , t h e g r e a t e s t burden of t h i s consequence of exposure i s borne by t h o s e o c c u p a t i o n a l l y exposed. B e r r y ' s review of t h e mortality p a t t e r n of B r i t i s h workers c e r t i f i e d with asbestosis by pneumoconiosis p a n e l s found mesothelioma t o be t h e c a u s e of death i n 9% (16). H e a l s o examined loss of longevity, f i n d i n g t h a t t h e e x t e n t of d i s a b i l i t y and t i m e of c e r t i f i c a t i o n by t h e pneumoconiosis p a n e l was a p o t e n t p r e d i c t o r o f s u r v i v a l . Compared t o t h e e x p e c t e d s u r v i v a l of 75% of t h e c o h o r t a t 10 years from c e r t i f i c a t i o n , had t h e death rates of England and Wales been a p p l i e d , t h o s e w i t h d i s a b i l i t i e s a t c e r t i f i c a t i o n of 10 o r 20% had o n l y 50% s u r v i v a l , o n l y a b o u t o n e - t h i r d s u r v i v e d a t 10 y e a r s i f i n i t i a l d i s a b i l i t y was 30 o r 4 0 % , and o n l y one- sixth were a l i v e a t 10 y e a r s i f i n i t i a l d i s a b i l i t y was 50% o r more. For a man aged 5 5 a t t i m e of c e r t i f i c a t i o n and awarded 10% d i s a b i l i t y b e n e f i t s , l o n g e v i t y would be reduced by 3 y e a r s ; i f I n i t i a l d i s a b i l i t y was 20%, t h e n l o n g e v i t y would be reduced by 5 y e a r s , If 30 o r 4046, t h e n by 8 y e a r s , and i f a t l e a s t 50% d i s a b i l i t y , t h e n r e d u c t i o n would be by 12 years. Goldsmith's a n a l y s i s of m o r t a l i t y of 11 c o h o r t s of a b o u t 32,000 a s b e s t o s exposed workers provided good evidence t h a t a t non-pulmonary s i t e s a s b e s t o s acts as a systemic carcinogen, but he a l s o showed the s i g n i f i c a n t r i s k of those exposed f o r developing mesothelio- r--- CLIN1CAL INTERPRETAT ION 273 tion workers, c l o s e d w i t h t h i s p r o p h e t i c comment, p e r t i n e n t t o the case under discussion, "Asbestos exposure i n industry w i l l not be l i m i t e d t o t h e p a r t i c u l a r c r a f t t h a t u t i l i z e s t h e mater i a l . The f l o a t i n g f i b e r s do n o t respect j o b c l a s s i f i c a t i o n ... i n s u l a t i o n workers undoubtedly s h a r e t h e i r e x p o s u r e s w i t h their workmates i n other trades; intimate contact with asbestos 18 p o s s i b l e f o r e l e c t r i c i a n s , plumbers, s h e e t -m e t a l w o r k e r s , steam f i t t e r s , l a b o r e r s , c a r p e n t e r s , boilermakers, and foremen... (18). I n 1968, S e l i k o f f r e p o r t e d t h e remarkably i n c r e a s e d r a t e of about 92- fold f o r smoking a s b e s t o s workers of dying from bronchogenic carcinoma ( 1 9 ) . Subsequent a n a l y s e s s u p p o r t e d the absolute increased r i s k f o r bronchogenic carcinoma, even among non-smokers exposed t o a s b e s t o s and t h e profound s y n e r gism i n r i s k f o r t h o s e who smoked and were exposed ( 2 0 ) . Henderson and Enteline have s t u d i e s the mortality experience a f t e r t h e age of 65 of a cohort of about 1,000 employees working i n a U.S. a s b e s t o s company and r e t i r i n g w i t h a company p e n s i o n (21). Cumulative a s b e s t o s d u s t e x p o s u r e was c a l c u l a t e d f o r each individula, based on personnel records and dust l e v e l estimates f o r each job and t i m e period. Plotting the data of the r e l a t i o n between t o t a l dose and mortality from r e s p i r a t o r y cancer yields a strong l i n e a r relationship with a c o r r e l a t i o n of .98; t h e p r e d i c t e d l i n e h a s t h e formula of S M R = 100 + 0.658 ( c u m u l a t i v e e x p o s u r e ) . The r e l a t i v e r i s k of d e v e l o p i n g lung cancer appears t o be independent of age a t f i r s t exposure. And a l t h o u g h t h e mean l a t e n c y f o r l u n g c a n c e r from t i m e of f i r s t 274 ROSENSTOCK exposure is about 25 y e a r s , t h e r e i s a l i n e a r i n c r e a s e i n excess r i s k of death from lung cancer which occurs very c l o s e t o t h e o n s e t of exposure and c e r t a i n l y a t no more t h a n 10 y e a r s (15). I d e n t i f i c a t i o n of tumor type i s probably of l i t t l e b e n e f i t i n assigning cause t o lung cancer i n the individual patient. Squamous and adenocarcinoma are t h e predominant t y p e s of asbes- b! tos- related cancers, but t h i s r e f l e c t s t h e p a t t e r n of lung gi c a n c e r s e e n i n t h e g e n e r a l p o p u l a t i o n (22). One d i f f e r e n c e between lung cancer i n those with a s b e s t o s exposure compared t o r 1 unexposed individuals is the location of t h e tumor; i n the i i general population, about 2/3 of lung cancers a r e found i n t h e ~ upper lung f i e l d s , whereas lower l o b e tumors are more l i k e l y i n a s b e s t o s - r e l a t e d l u n g c a n c e r (23). The r e a s o n s f o r t h i s are unclear, but perhaps include t h e predominance of asbestos- induced f i b r o s i s i n t h e s e same a r e a s . Although some i n v e s t i g a t o r s have reported a g r e a t e r number of p e r i p h e r a l tumors i n t h o s e exposed, t h i s was n o t found i n one c a s e - c o n t r o l s t u d y which a d d r e s s e d t h i s i s s u e (23). i I n t h e case p r e s e n t e d h e r e , t h e r e l a t i o n s h i p of t h e tumor -1 : ' t o h i s work e x p o s u r e s , w h i l e n o t a s c l e a r - c u t as i f he had $ mesothelioma, meets almost a l l c r i t e r l a which can be employed P: by t h e p h y s i c i a n i n d e t e r m i n i n g t h e w o r k - r e l a t e d n e s s of a I c o n d i t i o n . It i s b i o l o g i c a l l y p l a u s i b l e , t h e time c o u r s e i s a p p r o p r i a t e , and t h e r e is l a c k of e x p o s u r e t o known a g e n t s o u t s i d e t h e workplace which c a n c a u s e t h e same p r o c e s s . The presence of o t h e r manifestations of a s l c s t o s exposure would CLINICAL INTERPRETAT I O N 275 have provided more e v i d e n c e t o s u p p o r t t h e n a t u r e and e x t e n t of exposure. Two s t u d i e s have r e p o r t e d t h a t p l e u r a l plaques a l o n e , even w i t h t h e same d e g r e e of exposure, may c o n f e r a d o u b l i n g of r i s k f o r carcinoma ( 2 4 ) . The absence of t h e s e o t h e r r a d i o g r a p h i c manifestations, however, does not a l t e r t h e c o r r e c t n e s s of s t a t i n g h i s tumor is probably work- related. He h a s , a f t e r a l l , just on t h e basis of h i s exposure, multiplied h i s r i s k f o r lung cancer by 5- fold (20). But what i f t h i s p a t i e n t were a smoker? A similar d e c i s i o n t o s t a t e t h a t t h i s p a t i e n t ' s tumor was more p r o b a b l y t h a n n o t work-related can be soundly based on available s c i e n t i f i c evidence, with t h e smoking asbestos- exposed worker having a five- t o ten- fold increased risk for lung cancer than i f he or she did not have t h e asbestos exposure. This decision w i l l , however, be m e t with f a r more argument and controversy. Less so because of t h e s t a t i s t i c s , or so- called s c i e n c e , but because of t h e i m p l i c a t i o n s . Smoking is common, l u n g c a n c e r i s common, and a s b e s t o s e x p o s u r e i s common. If t h e same r u l e s of e v i d e n c e were t o a p p l y f o r a l l smokers who g o t l u n g c a n c e r who had a s b e s t o s e x p o s u r e , t h e c o s t i m p l i c a t i o n s f o r many i n d u s t r i e s i n terms of i n d u s t r i a l i n s u r a n c e , n o t t o mention t h o s e f o r a few i n d u s t r i e s i n terms of t h i r d - p a r t y product l i a b i l i t y , are enormous. The c o s t i m p l i c a t i o n s of t h e added r i s k posed by t h e asbestos exposure do n o t , of course, disappear with t h e judgment that these tumors are not work- related; they are j u s t s h i f t e d away from o r e x t e r n a l i z e d by i n d u s t r y , w i t h t h e g r e a t e s t burden 1-- 276 b o r n e by t h e a f f e c t e d p a t i e n t and h i s f h e r f a m i l y . In- depth a n a l y s e s of compensation f o r asbestos- related d i s a b i l i t y have shown t h e same t r e n d p r e v i o u s l y found, namely, t h a t workers' compensation pays o n l y a small s h a r e of t h e b i l l f o r d i s a b i - lities a r i s i n g from occupational disease ( 2 5 ) . Compensation f o r occupational disease i n general, and i n particular f o r those s i t u a t i o n s of m u l t i f a c t o r a l o r i g i n and less well- characterized r i s k goes w e l l beyond evidence and physician assessment of individual cases. Under t h e B r i t i s h system, a s b e s t o s i s and mesothelioma are prescribed d i s e a s e s , e n t i t l i n g the p a t i e n t or h i s o r h e r depen- d e n t s t o compensation. D e c i s i o n s a b o u t compensation a r e made I L. by a pneumoconiosis p a n e l , and c e r t i f i c a t i o n h a s r e c e n t l y been i. i;t :I expanded t o include p l e u r a l thickening, i f extensive. Under ! t h e i r s y s t e m , c a n c e r of t h e l u n g h a s been compensable only i f i t o c c u r s i n a s s o c i a t i o n w i t h a s b e s t o s i s , so t h a t claims re- j e c t e d d u r i n g l i f e may be a c c e p t e d a f t e r d e a t h If p o s t mortem examination reveals a s b e s t o s i s which had been not radiographi- ./ 1 c a l l y detectable. Recent recommendations from the B r i t i s h Industrial Injuries Council, using the relative risk estimates i i previously discussed, a r e t h a t smoking s t a t u s should be disregarded i n determining compensation a s should tumor type (26). Moreover, i t was recommended t h a t l u n g c a n c e r be compensated i f i t ocurrs not only In association with parenchymal asbestosis b u t w i t h b i l a t e r a l p l e u r a l p l a q u e s o r d i f f u s e t h i c k e n i n g . The B 1 33 a i m of these recommendations i s t o compensate those with suf- CLINICAL INTERPRETAT ION 277 f i c i e n t a s b e s t o s e x p o s u r e who g e t a f f l i c t e d w i t h l u n g c a n c e r . Although t h i s can be applauded a s a more r a t i o n a l and c o n s i s t e n t approach t o both t h e l e g a l and medical i n t e r p r e t a t i o n of t h e s c i e n t i f i c evidence, i t does not address the circumstance of the worker who, f o r unknown r e a s o n s , f a c e d w i t h t h e same amount o f exposure as a fellow- worker who develops p l e u r a l o r parenchymal f i b r o s i s , is s p a r e d from t h e s e s e q u a l a e b u t d e v e l o p s lung cancer. This circumstance of asbestos- related carcinoma i n the absence of o t h e r radiographic abnormalities, w i l l continue, particularly as the risk f o r fibrosis decreases with decreasing exposures. A t current allowable levels, depending on t h e r i s k assessment model used, i t is e s t i m a t e d t h a t t h e r e w i l l be a t least 5,000 excess lung cancer deaths f o r each m i l lion workers exposed ( 2 7 ) . The i n t e r a c t i o n between smoking and workplace h a z a r d s has been u n u s u a l l y w e l l - d e f i n e d f o r a s b e s t o s . It i s n o t s o much data which are lacking but an economic, philosophical and e t h i c a l consensus i n o r d e r t o answer t h e q u e s t i o n which was posed by S t e r l i n g s e v e r a l y e a r s ago: "Does smoking k i l l workers or working k i l l smokers?" (28). It is not s u f f i c i e n t t o pursue only one approach, namely, individual smoking cessation programs, p a r t i c u l a r l y when t h i s approach is a s s o c i a t e d w i t h s u c h low success rates. I n s t i t u t i o n a l interventions, such as eliminating tobacco subsidization and occupational carcinogens, a r e ones l i k e l y t o be a s s o c i a t e d w i t h f a r more a c h i e v a b l e r e s u l t s . 278 ROSENSTOCK Case 3 The p a t i e n t is a 45-year-old worker exposed f o r t h e p a s t 15 years t o benzene i n a chemical manufacturing process, a t l e v e l s t h a t were d e t e r m i n e d t o b e a t around t h e c u r r e n t s t a n d a r d o f 10 p a r t s p e r m i l l i o n . H e had been i n g e n e r a l l y good h e a l t h , without any medical evaluation i n t h e 10 y e a r s previous t o t h i s p r e s e n t a t i o n and diagnosis of a c u t e myelogenous leukemia. The question, then, is whether t h e p a t i e n t ' s benzene exposure on a more probable- than- not b a s i s i s r e l a t e d t o h i 8 leukemia. There have been multiple c l i n i c a l r e p o r t s of benzene- induced leukemia since the association was f i r s t reported i n 1928, so t h a t i n t h e l a s t 20 y e a r s , r e p o r t s of leukemia have outnumbered t h o s e of f a t a l pancytopenias (29). Only r e c e n t l y has benzene been shown t o be c a r c i n o g e n i c i n animals, l e a v i n g a r s e n i c and h e m a t i t i t e t h e o n l y known human c a r c i n o g e n s w i t h o u t . d e m o n s t r a t e d animal c a r c i n o g e n i c i t y . Two c o h o r t s t u d i e s have demonstrated an increased leukemia r i s k of up t o 20-fold, p a r t i c u l a r l y of t h e myelogenous form, from benzene exposure (30, 31). Excess chromosomal a b e r r a t i o n s have been d e m o s t r a t e d i n workers exposed t o c u r r e n t a l l o w a b l e l e v e l s of benzene a t 10 parts per million (32). Risk assessment a n a l y s i s of benzene exposure, based on t h e s e and o t h e r s t u d i e s , h a s been performed. The moBt c o n s e r v a t i v e r i s k a s s e s s m e n t h a s p r o j e c t e d , a t t h e minimum, a n e x c e s s of 140 t o 170 leukemia deaths p e r 1,000 l i f e t i m e exposed workers a t 100 ppm, t r a n s l a t i n g t o a r a n g e of 14 t o 170 e x c e s s d e a t h s a s approxin more cor f o r devt exposurt the bac' individi t h a t le. I need t o evidenc clear t our cor interes i n intc t o prot that tl causal: work-rc pation; t h e sa1 LXNICAL INTERPRETATION 279 w a n d high estimates f o r e x p o s u r e s a t 10 pprn ( 3 3 ) . Given t h e a v a i l a b l e d a t a , how should t h e p h y s i c i a n respond the q u e s t i o n of t h e p r o b a b l i t i t y of t h e r e l a t i o n of t h i s i t l e n t ' s leukemia t o h i s work exposures? The answer, I t h i n k , .. ould be y e s , on a more probable- than- not b a s i s . Using a n proximate l i f e t i m e r i s k o f 711000 of developing leukemia, t h e re c o n s e r v a t i v e e s t i m a t e s would i n d i c a t e a r e l a t i v e r i s k of 3 O r developing leukemia a s a r e s u l t of t h i s i n d i v i d u a l ' s benzene xporrures a t c u r r e n t a l l o w a b l e l e v e l s . I n o t h e r words, s i n c e he background r a t e of leukemia I s a t l e a s t doubled, any exposed ndividualwould on a more probable than not b a s i s have g o t t e n a t leukemia because of t h e benzene exposure. It is because of t h e s e and many o t h e r s i t u a t i o n s t h a t w e need t o do b e t t e r w i t h c o l l e c t i n g , i n t e r p r e t i n g and a n a l y z i n g evidence about occupational carcinogens. But i t should a l s o be clear t h a t It i s o f t e n n o t l a c k of a v a i l a b l e d a t a t h a t l i m i t s our c o n c l u s i o n s o r c a u s e s d i s a g r e e m e n t , b u t t h e v a l u e s and interests which we bring t o bear individually and c o l l e c t i v e l y i n Interpreting the data. As physicians, i t is our obligation to protect t h e i n t e r e s t s of our worker- patients. I would argue that t h i s would be b e s t a c h i e v e d , when i n doubt a b o u t t h e c a u s a l i t y of a problem, by e r r i n g on t h e s i d e of assuming i t i s wrk-related. Given t h e i n h e r e n t l y preventable n a t u r e of occupational cancers, I would hope t h a t a s a s o c i e t y w e would do z cs 280 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. CLINICAL INTERPRETAT I O N 28 1 15. Nicholson WJ, P e r k e l G , S e l i k o f f IJ. 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