Document 4a2XvQ0gLVMXDRDYXgb7npkr1

27 1 able-4 M t jr 2 0 u ars af u r first c m p io \ ttu m , b \ t aitse, in re la tio n to J u ra tio n o f s e n u ? ( uu\e *>f death* Ouratum o f / m/ u h i n I--* *-^ 2 0 '2 J ( itmpU'te ohitrt Ad causes Malignant neoplasms Respiratory Digestive Other Heart disease Respiratory tuberculosis Other respiratory Pneumoconiosis ( crcbrovascular Accidents <>thcr knon 0 24/ Ml 24 17 14 44 0 11 it*) 1M 11 17 SMH 1244 144 4 1MO 0 1u 4 120-4 i:< 146 1 i n , 1211 123 5 0 JX4 so 14 16 74 0 K (.') 14 s 24 W1H 04 0 i:s 1 144 4 128 4 164 4 104 4 I2h 2 1OK 4 64-2 40 4 0 1 0 24 4 s ls 44 0 4 tn s 29 SMR 104 M 114 0 122 6 60-6 140-4 84 7 -- *s 2 142-7 101 7 147 | 0 2W M 21 21 21 too 4 K 12) 20 7 3< SMR 47 2 1IK 4 14 4 1lf> 4 107 2 94.1 2M 3 42 2 102 4 Ml 6 87 u 0 wo 202 73 54 70 '12 4 33 (12) 67 2H 125 SMR low S 126 < 14K ** 114 4 l l< 9 102 5 145 9 114 n H4 1 10" 7 A s in table I. except that IC O cocks 160-64 arc here grouped under 'respiratory" malignant neoplasms and the "o th e r respiratory category includes only bronchitis, pneumonia, and pneum oconiostsllC D 490-502. 523-4) Table 5 gives SMRs by total accumulated dust exposure. The same ,, lack of any clear or systemic exposure-effect pattern is present.*; The SMR for respiratory cancer for men in the 2 highest dust groups combined (125.8) was higher than for the 2 intermediate dust groups combined (103.3) but still substantially belcw that for the lowest* exposure category (167.A). A similar pattern of relative risk was obtained from the Mantel-Haenszel analysis (Table 6), which showed an increasing risk only if the minimal exposure group is ignored. Table 5 Male deaths 20 years after fvst employment, by cause, in relation to dust exposure tm p cf v) AD c u k . Malignant neoplasms Respiratory Digestive Other Heart disease Respiratory tuberculosis Other respiratory Pncumncimimis Cerebrovascular Accidents " <Jther known n n A num uiated dust exposure tm p cf y) <10 !0-< 20 20-<40 0 SMR 0 SMR 0 SMR 546 144 ss 44 4S 60 2 21 <9) 43 ^ -4 nt 113 8 128-1 167 4 102 6 114 0 101 9 123 6 125 1 122 4 101 0 109-4 M9 22 6 4 7 14 0 s (1) M 3 15 92 3 104-6 101-7 134 1 H4 S 83-8 -- 135 6 101 7 86 4 102 4 71 19 5 N 6 13 0 (1) 7 0 15 *6-6 12(M 105-4 153 4 101 0 76-6 -- 74 4 1 18-4 -- 128 5 40-<R0 0 SMR h2 14 6 5 H 18 0 (1) S 10 110-2 1*3-4 162 8 120-2 176-6 106-4 -- 109-0 117 1 86-3 112 2 #0 0 35 W 1 3 4 13 2 3 (0) 4 i SMR 103-1 1179 126-6 JS0-4 43-0 1112-9 230-8 135-4 44 2 43 4 The more detailed analysis for respiratory cancer in Table 8 shews that the same patten is shared by men in the lowest accumulated dust category regardless of duration of employment. Table K Male deaths from respiratory cancer 20 years after fa st employment in relation to duration o f service and dust exposure Duration o f servue (vt I l-<5 >5 Dust exposure tm pcf v) --------------------------------------------------- <10 lti-< 40 *40 0 SMR :n:iHmici'sO I 4 | 50-0 0 SMR (1 2 02 y IIN-1 0 SMR 0II -- -- 7 I 25 4 Table Ti Rahlive risks o f respiratory cancer by dust exposure from ( I) Mantel-Haenszet analysts and (2) SMRs Mantel-Haenszcl Observed Bisected Relative m k Fran SMRs. Relative nsk mpcfy <10 Si 51 1 l 1 IO -<20 4 8-7 0-40 0-59 20-<40 5 46 0-91 0-64 40-<80 6 41 1-40 0-98 *80 1 15 113 031 Chi-square Difference Linearity 4-50 ooo The other respiratory group of diseases that included pneumoconiosis also shewed little indication of an exposure response. Six of the 12 whose deaths were frem pneumoconiosis (ICD 523) had worked in the plant for less than a year and only 3 of the other 12 had a total dust exposures index of 10 mppef-yrs. or more. Table 7 shows details from death certificates given ICD code 523. In no case was asbestosis mentioned but anthracosilicosis or silicosis were given^f- as the cause of death in all but 2 cases. It was further noted thafc- all 12 had either been b o m or had died in the coal mining area of ?" Pennsylvania. 1* Table 7 Deaths attributed to pneumoconiosis (ICD 52.1) Case No 1 *> 3 4 5 6 7 H 9 10 11 12 Employment Age at start (v) Duration 36 2 months 26 6 months 35 2 months 29 5 months 38 10 months 22 3 months 50 1 y IO m 47 3 years 35 3 years 51 20 years 40 16 years 31 30 years Birth plate Total dust (m pcf v) O l Sandy Run, Pa 0 2 Taylor. Pa O l W ilkes-Barre. Pa 0 2 Wilmington. Dc 0 7 Pennsylvania O l Wyoming. Pa 2 0 Mexico 6H 17-4 83 21 8 51 4 Scranton. Pa Nanticoke, Pa Scranton. Pa Nanticoke. Pa Nanticoke. Pa Death Age Place (V) 64 Freeland. Pa 57 Taylor. Pa 57 Wilkes-Barre, Pa 58 W ilkes-Bane. Pa 68 W ilkes-Bane. Pa 53 Wyoming. Pa 79 W indhcr. Pa 75 Scranton. Pa 58 Nanticoke. Pa 72 Bridgeport. Cl 68 Bridgeport. Ct 62 Bridgeport. Ct Lemfied cause Anthracosilicosis Silicosis and emphysema Anthracosilicosis 3* anthracosilicosis Anthracosilicosis Anthracosilicosis Coal workers pneumoconiosis Anthracosilicosis Silicosis Pulmonary silicosis Pneumoconiosis Pneumoconiosis CONCLUSION :s concluded that if it is accepted that the high mortality causes (including respiratory cancer) in men employed for leas than 1 year was probably due to some form of selection, then the results suggest that the adverse health effects of employment in this chrysotile friction products plant were small. 73 6. Workers in an asbestos textile factory, which were exposed to dust levels higher than current standards permit, were divided into 5 cohorts on the basis of duration and period of work in scheduled areas (Table 1). The ranker of deaths in each group attributed to lung cancer (includes mesothelioma), other cancers, respiratory diseases and other causes are compared in Table 2 with the ranker expected, vhich is calculated from national death rates by 5-year age-groups. TaMi 2 Nmm+rro fmriu oki trttd tmd tx ftrttd , ky tx fm rt rokmrt tmdrtmm Cmmriftm dH Cttrni fiy n w rf4 M 4 ievrwMTrjqprrW it li rW Laag w a r M i (142. 14) tmi 2 O M r AMWi <14*2) f memory m m i <4Slf> (Mm m m AMSMM l ) 4 9 | ] 3 4 5 I 2 ) 4 5 l 2 ) 4 S 1 2 1 4 9 is m i <j> * <2> 2* (2) XU 1 4 II 4 14 7 2) 4 17 21 M 44 II 44 4) J4 117 1 1 SS4 IS O 441 4-14 414 441 I7 7 t T il 144 412 Ml 17 111 19 24 I7V9 2457 71 11 *1 2M 4447 122-** 141 11 14 14 11 14 47 44 44 49 14 14 11 11 22 IS 11 14 44 49 2) IS IS 14 14 <4441 44M 4111 44 44 44 4941 4497 44 4771 <4441 4147 42 4N4 4114 443} 41 4447 4771 4779 <44 4412 4481 41 49 t Lung cancer mortality in the area of the factory was lcwer than the national average among men (SMR = 87) and similar for women (SMR * 104Trin 1959-63. Wea j g first exposed before 1933 (cohorts 1 and 2) suffered a h h SEBT"excess of lung cancer and respiratory disease, particularly those-with 10 or more years' exposure prior to 1933. There is also some excess mortality from lung cancer and mesothelioma (36 observed, 19.3 expected; p 0.001) and respiratory disease (35 observed, 25 expected; p * 0.03) in those who entered after 1933 (cohorts 3, 4 and 5 combined), although the excess is very much less than in the first 2 cohorts. There were 16 deaths attributable to gastrointestinal cancers ccnpared with 15.70 expected. No excess for any of these rubies approached statistical significance in any cohort, and no peritoneal mesothelioma was reported. In order to d&fSl^uish between exposures of 1933 and after 1950, observed and expected deaths for those first exposed between 1933 and 1950, and those first exposed later were determined (Table 3). There is clear evidence of some excess of lung cancer and respiratory deaths among those first exposed between 1933 and 1950, although very much less than in cohorts 1 and 2. There have been few deaths among those first exposed after 1950, but there still appears to be an excess of deaths from lung cancer 15 or more years after first exposure (5 observed, 1.86 expected; p = 0.04)). TaMa) Nm +tr fim ttu W K perW . * r t f This is shown in Table 4, in vhich deaths from lung cancer including pleural mesotheliomas in these groups are distributed according to the time since first exposure; the relative risk increases progressively with time since first exposure in both groups. TaM4 Q4amW km** w t m * m n f k m i t r m m The 6 workers first exposed after 1950 who died of lung cancer were all-smokers; five worked in areas there dust levels were high in one may have had previous exposure from another job. No gliomas have occurred in this group although in view of the 'rency period none would be expected yet. Asbestosis was found-in 3 of the 6 cases. The ranters are too small for the magnitude of the excess of lung cancer in those first employed after 1950 to be estimated with any precision. Dust levels associated with various processes are shown in Table 5. TaMi ) Otm M i - 31 - miHh frm t mm. I til- lt W mi II# 114# tn si# ii# i# ii# IM IM 14# tm imi m m II# If# 1 23# IM 14# II# a# m i tm m* CONCLUSIONS: ^ i n i T- ? Results for Groups 1 ancL2 were similar to that of Doll (1955) . : and Knox, et al. < 1 9 6 8 ) , in that there was a 10-fold increase iii" .risk of lung cancer in Group 1 and a three-fold increase for Groups * 2 There was approximately a 2-fold increase in lung cancer for Group 3 and no increase for cancer of other sites. A 2-fold increase in lung cancer was seen in Group 4 and a 3-fold increase in Group 5. No increase in gastrointestinal cancer was observed for all groups combined. 7. In a study^ of asbestos textile factory workers, excess lung cancer mortality has been reported. Observed and expected deaths due to lung cancer, other cancers, respiratory disease and other causes are shown in Table 1, together with death rates for asbestosis and mesothelioma. In men first exposed before 1951 (cohort 1), there, were 22 deaths due to lung cancer compared with 13.85 expected (P1 0.05) 20 or more years after first exposure; while in later epptdyees (cohort 2) there were 8 compared with 1.62 expected (P CL't j E ? If it were assumed that all men not kncwn to have died or eajpgEed were alive on the follow-up date, 31 December 1978, these d S 5 m &/expected ratios would become 22/14.12 (cohort 1; P 0.05) ancT 8/1.75 (cohort 2; P 0.001), respectively. ^All significant levels are one-sided. Tbli 1 : Mortality experience of 679 male asbestos textile workers ............... -- 1' 1 n 4l 1 I% i or 'i t e r ,, . s-c ................... I i n i > t < < |*l) u f * M H I - n d r- I l- 2025* 30* 35T o tal 10. i -* ' -til 1o ! 1 Mfai) 1760 14% >37 b07 -09 3 1123 r-:r (> ih 'i} un. . d m .o 1' 1 P u r .1 m r s o f n *1 i cm 0 i ---- ! Ml 1 r ih i 3 ] 97 1 10 4 SJ * 8 3 14 2 1 J 20 2 20 IH 6 3 7 ! 1 30 0 3 1 74 0 7 1 31 0 1 3 3. 0 12 4 *5 1 i 1 11' i3 -- '0 1 r 13 14 39 i: 03 1 *. )0 O tr v . c .tm fT> 3s t ' S L O S 1 s t,9 1^ - -- --- 1 * ' ' ,1 1 ih b S lh 21 b 5 4;1 13 S 4 2: 24 4 : 9J : J9 24 '5 07 10 0 l 62 0 y 2 i 2 16 3 00 1 64 s 3 3 37 P J3 = S HP 0 - O th, r r o s `r M r r < lu , ---- ! ,,1 9,, 4 5 J -C 26 24 '3 1 ,. -> ' 6 3 9 2 ' i; ! 1 4.' -- t > -- i oX b '( . *. * . * 4 The excess mortality 20 or more years after first exposure due to normalignant respiratory disease in men first employed before 1951? F (28 observed, 18.63 expected; F 0.01) was largely accounted for bjl deaths specifically attributed to asbestosis. The observed -V incidence of mesothelioma rose steadily from 0.0006 per annum at 20-25 years after first employment to 0.004 per annum beyond 35 years among pre-1951 ecployees. The absence of deaths due to asbestosis or mesothelioma in later ecployees may be due to their relatively short period of follow-up rather than to a substantial reduction in risk. Applying the incidence rates for asbestosis and mesothelioma observed in cohort 1 in successive five-year periods to the corresponding man-years of observation of cohort 2, only 1.9 deaths due to asbestosis and 0.4 due to mesothelioma would so far have been expected, and it has been reported that 10 men in cohort 2 have already been certified as having asbestosis (Berry et al., 1979)iU . There is no evidence of excess mortality due to any other cause of death: 14 deaths (12.60 expected) were attributed to gastrointestinal cancers (ICD nos. 151-154) in the two cohorts, including 6 (5.38 expected) 25 or more years after first exposure; and no peritoneal mesotheliomas have occurred. .data are shown in Table 2 f a r r r Previous and revised estimates of mean dust le v e ls in f i b r e s / H (weighted by the number o f men a t each l e v e l ) in selected years Previous estimates corresoonding to early fib re counts (Peto et a l . . 1977) Revised estimates c o rre s p o n ding to modern counting of sta tic samples' 1936 13.3 1941 14.5 1946 13.2 No measurements p r i o r to 1951 1951 10.8 32.4 1956 5.3 23.9 1961 5.2 12.2 1966 5.4 12.7 1971 3.4 4 .' These e s tim a te s are based on p r e l i m i n a r y data on 126 men f i r s t employed between 1951 and 1955. and should be regarded as p r o v i s i o n a l . - 33 - rs stated that the average dust levels were In the region of 30 f/ml in 1951 and remained high until about 1974. It was further stated that levels prior to 1951 were probably not much higher than this: The emulative exposures of the eight men first exposed in 1951 and who later died of lung cancer 20 or more years after first exposure are ccnpared with those of unaffected controls (Table 3). The analysis is based on emulative exposure up to the end of 1971, and the control group consisted of 42 men b o m between 1901 and 1914 who entered the factory between 1951 and 1955. The eight lung cancer cases all entered the factory before 1956 and died in 1972 or later; all but one, who was b o m in 1925, were within the age range of the controls, and all were cigarette smokers. There is no evidence that their exposures were anomalously heavy, although this may merely reflect the inevitable inaccuracy of individual exposure estimates. Table 3. Estimated exposures o f men f i r s t exposed between 1951 and 1955 . Men d y in g fro m lun g cancer over 20 years a fte r f i r s t exposure O th e r men b orn 1 9 0 1 -1 9 1 4 C u m u la tiv e exp o s u re ( f i b r e s / m l - y e a r s ) to December 1971 ^ 100- 150- 200- 300- 400-*- T o ta l 11 0 41 1 8 2 4 4 14 9 9 42 The observed relative risk for lung cancer 20 or more years after first exposure in post-1950 employees was 4.9 (8 observed, 1.62 expected; 95Z confidence limits, 2.1-9.7). This is significantly higher (P 0.01) than that observed in men entering between 1933 and 1950 (22 observed, 13.85 expected); but, as the majority of pre-1951 enployees in this study were still enployed in 1951, it s&|ikely that this apparently marked increase in risk is largely duMg^chance. The eventual relative risk for lung cancer among men wiljjgestimated emulative exposures of about 200-300 fibres/ml-years (the order of magnitude of the average exposures of men first enployed in 1951 or later (Table 3)) is therefore probably between 2 and 3. This is in reasonably close agreement with an earlier analysis (Peto, 1978)1 , vhich was based on the assumption that the relative risk would be about 2 in men who had suffered cumulative exposures of about 200 fibres/ml-years and indicated that lifelong exjx>sure to 2 fibres/ml might eventually cause lung cancer in about 4Z of men. - 34 - (JUNuHJblON: The risk of lung cancer 20 years after exposure in post-1950 workers was 4.9 (8 cbs. vs. 1.6 exp.), vhich is significantly higher than in workers initially exposed in 1933-1950 (20 obs. vs. 13.8 exp.). A relative risk of 2 to 3 for lung cancer among men with emulative exposures of 200-300 (fibers/air)(yrs.) was estimated. No clear-cut gradient in risk of lung cancer was associated with increased exposure, suggesting that exposure estimates may be imprecise. 85 8. Chrysotile textile workers (South Carolina) were studied to investigate the risk of exposure to this asbestos-type mineral. The mortality and exposure data were analyzed in two ways. The first followed the orthodox man-years life table approach of HilliU and others, whereby standardized mortality ratios (SMRs) are derived from comparison of observed Timbers of deaths with Timbers expected, from mortality rates in a standard population. In this case a g e - f - sex-, race (colour)-, and year-specific rates for South Carolina. were used. The second approach, essentially internal and ;\ case-control,.in type, followed the Mantel-Haenszel (or log rank) r procedure,103 yielding relative risks from entirely intracohort comparisons. In calculating SMRs a "lag time" of 10 years before death (or end of 1977) was inposed in determining exposure, and only deaths 20 years or more from first employment were included. In the Mantel-Haenszel analysis the same exclusions were applied, controls being selected from all other members of the cohort of the same sex and colour (black or white) who met the following criteria: (1) alive at death of case, (2) same year of birth, if in or after 1900, or within five years if before 1900, (3) within five years of date of first employment, before or after 1938. The statistical significance of differences between observed and expected Timbers in this analysis and for departures from linearity were calculated as Xz values by the method of Peto and Pike. Lines were fitted to exposure-response results by Liddell using the method of Hanley and Liddell (to be published). Eiftjites of dust concentration in millions of particles per cubic fa j S & Pppcf) and duration of exposure in years were established for LUiUTflurker. Tables 2 and 3 give exposure estimates. Table 2 Estimated average prevailing dust concentrations <mpef) in mam departments. 1930-70 Preparation Csdmg Spumine Winding Twntmg Weaving Finishing and inspection 19)0 1940 31 35 2-8 61 21 3-5 ' ' ' ' ' ' 14 1950 20 15 20 1-7 40 1-5 * 1 ' ' * * * mo 10 12 H O-M 'Apparent improvement usually associateli with technical change 1970 ' 0-8 oo Id 11 12 05 35 Table 3 . A g t Q jtart, duration o f employment, and dust exposure (men only) Length o f gross service fvrarr) No Average age at start (years) Gross service (yean) Net service (years) Average dust concentration (mpef) </ 950 25-6 0-39 0-37 2 11 1. <5 574 25-9 243 1 81 1 86 S. <20 421 26-5 ia s o 7-55 1*67 * Excluding five whose employment histones e ie incomplete 20 465 25-2 3186 2951 l 23 Total 2410* 25-77 7i 7 59 180 Mortality of the males of known age shown by age and cause is presented in Table 1. I able I Male dealhi by age and certified cause Cant* o f death (C D cod*) ' A d causes Malignant neoplasms: Lu n g (162-164) sophagus and stomach (15(1-151) Colon and rectum (152-154) Other abdominal.(155-IS9) Larynx (161) O th e r(140-48, 160. 165-205) H e a r disease (400-443) Respiratory tuberculous ( 001-0081 Other respiratory (470-522; 525-527) Pneumoconiosis (523-4) Cerebrovascular (330-334) Accidents (800-999) Other known causes Causes not known Age ai death 45-64 178 50: 1 47 0 13 13 0 to 0ft > 38 189 K4 10 27 2 12 s 30 67 4 : 24 89 IS I I ft5 177 18 2 4 T i 12 70 2 II 7 21 3 19 5 / otui 8<7 ft* 15 12 3 41 .:*7 14 4K 21 5ft 112 132 31 Table 4 sunaarizes the mortality experience based on the modified life table analysis. Overall, the SMR (all causes) is 271 above expectation and perhaps twice that in men employed 5 years or more. fri* Tabic 4 M a le deaths 2 0 years a fte r firs t e m p lo ym e n t, b y cause, in re la tio n to d u ra tio n o f service ( ause o f itealh ' Length o f gross sen ice (y< a r il <-! / <5 5. V,?0 20 t om plcir cohort 0 \M H <> SMH 0 SMR 0 SUN V SUN A ll cauTs #.' M a lig nan um op ths im . Respiratory A bdo m inal Other Mean dtwase Respiratory tuberculosis Other respiratory Pneumoconiosis Cerebrovascular Accidents Other known Not known 159 1074 K 78 2 ft 107 9 i : 130 2 6V 108-9 \ 231 8 .1 10) -- . <) 83 0 IK 1212 30 116 9 3 113 122 7 10 163 9 5 14ft-4 7 124-9 34 87 6 1 347 8 y H5-6 (0) - 14 193 0 8 89-7 28 175-5 3 120 1*ft l 15 m u i 7 241V \ V IMS v 45 141 7 1 307 9 2 78 3 (f0t) -- 107 S 5 75-K 2 ; 177 7 7 178 136-7 26 317 3 K 151 4 7 , 46 2 70 120-8 1 13| < 27 557 4 (20) -- 4 76 2 85 0 21 92 3 0 *70 127 4 5M | MM * 26 151 7 t * 127-5 218 113-7 4 222 8 7* 207-3 (20) -- 38 107 2 40 M7 0 102 132 4 13 ' As m table I except that K 'D codes 160-164 arc here grouped under " respiratory ' malignant neoplasms and the "o th e r respirators ' category includes only bronchitis, pneumonia, and pneumoconiosis (1CD 490-502. 523-4) - 36 - M m e r e is (a) a 11 excess of deaths even in men enployed less than one year, unexplained by any asbestos related cause of death, and (b) a 32Z overall excess in deaths of "other known causes," the SMRs are probably somewhat inflated, mortality in South Carolina having presumably provided an isperfect basis for ccoparison. Much of the excess, however, is clearly attributable to respiratory cancer, pneumoconiosis, and gastrointestinal cancers. Table 5 shows the cohort mortality, related to dust exposure. There is a steady gradient from 115.5 to 264.4 for mortality (all causes) and a much steeper slope for respiratory cancer and also for selected other respiratory diseases (which include pneumoconiosis). No clear trend is apparent in the other diagnostic categories. Tabic 5 Male deaths 20 years after first employment, by cause, in relation to dust exposure fmpcf. vI accumulated to 10 years before death ( ause o f death * A ll causa ' Malignant neoplasms- Respiratory A bdo m inal O th e r Heart disease Respiratory tuberculosis Other respiratory: Pneumoconiosis Cerebrovascular Accidents Other known ' Not known t)u%t exposure (m pcf v) e 10 10 < 20 0 SMR 0 5,MR 376 115-5 55 125-5 31 143-1 14 114-9 28 140-0 143 103 5 3 264 4 8 65 9 (0) -- 29 115 3 31 99-2 79 140 4 10 5 182-7 4 231-6 3 109 2 28 143 6 0-- 2 119 5 (0) -- 2 500 y 54-1 9 116 9 0 20 <40 0 S.MR 63 156-9 8 304-2 4 247-0 i 44 9 29 166-6 0-- 6 421-7 (3) -- 4 124-4 5 152 9 4 630 40 <HO 0 5MR 43 1708 7 419-5 4 383-6 0-- 10 88 6 1 634 4 13 1407-8 (*) -- 2 93 4 i 49-4 5 111 5 0 HO ____ 1 + ___ 0 S.MR -_ 33 264-4 f t 8 103 r-9 0-- 3 383 5 8 149 9 0-- 6 1296-0 (8) -- 1 99-8 1 120-0 5 J63-3 1 Table 6 shows the results of the posteriori Mantel-Haenszel analysis for certain diagnostic groups only. The number of deaths included in this analysis falls short of those used in tables 4 and 5-- for example, 490 compared with 570 from all causes; in the remainder no matching control could be found. There is clear confirmation of a statistically significant linear trend in lung cancer, pneumoconiosis, and deaths (all causes) but no convincing as8oy-iati-on for the abdominal cancers. Oaip-- Be death ascribed to mesothelioma was found-- a man b o m in 19SPflho died in 1967. He was first employed at the plant in 1925, worked as a mule spinner from 1933 to 1955 and as an oven helper until he left in 1965. The tumour was stated to be peritoneal but there was no necropsy. '| able -^WT\/V iposurv tn mule deaths ffitrtt seta ted a m m ' a n d eo ntnd s 1M a n te l-H tw n s z e l itn a lv u s 't l.ineunis l) u \ t esftosure im p* ( vi u a u m u la te d u p u * 10 w'um before death ,f tuv<' it jo /V 20- <v 40-7W *H0 ( Hi squat? Different* I k .ith* 1 xpcitcd Relative risk (K l)524) tl 0 1 - - 4 ID \K 41 4\* r th I urn* (.u n iiT ( l ( I ) WO 4) Ikjlh\ I xp itte d K c la liv c r>k *-> 42 4 1 X *4 0 '>H K S\ 2 ll5 7 4 * 4 : h I s (HI 24 OH 'NtxJ'iminut cancer ( K D I Ml- 4) I k 'jth s \ xpeited Relative risk i i ' l 4 :^ 1 b4 :. 1 JO 4 :i 7 6 0 0 4 Oh A ll cause* Deaths I xnectcd Relative risk i J4K t) 1 45 4h : 111 S4 4 S-5 14 47 : 4 1 51 24 15 0 :it 1442 l.ineant\ 10*< :o 4 > 2*4 HIM 4% This study shows that the relationship of lung cancer mortality tef " accumulated dust exposure is virtually linear. v* The pattern of mortality in this cohort of chrysotile textile workers is similar to that reported for Quebec chrysotile miners and millers, particularly those employed at Thetford Hines. Overall, die SMBs for the factory workers are somewhat higher than for the miners (perhaps due in part to questions of cccparability with the reference populations). There is the same scarcity of deaths attributed to mesothelioma and, in both cohorts, the relationship of lung cancer mortality to accunilated dust exposure is virtually linear. It is only when actual levels of exposure are examined that the astonishing difference between the experience of these two chrysotile-exposed cohorts is seen. This is illustrated in Fig. 1 there, to facilitate comparison, the SMBs in both cohorts are based on exposure accumulated to age 45. In fact, the slope of the exposure-response line for lung cancer in the textile workers is 50 timfemore steep than that observed in miners and millers. This cfl|BB almost exactly the findings of Dement et al. in their s n g | r cohort from the same plant; the agreement is very close (see The data shown in this graph are based on mortality for vhite men only, 15 years or more from first enployment and therefore differ somewhat from the figures in Table 5. - 38 - COO- CE s Vi4M $MR*CB75!*pc* ; RR * i0062"cy MO- o Probucton SMR, % 71*06 'c' y RR * i 0 0 0 * m ty ! Production fo- 0 CO 60 Oufti Mposuft (mocf y >occ^nutoM R og <$ Fig I Respiratory cancer SMRs in relation to Just exposure accumulated to age 45 in chrysotHe production and textile manufacture Fig 2 Respiratory cancer SM Rs in white men 15 years or more from fr it employment in relation to accumulated dust exposure. Comparison o f this study and that o f Dement et al CONCLUSION: Various reasons were discussed to determine whether the differences observed were due to errors in exposure estimates, etc. Assuming ^ errors, the difference remains at least 10 fold. 9. Another cohort of chrysotile asbestos factory (textile) workers in a Pennsylvania plant was studied, which included those employed during 1938-1959 for at least one month. Crocidolite and amosite were used at this plant also. Exposure data are shewn in Tables 2 and 3. Table 2 Estimated average prevailing dust concentrations IMPCF) in mam departments IVJP-70 le x tile Preparation Larding Spinning 1 wisltng W in d in g Cloth weaving 1 ape weaving Felted tape Rope 1930 IS O 14 0 IT ') * 9\ M) 72 30 79 71 :o 4O * 3-4 3 1 Fnetton: Woven M a n ' F-itm tga brakes S3E" Brake flm thm g Sanding and finishing Finishing and shipping 2 < M) 1 f M> 20 20 20 05 Packings, gaskets 13 Maintenance, etc 05 1940 35 32 2s 4-u 15 1O 2s 15 IS h-U 15 1S 15 13 05 1950 i9 *o 20 : o t8 18 -0 5 * * 0-9 14 * 0-5 i: io 10 4-0 1* ' I0 1 (1 ib l Oh 02 * 1h :i 0-8 i: | 9 T0 1S 15 O7 0-8 3-h 1? o 07 o: 0- 0-2 ` Asterisks shown against te ittlc processes indicate approximate date o f improvements usually associated with technical change Figures fsir frictio n and other departments are estimates for each decade Table 3 Age at start, duration o f employment, and dust exposure (male oni\ ) Length o f gross service <1 /. <5 No Average age at start (years) Gross service (yean) Net service (yean) Average dust concentration (mpef) 1248 28-80 0-40 038 2 60 90h 2*30 2 39 1-87 ' 2-40 Excluding two whoac employment histones were incomplete 5, < 2 0 855 3077 I I 01 8-06 2-73 20 1013 27-22 30-63 27-51 l 58 T o ta l 4022* 28-92 1071 9-18 2-32 - 39 - ty was analyzed as in #8 above, using Pennsylvania death rates for reference. Mortality data by age and certified cause are presented in Table 1. Tabic I Male deaths by age anil certified cause Casts* o f death (IC O code) A tc <v death Total <45 45-04 AD causes t VI 667 534 1312 Malignant ncuplasms. L u n g *(162-164) Oesophagus and stomach (150-151 > Colon and rectum { 152-154) Other abdominal* <15 5--15V) Larynx (161) O ther* (140-14. 160. 165-203) Heart disease (400-443) Respiratory tuberculosis (0 0 1 -0 0 8 )' Other respiratory (470-522. 525-527) Pneumoconiosis (523-524) Cerebrovascular (310-334) Accidents (800-119) O ther known causes* Ceuse not known 3 lt 3 0 16 43 5 6 2 3 74 23 10 44 7 21 16 0 57 285 4 17 48 33 44 73 13 1ft 7 0 6 14 12 35 5 24 U0 40 113 24? 573 11 25 48 24 74 44 80 20 138 80 , 176 13 _______ In 13 cases in these categories, mesothelioma was given as the cause o f death, in one death ascribed to asbestos, mesothelioma ifas also mentioned. ' : i-- -t The SMR for all causes of death was 109.0. Those employed for less than 1 year had a SMR of 87.2, and those who had worked 20 or more years, 127.2. (Table 4) T a b ic 4 Hale deaths JO vears after first employment, by cause, in relation to length o f service ( amc t>f death * Length o f fro s t sen e vears <t /. <5 5. - 30 r-JO Complete cohort 0 VMM 0 SMR 0 SMR 0 SMR 0 SMR A ll causes Malignant neoplasms Respiraiory Abdominal Other Heart disease Respiratory tuberculosis ( >ihcr respiratory Pneumoconiosis ( crebrovasculat Accidents Other kamaa. N .u lg g w 171 K 7 : u 64*6 H 721 14 132 4 77 v : 7 04 54 2 (21 -- 7 54 4 13 117 3 30 75-2 4 154 106 2 3 32-1 11 133-7 16 152-0 77 1 2 ' 1 i 133 4 *i .38 1 (M -- 10 106 5 15 161 1 15 52 4 4 187 104*5 14 11 15 78 0 11 (10) 10 8 37 3 128 8 103 0 118 5 100 2 -- 161 0 __ 7^7 87 2 103-0 363 127-2 27 24 32 153 5 50 (46) 20 4 62 4 158 1 131 3 155-3 115-7 67 3 442 4 __ 87-6 601 107 1 84* 101-0 53 54 82 385 3 67 (511 47 4* 144 15 105-0 112 7 141 1 108 5 31 7 215 0 81-2 103-5 87-2 " A S j l B S E j except that IC O codes I M M M are here grouped under `'respiratory" malignnt neoplasms and the "other respiratory' c a te jp ^ m d u < k s only bronchitis, pneumonia, and pneumoconiosis (IC D 440-502. $23--4) ` Malignant neoplasms, heart disease, and "other respiratory" disease were mainly responsible for the higher SMR in these long term workers. The other respiratory category included bronchitis and pneumonia (ICD 470-502) and pneimoconiosis (ICD 523-4) and was chosen for study because expected figures for pneimoccniosis alone were not available. Table 5 shows SMRs by cause and by accumulated dust exposure. The SMR for all causes rose steadily from 93.1 for - 40 - men lath an exposure at under 10 npcf.y to 215.2 in the highest category ( 80 npcf.y). Respiratory, abdominal, and other malignant diseases and the non-malignant other respiratory group all contributed to this rising trend. On 14 death certificates a diagnosis of mesothelioma was specified: 10 were pleural tumours and four peritoneal. These deaths occurred in the period 1960-75. One (in 1960) was 16 years after first enployment; the remaining 13 occurred 25-53 years after first employment. Two of the deaths from mesothelioma had been given the ICD code 199 (malignant neoplasms of other and unspecified sites); another 30 deaths 15 or more years after first enployment were given the code 199. Seventeen of these 30 deaths occurred before 1965, the year after which most of the deaths from mesothelioma occurred. The diagnosis given in many of these cases was consistent with an unrecognized peritoneal mesothelioma. Table 5 Male deaths 20 years after frst employment, bv cause, in relation to dust exposure (mpcf.v) accumulatedjo^.0 years before death Cause o f death* (Set table 4t bust exposure im p if yt <10 !0 < 20 20 < 40 40 < ftO ; Lf .| SO 0 SttR 0 SStR 0 SMR 0 SMR 0 SMR A ll causes Malignant neoplasms Respiratory A b do m inal Other Heart disease Respiratory tuberculosis Other rcsptratr> Pneumoconiosis Cerebrovascular Accidents Other known Not known . 47(1 1.7 1 21 66-9 26 *U 2 47 130-4 221 102-7 1 34 3 * 43 6 (4) -- 27 78-3 n 120 1 74 73 3 12 86 82 1 5 83-6 8 130-5 5 68 5 41 89-2 0-- 5 12: o in -- i 13 3 3 5n 2 17 800 l 130 125-6 10 5 n 60 -- 10 (9) 10 I 23 0 156 0 79 7 I48 6 130-6 -- 263-0 -- 133-5 18 6 109-7 105 174-9 6 160-0 8 218-8 7 164-7 34 130-5 1 169-7 14 623 3 () -- 8 187-2 6 193 9 21 172-2 0 104 215 2 11 416-1 7 237-2 12 372-8 29 108-5 i 163 6 30 1689 2 (36) -- 1 29-3 2 910 9 97-8 2 The Mantel-Haenszel (log rank) analysis (table 6) bore out the exposure-response relationships observed in Table 5. There is a canafjl shortfa11 (5Z overall) between the nunbers of cases used in ^fttnralysis and in the man-years analyses presented in Tables 4 anJjflKr The deficiency is explained by failure to find matching caHBoIs for every selected case. - 41 - Table 6 ij.n n exposure in male deaths from selected causes and controls IMantel-Haenszel analysis') Pneumoconiosis (IC D 523) Death Expected Relative risk U a | cancer (IC D 162-4) Deaths E je cte d Relative nsk AMasninal cancer (IC D 130-9): Deaths Expected Relative nsk A ll causes Deaths Expected Relative nsk Oust exposure tmpcf.y) accumulated up to 10 years before death o f case < 10 10 < 20 20 < 40 40 < 80 80 CMi square Difference 3 14 6 1 20 24-4 I 26 2*8 1 451 476-6 1 A 81 4 04 4 5-2 0-83 8 68 115 81 104 5 082 10 109 13-72 10 80 1-54 5 7-0 066 121 118-6 1-20 11 81 14-93 f> 56 2-90 8 3-3 2-45 100 80-4 1-6 28 14 3 37 90 II 7-7 6-82 7 6-1 285 99 72-0 2-12 39-56 5-77 3-22 34-66 Linaamy 39-17 498 1-09 26-12 The present cohort In the Pennsylvania plant was constituted in .* exactly the same way as that in the,.S o u t h Carolina chrysotile ] textile plant described elsewhere.00 - The Pennsylvania cohort was exposed to a scmevhat higher average dust concentration: 2.32 mpef compared with 1.80 mpef in South Carolina. The mortality pattern in Pennsylvania resenbled that in South Carolina in showing a rising SMR with increasing dust exposure for all causes of death, for respiratory cancer, and for pneumoconiosis. For respiratory cancer, however, the SMR for the lowest exposure group (less than 10 npcf.y) was 115.5 in South Carolina but only 69.9 in Pennsylvania. By contrast with South Carolina, where the SMRs tended to be above 100 for causes unrelated to asbestos, and for all causes in very short-term enployees, the opposite was true in Pennsylvania. It seems likely that in both cohorts lack of comparability with the relevant state populations may be the explanation. Having regard for this possibility, the use of relative risks is perhaps more appropriate than SMRs for cccparing the respiratory cancer mortality of the two cohorts. T^ f t f P shows that the relative risks of death from all causes, ri||Eetory cancer, and pneumoconiosis in the two plants were efca@rdinarily similar. In both cohorts the relationships of respiratory cancer to exposure were essentially linear (figure) with slopes that were nearly identical (South Carolina, RR 1 + 0.059 mpcf.y; Pennsylvania, RR = 1 + 0.051 npcf.y). - 42 - Table in've risks based on SMRs by cumulative exposure m two plants m p e fy <10 10 < 20 20 < 40 40 < SO A ll carnet: Sondi Carolina plani Ptnmylvania plani K n o w alary cancer Snudi Carolina plani ftuaytvania plant B raudutt*. pneumonia, and mmoCOIMOIIt. south C iro k n i plant Pennsylvania plant 10 10 10 1132) 10 11-26) 10 10 109 0 88 1-28 II-6S) t-25 US) 1-81 2 79 1 36 1-35 2-13 12*0) 2 33 12-94) 6-40 6-03 1-48 1-88 2-93 (3 *6 ) 2 39 (3 *3 ) 21-36 14-29 Figure* in tiahct ere relative m k i calculated from SMRs at zero exposure derived from fitted line. Mt/> ___ 2 29 2 31 . 7-21 (949) 622 (7 *7 ) 19-67 38-74 , Similar proportions of all deaths in the two cohorts were from malignant disease (17% in South Carolina and 181 in Pennsylvania), but the types of malignancy differed. In South Carolina respiratory cancer accounted for 47%, abdominal 25%, and other types 28% whereas in the Pennsylvania plant the corresponding proportions were reversed, 27%, 29%, and 44%. Moreover, in South Carolina no : systemic relationship with exposure was seen for abdominal or otherf- types of malignant disease whereas in Pennsylvania there was evidence of such a relationship. ' Retati i e risk o f respirators ea rner a n il accum ulateli dust espi sure in isso m u in lv te s tili p lan ts I I n n s fitte d bs I l> K l.td d e ll usim i the methods o f Hantes and la ttite li ) - 43 - risk of mesothelioma in the Pennsylvania plant (14 cases in 1392 male deaths (1Z) compared with one case in 867 (0.12) in South Carolina) raises the question of Aether the abdominal and more particularly other types of cancer included undiagnosed cases of mesothelioma. There is some support for this idea in the substantial number coded to ICD 199 (malignant disease of other and unspecified sites) and the fact that 17 of these deaths occurred before 1964 when malignant mesothelioma started to become more generally recognized. Once again there is evidence in this study of the special risk of mesothelioma associated with exposure to even quite small proportions of anphibole, in this case predominantly amosite. CONCLUSION The very similar exposure-response relationships for respiratory cancer and asbestosis observed in this and the South Carolina plant support the previous conclusion that the risks of these diseases iff|- chrysotile production (mining and milling) and in textile 1 i manufacture are quite different. In the third plant studied, a tf- fricticn materials plant in Connecticut, there vos little or no excess risk of respiratory cancer or asbestosis. This was also true in a friction materials plant in the United Kingdom. Possible reasons for the striking epidemiological differences-- fibre size distributions in particular-- have been discussed elsewhere. ' 10 ' 10. Mortality was studied^ among asbestos-cement workers who had been hired prior to 1960 and who had been enployed for a nriniiiun of 9 years. Table 1 gives the mortality rates for each of the three exposure groups of production workers, for the interval 20-33 years from first exposure. Table 1 AlortaiitY rata in the inters al 20-Jd years from first exposure and estimated dust exposure o f three groups dumber o f deaths in parentheses) . L ip o s u re \*roup (.roup A (roup (. O nturiv m enT Utites (fH'f HMM) man-veurst* M tM 'the lio m j 1 une career <. tro in tc s tm .il c jr u c r A l' ru ltg n jiK V s M . sothclioftia crude rates 1 M in u te d exposure range ( 1-v m il l M inuted mean exposure (l-> m l) Stand.uJ deviation 1 `M U I'M ') 17 l ( 7 | :. '( !i tt-W 44 114 4V Cl 2b 1 (?) 2 5 (1) IS d ( M ) 4b Cl 15 8 i l y> ( m) 11 ' (# M l (.') .'1 S ( If) II (M i:;-4 :o ISO S7 ' 1b (lb 47 'S tandardised 1" jg e d is trib u tio n ol group C *H .istd on O n ta rio vital s ta tu te s t^7l>-4 - 44 - T h e n a n exposure levels (in f-y/ml) were: Group A-44; Group B-92; and Group C-180. The mortality observed among the employees was cccpared with the mortality predicted from Ontario population rates (Table 2). To increase the man-years of observation in each cell, the second group, listed as P + M in the table ccnfcines the experience of the production and maintenance employees, all of whom were exposed to asbestos. Table 2 Mortality among the factory workers compared wtth the population o f Ontario Cause Croup Years sincefirst exposure 15-19 20-24 25-3) Total: 20-33 Obs Exp OlE Obs Exp CUE Obs Exp OiE Obs Exp Oi A ll causes A ll malignancies ICO. 140-209 Lung cancer IC D 162 Mesothelioma IC D 163,158,228 Gastrointestinal cancer ICO. ISO-154 Non-malignant respiratory disease IC D 460-519 Ischaemic heart disease IC D 410-414 P P+ M C P P+M C P P M C P P P M C P P M C P P+ M C 8 8 9 1 16 118 14 34 11 6 2 9 SO 234 2 1 I I 11 9 1 22 15 5 1 4 39 15 1 2 6 61 30n 7 s o 14 7 5-9 12 7 7 4 \ 14 13 3 . * 2 19 1 9 2-8 3 2 20 2 9 6 9 29 5 7 2 2 5 1 11 3 7 3 0 23 3-7 6 2 34 7 4 t 3 II 27 3 1-4 2 1 1 18 1 4 32- i 1 06 1 1 0-8 1 0 03 0 6 10 60 II 1 0 11 0 17 2 0 -8*5 7 1 2 5 8 12 1 3 9 2 19 2 5 7 t> 0 05 0 1 06 I l 1 1 l 1 -- 2 -- 4 - - h -- 0 OS 0 0 07 0 1 03 1 1 07 1 1 0-9 1 1 03 1 0-7 2 9 3 3 09 3 3 4 14 18 2* ^1 0 0 4 0 i 0-7 1 1 04 1 1 06 1 0 0-3 0 1 0-7 1 3 08 38 4 1 5 2-7 3 0-9 3 3 4 10 40 7 19 3 7 0 0-4 0 1 05 1 1 09 1 4 3-9 1 2 4 7 04 5 46 i 7 9 3 0-8 7 4 9 1 4 3 6-2 0 5 6 6-0 i 9 12 2 0 7 3 21 1 1 2-4 0-4 2 2 9 i 3 5 3 06 P = Production w orker* M * M.unicnjncc- workers C = l 'nespoced workers There were 10 deaths from malignant mesothelioma (5 pleural, 5 peritoneal) aneng the 58 deaths occurring in the production w c a B i -- a proportional mortality of 17Z (table 3). In addition, O M S r t h e maintenance workers died of a pleural mesothelioma. All o^Sse men had been exposed to both chrysotile and crocidolite in the pipe plant. The mean age at death of these 10 men was 51 years and none was over 60 (table 4). Tabic 3 h iom tity rales from mesothelioma and lung cancer among the production workers (based on best evidence) Time sincefirs t exposure 1y ru rjf hge 35-44 45-54 55-64 65-75 75 o r m orr Mesothelioma 15--33 20-33 Lung cancer lf-3 3 20-33 No o f cases Man-years Rate (per 1000 man-years) No o f cases Man-years Rate (per 1(100 man-years) No o f cases Man-years Rate (per 1000 man-years) No o f cases Man-years Rate (per 1000 man-years) O ntano rates (based on vital statistics 1970-4) (per 1000 man-years) 2 413 48 1 124 80 0 413 0 0 124 0 01 5 865 58 5 493 10-1 0 865 0 0 493 0 0-5 3 694 43 3 485 62 13 694 18-7 11 485 22-7 1-7 0 244 0 0 213 0 6 244 246 6 213 282 35 0 21 5 0 0 21 5 0 1 21 5 46 5 l 21 5 46 5 3-8 The mortality rates for mesothelioma among the production workers are displayed in table 3 as a function of age. Table 5 gives the crude incidence rates for mesothelioma among all the * asbestos-exposed employees, as related to the time interval since t first exposure. Peto et al. have suggested that the incidence ofj mesothelioma follows a power function relationship with time. Ther' data are consistent with this suggestion, with an exponent value of between three and four. There were 20 deaths from lung cancer among the 58 deaths in the production workers-- a proportional mortality of 34Z. Pathological Information about 17 of these 20 cases indicates four were adenocarcinomas, eight were squamous, four were small cell undifferentiated, and one was a large cell undifferentiated tuner. As a group, these men were first exposed to asbestos in this plant at an older age, and they died later in life than the men dying of mesothelioma (table 4). Table 4 Some characteristics o f the cases o f mesothelioma and lung cancer IClassified according to best evidence) Mean Range Sian.larii de\ muon Mesothelioma tA--- 1&) Age >1 first m a M f Age at death - ^ ^ ---- Latency (yeamiK' Lung cancers (n " ' if) Age at lirst exposure Age at death Latency ( years i* 51 25 -W 64 25 19-32 42-57 17-30 31-52 55-78 17-29 *1 utcncy is the interval from first exposure to death 4? 54 >8 64 5 }6 CONCLUSION Table 5 Incidence rates of mesothelioma among the production and maintenance workers exposed to asbestos Tune since first exposure (years) 15-19 20-24 25-29 30-34 No o f cases Man-years o f nsk Incidence rate (per 1000 man-years) 1 1182 0-8 4 1061 3-7 5 555 9-0 1 104 96 Workers at this asbestos-cement factory exposed to historical dust conditions have experienced increased mortality rates from respiratory and malignant diseases. The lung cancer mortality rates - 46 - did not increase steadily with increasing estimates of emulative exposure; in fact, the men in Group C experienced the lowest cancer rates of all. This may have been due to the small nmfcers involved, to differences in smoking habits, etc. Rates of death from mesothelioma were related to the magnitude of the emulative exposure. The emulative exposure among production workers was estimated (to within a factor or 3 to 5) to have been about 100 f-y/ml, and the SMR for the period after 20 years was 850. The authors concluded that the lung cancer rates, at a emulative exposure of 100-f-y/ml, may be raised several-fold. 11. Table 1 presents observed deaths and standardized mortality ratios (SMRs) for selected causes of death for the cohort of production and maintenance-service workers (1075 men) for the intervals 1941-69 and 1970-3, which correspond to the original follow-up and the update periods, and for the total follow-up period 1941-73. For th|[ period 1941-73, this cohort had an overall mortality rate 20.4Z ?*- higher than that of all United States v M t e males. This excess is; 1 due almost entirely to cancer and diseases of the respiratory " system. For cancer, the greatest excess is in cancer of the respiratory system but with seme excess also in cancer of the digestive system and all other cancers. For respiratory disease, the excess is due entirely to pneumoconiosis and pulmonary fibrosis, 19 cases of which were due to asbestosis (ISC 523.2). The pattern of deaths was similar during both of the follow-up periods, although overall mortality and cancer rates were somewhat higher during 1970-3. The increase in overall mortality for 1970-3 was primarily due to a large increase in death rates for stroke. Whether this increase is in any way related to occupational exposures is unknown. T aIF i O aM KS M ) 1)1 M ils A M ) S M R s I OH S lIM T F O C A IS IS O ) O tATH BV P m iO D Ot FollC'VkIP , 1075 M i n R p t i h i m . ih o m a I K i t i i ) S t a t f s A ssfstos C o m p a s s 1941 67 a n d I'O IIO U FO TIIHOU.il 197) Cause of Death All causes Cancer (140 205) Digestive) D O -1$9) Respiratory (162 16)) All other cancers Stroke 0 ) 0 ))4 ) Heart disease (400 4 4 )) Respiratory disease (470- 527) Pneumoconiosis and pulmonary fibrosis (52) 525) Asbcslosis (52) 2) All other causes Death certificates not located 1941 7) 1941--69 1970-) Observed Observed Observed Deaths SMR Deaths SMR Deaths SMR 781 120 4 616 115 8 165 141 6 17) 1590 1)8 154.5 )5 179 5 55 1)7 8 46 1)6.1 9 147 5 6) 270 4 49 270 7 14 269 2 55 120 6 4 ) 115 0 12 146.) 74 964 48 76.7 26 I I ) 1 )2 I 106 5 269 108.4 52 97 7 68 17)0 54 178.2 14 155 6 )l 25 6 -- 19 - 16 3-- I I ) 92 5 96 946 17 82.5 )2 - II 21 - 47 - Esflmtes of exposure were based on midget impinger counts expressed in million particles per cubic foot (nppcf). Five classifications were used. These were: no exposure (0), less than 5 mppcf (2.5), 5-10 tqppcf (7.5), 10-30 mppcf (20.0), 30-50 nppcf (40.0), 50 or more nppcf (62.5). To compute emulative dust exposure for each man, the dust level at each job and time period was multiplied by years at that job and sunned across all jobs during his working lifetime. This total emulative exposure can be thought of as nppcf-years. Take 2 Ooseaveo Deaths ano SMRs pod Respieatoov Cancbe ev Total Dust Exposure and Febioo or Follow-up. 1075 M en Retisino 1941 -7 and Followed through I47J Total D ial Mean Exposure Number Exposure (mppcf-ycors) of Men (mppef-yeara) Under 125 125-249 250--499 500-749 750* 4J7 224 265 105 44 62 1(2 352 606 976 1941 -73 Deaths SMR 19 197.9 9 110.0 19 3276 9 430.0 7 777 1941-69 Deaths SMR 15 200.0 200.0 13 309.5 1 470 6 5 7143 I970-7J Deaths SMR 4 190.5 1 100.0 6 3750 1 333 3 2 1000.0 Th Table 2 shews the relationship between total dose expressed as mppcf-years and mortality from respiratory cancer. For each dose interval, actual means are shewn. These data, plotted on arithemetic paper, are also shewn in Figure 1.* A'lRe"relationship shewn is not sinply the result of time and the consequent fulfilling of latent period requirements. As noted.in a previous paper, the dose rate makes an important contribution. u There were 5 mesothelioma deaths observed in this cohort, of vhich 3 occurred during 1970-1973. - 48 - ih 100 2 0 0 300 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0 9 0 0 1000 CUMULATIVE OUST EXPOSURE (m ppct - yr*> E'k.l r i I Total asbestos dust exputure and respirator) cancer mortality. In an earlier report, it was speculated that the mathematical form of the dose-response relationship was the emulative normal. The theoretical basis for this conjecturggwas the response curve in bioassay experiments. Schneiderman 0 has fitted a different curve to these data, while Petoluv believes it is best described by a simple linear relationship. It does appear that emitting the Canadian data and adding 4 more years of follow-up change the relationship and make a linear relationship more likely. By use of the five data points from Table 1, this relationship can be .expressed by the equation: predicted SMR - 100.0 + 0.658 (ajSSZative exposure). The~eorrelation between cumulative exposure and respiratory cancer SMR is 0.982. This prediction line is superimposed in Figure 1. CONCLUSION Respiratory cancer risk increased as the quantitative exposure level increased. The SMR for the lowest level was 2.0; for the highest level, 7.8. - 49 - Theeffects of asbestos exposure with respect to lung cancer risk continued well past the termination of exposure. The study population of retirees are "survivors," and mortality experience may not reflect actual risks associated with asbestos exposure. Most likely, risks were underestimated. 12. Mortality of asbestos factory workers exposed to crocidolite, chrysotile, and/or amosite in the production of textiles or insulation materials has been reported. The levels of exposure were reported as follows: (1) before 1945 the dust levels in certain jobs were said to average 20 fibers/ml or higher; (2) jobs classified as "low-moderate" were probably 5-10 f/inl; (3) in non-production jobs and some departments the levels were below 5 f/ml; (4) after 1955, many areas were probably above 2 f/ml. laggers were considered separately. The male cohort consisted of 4600 men and 922 women. There have been 775 deaths among the male workers. An analysis of the 545 deaths that occurred among workers, excluding laggers, who had been followed for 10 years or longer is presented in Table 1. Asbestos-related disease is rarely if ever manifest in those dying within 10 years of first exposure. In the Tables, the deaths from msothlial tutors are given in parentheses but are included in the total runber of observed deaths in any particular diagnostic category. T abif t MC*TAUTY Exkkifnces or Male Factory Workers Came of Death A l caae Caacen of laag aad picora (IC D 162.163) GoMroMMMMol caacer (IC D 150-1$) Other caacsn ' Chrowc to p n w y dtaaaxe *p <0001 p <0.0$ I p <0.01 Eipowre Category Low to Moderate <2 Yean (<4) Obeerved Expected >2 Yean (554) Observed Expeeled M<4) 17(3) 10 6 19 1110 11.01 90 7. 17 5 *9 (7) I6 t(l) 9 (4) < (1) 16 95 3 90 73 5. 14 7 Severe <2 Yean (937) >2 Year (512) Obacnwd Expected Obeerred E I6 2 *(I6 ) 3 I*(6) 201(6) I6 |(3 ) 20 (1) 122.2 12. 95 79 17 6 176*09) S6*(7) I9K ) I6 f4 ) 2*1 102-5 I0l4 5.2 6.3 159 - 50 - There were 46 deaths from msothlial tuners, 19 pleural and 27 peritoneal. All have been validated by histologic examination. Nearly all of the pleural tunors were identified among the intrathoracic timers (carcinoma of the lung and pleura, ICD 162, 163). The peritoneal timors were included with gastrointestinal tumors if certified as a peritoneal mesothelioma (ICD 158) or if confused with carcinoma of the bowel or pancreas. They were included with "other cancers" if certified as carcinomatosis (ICD 199) or as sarcoma or other timors. Ttoo deaths from msothlial timors were identified among causes of death not shown in the Tables. There were, apart from pleural mesothelioma, 103 deaths from carcinoma of the lung, which remains the most cocmon timor of asbestos workers. Statistically significant excess mortality from chronic respiratory disease is seen only among those with long and severe exposure. Asbestosis was given as the cause of death in 13 instances but as the underlying cause of death in 34 of the deaths from lung cancer, and in 27 of the deaths from either pleural or peritoneal mesothelioma. In four instances, coronary threnfcosis was the actual cause of death. In the majority of the above cases, exposure had been long and severe. Table 2 shows the mortality experiences of the laggers. The majority of these men were first employed after 1955. It is the custom, however, for laggers to work on contract for various employers, and some may have had previous exposure, so the authors are not entirely sure of their durations of exposure. Only approximately 21 of the entire group has been followed for 30 years or longer, but to date their experience is not dissimilar from that of other severely exposed male workers. Tamf 2 L a m .Fits a n d M at fs (1368 m a i f s ) All causes Cancers of lung and pleura (IC D 162.163) Gastrointestinal cancer ( ICD 1SO-158) Other cancers Chronic respiratory disease p- 0001 Observed 3*110) 25*(4) 8 (S) 8 12 Espected 57 2 36 43 41 74 Mortality experience was also examined according to the length of follow-up, and an analysis of the standardized mortality ratios (SMRs) for cancers of the lung and pleura is presented in Table 3. general, the SMR increases with increased length of follow-up and with increasing exposure, but for those with long exposure, the SMRs are higher in the group with follcw-ups between 20 and 30 years. Only 20% of these workers have been followed up for 30 years or - 51 - , and currently about half of the deaths from mesothelial occurred between 20 and 30 years after their first T ar ie 3 C a m i s o f n i l l.i m . a m i Pi h * a in M a i i s (S M B s ) Length of Follow-up (years) 10-20 20 30 30 Low to Muderete Exposure 2 Yeert 104 159 278 -2 Yceri 112 261 184 Severe Exposure 2 Ycere >2 Yeri 25 463 218 67) 26) 446 employment. However, as has been demonstrated previously, the luufcer of deaths from mesothelial tumors will continue to rise for some time. In Table 4, a finer subdivision of job categories and of periods of enployment in the factory are presented. It is noteworthy that in categories 1 and 2, ground workers, canteen workers, and production workers with very little and short exposures to dust, the SMR was 176, and there were three deaths from mesothelial tumors. Up to 1955, the estimated level of asbestos in the air was 2-5 fibers/ml^ Exposure Category Low to moderate 12 3 Severe 4 5 T a r ie 4 C a m ERs o f L i n o a n d Pi e i r a ( S M R s ) >2 Years Duration of Exposure 2 5 Years 5 or More Years 176 0 126 351 247 227 238 236 216 152 714 567 However, looking at the death rates for mesothelial tumors graded by exposure category (Table 5), it is found that the rates reveal a very definite relationship to length and severity of exposure. .----.. ---- Exposure Category and Duration (years) Males Low to moderate <2 >2 Severe 2 >2 Laggcrs 2 >2 Females Low to moderate Severe <2 >2 T ari e 5 Misotiieiioma Death Rates Pleura 3 3 6 7 3 1 1 8 4 Peritoneum 1 4 10 12 2 4 0 5 3 S years 12.031 7.500 15.428 7.827 7,893 2.690 2.066 9.538 4.388 Rate per 100.000 S years 33 93 104 24) 63 186 48 136 360 women were ecployed in the traditionally female jobs of carding, spinning, and doubling; 100 were employed in mattress making. Crocidolite was used heavily in textile departments, exposure was generally estimated to be very high, and women were also employed in other production departments, as well as in offices, canteens, and other lew-exposure departments. The same pattern of analyses has been adopted, and Table 6 shews the observed versus the expected mortality in the general population, for groups with 10 years or more of followup. T able 6 M o rtality Ex fe r ie v . es of Fem ai e Factort Workers Cause of Death All causes Cancers of lung and pleura ( ICD 162.1631 Gastrointestinal cancer (IC O 150-158) Other cancers Chronic respiratory disease p < 0.05 tp <0.0l. *p < 0.001 Low to Moderate (98) Observed Expected 34*< 1) 3*( 1) 3 4 3 220 0.5 1.9 32 23 Expoturc Category Severe .2 Years (396) Observed Expected >2 Years (19*) Observed 8 8 t(i3 ) 65 6 78*<7> 4 I5*<7) 1.9 2I*<4) 0.8 14t( 4) 5.7 97(2) r- 1* 16 (2) 11.9 I6 *(l) w 5.3 6 6 8 107 3.2 In the lew-moderate exposure group, there was one death from a mesothelial-pleural tumor. In all, there were 13 pleural-mesothelial timers identified and eight peritoneal tumors, approximately the same proportion of all deaths (101) as among the males. Among the severely exposed women with long exposures, there was a greater excess of lung cancer than among males with similar exposure. Also, apart from peritoneal mesotheliomas, there was an excess of deaths from gastrointestinal tuners and other cancers. Cancers of the ovary, uterus, and breast were analyzed separately. In the group of severely exposed women with long periods of employment, statistically significant excesses of cancer of the breast (obs., 6; exp., 2.1; p 0.05) and ovary (obs., 3; exp., 0.74; p 0.05) were noted. Not too much reliance can be placed on a slft&le set of figures from one comparatively small cohort of weqgar and other factors related to marital status and parity that may operate in industrially employed women may be of importance. As in the males, the mesothelioma death rate (Table 5) relates clearly to the degree and length of exposure. CONCLUSION In the male cohort, SMR of 5.A for lung cancer was observed in the severely exposed workers ( 20 f/cc) with 2 years of exposure (54/10.4) and 2.4 for those in the lew to moderately exposed group (5-10 fibers/cc) (31/12.8). Risk increased with duration of follcw-up and severity of exposure. Nineteen pleural and 27 peritoneal mesotheliomas were observed. - 53 - iL- InTfiffemale cohort, the SMR of 6.0 (3/0.5) for lung cancer was observed in lew to moderately exposed group; 7.9 (15/1.9) and 26.3 (21/0.8) in the severely exposed groups with 2 years and 2 years of employment, respectively. An apparent excess of breast (6/2.1) and ovarian (3/0.7) cancer was observed in the severely exposed group. Thirteen pleural and 7 peritoneal mesotheliomas were observed. 13. The experience of insulation workers in the U.S. has been reported by Selikoff, et al. With regard to exposure data, reconstruction of work situations and extrapolation to the past suggests that these workers would have been exposed to dust levels of 4-12 fibers/ml (as time weighted averages). While there might have been periods of little or no exposure, there could also have been times of peak exposures much higher than the calculated averages. Ta m 2 S u m n o and O aaravto (H a tim amomc * 2 ) AM urre I wuulatio Wo b k c u N rw Yoaa-N aw Jraatv. 20 oa M oar Y kab A rre t O w u rror Woaa Januabv I. 1943-Dk f m n b 31. IM 2 (1343 Maa-yaan of Obaarvation) Uadortyia Ctaao o f Oooih T flU l dOOlht-flll C0BBB4 T o u t caBoor-all t it C ao o tro f loo R a m i m tM iboliom i NriM BBal BMMholioaM Caacar o f maphagai. ttomach. coion-ractum Caooor o f laryna. pharynx, buccal cavity Caacar o f kidoty A ll atbar cancar Noaiafootiooa pulmonary diaaaira. total AH othor caoaaa Eapoctod* 193 4 32.1 60 t t 97 17 0.7 140 4.0 t 139 J Obaarvad 233 93 42 3 4 29 2 0 1) 14 12 144 *Eapocaa4 daatba a n baaod pan white male apa-epaciAc U-S death rate* o f the U S. National Canter for Health S u m iics. 1949-1962. Rates for i pacific causes of death for 1943-194 were extrapoUled from rates for 1949-1933. Ratos are not available, but these have been rare causes of death in the general population TdbTB"2 shows the mortality rates for workers with 20 + years of e n s u r e followed to 1962. The authors point out that while deaths related to asbestos exposure seen in insulation workers may sometimes occur in less than 20 years from first exposure (lung cancer, asbestosis, and occasionally, mesothelioma), these are not conmon and, therefore, data on experience beyond the 20-year point was thought to more clearly define the influence of exposure. Observation of survivors was extended to 1976 (Table 3). The same overall pattern of causes of death continued, although distribution of deaths by cause changed somewhat, reflecting a lumber of epidemiological influences. Thus, pleural and peritoneal mesothelioma, which tend to occur somewhat later than bronchogenic - 54 - cafQKcma, became proportionately more cannon. Thus change also reflects the smaller proportions of older men who ever smoked cigarettes, and also a "survivor effect." Since the smokers in the original group had increased mortality risk (especially from lung cancer and cardiovascular disease) there would likely have been comparatively fewer of these and still fewer vfoo continued smoking at least the same amount, among the cohort survivors, as the years went by. Except as influenced by other factors associated with advancing lapsed time since onset of exposure, this would make for fewer deaths of lung cancer, with more men at risk of dying of other asbestos-associated disease. Take 3 Expected and Observed Death* Aiming 632 New York-N ew Jersey Assesto* Insulation Workers January l. 1943-D ecemrer 31. 1976 (13.923 M aa-yan of Observation) ___ Uadcriyiaf Cause o Dcath Tosai astia, all caos Tosai cascar, all Mtcs Cascar oflaag H a rii mmoihalinma raritnaal masbetona Cascar of saophagm Cascar of nomadi Cascar of ootcs-ractum Cascar oflarynt. pharyns. bucai cavity Casar of Sidney All ber ancer Nosinfectious pulmonary discas, toul Asbassoets All bar a u s a Expected* 326.9 57.0 13.3 t t 14 34 83 26 13 24.3 93 t 262.6 Observed 478 210 93 II 27 1 19 23 6 2 28 4) 41 223 Expected S a lta an baaed upon white male s|e-*peciftc U S death rates of the U S N ationl Center for Health Statistics. 1949-1976. Rat for specific cause of death Tor 1943-1946 were extrapolated from rat for 1949-19)). tR ata are not available, but these have been rare causes of death in the general population. Lung cancer remained the most important cause of excess deaths, with 93 observed, 13.3 expected. Gastrointestinal cancer was also increased as seen in the original report (43 observed, 15.1 expected). Seventy-six percent of the original cohort enrolled in 194TTBd died by 1976. - 55 - ~k Variations in distribution of deaths by cause over time are shown in Table 4. T u ie 4 Expected ano Oebeeved Deaths among U 2 N e Yook-N e Jebsev A w m s I* ia t o * Woaeats Januaey I. IM T-D ecemeei 31. i *7 * N w k v of M m Atteimag Category Maa-yean of O k N rn lio i Underlying Co-- of Da) Total deaths, all canta T o a lc aa cv. aN utm C aaovof taag Canea of iloaaac* Caao of oeea-raciam Caaew of larynx. pharyax. haocal canty C aaovof hidacy A l o tbv cancer Lav than 20 Yean 325 I 70 Fspanad*_______O N ffw f *0 l.l 2 A2 0 t0 t0 0.02 0 0.1 0 0.2 0 0.03 2 0.03 0 0.3 0 70->4 Yoon Ml *203 80.4 11 13.3 53 3.0 2* t4 3 A4 0 1.3 * 1.9 7 At 2 A4 0 3.5 5 IS I 139.3 42.4 IA I t t 1. 38 A2 1 A IA S 190 IS3 *7 7 24 1 13 1* ~2 T3 total A ll other caaMi 0.1 0 1 * 4 7 * 41 t 0 3 38 7.8 7 *3 .3 *2 189.3 IS4 T if E i a l deaths arc hated boon *htte a u k xgr-ipscihc U S. death ra ta of the U S Nattaaal Ceatcr far Health S u in g . | 4 -|*7 a R a ta far |-~ a- caaea of d a th for 1943-194* are extrapolated fro ra ta far 1 *4 *-155 tR a ia arc a a avilla bk. bat thsa have boca rare caaea of d a th m the fcaeral papaktioa The experience of workers exposed after 1943 (reflecting postwar "cleaner" conditions) has also been reported. In the 15,520 man-years of observation during the less than 20-year period (Table 6), there was no unusual mortality experience. Altogether there were fewer deaths than expected, and there was no increase in cancer deaths. Table 6 Expected ano Obkeveo Deaths Among 833 Ne Yoek-N ew Jeesev asbestos Insulation Woekees Fiest Employed Jancaey I. 1943-Decem ke 31. 19*2. and Oescbved feom Fiest Emplovment-D ecemeee 31. 197* (Deration from Oatot of Employment) L o t than 20 Y m n 20-34 Yeart N om bvof Mott Attaining Catefory Maa-ysan of Oborvatioa Uaderlyiag Caaac of D a th Total fa lb i, a i tarn Total eaaoar. aO tk a Risarai aaaakdiom a C aaovof amphagm. ttaatacb. oofan-ractam C aaovof larynx, pharynx, baccal cavity C aaovof hidaey A R athvcaacv Navafacuoa palmoaary ditesv t . toul ABotbveaaam 833 15.520 Expected* Obtarvod 398 51 1.1 t t 23 5 2 0 0 523 3281 Expected* Observed 24.8 39 5.0 15 18 8 t2 t1 0.7 1 0 8 2 0.2 1 03 1 01 0 01 1 30 1 20 0 0.5 0 0 * 7 t 0t * 342 18 19.2 17 Eipanad dntha arc baaad apoa bite mak tgc-tpsctftc U S d a th ra ta of the U S. National Coat far Health SutMtwe. 1949-197*. R ata far tpecifk cauia of d a th far 1*43-1*48 crc extrapolated from rates for 1949-1933. tR a ia arc a availshk. bat tbaa have ban rare caasm of d a th in the general popakuaa. In " t K e 3281 man-years of observation 20-34 years from onset of exposure, there were 3 times as many cancer deaths as expected, primarily due to lung cancer. CONCLUSION No dose-response inference is possible because of the lack of exposure data. 14. Observations on 17,800 asbestos insulation workers in,the U.S. and Canada followed from 1967 to 1976 is discussed below. During the decade of observation 2271 deaths occurred (Table 12), whereas only 1658.9 deaths were expected. The excess deaths were primarily the result of an increased number of instances of cancer at several sites. T a m I 12 ( H a h i s A m oak. (7.100 Asararoe I n s i ia t iu n W oeatea in th* llfc in n S t a t m a n d C a n a d a Ja n i.a b y I. 19*7 Dt< i-m i m J|. 1976 N lM a tn cm M i n 17.600 M a N-VMKS CM O M tlV A TW N 166.153 Underlying Cause of Death Total daatha. all caaaes Toul cancer, all anca Cancer of lung Heural meaothcliotna Peritoneal maamhelwma Metalheliwua. no.a Cancer of esophagus Cancer of stomach Cancer of colon-rectum Cancer of laryaa Cancer of pharynx, buccal Caacer of M a ry AU other caacer NoatafcctMM pulmonary dmettra, total Aabaauata All other camma Eapected* 16319 JI9 7 1036 t t t 71 142 36 1 4.7 10 1 6.1 131.6 390 12602 Obaerved (BE) (D C ) 2271 995 466 63 112 0 16 22 39 II 21 19 164 2271 922 429 25 24 55 16 16 56 9 16 16 252 212 166 1064 166 78 1161 (Uno o/e (BE) (D C ) 1.37 3 11 4.60 -- ___ -- 2.53 1.54 1.55 2.34 2.06 2.36 1.40 1 37 266 406 -- -- -- 2.53 1.26 1 52 1 91 1 59 223 1.91 3 59 -- 0 63 3 19 -- 091 t A M h l K f butt Mna while male ape-tpacific U.S death rates of the U. _ Naumml Center for Health S U M tiO . 1967-1976 7 * w arc m i avadahie. bat ihaaa have hatn rare can*** of death in the general papulation (BE); Ban rwdeuce New her of daatha caiepon/ed after review of beat available information (autopsy. aarpeal. dimeal). (D C ) N amber atdeath* a* recorded from death certificate i tformaiion only. % Apart from lung cancer, mesothelioma, gastrointestinal cancer, cancer of the larynx, pharynx and oral cavity and cancer of the kidney, there was still an excess of cancer of other sites, with 184 observed, 131.8 ejqpected (Table 13). Ta re I) Death* Among 17.100 Aaaesroa In* u a tio n Workers in the United Statu ano Canada Jancarv I. 1947-Dccemsee Jl. I7* Ncmeer or Men 17.100 M an-v m u or Oreervatwn lt*J 5 3 U apart)tag Caaaa of Daatb Tout Raatba. aH caaaaa Death* of laaaoommoa Eapocted* 1*31.9 3197 Obam a* (BE) (D C ) 2271 993 2271 922 IU im o/ (BE) (D C ) 1.37 1 37 3.11 2.M Liver. biliary paaaagea M 4m Tm Prostata Lm M m i Lymph tan Skia Bran 175 72 91 1.9 20.4 13 1 20.1 *.* 10.4 23 49 1 32 2.SI 5 19 07 0 2.43 9 7 0.99 077 21 30 21 1.47 1 37 15 15 115 1 13 19 1* 0.95 oao 12 1 1.12 1 22 14 17 1.35 1 *3 ` Exgacaad t o i l baaad agon white male iq ipanftc U S death ratea of ihc U S . NationalCeatar far Haaith Stauauca. 19*7-1976. (BE): I rm m tm a t Namber of daatha calcgonzad afu r review of baa available information (DC ): NnaWar of death* a* raoorded from death ceniftcau taformatioa only % Prom a purely statistical point of view, in view of the increased incidence of cancer of several sites among asbestos insulation workers, it was expected that a proportion of these men would suffer multiple cancers simultaneously, even beyond the tendency of such findings to be made among individuals with cancer, in general.1Z Again, this would not be reflected in tabulations of causes of death by single underlying cause, as is the usual practice. Analysis demonstrated one hundred malignant neoplasms present but not causing death (Table 14). Sometimes these additional neoplasms were TaR(E 14 Mortaiitv EirtaitNC* Among 17,100 AnRaaroa Imaui atmn Worker* in the United Stater and Canada IM 7 IR7* Orrervationa in 2271 Consultive Death* MaMgaaat Neaplaimi Praaani. bi not Caaaiag Daatb* i b Member Lm Neural maaothellcma BinlDRRRl maaOthelbmu Eaopbaga* Stomach CofaR OroRbaryaa Laryai Kidary Olhar 24 2 i 0 i |9 ) 5 3 42t HBi o f Ib W OOOpIlOIM O ff IfWMtOMd on iha daaik caniflcata (fa il arc not catagartaod a* aadartymg caaaa o f death). tladadiag laRkaima 3. lymgboma 3, Madder 3. proauie 13. ihyrafa. ate tl> 92 mdividwala; total ik M * m allipk cancan in atglH caaaa.  - - 58 - mentioned on the death certificate but as an "other significant condition," not in the section on the underlying cause of death. Forty were present among the 1064 cases where death was due to causes other than cancer or asbestosis (Table 15). Among the 168 deaths of asbestosis, cancer was also present in 7, 6^ of these being bronchogenic carcinoma. Analysis of the circusstances leading to death, however, indicated that the underlying cause was asbestotic pulmonary insufficiency, and that the lung cancers were present but with no decisive influence at the time of death. Nineteen other cancers were present among the 486 deaths of lung cancer and 10 other cancers accompanied the 175 deaths of mesothelioma. There were 9 "incidental" neoplasms among the 99 deaths of gastrointestinal cancer. Although experiences are so far limited, it may not be wholly unexpected that there were proportionately more incidental neoplasms accompanying deaths of colon-rectum cancer, compared to those of lung cancer (8.5Z vs. 3.9Z). One may speculate that this could be due to the longer Ta k e I) Mortality Experience Among 17.100 Asbestos Insulation Workers in the United States and Canada 19*7-1*76: Omervations in 2271 Consecutive Deaths Number oe Incidental M alignant N eoplasms (not Causing Death) in Relation to Underlying Cause of Death as Established sv Best Evidence (BE) Underlying Came of Death Cancer all Mint P lM fi! m m c M o m AvifflMBl M M lk lliO M C iM flfM p k p i Cancer of Memach Cancer of colon reelam Cancer of larynx Cancer of pharynx, bnccal cavity Cancer of kidney A ll other cancan Nomafacitotu pnlmonary diaantei. total A ih e u ttM Ad other causes Total Number of Death* of Underlying Caine 995 4M 63 112 II 22 59 II 21 19 114 212 161 1064 2271 Incidental Malignant Neoplasms No. of Death* Tout Caneen 45 50 17 19 44 56 11 33 55 00 23 00 89 10 10 7 7* 37 40 92 100 *Six of (hoe were lung cancer. - 59 - clinical course of many patients with colon-rectun cancer, compared to lung cancer, with greater opportunity, simply in terms of time, to develop additional disease. Multiple cancers were present, overall, in 2.11 of deaths among these asbestos insulation workers (48 of 2271). It is perhaps to be expected that this was more likely to be the case among those for whan cancer was the primary cause of death (4.5Z), while only 3 of the 1276 other deaths had this finding. It is now well appreciated that most asbestos associated disease is first seen after considerable periods from onset of exposure in both occupational and environmental circixnstances. This is true both for the presence and extent.of parenchymal fibrosis and pleural fibrosis and/or calcification, ' J and for asbestos-associated neoplasms. Some limited excess disease was observed in less than 20 years frco^. onset of exposure (Table 16). Among 12,683 men with such experience, covering 89,462 man-years of observation, the timber of cancer deaths was about doubled, with 42.6 deaths expected and 83 observed. There were no excess deaths of gastrointestinal cancer and only 5 deaths of mesothelioma, with these in the 15-19 years from onset category. Age, year and sex specific mortality data of the U.S. National Cancer for Health Statistics indicated that 11.9 deaths of lung cancer were to be expected. Thirty-six occurred. There were 8 deaths from asbestosis. Deaths Among 17.100 Asbestos Insolation Woekebs in the United States and Canada Janoaev l. 1967 __________________ Analysis by Doeation no* Onset op Employment >i . m Total M m Maa-ycars of Obaervatioa a te 20 Yaan fraaiOasct 12.693 19.462 Ratio o/e 20 or luTl' 77J9I Uaderlyiag Caaae of Death Total deaths, all eaates Caacer. aH sue* Caaearof hmg Plaaral aMaotbetasaa m k m M mmui Mm M m II. K.O.* Caacer of caophages Caacer of ttotnodi Caacer of coloa-rectem Caacer of laryax Caaearof pharyax, baccal Caacer of kidaey A ll other caacer Noatafectmas palmoaary diseases, total Aahaatoait AH other caaae* Expected* 292.9 42.6 11.9 t t t 06 IS 4.1 0.4 13 11 21.7 52 t 235.1 (B E ) 325 13 36 2 3 0 1 | 4 2 3 3 29 9 9 234 (D C ) 325 77 32 2 0 1 1 0 4 2 2 3 30 II 2 237 (B E ) 1.15 195 303 _ -- _ _ -- -- -- -- -- 1.29 1.54 -- 1.00 (D C ) 1 IS 1II 2.69 _ -- _ _ -- -- -- -- -- 1.39 2.12 -- 1.01 lp ^ o i* 1376.0 277.1 937 t t t 45 12.7 34.0 4.3 9.9 7.0 1149.1 53.9 t 1045.1 (K ) 1946 912 450 61 109 0 17 21 55 9 19 16 156 304 160 930 (D C ) 1946 945 >97 23 24 54 17 19 54 7 14 IS 222 177 76 924 (BE) 1.41 3-29 4J0 _ 2.64 1.65 1.62 2j09 2jB5 229 1.42 3.1 0 .7 * 'Expected death* arc bated apoa while male age-specific U.S. death rata* of the U S . Nam al Ccater for Haahh Staoaua. 1967-1976. tRaiea are aet available, bat th e * have been rare caaaei of death ia the fcaeral popalauaa (E ): le u evideace. Number of deaths categorized after review of beat available tatematma (aetapay. surgical, -hnirsl) (DC ): N ember of death* as recorded from death certificate latem attoa oaly. f* (DC) 1.41 IBS 4J4 2jM 1.42 IJ 9 163 IJ B 2.14 2j2 3.39 199 - 60 - Oh tile other hand, extensive disease was seen among the 12,051 men who had reached 20 or more years from onset during the decade of study. Here, 1376.0 deaths were anticipated; 1946 occurred. There were 160 deaths of asbestosis and 912 of cancer. It was at this time that bronchogenic carcinoma made its heaviest contribution, with 93.7 such deaths expected and 450 observed. One hundred and seventy deaths of mesothelioma were then seen and the increase in gastrointestinal cancer found. Table 17 depicts these data in some detail, in five-year periods from onset of employment. Lung cancer data are given as both expected and observed cumbers of death. This practice cannot be followed for mesothelioma, \here expected deaths cannot be computed for the general population. Instead, both the number of deaths of pleural and peritoneal mesothelioma, as well as the cumber of deaths of these causes per thousand persons years at risk are provided. The latter does not take into account variations in achieved age, but this may have less influence than achieved duration from onset of employment. It will be seen that very majon increases in cumbers of deaths of lung cancer are first seen at r 15-24 years from onset of work, with continued further increases. The extraordinary increase in deaths of mesothelioma, both of the pleura and the peritoneum, is not observed until some&hat later, reaching 2.78 deaths per thousand person-years at risk for pleural mesothelioma at 35-39 years from onset of work, and 5.47 deaths of peritoneal mesothelioma per thousand person-years at 45 + years from onset. T able 17 O aths A m o m . I7 .N 0 Asbestos I nsulation Woblebs in U nited States and Canada. Ja n la b v I. IW - O e c e m b b ) l . IB M A n a i v s b by Dubatio n n o n Onset o# Employment LbagCaaccr n s era! Meat Daraino from Oaact (Yean) Number of Mca Renoa-yean of Qbecnratios Eap* (BE) (DC) Ratio o/c (BE) (DC) No (BE) (DC) No./IO N (BE) (BE) (DC) M oyne (BE) - 10 IO -I4 15 19 20-24 25 29 JO- 54 J5-J9 40-44 45 1.190 9.003 9.940 0.007 6.59* J.547 2.020 1.100 1.440 26,393 29.003 34.066 31.260 20.657 11.590 5.403 3,160 5.305 07 0 0 -- -- 0 2.7 7 5 2.55 1 02 0 0.5 29 27 340 3 17 2 17.0 59 57 340 3.36 6 21 0 105 96 500 4.50 13 10.4 112 103 6.00 5.59 9 I I 5 65 37 5.60 4.90 IS 0 1 40 131 4.93 3.02 4 170 69 53 3.09 2.90 14 0 0 2 4 3 3 4 3 4 0 0 006 O I9 0*3 070 2.70 1.27 264 00 00 30 32 19 3 23 6 19 5 1* 3 29 5 0 0 ON ON 092 IN 3S2 306 547 'EipacuE deaths arc baaad upas hue male afc-ipsohc U S. death ralce of the U S. Nauoaal Caster far Haahh Smbmkl IW -W H . hahits aot takes mto accoaat. (BE) Beat ctndeace Number of deaths ctteponred after review of heal available lafdrmatna (aatopay. mrptcal. rk--ral). IOC): Number of deaths as recorded from death certificate mformaiMB oaiy. - 61 - Thlnother reflection of the clinical concerns among these workers, Table 18 indicates that approximately one-third of all deaths were due to lung cancer at 30-34 years from onset, while mesothelioma accounted for 13Z of all deaths at 35-39 years. Altogether, lung cancer was responsible for 211 of all deaths observed in this cohort and mesothelioma for 8Z. Tam. II O lA rN U A M U M , IT ,M O A M U 7 U 0 I n o L IA T IU N W o t k k U IN T N I U N H I D S T A T U A NO C a n a d a , J a n u a b v I. 1*67 O u t m u m J l. I f 7* 0A N A I V M O l i t A T I O N n o M O n m t E m k u v m c n t P t r co iH o f A ll D o o tk a Y o o n from Om m of Employ" h i <10 10-1 15-1* 2 0 -2 4 2 5 -2 * JO -J4 J5 -J* 4 0 -4 4 45 Tout Tout D u ih i 51 15 II 120 Ml >40 25) 20) 442 2271 Loaf C am r (BE) ( D C ) 0 2 IS ) 11.4 27 1 )2 * 2 5 .7 1*7 IS * 2 1 .4 0 5* 14) 17.1 2 4 .7 K .) 2 2 .) 15) 1 2 .0 II. P tm ral (BE) ( D C ) 00 00 l.l l.l 1 * 1.) ) 4 1) 27 0 * 5 9 16 2 .0 1.5 )2 0* 2.1 1 1 FffffO M ol (BE) ( D C ) 00 00 16 0 0* 06 4 * 0.1 61 II 7 ) 20 79 IS 6 6 l.l 4 9 l.l T otal (B E) ( D C 0 0 2.7 2 .1 1 .) .4 1 )4 9 .9 9 .7 7 .7 0 0 16 2 .5 5 .2 6 .5 7* 6 .4 4.1 44 T o ta l m c ta m mii m c iik tr p lu r a l or p cm onm l. (BE) Baal w O n c i Namfccr of t a lk caioponzod tfio r ro*w of boot available inform aim ( O M a p y . t a p u l . C hlM C il). (D C )- Nombcr of t a lk * u rocorta from t a lk o c rtita u mformoiioo only CONCLUSION The study results indicate a high increase in risk of lung cancer associated with asbestos exposure, but the lack of exposure data -> makes it difficult to show a dose-response relationship. 87 1 15. Asbestos cement building materials plant workers have been studied * to determine the risk of respiratory malignancy in relation to duration, degree, and fiber type of exposure to asbestos. Subjects were classified into 5 total dust categories for which mean length of follow-up and mean age at initial exposure are comparable. (Table 1) : TABU 1 , COHORT V FOLLOW-UP WITHIN : f e x p o s u r e c a t k o o w i m ____________________________________________ T o ta l O u at w i t t i o 2 0 V o< i m t m E x o o b w i* { m p p c ty r ') NO < 10 1 1 -0 0 9 1 -1 0 0 1 0 1 -1 0 0 > 200 3 .0 3 7 1 .3 0 3 303 344 67 ` Million partial# par w M c fp p tv r. M am P o M p arU p (rr.1 3 6 .7 3 7 .3 3 0 .1 3 7 .3 30 7 m m a m mi Ir M I M M i f * 3 7 . 3 7 .4 3 7 . 3 7 .7 300 - 62 - the standard man-yr approach, expected rankers of deaths for each exposure category were calculated on the basis of race-age-cause-specific rates for both the U.S. and Louisianna male populations for 1950, 1960, and 1970. Cause-specific standard mortality ratios, SMR (100 x observed ranker of deaths/expected ranker), were obtained for various causes for each of the 5 exposure categories (Table 2). SMR for all causes ccckined remain generally lew, but increase slightly with degree of exposure: 60, 64, 75, 80, and 94. SMR for respiratory system neoplasms remain lew for the 3 lowest exposure groups, but exceed 100 in the 2 highest categories: 77, 70, 26, 290, and 226. The very low SMR in the middle dust category is probably a chance occurrence; with only 3.8 respiratory neoplasm deaths expected, the probability (assuming a Poisson distribution) of observing one or fewer is 0.11. TAOLI a STANOARO MORTALITY RATIO |V CALM WITHIN OXROOURO CATIOORIC % ra ta l Ouat Widnn 30 y a* Initial Oaaaaura MRRO C k i a O aa d < 10 in - 1 0 3 * 0 /0 f OMRt 11 - M (M - f.JOJl 0 /0 OMR 01-100 W -a 0 /0 OMR 101 in - SMI 0 /0 OMR AM l M M AM m adgnw t 300/433 7 0 0 1 4 1 /3 1 0 0 04 00/70 1 70 m m tm m t (140 3001 0 4 /7 7 3 70 37/37.1 73 7 /1 3 .0 04 O*oaat>va a rnam 1140-1 M l 10 /34.0 41 10/11.0 04 3 /4 .3 71 N w w a M n r avt- m m (100-143) OOtar (laaiaual) M a t r carata- 10/34.7 30/M -0 77 M 0/11.4 0/13.0 70 00 1/3.0 3 /4 .0 30 01 aantiar taaaaaa 1300-440) All Mac i n i a i 130/310.7 00 70/140.7 M 70/113.0 33/40.1 03 30/47.0 04 13/10.3 74 43/03 3 M 14/0.0 147 0 /3 .0 0/3.1 0/3 4 300 147 14/30.0 0/11.0 03 70 *> >1 m 0 /0 OMR 103/110.1 04 10/10.0 3 /0 4 14/0.3 3/7.3 01 31 330 30 01/07.4 30/33.0 1M 04 * M anana 1 aa rnclaa M > eu*<e fa a ty r t R a d * a t t M n N to o f a M IO I a uo io o ro m artaM ty ra tio ( a < 0.01 In u n O M o t o o o n tO O M M com oorad to M o nutnO or aopoctoO. mmnulwp a Aotaaon O M r M H a l. In the 3 lowest exposure categories, the SMR for over-all mortality and respiratory neoplasms are comparable, as demonstrated graphically (figure 1) by the extensive overlap of their respective 95 per cent confidence intervals (based on a Poisson distribution). On the contrary, there was no overlap in either of the 2 highest exposure groups. Assuming no association between trace and cause of death, the close agreement of the over-all and respiratory malignancy SMR in the low exposure groups is additional evidence that, although some underestimation might have occurred because of those lost to view, there are no excess respiratory neoplasms in these categories. - 63 - it, e w e * mh)w .itv M r * (OO'OHBMB/IWKTCOI WltM N o n n e i m t im l i e hum i c m ,, xm UCM OP PIV U N M CATMOMCS | 00- w oo- If j --------------------------------------- 1 o-- 4-- 4 " 4 A 4 Uo ib 4 CtmMn* C M (<1 rif l 111* 1 aorulkr fMM w*li M par cmm < AHnn iwarvah by ataaa npaaurr farnek af i nfm No excess mortality occurred in any exposure group for any cause % other than respiratory neoplasms. Hie analysis was also performed with the nudber of deaths expected on the basis of Louisiana death rates. Because lung cancer rates are higher in Louisiana than in most states, the expected mufcers of respiratory neoplasms are greater than with the U.S. rates, thus resulting in lower SMR. The patterns observed for the 5 exposure categories were the same as with the U.S. rates; over-all mortality SMR were 56, 64, 71, 73, and 83; respiratory neoplasm SMR were 64, 59, 23, 225, and 187. As with U.S. rates, no excess mortality other than for respiratory neoplasms were observed. Ttoo pleural mesotheliomas were diagnosed in the total study population: one person was employed for 10 months (with known exposure only to chrysotile), the other for 14 yr (with most of his employment in the pipe plant, which resulted in exposure to both chrysotile and crocidolite). Because these men died 18 and 19 yr after initial employment, respectively, neither fulfilled the cohort criterion of a minimum of 20 yr of follow-up and therefore are not included in this analysis. It was considered possible that this tumor was underdiagnosed in this population. 112 Hie results of Newhouse suggest that the latent period for the development of asbestos-related neoplasms may be less than 20 yr, as with the 2 mesotheliomas found here. Using Newhouse's methodology, the effect of latency on the mortality experience of this population was assessed by performing the analysis by 5-yr periods after initial employment. In each analysis, persons with follow-up of less than the prescribed ntinimtm are excluded; an individual person's exposure is calculated at the start of the particular time period. Because each period is only 5 yr in length, it was necessary to condense the original 5 exposure categories into three, although the expected timbers of deaths remain very small. - 64 - Results for the 2 lowest exposure categories (representing the original 3 lowest groups) indicate no discernible pattern for respiratory neoplasm SMR as time since initial exposure increases; those for the highest exposure category exhibit an increasing trend as long as 30 yr. since initial exposure (Table 3). TAOLI 3 RESPIRATORY MALIGNANCY STANOARO MORTALITY RATIOS OY S-YR FOLLOW-UP AND TOTAL OUST AT START OP PSRIOO T a t Ovat at Otart a t O V r Faria I4MM*8r> Yr unca Initial Caaura Ne. < 10 0/0 OMR 10-100 o /c OMR > 100 0/0 OMR 1 0 -1 * IP -20 20-28 2 8 -2 0 2 0 -3 8 > 38 8.330 8.144 8.848 4.307 1.320 313 7/4 4 1/0.0 10/13.1 8/10.1 3/1 0 0/0.8 too 1/3.4 43 1/1.3 04 8/4.3 110 3/3.4 03 8/8.4 70 0/3 .0 88 3/8.4 00 7/3.0 187 1/3 3 48 0/1.8 0 0/1 0 0 4/1 3 77 130 108 333* Far aaltnitlaoa at aOOranlattaaa. Ma M M 2. *P < O N In u n ia r N N i M aOaarvaa Muminl)-- n4latri0tin). < nu m M r 0 8aait -- pat tad. To conpare the preceding results with these which would have been obtained with a different study design1 3 , an alternate method of analysis was performed for this cohort (men with at least 20 yr of follow-up) by considering 4 control subjects for each case of lung cancer. These control subjects were selected at random from among men in the cohort who were b o m in the same year as the cancer patient, were of the same race, had survived at least into the year following that in which the patient died, and if they subsequently died, did not die of a malignancy. The mean total dust exposure (accumulated within 20 yr. after initial employment) was 164.1 mppcf-yr. for the cancer patients and 77.8 for the control subjects. A 2-way analysis of variance (the matched sets acting as a blocking factor), with Scheffe's multiple comparisons, found that there were no differences among the exposure means of the 4 sequences of control subjects, but that the mean dust exposure for the patients was significantly greater than that of the control subjects (P 0.005). The distributions of the cancer patients and the control subjects by total exposure to dust are presented in Table 4. The odds ratio, an estimate of relative risk, was calculated for each category relative to the lowest degree of exposure. - 65 - TASL I 4 LUNQ CANCON CA M ANO MATCMOO OONTNOL* M NON C A M ); TOTAL OUST U K M I ANO 0 0 0 NATIO* T M 0 mm M M Vr * i m t u t Immmmtrm I-- < to 1 0 -0 0 00-100 100-000 >000 tm m N*. CMH 1? 1 0 14 4? *M. C M V M l 01 00 11 10 a* 100 D4M NM 4* IN M M W M LMMM C l-- 1 l l 1.00 1.14 0L00 0t 2 .7 0 * * -- Mm H n l M M r m W *M -yr. tUMMMMKiMMrM. 4 < M L M M M i x 1 <11 OM fM itM . . *T M m ml 1 r-- ir-- iy -- m m v A H I IH M a a m im i-- M m mi M A H u t M fta a lM . *mm i m m m* - The over-all pattern of the odds ratio is similar to that of the respiratory malignancy SMR: the risk in the second exposure category is comparable to that in the lowest, an unexplained dip occurs in the third category (doubtless the sane chance occurrence), and a significantly greater risk is observed at the 2 highest exposure categories. Because information had already been collected on the entire cohort, the case-control approach, using only a subset of the population, does not make full use of the data available. Moreover, although this alternate approach provides estimation of the risk for each exposure category relative to the lowest category, no assessment of the risk experienced in the lowest category is possible. Despite these limitations, the observed pattern of risk across exposure categories was similar to that obtained with man-yr., prospective design, and analysis. The preceding analysis was based on emulative dust exposure, which has 2 components: (1) duration of exposure, and (2) average dust concentration. To assess the contribution of each, the population was divided into 9 duration-by-average-ccncentration categories. For these groups, the mean values of each variable within a fixed category were comparable across the categories of the other, and mean follcw-up times were homogeneous (Table 5). !i i - 66 - TASU * COHORT V DURATION ANO CONCSNTRATION O f EXFOSURf Our *Em Urm w l lyrl <a 3- 0 > 10 < 0-20 > 20 I N I 4.0t at* 30.01 n 1A01 173 at 27.0 n - 704 MJ 0.7 27.1 n - 30 43 4.7 37.S n 301 13.0 4.0 303 n SMI 30.4 4.4 30.7 ft 144 3.3 31.0 303 ft 444 123 21.7 37.0 n 174 30.7 33.0 307 *MMHh NfMtftimw M (Ml. tu mrnrnmm0t (iwaarf). (mmh rnipltannimi (yrl. iM a a n laii l at tallaw a lyrl. The SMR for respiratory malignancy for these groups (Table 6) generally indicate increasing risk with duration of employment, which is concentration dependent, and increasing risk with average concentration, vhich isgduration dependent. These results are consistent with others, which indicate^ that it is not sufficient to equate total exposure with either duration or average concentration; each constitutes an important canpcnent of risk, and each exhibits degrees with no apparent excess hazard. TASU VTANOAAO MORTALITY RATIOS FOR AMORATORY MAUSNAN6Y SV DURATION Of IM fLOVMSNT ANO AVIRASI OUST CONCENTRATION A m m Owm C ow m troti (OOR* <0 0-30 OuroOON o* 0H o i -- lyrl <1 3-10 > 1 AH Oh i-- 1 7/1 00* 70 13/17.1 TO 3/3.3 01 1 /3 A 30 1 /1 3 00 13/B.S 331* 1 0 /1 0 1 71 IM O I 100 >30 AH Oust i m m m M m 0/0.3 00 3 4 /3 0 4 74 3 /3 .0 130 0 /7 .0 00 *1 1 1 1 M I M I m W M f. t**a*M a m mm*m m*mm**i- * F < A O I I m m mn H i m 4 u r ta m i I 7/3.3 310* 3 0 /0 3 310* IV I ! 100 - 67 - Insssessing the possible influence of fiber type exposure on risk of respiratory malignancy, workers with exposure to chrysotile only (n * 4,201) were compared with 2 groups of workers exposed to crocidolite: those with steady employment in the pipe plant (n 1,004) and those with intermittent exposure to crocidolite through occasional maintenance work in that area (n * 235). Persons with exposure to amosite (n = 205) were excluded from this analysis. All follow-up times were similar, and total fiber exposures were comparable among the fiber type groups within each category of exposure (Table 7). TASLI 7 COHOST IV TVFt ANO LSVCL 01 TIM S IXFOSURC* (aura No croeMoiiti oapoauro Intarminan, aapaaura to croctaailaa m pipa plant ttooOy ompioymont mpipo piont oHIi crociootiaa oapoauro Tmat FMar tap o n a a40Mn M Vr of Initial Imptavaaant <M M -M t > MS n - 3.M3 It ) M 0 n * 44 t.a .4 n- Ml io.o IM n 1.337 4.0 3S.3 n * SO 00.7 37.3 77.0 M.O a-M l M p IM m* n 4M " S .* ' U piac t t HPi M U I* a amaalM 4*4 M IIU tM I M W . t M inia n a* a o rtic Im aor cuM c f -- t iwon o ia . I m m t total A ta W M W t (mapa* a w l. I Moan lonatn at lanaua tvrl. The pattern that emerges from the SMR (Table 8) suggests that the * addition of crocidolite to chrysotile enhances the risk for T respiratory malignancy, particularly for those workers exposed intermittently in maintenance jobs. The exposure history of this latter group is characterized by exposure to high concentrations of dust for short periods of time. TAIL! I STANDARD MORTALITY NATIOS FOR RESFIRATORY MALIGNANCY V FUER TYF No erociooiita oapoauro murmittent oapoauro to erociOOllto in piOOplant StooOV employmont mpip#plant Miffi erociooiita oapoauro Total Pifeor fapoouro oMMft 99 Vr of initial (mptayinant IM F ll'mm') 4M 30-300 >300 Tow 13/31 4 M 3/0.3 vooot 1/1 0 100 10/13.0 77 0/0.7 0 1/1 3 a/4.4 103 0/1.4 307t 7/3.0 34 30/30.0 77 7/3.3 304t O/tO 10 *Million pomo por cupte loot monpi. ta < O M 4 - 68 - The risk increased more steeply with increased quantitative exposure than with increased duration of employment. Excess mortality for lung cancer was observed only for groups with moderate and high cumulative exposure (SMR 2.9 and 2.3). There was no detectable excess risk of lung cancer in persons ecployed for less than 2 years or with low exposure. The risk appears high r two subgroups exposed to crocidolite, but only in the high exposure group ( 200 mppcf-yr.). There was no increased risk observed for gastrointestinal cancer in any subgroup. There were 2 pleural mesotheliomas observed (one employed less than 1 year and one for 14 years). There was no increased risk of respiratory cancer for exposures below 10 mppcf-yrs. There was a low (75%) tracing rate. 35 16. In a study of female asbestos workers , compared with national rates there was an excess overall mortality among those who worked in jobs with lew to moderate exposure (Table 2), which was partly accounted for by deaths from cancer. Table 2 Mortality of Women with Lew to Moderate Asbestos Exposure Registered cause of death All periods of employment (126 women) Obs. Exp. All causes Cancer of lung and pleura Other cancer Respiratory disease excluding cancer Other disease --05 29n 18.1 21 0.3 8 4.4 2 2.2 17 11.2 In the group with severe exposure vho had worked for less than two years (Table 3), there was an excess of cancer of the lung and pleura.  - 69 - Table 3 Mortality of Women with Severe Exposure Duration of employment Registered cause of death Less than 2 yrs (557 women) More than 2 yrs (239 women) Obs. Exp. Obs. Exp. All causes Cancer of lung and pleura Other cancer Respiratory disease excluding cancer Other disease 553 49.9 63 1.0 16 12.4 10 7.4 23 29.1 563 148 24.5 0.5 178 6.1 2 i r 3.6 14 14.3 b ""OT T> 0.001 However, the most marked increased mortality was in those with severe exposure *Aio had worked for more than two years in the asbestos factory; in this group there were excess deaths from cancer of the lung and pleura, from other cancers, and from respiratory diseases. Three deaths registered as cancer of the pleura were identified as pleural mesotheliol tumors; in all there were 11 mesotheliomas, six of pleural and five of peritoneal origin. In this study the results were assessed by comparing the number of observed deaths with the number of expected deaths. The "expected" deaths were calculated by the "man-years" method, multiplying years of risk by death rates. Excess mortality has been tested by treating the observed number of deaths as a Poisson variable with expectation equal to the man-years expected number of deaths. Mortality as a function of length of time from first exposure is shown in Table 5. ' - 70 - Table 5 Mortality by Length of Follcw-Up since First Exposure Years since first exposure Registered cause of death Less than 10 10 to 20 (922 women) (692 women) More than 20 (655 women) Obs. Exp. Obs. Exp. Obs. Exp. All causes 25 Cancer of lung and pleura 0 Other cancer 5 Respiratory disease excluding cancer 9 Other disease 11 h 0.05 JP 0.001 23.7 361 29.3 0.2 31 0.6 4.2 10 7.8 6.1 5 13.2 18 3.4 17.5 793 193 26J 1 91 25 39.4 1.1 10.8 3.7 23.8 There were four deaths in all registered as cancer of the ovary; three of these occurred among women with severe and long exposure and, compared with the expected nunber of 0.6 in this particular group, this was a significant finding (p-0.0025). The histological review suggested that at least two of the other deaths in the group that were registered as carcinomatosis were due to this cause. The possibility that ovarian cancer may be caused by exposure to certain hydrous magnesium silicates such as talc and asbestos has been raised by several researchers. Strong evidence of a link was found by Graham and Graham, who injected mice, hamsters, guinea pigs, and Dutch rabbits with tremolite asbestos. The mice and hamsters showed no lesions, presumably because of a protective layer of peritoneum surrounding their ovaries, which is absent in the guinea pig and rabbit. Both of these latter species developed an atypical papillary pattern of ovarian epithelial hyperplasia, tfiich the authors suggested was similar to early ovarian epithelial tumors in women. Additionally, birfringent bodies were observed in sections of six out of twelve ovarian tumors, and none of nine normal controls. These bodies were thought to be asbestos (but were not examined). APPENDIX II 1. Mesothelioma in Pet Dogs Associated with Exposure of Their Owners to Asbestos. Glickman, L.T., Domanski, L.M., Maguire, T.G., IXibielzig, R.R., and Churg, A.^ Environ. Res., 32, 305-313 (1983) This paper describes the findings of an epidemiological study of pet dogs and the incidence of mesothelioma and asbestos exposure. Eighteen histologically-confirmed canine mesotheliomas were diagnosed at the Veterinary Hospital of the University of Pennsylvania (VHUP), Philadelphia, from April 1977 to December 1981. An asbestos-related occupation or hobby of a household member and use of flea repellents on the dog were significantly associated with mesotheliomas. In addition, there was a trend indicating an increased risk of mesotheliomas with an urban residence. Lung tissue from three dogs with squamous cell carcinoma of the lung had higher levels of chrysotile asbestos fibers than lung tissue from control dogs. The VHUP is a major veterinary referral center for the Northeast and Middle-Atlantic regions of the U.S. Each year there are approximately 17,000 admissions and visits to the VHUP and an additional 6000 submissions of biopsy specimens to the Pathology Department (could not ascertain whether these ranters refer to all animals or to dogs only). A cancer and noncancer control patient were selected from hospital records and matched to each mesothelioma case by age and date of diagnosis ( 1 year), sex, and breed. Excluded from the noncancer control group were dogs with any respiratory disease or suspected . malignancy. Dogs with respiratory cancer were excluded from the cancer control group. Because controls had been matched on age, sex, and breed, these characteristics for the cases were first compared to the entire canine hospital population. The odds ratio (OR), an estimate of the relative risk of disease for each category, was determined using the Mantel-Haenszel procedure.1 Age was controlled in sex comparisons, and sex was controled in age comparisons. Odds ratios for other risk factors were determined for matched pairs using the cancer and non-cancer groups separately. The control groups were then combined and odds ratios calculated for matched triplets. Using a 95Z confidence interval, the null hypothesis of an odds ratio equal to one^was tested with computer programs developed by Rothman and Boice. Characteristics of the patients with mesothelioma and the source of asbestos exposure of their owners are listed in Table I. The distribution of mesothelioma by site was six (33Z) peritoneal, five (28Z) pleural, five (28Z) both peritoneal and pleural, and two (11Z) pericardial. The mean age ( 1 SD) of the mesothelioma dogs was 8.0 1.9 years; 17 (94Z) were male and 15 (83Z) were purebreeds. When compared to the entire canine hospital population, males had a relative risk for T M il.h I CHARAmgjsrics oi IM C a m m Path s is |) ia<.saisi n with M is o t h i i i"M a a i Patient 1 Breed Mixed Age ai Sue of diagnosis Year of meso Sex (sears) diagnosis thelioma" M 12 I9'K P 2 German Shepherd M 7 197* P German Shepherd M 9 I97M P 4 Doberman Ptnscher M 5 Insh Setter l-S " K M 6 Bouvier des Flandres 7 Mixed' S Bouvier des Flandres MK M 10 MK 9 German Shepherd M 10 Boston Terrier I I Insh Setter M M | 1 German Shepherd M I t Hernese Mtn l)og M 14 Old Fng Sheepdog M 1? ( ierman Shepherd M |h German Short M Flair Pointer P Mixed M 18 (ierman Shepherd M < lu J h H n M h I97M 1979 1979 p r9 1979 PA PI l*e P PA PI PI I9' 9 |9'9 I9K0 |9S| |9H | |9X | |9 h | |9H | |9H | PA PI PA PI PI PA PI PI Pe P PI PI P * P - peritoneal. PI = pleural. Pe = pericardial * Female-spayed e Sot included in case-control analysis L nahlc to contact owner for inters iesx V H U P Hf rw ri n I977 am il IW I. ANIl 1 HU* lA H 'S l *1 in AsHhsms Type of asbestos exposure Owner occupation (O) hobby (H i Household nei^hhorhiHKl ( Mher possible Auto bods repair l()i Aulii mechanic (Ml Iruck repair i()l adjaccnl lo shipyard None Plumbing heating sheet rink spas kling Ilf I Sunt 1 xtensive home remodeling ( hange ol heating sAslem None None ( emcnl f.u.tor\ None None None Accompanied on net lo |oh adiate ni lo shipyard Ni ne None 1 lea powder None None None Sheet rock spas kling at shipsard (Ol None None Pipelining jt shipsard l()l None None Xii'.o mcshjms i(b Demolition and construction site None Home insulation, construction site None 1lea powder None Rea powder Flea powder None Demolition & con struction sues Home insulation None None None Oil burner and lurnasc installation l( )> Auto body and used parts supply tOi None None Flea powder Accompanied owner to work lA H L t : M M l Iti 11 I* MK \N SI VSIS I >1 K l'g f V7I` >MS I . >g C sMS K Ntl S 'IM H li "< N Noln.lIKC'l t*tflirols 1 anccT contiol. Risk l.u.ti'1 Odds No 1il14 it r l onfidem c t MiIn S o limns r.tito H I " l onlidetu limits in' . | ) Stlv Ulti t14MCI OU lip.ttlun.il C\pMIICS Home remodeling 01 u'nNliikiion Aitili (i>>n ol hi me msuiuhon Home in vicinus ot asbestos- related mdustrs Occupation >1 hobbv asbestos related I'rhan tvs riunii residence of dog first residence 1ongest residence Residence at diagnosis Management ot do Source stray ss all other 1imc outside -stK 1 ss S(t>, Supervision allowed to roam v> vontincd Pesticides uscii on dofci 1 leu possder 1Ic.i Npr.iN i Ic.i dip 1 leu collar Anv pesticide 0 1) S : it H0 40 : <t :h t0 :o S0 0 ;s 1 11 0 X h 6 b \ 6 b 4 7 7 < it i i : 0 I-: n 0 4-10 b i 4-m n -- 0 -0 ' 0 N-|0 h 0 2--'l II 0 7 - 4 < (1 t_7 g 0 ' ->4 s o 4 -;s g 0 s-1 : : iii-'s i '- k: i 0 4 to 0H 0K * 2 i III i< 4 i : 11 1 0 10 -4 1N t 0 }t 1 ' JS 1 < 10 1 s 10 10 h s It b 0 l-l h n.M ; o it n-g ' (1 4-< t 0 4-1 4 -- -- o* -i: : 0 '-! g 0 4-ft Si 0 4 -s \ 0 4-< * -- o< " Num bci nt D iscoid.m t l l.urs . * S u l able to calculate. The cases w e ie .ill strass w hile the controls were o f know n origin S o l able io calculate. I he cases .ill had an uthnn residence w hile the controls had a rural residence IAHI I 1 11A s m m i i s I i m k ('< in n I is I i s i, I i s s i i m l ) m . s Patient ( jlcgory Age al Diagnosis 1>Calsi l iber t>pe (N o g dr> w l 1 -- Chrv solile Amphibole Mesothelioma 12 14 lit Lung Cancer A Squamous cell carcinoma B Bronchial alveolar carcinoma C Hronchinl-.ilveolnr carcinoma Controls'1 1) E E G H 1 10 h b 12 n s y fi h ft K .M IM I** 7.2iiui*> 22.000.1111 1.200.1*1) 210.(111 h V .IIII 2V111I ' ID.OOO VMM11) 2.`1*.l**l 1. MIMMI) 0 0 L 00.1*11 7t.(1D 4.m i.i*iu 210.1*1) 0 gl () 0 200 ("It 72tl (11 0 ' 40.1111 * Non-respirators disease and noncancer mesothelioma of 16.6 (CLgc* 6.4-97.3). When dogs 1 to 4 years of age were assigned a relative risk of 1.0 the greatest risk was observed in dogs 5 to 9 years of age (OR = 16.9, CLqc* 3.4-84.3). The risk for purebreed dogs vhen cccpared to dogs or3mixed breeding was 1.7 but this difference was not statistically significant (CLc0.51-5.9). The relative risk for individual purebreeds represented* by more than one dog with mesothelioma was Bouvier des Flandres (OR - 124.3, C U ,, 62.6-246.7), Irish Setter (OR - 5.3, CLq .. 1.4-9.6), and German Shepherd (OR - 3.3, C L ^ 1.3-8.2). The cancer and noncancer control patients represented a wide variety of diseases and conditions; not more than two dogs had the same diagnosis. Owners of 16 of the 18 mesothelioma patients were contacted and interviewed. The OR for suspected risk factors for canine mesothelioma are shown in Table 2. The findings were similar when mesothelioma patients were compared to either the cancer or noncancer control group. However, for 11 of the 14 risk factors studied, a stronger association with mesothelioma was noted in the analysis using the noncancer controls. Exposure of the owner to asbestos at work or through a hobby was found to be significantly associated with mesothelioma in the analysis using noncancer controls, (OR * 8.0, CLgc- 1.4-45.9); when cancer controls were vised the odds ratio was 2.3,*oCLt was not significant (CLqc 0.6-8.7). The relative risk for mesothelioma with both control groups combined was 3.5 ( C L ^ 1.1-11.0). Information on the use of pesticides and insect repellents was obtained because talc may be contaminated with asbestos and other mineral fibers. The relative risk for all forms of pesticides was elevated and was significant when any pesticide vise was considered in comparison to noncancer controls (OR-11.0, CL^e* 1.5-82.1). The risk associated with any pesticide use vhen the control groups were conbined was also significant (CR~ 7.6, CLqc* 1.2-49.0). Preliminary microscopic observations of seven comnercially available pet flea powders and sprays revealed large amounts of quartz, silicates, and silica, and small amounts of antigonite, a fiber closely related to chrysotile asbestos. While asbestos fibers were not specifically identified, exposure of humans to other mineral fibers has been associated with pulmonary disease (e.g., silicosis). Results of the lung tissue fiber analysis are presented in Table 3. The three dogs with mesothelioma had the highest levels of chrysotile fibers. The amphibole consisted of tremolite and actinolite, except in the case of control dog 1, where it was ccnmercial amphibole in the form of amosite and crocidolite. The authors stated that the tremolite and actinolite were probably contaminants of the chrysotile. references 1. ` Mantel, N. and Haenszel, W . , J. Natl. Cancer Inst., 22, 720 (1959) ~ 2. Miettinen, O.S., Biometrics, !>, 339 (1969) 3. Rothman, K.J. and Boice, J.D., U.S. Depart. Hlth, Edu. & Welf., NIH Publ., 79, 1949, Washington, D.C. 4. Blejer, H.A. and Arlon, R., J. Occup. Med., 15, 92 (1973) 2. An Animal Model for Inhalation Exposure to Talc; performed by Wagner, J.C., Berry, G., Hill, R.J., and Skidbore, J.W., In: Dust and Disease, ed. Lemen, R. and Dement, M.J., Pathotax. Publ. Inc., pp. 389-392 (1979) Methods: Ninety-six male and 96 female (barrier protected caesarian derived; Wistar strain) 6-8 week old rats were randomly allocated to one of the following groups: (a) talc - Italian 00000 grade (92% talc mineral, 32 chlorite and 12 carbonate minerals; quartz was found in the powder at 0.5-1.02 level); no asbestos minerals of either tremolite or chrysotile varieties were detected; (b) super fine chrysotile asbestos (SFA chrysotile); (c) controls - no exposure to either material. The animals were housed four to a cage except when in inhalation chanters (in a separate room) vrtien there were 6 to a cage. Rats were fed on a proprietary brand of autoclaved cubes and water ad libidjn; home cages were supplied with filtered air. There were sacrifices ten days after the end of each exposure period and at one year. The remaining animals were allowed to live until they died or appeared to be distressed. A full necropsy examination was carried out on all animals. The dust clouds were generated for 7% hours a day, 5 days a week. After 6 months' exposure half of the rats were removed and transferred to ordinary cages and were replaced by another 24 animals per dust. These rats were in turn removed and replaced after 3 months' exposure, and all exposure ceased after another 3 months (48 rats were exposed for 3 months, 24 for 6 months, and 24 for 12 months). The dosage was calculated as the product of concentration and time. The mean respirable dust concentration was 10.8 mg/mr for each dust and the cumulative doses, i.e., the product of concentration and time, were approximately 4100, 8200, and 16400 mg/nr hrs. for the 3-, 6-, and 12-month exposures. - 2- Results: Survival data were not presented. The amount of dust in die lungs was determined for the sacrificed rats. For talc, the mean amounts of dust in the lungs were 2.8, A.5, and 12.3 mg per rat at the end of exposures of 3, 6, and 12 months, respectively. In contrast, the amount of SFA crysotile was close to the detection limit of the method and was estimated as only 0.6 mg/rat after 12 months' exposure. An assessment was made of the severity of fibrosis in the lungs of rats sacrificed at the end of exposure and one year later (see Table 1 below). TABLE 1. Inhalation Experiment Mean Fibrosis at End of Exposure and One Year Later (Number of Rats) Matenal Italian talc Time End of exposure 1year later 3 months 2 2 (8) 2 4 (8) Length of exposure 6 months 2 7 (6) 34 (4) 12 months 34 161 4 6 141 SFA chrysotile End of exposure 1year later 2 8 (8) 2 2 (8) 30 (6) 3 2 (4) 3 2 16) 4 2 (4) C ontois End of exposure 1year later 18 (8) 1 6 (8) 1 9 (6) 1 5 (3) 1 3 16) 1 9 (3) The main features are that both Italian talc and SFA chrysotile produced fibrosis to a similar extent, and that there was some evidence of progression after exposure was discontinued in the longer exposed animals. The number of rats with lung tumors are shewn in Table 2. One adenoma occurred in the control group, two adenomata were observed in the rats exposed to talc, and 13 lung tumors, including one mesothelioma and 3 adenocarcinomata were observed in the SFA chrysotile group. TABLE 2. Inhalation Experiment Lung Tumors Matenal Italian Talc Exposure 3 months 6 months 12 months Number at risk' 39 18 24 Adenomas 0 0 2 Number of lung tumors Adenoma tosis Adeno carcinomas 00 00 00 SFA C hrysotile 3 months 6 months . 12 months 40 18 22 0 t 3 0 2 3 0 1 2 Controls 71 1 'Number surviving at least 300 days from start of exposure 0 0 Mesothef* lomas 0 0 0 1 0 0 0 references 1. Food and Cosmetics Toxicology (1973), Editorial, Living in a Cloud of Talc? Food and Cosmetic Tox., 11, 345-346 (1973) 2. Molnar, J.J., Nathenson, G., and Edberg, S., Fatal Aspiration of Talcun Powder by a Child, New Engl. J. Med., 266, 36-37 (1962) 3. Jacobziner, H. and Raybin, H.W., Accidental Chemical Poisonings: Camphorated Oil, Talcun Powder, and Lead Poisonings., N.Y.S. Journal of Med., 63, 3575-3577 (1963) 4. Jenkins, M.W., Dusting Powder Inhalation, J. So. Carolina Med. Assoc., 59, 62 (1963) 5. Hughes, W.T., and Kalmer, T., Massive Talc Aspiration: Successful Treatment with Dexamethasone., A. J. 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Newhouse, M.L., Berry, G. , Wagoner, J.C., and Turak, M.E., A Study of the Mortality of Female Asbestos Workers, Br. J. Indust. Med., 29, 134-141 (1972) 35a. Case, R.A.M. and Lea, A.J., Mustard Gas Poisoning, Chronic Bronchitis, and Lung Cancer, Br. J. Prev. Soc. Med., 9_, 62-72 (1955) 36. Graham, J. and Graham R., Ovarian Cancer and Asbestos, Environ. Res., 1, 115-128 (1967) -4- 37. Cramer, D.W., Welch, W.R., Scully, R.E., Wojciechowski, C.A., Ovarian Cancer and Talc: A Case-Control Study, Cancer, 50, 372-376 (1982) 38. Churg, A. and Wamock, M.L., Correlation of Quantitative Asbestos Body/Counts and Occupation in Urban Patients, Arch. Pathol. Lab. Med., 101, 629-634 (1977) 39. Langer, A.M., Baden, V., Hamnond, E.C., and Selikoff, I.J., Inorganic Fibers Including Chrysotile in Lungs at Autopsy: Preliminary Report, pp. 683-694 in W.H. Walton, ed., Inhaled Particles III, The Gresham Press (1971) 40. Pooley, F.D., Oldham, P.D., Chang-Hyun, U., and Wagner, J.C., The Detection of Asbestos in Tissues, pp. 108-116 in H.A. Shapiro ed., Pneunoconiosis. Proceedings of the International Conference in Johannesburg, Oxford Univ. Press, Cape Town (1970) 41. Wagner, J.C., Berry, G., and Pooley, F.D., Mesothelioma and Asbestos Type in Asbestos Textile Workers: A Study of Lung Contents, Br. Med. J. , 285, 603-606 (1982) 42. Wagner, J.C., Sleggs, C.A., and Marchand, P., Diffuse Pleural Mesothelioma and Asbestos Exposure in the North Western Cape Province, Br. J. Ind. Med., 17, 260-271 (1960) 43. Anderson, H.A., Lilis, R. , Dauv, S.M., and Selikoff, I.J., Asbestosis Among Household Contacts of Asbestos Factory Workers, Ann. N.J. Acad. Sci., 330, 387-399 (1979) 44. Weill, H., Asbestos-- A Sunming Up, IARC, 30, 867-873 (1980) 45. Peto, J., Dose-Response Relationships for Asbestos-Related Disease, Implications for Hygiene Standards, Part II, Mortality, Ann. N.Y. Acad. Sci., 330, 197 (1979) 46. 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Peto,2R. and Pike, M.C., Conservatism of the Approximation (0-E) /E in the Log Rank Test for Survival Data or Timor Incidence Data, Biometrics, 29, 579-584 (1973) 107. McDonald, J.C., Aspects of the Asbestos Standard, In: Gee, J.B.L., Morgan, K.C., Brodes, S.M., eds., Occup. Lung Disease, N.Y. Raven Press (1983) 108. Schneiderman, M.A., Safe Dose? Problem of the Statistician in the World of Trans-Science, J. Wash. Acad. Sci., 64(2), 68-78 (1974) 109. Peto, J., The Hygiene Standard for Chrysotile Asbestos, Lancet _I, 484-489 (1978) 110. Enterline, P., DeCoufle, P., and Henderson, V., Respiratory Cancer . in Relation to Occupational Exposures Among Retired Asbestos Workers, Br. J. Ind. Med., 30, 162-166 (1973) 111. Newhouse, M.L. and Berry, G., Predictions of Mortality from Msothlial Tunors in an Asbestos Factory, Br. J. Ind. Med., 33, 147-151 (1976) 112. Nevhouse, M.L., A Study of the Mortality of Workers in an Asbestos Factory, Br. J. Ind. Med., 26, 294-301 (1969) -lo rn. Liddell, F.D.K., McDonald, J.C., and Thomas, D.C., Methods of Cohort Analysis: Appraisal by Application to Asbestos Mining, J. R. Stat. Soc., 140, 469-91 (1977) 114. Letter to R.M. Schaffner fron Johnson and Johnson, dated September 6, 1974 .Study Ty|>e o f F i b e r No. Activity Type Exposure No. in (how measured*) Cohort Total Deaths (0/E) SMR No. mesothel iomas Iring C a n c e r Ohs exp. 9iR Slope Gastrointestinal Time Cancer since obs exp SMR RR first exposure 57 81 65 83 73 A mining mining chrysotile chrysotile uppcf 10,939(H) 4 4 6 3 (Hi " 1 0 ( H ) low: 2.5-4.2 medium: 4.3-9.4 high: 14.4-23.6 440(F) (1.06) 84(f) (0.9) 1(F) very high: 46.8 82.6 (1) 10-36T/'ml ---- 555-- 178-- ---- 1 (8) (1.11) " 2 3 0 184 '1725 ' 28 l l . T 275 "0715 276 272.4 1.01 " Z&T mppef-yr years nppef-yr " T O 0.30 9.5 1.05 20 yrs mining chrysotile Cumulative exposure <100 f/y >100 f/y (2,3) 952 friction materi als fricticxi materi als textile chrysotile chrocido- lite emulative exposure (f-y/ml) (6) 0-9 13,550-- 10-49 50-99 100-356 chrysolite nppcf yrs tr~ (1) level 2728" 3641 1>5 2.06 5>20 1.56 >20 1.06 Total 1.84 chrysolite "1951- 10.8 V c T crocido- 1972 - 2.9 f/cc lite 522 (M) 284 (F) (2,3) "132 ---- 1------ " 11 10.5 106 (1.55) 20 yrs: 1 1.7 59 20 yrs 20 yrs: (207) 10 8.7 115 20 yrs (137) " M 1339" 8 H (0.9) 151 139.5 1.09 F F 299 2 8 11.3 0.71 (0.9) "0717 f/ml-yr f/mlyrs 0.06 1267 0 73 148.7 0.16 293 (1.3) 24 (1.0) 9 1 51 23.8 2.1 F 3 0.9 3.3 19 19.3 20 yrs: 4 4.8 98 83 20 yrs: 15 14.5 103 103 107 0.96 29 27 1.1 59 114.4 16 15.7 1.02 20 yrs 20 yrs 20 yrs f r o m lU to greater tlian 20 yrs [Xiratlon of Exposure Type of Control Analysis method At least one month Quebec population a,b 20 y r s At least 30 days Canadian death rates National death rate (Italian) a,c At least 10 yrs National rates in U.K. a,d At least 1 month Connect icut rates e.f At least 10 yrs National death rates Study Type of Fiber No. Activity Type Exposure (how measured*) No. in Cohort cement chrysotile f-yr/ml products crocido- (mean) (1) lite A - .A B - 92 C - 180 70 P=production workers 18 yr-112.5f- yr/ml H=maintenance workers general manufac turing C=unexposed workers chrysotile n p p c f (1) crocidolite cimulative anosite dust exposure 67 <125 (62) 125-2A9 (182) 250-A99 (352) 500-7A9 (606) 750 + (976) general chrysotile manufac- crocidolite f/ml turing amosite 2 6A (textiles 5 5-10 insula- 20 tion m a t e r i a l s ) _______ insula- chrysotile ( 6) tors crocidolite A-12 7A anDsite f/ml 328 186 1075 A600 (M) 922 (f) 632 Total deaths (0/E) No. mesothelionias Lung Cancer Slope Gastrointestinal Cancer _______________________________ O b s E x p S M R R R Time since first exposure Duration of Exposure Type of Control Analysis method 125 11 37 5.6 6.6 f/ml-yr 8 5.A 1.A8 A.82 20-33 yrs at least Ontario 9 yrs ' death rates 58 (1.7) 10 20 3.3 6.1 K-0.067 2.5 1.6 18 yrs 781 (1.2) 5 5A5 (1.2A) 200 (1.69) A6 21 19 197.9 9 180.0 19 327.6 9 A50.0 7 777.8 63 270.0 103 A3.2 2.A 27 3.2 8.A 55 39.9 l.A 0.658 nppcf-yr retired workers A0 3A 20 10.2 118 196 from 10-30 yrs Ave. 25 yrs (3-51) US male population g variable national death rates of U.K. A78 38 93 13.3 699 A3 15.1 285 20+yrs U.S. death -Y f" ) Study Type of Fiber No. Activity Type Exposure (hew measured*) No. in Cohort insula chrysotile tors anosite <i-12 74 f/ml 17,800 (6) general clirysotile mppet manuf. crocidolite 1348 amosite <125 88 125-2A9 250-400 500-749 cenemt 750+ T645 products crocidolite w/in 20 yrs initial exposure mppef-yr 87 (1 ) <10 11-50 51-100 101-200 . >200 Total deatlis (0/E) No. mesothelicmas Lung Cancer 2271 (1.4) 175 429 105.6 4.60 754 (115) not reported 58 21.7 267.3 Slope Gastrointestinal Cancer PA .0107 94 1.01 (f/m/yr) CJCP oru\ K K 59.4 1.67 Time since first exposure under 20 yrs o v e r 20 years 53 41.8 126.8 20 yrs (0.7) "TT T 9 24.7 .77 11-50 T T 1 . 4 .70 51-100 ~ T 3.8 .26 101-200 " 9 9.1 2.90 >200 ~ W 6.2 2.26 mppcf- yr .44 10 24.6 10 11.9 3 4.2 03 2 6.4 .41 .84 .71 - .31 Total TT! 49.2 1.0 Total T T 50.1 0.5 >20 yrs Duration of Exposure Type of Control Analysis method U.S. death rates ave. 25 yrs urban population US males - US and L o u i s i a n a (a) death rates '.i-'- k * `V - \\. }y f Study Type of Fiber No. A c t i v i t y T y p e Fjqxtsure (how measured*) No. in Cohort lextile chrysotile emulative 579 crocidolite e x p o s u r e (1,5) 84 (f/ml-yrs) 100-400+ 30f/ml (ave.) Textile chrysotile mppcf crocidolite (ave. dust cone.) 2410 yrs level < r^ "o r IS 1 ,<5 1.86 5,<20 1.67 >20 1.23 Total 1.8 (1) Textile chrysotile nppcf ~w n amositc (ave. dust crocido- cone.) 86 lite <P level T75 l.<5 2.40 5,<20 2.73 >20 1.58 Total (1) 2.32 Total No. dcaLlis m e s o t h e l - (0/E) iomas 201 7 857 (1.27) 1 lung Cancer 28 18.6 1.5 Slope Gastrointestinal Time Cancer since Obs 1/ml-yr ~ 1 4 1.0 Exp SMR R R 17.6 1.1------ first exposure 10-30 yrs 12 4.65 2.6 10-25 yrs 66 (not given) 8.2 36 (not given) 59 199.5 mpef.y 26 0.059 151.7 at least 10 yrs 20 yrs Duration of Exposure Type of Control Analysis method at least 10 yrs national death rates at least one month S.Carolina rates e,f 1392 (SMR= 109) 14 70 53 105 n p c f .y 0.051 73 54 20 yrs 112.7 at least Penna. 1 month rates e,f Analysis method used (a) m a n - y e a r s m e t h o d - c a s e (b) c a s e - L e a - m u l t i p l e cont r o l s analysis (c) M c D o n a l d & L i d d e l l (d) cas e - c o n t r o l - L i d d e l l (e) M a n t e l - H a e n s z e l l o g - r a n k m e t h o d (f) m a n - y r s life table m e t h o d - Hill (g) m o d i f i e d lif e t a b l e m e t h o d - Enterl i n e Exposure measurement procedure ( 1) midget inpinger ( 2) m e m b r a n e filter collec t i o n (3) p h a s e contrast m i c r o s c o p y thermal precipitator (5) st a t i c m e m b r a n e filter 6( ) s i n u l a t e d conditions (7) ac t u a l conditions ( 8 ) NIOSH methods (9) ( 10) n o t sta t e d r ' , - * ?rV; ' h-t -.. /. - v w ' - 7 7 , 7 7 ; ;S i. 'i 7 Risk Assessment I Exposure, la b o ra to ry , and e p id e m io lo g ic a l d a ta provided e a r l i e r in t h i s r e p o r t a re u sed in t h i s c h a p te r to make q u a n t i t a t i v e and q u a lita tiv e (o r co m p arativ e) assessm en ts of r is k s from exposure to a s b e s t i f o r m f i b e r s . To p l a c e th e d i s c u s s i o n in c o n t e x t , th e c h a p t e r b e g in s w ith a b r i e f g e n e ra l d is c u s s i o n o f r i s k a ss e ssm e n t and a few sp e c ia l c o n s id e ra tio n s co n cern in g a sb e sto s and re la te d fib ro u s m a te ria ls . V arious d i f f i c u l t i e s o fte n lim it the accuracy and p re c is io n w ith w hich r i s k to human h e a lt h can be e s tim a te d . N e v e rth e le s s , when the d a ta base is good, th e r i s k e s tim a te s can be s u f f ic i e n tl y in fo rm a tiv e to a i d p o l i c y ju d g m e n ts . Some o f th e f a c t o r s t h a t e n h a n c e th e u s e f u l n e s s o f the d a ta in c lu d e d o se -re s p o n s e in f o rm a tio n b ased on s e v e r a l a c c u ra te ly known ex p o su re le v e ls ; know ledge of p h y sio lo g ic and m e ta b o lic f a c to r s th a t a f f e c t exposure o f body t i s s u e s ; an u n d e rsta n d in g o f the m echanism by w hich the su b stan ce r e s u l t s in to x i c it y ; know ledge o f the e x te n t to w hich e x p e r im e n ta l sy stem s mimic -the human re s p o n s e ; and an u n d e rsta n d in g o f the p ro p e r tie s o f a complex and v a ria b le substance th a t account for its to x ic ity . Many o f th e s e i s s u e s a p p ly in th e a s s e s s m e n t o f r i s k from a sb e s tifo rm f ib e r s , w hich have v ary in g p h y sic a l and chem ical p r o p e r t i e s . Some m em bers o f th e c l a s s , th e commonly u s e d n a t u r a l l y o c c u rrin g form s o f a s b e s to s , have been c l e a r l y shown to cau se f i b r o s i s of the lung and p le u ra as w ell as c an cer o f the lung, m esothelium , and p o s s i b l y th e g a s t r o i n t e s t i n a l t r a c t in h u m an s. Some o c c u p a t i o n a l d a t a on o th e r f i b e r s a re a ls o a v a ila b le , and c o n s id e ra b le numbers of e x p e rim e n ta l s tu d ie s have been c o n d u cte d . I t is re a s o n a b le from a b io lo g ic a l v iew p o in t to use d a ta from o c c u p a tio n a l s tu d ie s to d e riv e e s tim a te s o f r i s k from n o n o c c u p a tio n a l ex p o su re . However, d if f e r e n c e s in ro u te of ex p o su re, type and c h a r a c t e r i s ti c s of fib e r , exposure le v e ls , and tim e p a tte r n s m ust be c o n sid e re d . M oreover, because w orking p o p u latio n s are g e n e ra lly h e a lth ie r than the pu b lic a t la rg e , the l a t t e r may c o n t a i n a h i g h e r p r o p o r t i o n o f m ore s u s c e p t i b l e i n d i v i d u a l s . THE PROCESS OF R IS K ASSESSMENT The p r i n c i p l e s g u id in g th e a sse ssm e n t o f h e a lt h r i s k s from en v iro n m en tal su b sta n c e s were re c e n tly review ed by a com m ittee o f the 200 201 N atio n al R esearch C ouncil (1983). These to provide a framework fo r a s s e s s in g the asbestiform fib e rs. p r in c ip le s a re sum marized h ere h e a lth r is k s from exposure to The num erous term s used to d e s c r ib e d i f f e r e n t a s p e c ts o f r i s k assessm ent include "hazard assessm ent," "hazard id e n tific a tio n ," "risk assessm ent," " q u a lita tiv e risk assessm ent," "dose-response assessm ent," "com parative r is k a ssessm en t," " q u a n tita tiv e r is k asse ssm e n t," and " ris k c h a r a c t e r i z a t i o n . " The use o f th e s e term s has n o t been s ta n d a rd iz e d . Three co n cep ts are g e n e ra lly in c o rp o ra te d in to the r is k assessm ent p rocess. F ir s t is the id e n tif ic a tio n of the kinds of harm ful h e a lth e f f e c t s , e . g . , anem ia, b ir th d e f e c ts , o r c a n c e r, th a t can r e s u lt from s u f fic ie n t exposure to a substance. Second is the dose-response curve fo r a p a r t i c u l a r e f f e c t , i . e . , th e s e v e r ity o f damage a n d /o r the p e rc e n ta g e o f p eo p le o r an im als l i k e l y to be a t v a rio u s ex p o su re le v e ls. Third is the number o f people in a p a r tic u la r p o p u latio n , e .g ., re s id e n ts of the U nited S ta te s or w orkers in a p a r tic u la r in d u stry , lik e ly to be harmed under p a s t, p re s e n t, o r p ro je c te d le v e ls and conditions of exposure. In th is re p o r t, the com m ittee has used " r is k assessm ent" as a broad term encom passing a l l th re e of th ese c o n cep ts. "Hazard id e n tif ic a tio n " re fe rs to the f i r s t concept, "d ose-response" curves or re la tio n s h ip s are used in d isc u ssio n s o f p a r tic u la r s e ts o f d a ta , and " q u a n tita tiv e ris k a ss e ssm e n t" r e f e r s to th e e s tim a te s o f r i s k to humans d e riv e d by m ath em atical e x tr a p o la tio n s from th e s e d a ta . "P o p u la tio n r i s k e stim a te s" d escrib e the expected frequency or incidence of a harm ful e f f e c t in a s p e c if ic group o f humans u nder d e fin e d c o n d itio n s of exposure. The am ount a n d c o m p l e x i t y o f i n f o r m a t i o n n e e d e d i n c r e a s e a s we p ro g ress from hazard id e n t if ic a t io n to d o se-resp o n se assessm ent to p o p u la tio n r i s k e s tim a tio n , a lth o u g h each s te p b u ild s on the p reced in g one. Hazard id e n t if ic a t io n c h a ra c te riz e s the n a tu re o f to x ic e f f e c ts th a t a su b stan ce is capable of cau sin g in la b o ra to ry anim als o r humans. D o se-resp o n se c u rv e s b ased on e x p e rim e n ta l o r e p id e m io lo g ic a l o b se rv a tio n s d e fin e the frequency and som etim es the s e v e r ity o f th ese toxic e ffe c ts a t sev eral le v e ls of exposure. The d o se -re sp o n se in fo rm a tio n is used in q u a n tita tiv e r i s k e s tim a tio n . Through m a th e m a tic a l m o d elin g and a p p li c a ti o n o f known b i o l o g i c a l p r i n c i p l e s , a tte m p ts a re o f t e n made to e s tim a te r i s k f o r dose le v e ls , exposure c o n d itio n s , or sp e c ie s o th e r th an th o se fo r w hich dose-resp o n se d a ta have been o b tain ed . For exam ple, q u a n tita tiv e ris k assessm en ts o fte n r e ly on d o se -re sp o n se d a ta from s tu d ie s o f la b o ra to ry anim als exposed to r e la tiv e ly high exposure le v e ls in o rd e r to estim a te the r i s k to humans exposed to low er le v e ls . A ssum ptions and u n c e rta in tie s involved in the a p p lic a tio n of q u a n tita tiv e ris k a ssessm en t to c a n c e r in d u c tio n have been d is c u s s e d e x te n s iv e ly (Food J 202 S a fe ty C o u n cil, 1980; I n te r n a tio n a l R e g u la to ry L ia iso n Group, 1979; O ffice of Technology A ssessm ent, 1981). P o p u la tio n r is k e s tim a te s b rin g to g e th e r q u a n tita tiv e r is k e stim a te s and d a ta on exposure o f a s p e c ific group o f humans to id e n tif y t h e i r r i s k under a c tu a l o r a n tic ip a te d exposure co n d itio n s. The m ost r e l e v a n t in f o rm a tio n fo r c a te g o r iz in g th e h a z a rd o r the d o se-resp o n se fo r humans is d eriv ed from s tu d ie s of exposed humans. U n fo rtu n a te ly , ev id en ce from th is source is o fte n u n a v a ila b le or in c o n c lu s iv e a t tim es when d e c is io n s ab o u t a c c e p ta b le ex p o su re m ust be m ade. Humans a re e x p o se d to so many d i f f e r e n t s u b s ta n c e s th ro u g h fo o d , m edicines, a i r , w ater, household m a te ria ls , and o ccu p atio n al en v iro n m en ts th a t s o r t i n g out th e c a u se s o f h arm fu l e f f e c t s on h e a lth is o fte n d i f f i c u l t . Perhaps of most im portance is the fa c t th a t evidence of human h e a lt h h a z a rd s from s u b s ta n c e s in tro d u c e d in t o o u r environ m en t can n o t be o b ta in e d d i r e c t l y from o b s e r v a tio n s in humans u n t i l p eo p le have been harmed. For th e se re a s o n s, ev id en ce from la b o ra to ry anim als o r from o th e r b io lo g ic a l te s t system s is o fte n used as an a lte r n a tiv e or as a supplem ent to d a ta on humans. A s u b s ta n tia l body of evidence has dem onstrated the u t i l i t y of th ese ex p erim en tal system s (D oull e t a l . , 1980; N a tio n a l R e search C o u n c il, 1977; Richmond e t a l . , 1981). A v a rie ty of m athem atical m odels have been developed fo r using d ata at high d o ses, u s u a lly only a v a ila b le from s tu d ie s in an im als, to e stim a te r i s k s f o r humans a t low d o se s (A rm ita g e , 1982; C o r n f ie ld 8 1 . , 1978; Crump e t a l . , 1976; F is h b e in , 1980; Food S a f e t y C o u n c il, 1980; K rew ski and Van R y z in , 1981; Van R y z in , 1 9 8 0 ). B ecau se t h e r e a r e e x t e n s i v e d a ta on th e e f f e c t s o f a s b e s to s and some o t h e r f i b e r s in hum ans, th e q u a n tita tiv e r is k assessm en ts in th is c h a p te r are based e x c lu s iv e ly on d a ta from e p id e m io lo g ic a l s tu d ie s in humans, w hereas th e com parative r i s k a sse ssm e n ts a ls o tak e in to c o n s id e r a tio n d a ta from la b o ra to ry s tu d ie s. E very s c i e n t i f i c s tu d y o r te c h n iq u e h a s some lo w er l i m i t to i t s s e n s i t i v i t y . A s e n s i t i v e m ethod in a n a l y t i c a l c h e m i s t r y may be c a p a b le o f d e te c tin g a few m o le c u le s o f a p a r t i c u l a r c h e m ic a l among a b i l l i o n o th e r k in d s o f m o le c u le s b u t in c a p a b le o f d e t e c t i n g a few among a t r i l l i o n . The s e n s i t i v i t y o f an anim al t e s t fo r t o x i c i t y i s lim ite d by many f a c t o r s , su ch a s th e num ber o f a n im a ls t h a t i t i s p r a c t i c a l to study, the s u b tle ty of the e ffe c t of in te r e s t, the occurrence of sim ila r e f f e c ts in anim als not exposed to the m a te ria l under t e s t , and lim ita tio n s on the amounts o f m a te ria l th a t can be a d m in iste re d and on th e m ethods used to a d m in is te r them. O ther d i f f i c u l t i e s lim it the power o f ep id em io lo g ical stu d ie s. For exam ple, i t is o fte n d i f f i c u l t to s e le c t a p p ro p ria te c o n tro l groups, e stim a te ex p o su re, or d e te c t h e a lth e f f e c ts from the exposures of c o n c e rn , e s p e c i a l l y i f th e e x p o su re s a re much low er th a n th o se th a t o c c u r among o c c u p a tio n a l g ro u p s . S e v e r a l k in d s o f in f o r m a tio n a re u s e f u l f o r e s t i m a t i n g r i s k s a t low exposure le v e ls on th e b a s is of o b s e rv a tio n s a t h ig h e r e x p o su res. These include the shape of the d o se-response curve in the range of exposures s tu d ie d , know ledge o f th e m echanism by w hich the type of to x ic e f f e c t o c c u rs, and in fo rm a tio n on d o s e - r e la te d changes in the u p tak e, d is tr i b u ti o n , chem ical o r p h y sic a l m o d ific a tio n , and e x c re tio n of the substance, i . e . , pharm acokinetics. S ubstances vary m arkedly both in the q u a n tity re q u ire d to produce a to x ic e f f e c t and in the r a p id ity w ith w hich the in cid en ce of to x ic e f f e c ts d ecreases w ith d ecreasin g dose, i . e . , the shape of the d o s e -re s p o n s e c u rv e . In an ex p e rim e n t c o v e rin g a s u f f i c i e n t l y wide ra n g e o f e x p o s u r e l e v e l s , i t i s p o s s i b l e to f i n d some l e v e l s t h a t a r e t o x i c and some lo w e r l e v e l s a t w h ich no t o x i c i t y i s o b s e r v e d . The h ig h e s t dose a t w hich no to x i c it y is seen is o fte n c a lle d the " n o - o b s e r v e d - e f f e c t l e v e l , " o r NOEL ( K l a a s s e n a n d D o u l l , 1 9 8 0 ) . H owever, any e x p e rim e n t w i l l have some l i m i t in i t s s e n s i t i v i t y to sm a ll e f f e c t s , a n d t h e t r u e n o - e f f e c t - l e v e l , i f a n y , m ay b e b e l o w t h e NOEL i n a p a rtic u la r experim ent. T h e f u n d a m e n t a l a s s u m p t i o n u n d e r l y i n g t h e NOEL s a f e t y f a c t o r a p p ro a c h i s t h a t some m in im al l e v e l o f a to x i c s u b s ta n c e i s r e q u i r e d to c a u se damage and t h a t th e s u b s ta n c e is n o t to x i c b elo w t h a t l e v e l . The NOEL t y p e o f e x p e r i m e n t i s u s e d t o f i n d t h a t l e v e l . The maximum d o se a t w hich no t o x i c i t y w ould o c c u r i s c a l l e d th e " th re s h o ld " fo r th a t s u b s ta n c e . However, s e v e r a l m ath em atical models f o r q u a n t i t a t i v e e s t i m a t i o n o f c a n c e r r i s k assum e th a t th e r e i s no t h r e s h o l d ; r i s k d im in is h e s w ith d e c r e a s in g d o s e , b u t some r i s k is assumed to rem ain as long as th e re is any exp o su re. The d e te r m i n a ti o n o f w hich o f th e s e two a ss u m p tio n s is c o r r e c t w i l l probably depend on the n atu re of the to x ic e f f e c t. Thus, understanding the m echanism o f to x i c i t y can p ro v id e g u id an ce in s e ttin g a c c e p ta b le ex p o su re le v e l s . For a su b s ta n c e t h a t e x e r t s i t s to x ic e f f e c t by in a c tiv a tin g an enzyme p re s e n t in abundance in each c e l l , i t is re a so n a b le to assume th a t a th re s h o ld would e x i s t . I n a c tiv a tio n of a few m o l e c u l e s o f t h e en z y m e i s u n l i k e l y t o d a m a g e t h e c e l l . On t h e o th e r hand, a chem ical th a t is m utagenic or carcin o g en ic because it d a m a g e s s o m e c r i t i c a l s i t e o n a DNA m o l e c u l e t h a t s t a r t s t h e carc in o g e n ic p ro cess can reaso n ab ly be assumed not to have a th re sh o ld . The l i k e l i h o o d t h a t a c r i t i c a l s i t e w ould be damaged w ould d e c re a s e w ith d e c re a s in g d o se, but th e p o s s i b i l i t y th a t t h i s damage could o ccu r rem ains a t any exposure above zero . F o r many e f f e c t s , th e s e v e r i t y o f th e to x ic e f f e c t , as w e ll as the p ro b a b ility th a t i t w ill o ccu r, a ls o d e c re a se s w ith dose. For exam ple, a d o se t h a t dam ages a h ig h p r o p o r t i o n o f c e l l s in th e l i v e r may be l e t h a l ; one t h a t dam ages a m o d e r a te n um ber may c a u s e s e v e r e i l l n e s s b u t n o t d e a t h ' a sm a ll d o se t h a t c a u s e s damage to a few c e l l s may n o t le a d 204 to any c l i n i c a l sym ptom s. The e r r o r tr u ly e x is te d would g e n e r a lly n o t be of disease in th is situ a tio n . in assum ing expected to a th resh o ld if none lead to se rio u s cases By c o n t r a s t , t h e s e v e r i t y o f c a n c e r and o f m u t a t i o n s i s n o t r e l a t e d t o t h e d o s e o f th e s u b s t a n c e c a u s i n g th e m . Low d o s e e x p o s u r e t o x - r a y s o r c i g a r e t t e smoke c a u s e s few er c a n c e rs th a n d o es h ig h dose e x p o s u re , b u t t h e r e s u l t i n g c a n c e r s a r e j u s t a s l e t h a l . T h u s, a l t h o u g h t h e r e may be some s u b s t a n c e s t h a t show a t h r e s h o l d f o r c a n c e r i n d u c t i o n (H o el e t a l . , 1983), an e r r o r in assum ing a th r e s h o ld when none r e a l l y e x i s t s w ould s e v e r e ly harm th o s e p e rs o n s who g o t th e d is e a s e d e s p i t e a low exposure. A ccurate docum entation of exposure is im portant fo r d eterm ining the d o se -re sp o n se c u rv es fo r t o x i c i t y in an im als o r humans and a ls o fo r estim atin g pop u latio n ris k s . E rrors in the estim atio n of exposure w ill lead to e r r o r s in d e fin in g th e d o se -re sp o n se curve and in making q u a n tita tiv e risk estim ates for in d iv id u als or sp ecific populations. The am ount o f a to x i c s u b s ta n c e o r i t s a c t i v e m e t a b o li te t h a t r e a c h e s the body s ite th a t is s u s c e p tib le to i t s e ff e c t is the exposure th a t accounts fo r to x ic ity , but such m easures are alm ost never a v a ila b le (Hoel t a_l., 1983). O ther m easurem ents, such as amounts in th e blood, amounts e n te r in g th e body, o r c o n c e n tra tio n s in the a i r o r w a te r o f a com m unity, a re o f te n u s e f u l s u r ro g a te s , b u t as n o ted e a r l i e r in th is re p o rt, they are a lso o fte n u n a v a ila b le . The s e n s i t i v i t y o f th e exposed p o p u la tio n is a n o th e r c o n s id e ra tio n i n th e r i s k e s t i m a t i o n p r o c e s s . Some i n d i v i d q a l s may be m ore s e n s i t i v e than o th e rs to sp e c ific environm ental in s u lts because o f n u tr itio n a l d e fic ie n c ie s , g e n e tic p re d is p o s itio n , and fo r c h ild re n , sm all body siz e , developm ental im m aturity, and in c re a se d m etab o lic and re s p ira to ry ra te s (C alab rese, 1978, 1980). W ith t h e i r ra p id m e ta b o lic r a t e , c h ild re n consume p ro p o r tio n a te ly more food and in h a le g r e a t e r volum es o f a i r th a n an a d u lt f o r a g iv en body w e ig h t. T hus, th ey would a ls o consume o r in h a le p r o p o r tio n a te ly more o f any c o n ta m in a n ts th a t a re p re s e n t (B abich and D av is, 1981). Human i n f a n t s do n o t h a v e m a tu re h e p a t i c d e t o x i f i c a t i o n s y s te m s u n t i l th ey re a c h 2 to 3 m onths o f age (P elkonen e al^., 1973; Rane and Ackerman, 1972). Serum im m unoglobulin does n o t a t t a i n a d u lt le v e ls u n t i l c h i l d r e n a r e 10 t o 12 y e a r s o l d ( C a l a b r e s e , 1 9 7 8 ) . S t u d i e s i n a n im a ls have a ls o d e m o n s tra te d a g r e a t e r s e n s i t i v i t y among th e young a f t e r exposure to ch em icals by a v a r i e ty o f ro u te s (G o ld e n th a l, 1971). C h il d r e n 's lu n g s may a l s o be e s p e c i a l l y s e n s i t i v e to e n v iro n m e n ta l p o llu ta n ts. Tager t (1983) have observed m easurable d iffe re n c e s in lung fu n c tio n betw een c h ild r e n o f sm oking m others and c h ild r e n whose m others d id n o t smoke. 205 P o p u latio n r is k e s tim a tio n is based on a l l th e p reced in g s te p s . F ir s t, the exposure of the study p o p u la tio n m ust be known. H eterogeneity o f the p o p u latio n w ith re sp e c t to le v e l o f exposure or s e n s itiv ity to the to x ic m a te ria l should a ls o be co n sid ered in the c a lc u la tio n s. Exposure, dose-response curves, d is trib u tio n of s e n s itiv ity fa c to r s , and the s iz e of the p o p u la tio n are then used to e stim a te the number of people lik e ly to s u f f e r to x ic e f f e c ts from the su b sta n c e o f i n t e r e s t . I f the m a te r ia l c a u se s more th a n one ty p e o f toxic e ff e c t, each e ffe c t req u ires sep arate c a lc u la tio n s. Id e a lly , c a lc u la tio n of ris k is an o b je c tiv e , s c ie n tif ic a c tiv ity ' d e v o id o f p o l i c y ju d g m e n ts . The l a t t e r a re made s e p a r a t e l y when d e c id in g th e a c c e p ta b le le v e l o f e x p o su re . However, p o lic y d e c is io n s can seldom be d iv o rc e d co m p letely from th e p ro c e ss o f r i s k a ssessm en t. The re a s o n f o r t h i s l i e s in th e u n c e r t a i n t y o f many o f th e s c i e n t i f i c judgm ents r e q u ir e d . For exam ple, i f one e x p e rim e n ta l s p e c ie s is more s u s c e p tib le to the to x ic ity of a m a te ria l than a n o th e r and d a ta on humans are u n a v a ila b le , w hich s p e c ie s should be used fo r e s tim a tin g human r i s k ? Which m a th e m a tic a l m odel sh o u ld be a p p lie d to th e d a ta ? These and many o t h e r q u e s tio n s o f judgm ent w ere d is c u s s e d in th e re c e n t N atio n al R esearch C ouncil (1983) re p o rt. In the fo llo w in g s e c tio n s , th e com m ittee has used e p id em io lo g ical d a ta , m ostly from o c c u p a tio n a l s e ttin g s , to develop a q u a n tita tiv e model * of the r e la tio n s h ip betw een f ib e r dose and ca rc in o g e n ic response fo r a g e n e ra liz e d " a s b e s to s " ex p o su re r e s u lti n g in e i t h e r lung c a n c e r o r m esotheliom a. That d o se-response re la tio n s h ip is then ap p lied to a h y p o t h e t i c a l , b u t re a s o n a b le , e x p o su re le v e l to show p o t e n t i a l p o p u la tio n r is k le v e ls in p o p u la tio n s of a r b itr a r y s iz e . In the fin a l s e c tio n , the com m ittee a ss e sse s r is k s fo r o th e r types of f ib e r s and, in some c a s e s , f o r o t h e r d i s e a s e s by q u a l i t a t i v e c o m p a riso n s w ith th e b a se case of a generalized asbestos exposure. QUANTITATIVE RISK ASSESSMENT In the p rev io u s c h a p te rs , the com m ittee e x te n s iv e ly review ed in fo rm atio n on the h e a lth e f f e c ts o f a sb e sto s and o th e r a sb e stifo rm fib e rs . In p rep arin g th is se c tio n , i t a ls o reviewed sev eral ris k assessm en ts fo r a sb e s to s in the open l i te r a tu r e and in governm ent d o c u m e n t s . On t h e b a s i s o f i t s e v a l u a t i o n o f t h e q u a l i t y a n d c o v e r a g e o f the in fo rm a tio n and the assessm ent te c h n iq u e s, the com m ittee decided th a t a q u a n tita tiv e assessm en t o f th e r i s k s fo r m esotheliom a and lung c a n c e r from n o n o c c u p a tio n a l e x p o su re s to a s b e s to s would be m ean in g fu l. I t a ls o co n clu d ed th a t th e in fo rm a tio n b ase was i n s u f f i c i e n t fo r u s e fu l q u a n tita tiv e assessm en ts fo r o th e r f ib e r ty p es and d is e a s e s , but th a t in some c a s e s a q u a l i t a t i v e , c o m p a r a tiv e a s s e s s m e n t was f e a s i b l e and u s e f u l. These d e c is io n s do not mean th a t the a s b e s to s assessm en t is w ith o u t m ajor u n c e r ta in tie s nor does i t mean th a t the com parative assessm en ts-are of poor q u a lity . In both c a se s, the o b je c tiv e is tc 206 p resen t inform ation u sefu l fo r ev alu a tin g the h e a lth risk s of asb estifo rm fib e rs in nonoccupational s e ttin g s . F ir s t, an overview of m athem atical m odels fo r c a rc in o g en ic r is k assessm ent is p resen ted to provide a co n tex t fo r the assessm ents fo r lung c a n c e r and m esotheliom a, w hich a re o f p r in c ip a l i n t e r e s t . Next, th e re is a review of s e v e ra l assessm en ts fo r a sb e s to s th a t were based su c h m o d e ls . F i n a l l y , t h e s e a s s e s s m e n t s and t h e c o m m i t t e e 's own analyses are ap p lied to the inform ation p resen ted in e a r lie r ch ap ters produce q u a n tita tiv e ris k e stim a te s fo r nonoccupational exposures to asb esto s in am bient a ir . on to M ath em atical Model fo r C arcin o g en ic R isk E stim ate As e x p l a i n e d e a r l i e r , i t i s n o t n e c e s s a r y t o u s e d a t a on a s b e s t o s exposure from anim al ex p erim en ts to e s tim a te r is k s fo r humans, but i t is n e c e ss a ry to e x tr a p o la te from the h e a lth e f f e c ts observed a t high o c c u p a tio n a l l e v e l s o f e x p o su re to much lo w er n o n o c c u p a tio n a l expo su res. O ccupational epidem iology makes i t p o ss ib le to d e sc rib e the p ro b a b ility of dying from a p a r t ic u l a r type o f c an cer as a fu n c tio n of age a t f i r s t ex p o su re, le v e l and d u ra tio n o f ex p o su re, and c u rre n t age. M athem atical e x tr a p o la tio n m odels based on th e m u ltis ta g e th eo ry of c a r c in o g e n e s is make i t p o s s ib le to e s tim a te th e p r o b a b i l i t y o f d y in g from th a t type o f c a n c e r fo r d if f e r e n t ages a t f i r s t ex p o su re, d if f e r e n t (low er) exposure le v e ls , and d if f e r e n t (o fte n longer) d u ra tio n of e x p o s u r e , a l s o a s a f u n c t i o n o f c u r r e n t a g e . By c o n s i d e r i n g t h e cum ulative p ro b a b ility throughout a life tim e , the "life tim e ris k " of c a n cer m o r ta lity can be com puted. At any a g e , an i n d i v id u a l fa c e s some p r o b a b i l i t y o f re a c h in g an end p o in t th a t is re la te d to can cer in the next y e a r, fo r exam ple, dying of lung c a n c e r. Suppose th a t a t a g iv en age, a, th e p r o b a b ility is g iv e n by p ( a ,d ) , w here d is th e dose o f th e c a rc in o g e n -- in th i s c a se , a s b e s t o s . When d = 0 , p ( a , 0 ) i s th e p r o b a b i l i t y o f th e end p o i n t f o r u n ex p o sed p e o p le . I f t i s some age o f i n t e r e s t , th e n th e c u m u la tiv e p r o b a b ility P ( t ,d ) o f re a c h in g th e end p o in t b e fo re th a t age is g iv e n by th e sum o f th e a n n u a l p r o b a b i l i t i e s up to t h a t a g e : P ( t , d ) * th e sum o f p ( a , d ) o v e r a l l a g e s , a , < t. (1) R eaching the end p o in t by tim e t is analogous to the " f a ilu r e tim e" fo r a g e n e ra liz e d sy stem th a t i s no lo n g e r e f f e c t i v e a f t e r tim e t . G en eral m a th e m a tic a l a n a ly s is can be used to show t h a t th e p r o b a b i li ty o f f a ilu r e as a fu n c tio n o f tim e can be w r itte n as fo llo w s: P (t,d ) = 1 - e - I ( t ,d ) > (2) where I ( t , d ) re p r e s e n ts th e cu m u lativ e in c id e n c e fu n c tio n (o r cu m u lativ e hazard fu n ctio n ) of occurrence of the o b servable f a ilu r e p r io r to tim e t. 207 Arm itage and D o ll (1 9 6 1 ), P eto e t a l . (1 9 8 2 ), K a lb fle is c h and P re n tic e (1980), H a rtley and S ie lk e n (1977), H a rtle y t a l. (1981), and K alb fleisch e t a l. (1983) have a p p lie d th is model to c a rc in o g e n e sis. If the c u m u la tiv e in c i d e n c e l ( t , d ) i s s m a ll , th e n e q u a t i o n (2 ) may be simplified t o P (t,d ) i I(t,d ), (3) where = means a p p ro x im a te ly . In c a rc in o g e n ic r is k asse ssm e n t, a t t e n t i o n is u s u a lly focussed on the cum u lativ e in cid en ce fu n c tio n l ( t , d ) r a th e r than on the p ro b a b ility fu n c tio n P ( t , d ) . The A rm ita g e -D o ll (1961) m u ltis ta g e th e o ry o f c a r c i n o g e n e s i s s u g g e s t s t h a t l ( t , d ) c a n be w r i t t e n as a p r o d u c t o f two term s-- g (d ), depending only on d o se, and h ( t ) , depending only on tim e. That is , l( t,d ) - g(d) h (t). (4) If th ere are k dose-dependent sta g e s in the process of carcin o g en esis and the ra te of tra n sfo rm a tio n from one stag e to the next is assumed to be a li n e a r fu n c tio n o f d o se , th e fu n c tio n g (d ) would be a p o ly n o m ial o f d eg ree k in th e d o se . The f u n c tio n h ( t ) depends o n ly on tim e . T his model and i t s g e n e r a liz a tio n and j u s t i f i c a t i o n have been d is c u sse d by Crump e t l . ( 1 9 7 6 ) , H a r t l e y ejt 1 . ( 1 9 8 1 ) , a n d K a l b f l e i s c h e t a l . (1983). To d e te r m in e th e v a lu e s o f th e c o n s t a n t s in th e p o ly n o m ia l g ( d ) and th e f u n c tio n a l form f o r h ( t ) , th e c u m u la tiv e in c id e n c e fu n c tio n m ust be f i t t e d to d a ta -- p r e f e r a b ly to d a ta based on o b s e rv a tio n s in human p o p u la tio n s . The m u l ti s t a g e m odel d e s c r ib e d above has been f i t t e d s u c c e s s f u l ly to many s e t s o f c a n c e r d a ta , in c lu d in g d a ta on a s b e s to s , and ap p ears a t p re s e n t to be a g e n e ra lly adequate model fo r a ss e ssin g cancer r is k . F ittin g eq u atio n (4) to d a ta involves e stim atin g the c o n s t a n t s in th e m odel f o r some s u i t a b l y d e te r m in e d f u n c t io n h ( t ) . T h is model has been a p p lie d to b o th m esotheliom a and lung c a n c e r d a ta on a s b e s to s - e x p o s e d w o rk e rs . The form o f h ( t ) and th e v a lu e s o f th e c o n s t a n t s from th o s e s t u d i e s w i l l be d is c u s s e d in th e n e x t s e c t i o n . The fu n c tio n g (d )-- and thus the cum ulative ex cess in cid en ce fu n c tio n l ( t , d ) -- can be appro x im ated as a li n e a r fu n c tio n o f dose in the low -dose range th a t e q u a ls 0 when d 0. T his r e l a ti o n s h ip can be used fo r e x t r a p o l a t i n g from h ig h to low d o se s and h as th e fo llo w in g form : I(t,d ) * cdh(t). (5) T his form assum es th a t th e re is a t le a s t one d ose-dependent sta g e o f c a n c e r d e v e lo p m e n t. The arg u m en t f o r a l i n e a r (w ith r e s p e c t to d o se ) approxim ation fo r low -dose exposures has been j u s t i f i e d on the b a s is th a t the exposure dose d is added to a background le v e l (H oel, 1980; P e to , 1 9 7 8 ). T h is a s s u m p tio n may n o t a lw a y s be j u s t i f i e d in a p p l i c a t i o n 208 ( s e e C o r n f i e l d e t a l . , 1978 and Van R y z in , 1 9 8 1 ), b u t i t s h o u ld le a d t o an a p p ro p ria te upper bound fo r the co m m ittee's r is k assessm en ts fo r a s b e s to s . F u rth e rm o re , and more im p o rta n tly , r u lin g o ut a li n e a r dose te rm f o r a s b e s t o s e x p o s u r e d o e s n o t seem j u s t i f i e d by th e d a ta now a v a ila b le (N icholson, 1983; P eto, 1982; Schneiderm an e t a l . , 1981). Thus, the model adopted fo r r is k assessm ent in the next th re e se c tio n s o f t h i s c h a p te r is b ased on th e c a n c e r m o r t a l i t y in c id e n c e c a lc u la te d by equation (5). PUBLISHED RISK ASSESSMENTS T h is s e c t i o n re v ie w s some p u b lis h e d r i s k a s s e s s m e n ts f o r lu n g c a n c e r and m esotheliom a. These assessm en ts h elp ed the com m ittee s e le c t a f u n c t i o n a l form f o r h ( t ) f o r th e two d i s e a s e s and to e s t a b l i s h th e v a lu e of the co n stan t c in eq u atio n (3 ). Lung C ancer R isk from N o n o ccu p atio n al E n v iro n m en tal E xposures The fo llo w in g summary o f r i s k a s s e s s m e n ts f o r lung c a n c e r from a s b e s to s e x p o su re s is based on d a ta on ex p o su re o f w orker p o p u la tio n s . These d a ta su g g est th a t the fu n c tio n l ( t , d ) in e q u atio n (5) becomes I ( t ,d ) * c*T0d I0 ( t ) , (6) w h e r e Tq is t h e d u r a t i o n o f e x p o s u r e t o a s b e s t o s a t d o s e d , I o ( t ) i s the cu m u lativ e m o r ta lity in cid en ce fo r lung c a n c e r up to age t fo r those who h av e n o t b e e n e x p o se d to a s b e s t o s , and c* i s a c o n s t a n t t h a t d ep en d s on th e c o h o r t u n d e r s t u d y , b u t n o t on d o se o r a g e . As u s e d in eq u atio n (6) and in the rem ainder of th is se c tio n , d is the c o n c e n tra tio n o f f i b e r s in th e w orkplace a i r , u s u a lly m easured in f i b e r s / c m ^ . A lth o u g h d i s r e f e r r e d to a s d o s e , some a u t h o r s w ould c a l l i t d o se r a t e and w ould r e f e r t o th e p r o d u c t Tgd a s ( c u m u la t iv e ) dose. E quation (6 ), d e riv e d by Peto (1982), is c o n s is te n t w ith h is e a r l i e r stu d ie s of c h ry s o tile w orkers (P eto , 1978). This eq u atio n is a l s o s u p p o r te d by f o u r s t u d i e s re v ie w e d by N ic h o ls o n (1 9 8 3 ), who n o te d th a t the r e la tiv e r is k o f lung can cer death s fo r asb esto s w orkers com pared to a s i m i la r p o p u la tio n was l i n e a r l y r e l a te d to th e accum ulated dose y e a rs, i . e . , fib ers/cm ^ x y e a rs, or (fib e rs/c m ^ iy r. In equ atio n (6 ), the underlying incidence ra te Ig (t) is co n sid er ably d if f e r e n t fo r sm okers and nonsm okers of each sex. T h erefo re, the ris k s fo r each o f th e se groups m ust be a ss e sse d s e p a r a te ly . A nother consequence o f e q u a tio n (6) is th a t th e r e l a t i v e r is k o f lung c a n c e r due to a s b e s to s ex p o su re does not depend on age a t f i r s t ex p o su re. Thus, lif e lo n g r is k o f lung can cer r e s u ltin g from exposure to a s b e s to s can be c a l c u l a t e d q u i t e sim p ly by u s in g e q u a tio n ( 6 ) . As exam ple, c o n sid e r the fo llo w in g c a lc u la tio n g iv en by Peto (1982). an V 209 C o n s i d e r t h e e f f e c t o f 10 y e a r s o f e x p o s u r e a t 1 f i b e r / c m 3 . i f we assume t h a t th e r e l a t i v e r i s k f o r lu n g c a n c e r among i n s u l a t i o n w o rk ers i n c r e a s e d a p p r o x i m a t e l y f o u r f o l d [Hammond e a_l. ( 1 9 7 9 ) r e p o r t e d 4 . 2 f o r nonsm okers and 3.9 fo r sm okers] and th a t t h i s r i s k is based on a c u m u la tiv e d o se o f 600 f ib e r s /c r a 3 (20 y e a r s a t 30 f i b e r s / c m 3 ) , th e n 10 y e a r s o f e x p o s u r e t o 1 f i b e r /c m 3 w i l l i n c r e a s e th e r e l a t i v e r i s k by 4 . 0 x 1 0 / 6 0 0 * 0 . 0 6 7 . S i n c e a p p r o x i m a t e l y 15% o f l i f e l o n g s m o k e r s d i e of lung c a n c e r, th i s m o r ta lity ra te w ill in c re a se to 0.15 x 1.067 x 100, o r 16%. T h u s, t h e d i f f e r e n c e (1%) i s t h e e x c e s s d ue t o a s b e s t o s a s p r e d i c t e d by th e e q u a t i o n . S in c e o n ly 0.5% o f n onsm okers d ie o f lung c a n c e r, t h i s w ould become 0.533% (0 .0 0 5 x 1.067 x 100) f o r an added r i s k o f 0.033% due to a s b e s t o s e x p o s u r e . M esotheliom a R isk from N onoccupational E nvironm ental Exposures The co m m ittee re v ie w e d two e s t im a ti o n s o f m e so th e lio m a r i s k , one by P e to and h i s c o lle a g u e s ( P e to , 1982; P eto e t a l . , 1982) and th e o th e r by N icholson (1983). These a n a ly s e s and t h e i r consequences a re summarized in th is sectio n . U s in g t h e d a t a o f S e l i k o f f et^ a_l. ( 1 9 7 9 ) on m o r t a l i t y among 1 7 ,8 0 0 members o f th e I n t e r n a t i o n a l A s s o c ia tio n o f Heat and F ro s t I n s u la to r s and A s b e s t o s W o r k e r s , P e t o t al_. ( 1 9 8 2 ) show ed t h a t t h e m o r t a l i t y r a t e from m esotheliom a in th e se w orkers was dependent on the tim e sin c e f i r s t e x p o s u re , b u t d id n o t depend on th e age a t f i r s t e x p o s u r e . From t h i s fin d in g , and the a p p lic a tio n of the m u ltista g e theory of carcin o g en esis through e q u a tio n (5 ), the cum ulative in cid en ce fu n c tio n becomes: I( t,d ) = cd (t - t 0 )k , (7) w here t - t q r e p r e s e n t s tim e s in c e f i r s t e x p o s u re a t age to* F o r any g ro u p o f w o rk e rs ex p o sed a t th e same d o se le v e l d, th e p ro d u c t cd = b is a c o n sta n t depending on the type o f a sb e sto s exposure. E quation (7) su g g ests th a t the r is k fo r m esotheliom a is p rim a rily dependent on the tim e s in c e f i r s t e x p o su re ( t - t g ) . T his same phenomenon was n o te d by Schneiderm an e t a l. (1981) and N icholson (1 9 8 3 ). F it ti n g e q u a tio n (7) w i t h b = c d t o t h e d a t a o f S e l i k o f f et_ ajL. ( 1 9 7 9 ) f o r men u p t o a g e 80 by th e m ethod o f maximum l i k e l i h o o d e s t i m a t i o n r e s u l t e d in an e s t im a te o f k * 3 . 2 w i t h a s t a n d a r d e r r o r o f + 0 . 3 6 a n d b = 4 . 3 7 x 1 0 " . U s i n g t h i s c a l c u l a t i o n , P e t o t_ a l . ( 1 9 8 2 ) e s t i m a t e d t h e l i f e l o n g m e s o t h e l i o m a r i s k f o r t h i s w o r k e r g r o u p t o b e 1 5 % , 7%, a n d 3% f o r a g e a t f i r s t exp o su res o f 20, 30, and 40 y e a rs , r e s p e c tiv e ly . These fig u re s have been a d ju ste d fo r o th e r com peting causes of d eath . U sing e q u a tio n (7) w ith k * 3 .2 , P eto and c o lle a g u e s d eterm in ed th a t b x 10 r a n g e s i n v a l u e f r o m 2 . 9 4 t o 5 . 1 5 f o r f o u r o t h e r s e t s o f d a t a (see T able 7 -1 ). Using k * 3 .5 , P eto (1982) com puted a lif e tim e m e s o t h e l i o m a r a t e o f 1 i n 1 0 0 ,0 0 0 c h i l d r e n e x p o s e d fro m a g e 12 t o a g e 18 0' I 7 210 TABLE 7 - 1 . M esotheliom a D eath R ates In V arious S tu d ie s and P re d ic tio n s of R isk3 Study P o p u latio n and R eference N orth A m erican in s u la tio n w o rk ers' (m ixed ex p o su re) S e lik o ff e t a l . , 1979 F a c to ry w o rk ers (m ixed exposure) Newhouse and B e rry , 1976 C hrysotile te x tile fa c to ry w orkers P eto, 1980b A ustralian cro cid o lite m iners Hobbs e a l . , 1980 U .S. a m o site fa c to ry w orkers Seidm an e t a l . , 1979 R e la tiv e R isk (b x 108 ) 4.37 4 .9 5 2.94 5 .1 5 4.91 C orresponding L ifetim e R is k (%)b by Age a t F ir s t Exposure (y rs) 20 30 40 15 7 3 17 8 3 10 5 2 17 8 3 17 8 3 a A dapted from P eto e t a l . (1 9 8 2 ). The d e a th r a t e a t tim e t - tg s in c e f i r s t exposure a t ag e tg i s p ro p o rtio n a l to b, o b ta in e d by f i t t i n g eq u atio n (7) w ith k * 3.2. 8The c a lc u la tio n o f " lif e tim e r i s k , " i . e . , th e p e rc e n ta g e o f s im ila rly ex p o sed men who w ould d ie o f m eso th elio m a b e fo r e ag e 8 0 , i s based on an a c t u a r i a l c a lc u la tio n u s in g 1977 U .S. r a t e s f o r w h ite m ales f o r a l l cau ses o f d eath o th e r th an m esotheliom a in f la te d by a f a c to r o f 1 .2 6 , the o b serv ed r e l a t i v e r i s k among in s u la t io n w o rk ers ( S e lik o f f e t a l . , 1979). ( i . e . , 6 y e a rs o f sch o o l a g e ) , assum ing th e f i b e r le v e l was 0.003 fib e r/c m 8 (1/1,000 o f th e exposure of th e in s u la tio n w orkers). A se c o n d r i s k a s s e s s m e n t w as done by N ic h o lso n (1 9 8 3 ), who c r i t i c i z e d th e P e t o ejt a l . ( 1 9 8 2 ) a n a l y s i s f o r f i t t i n g e q u a t i o n ( 7 ) t o o n l y t h o s e men who d ie d of- m e s o th e lio m a up t o a g e 8 0 . By i n c l u d i n g a l l i n s u l a t i o n w o r k e r s , he estim ated k to be 5.0. quantitative risk assessment for nonoccupational environmental exposures As a s t a r t i n g p o i n t f o r a s s e s s i n g t h e r i s k fro m n o n o c c u p a t i o n a l enviro n m en tal exposure to a s b e s tifo rm f i b e r s , th e com m ittee adopted e q u a tio n (6) as re p r e s e n tin g th e cu m u lativ e m o r ta lity up to age t , which is a p p r o p r i a t e f o r lu n g c a n c e r in d u c e d by a c o n tin u o u s e x p o su re o f Tq y e a r s a t dose le v e l d in fib ers/cm ^. This model im plies th a t any given to ta l dose b e fo re tim e t w ould have th e same e f f e c t on th e r e l a t i v e r i s k a t tim e t , r e g a r d le s s o f th e tim e a t w hich ex p o su re s t a r t e d o r i t s d u r a tio n . The model th u s ig n o r e s a minimum la te n c y p e r io d , w hich m ig h t c a u se th e m odel to o v e re stim a te e f f e c ts , but a ls o ig n o res th e d if fe re n c e betw een exposures a t e a r l i e r and la t e r a g e s, w hich m ight cause th e model to u n d e re stim a te e f f e c ts . E q u atio n (7) was assum ed to be a re a s o n a b le r e p r e s e n ta t io n o f th e cu m u lativ e m o r ta lity from m esotheliom a up to age t fo r c o n tin u o u s exposure to a s b e s t o s a t d o s e l e v e l d i n f i b e r s / c m ^ fro m a g e tQ u n t i l a g e t . In t h i s c a se , la te n c y is im p lic itly in clu d ed in th e dependence on ( t- tQ ) , because k i s g r e a t e r th a n 1, b u t no minimum la t e n c y i s assum ed. These a ss u m p tio n s a r e s u p p o r t e d by t h e w o rk o f P e t o ( 1 9 8 2 ) , P e t o ejt al_. ( 1 9 8 2 ) , N i c h o l s o n (1 9 8 3 ), and S chneiderm an e a l . (1 9 8 1 ), who e x te n s iv e ly rev iew ed th e b a s is for th e se assum ptions by exam ining th e m odels and th e i r c o n siste n c y fo r se v e ra l observed w orker co h o rts exposed to am bient co n c e n tra tio n s o f asb esto s fib e rs . These au th o rs have suggested th a t asb e sto s a c ts as a la te -s ta g e carcin o g en in producing lung can cer b u t a c ts a t e a r l i e r sta g e s in the developm ent o f m esotheliom a. U sing th e s e m odels, th e com m ittee developed li f e t im e e s tim a te s o f r i s k fo r lung c a n c e r and m eso th elio m a m o r ta lity from continuous n o n o ccu p atio n al exposures to 0.0004 fib ers/cm ^ and fo r 0.002 fibers/cm ^. For lung c a n c e r, th e com m ittee a ss e sse d th e r i s k fo r fo u r exposure subgroups: m ale sm okers, fem ale sm okers, m ale nonsm okers, and fem ale nonsm okers. For m eso th elio m a, o n ly one c a lc u la ti o n was made, s in c e e q u a tio n (7) and the su p p o rtin g d a ta in th e papers c ite d above su g g est th a t m esotheliom a m o r ta lity does n o t depend on sex o r sm oking h i s t o r y , b u t does depend s tro n g ly on age a t f i r s t exposure. L ifetim e R isk E stim ates fo r Lung C ancer and M esotheliom a Table 7-2 sum m arizes life tim e r i s k e stim a te s fo r lung can cer and m esotheliom a fo r n o n o ccu p atio n al en v iro n m en tal exp o su res to 0.0004 fibers/cm ^ (a m edian le v e l) and 0.002 fib ers/cm ^ (a high le v e l) . I t is assum ed t h i s e x p o s u r e i s c o n tin u o u s from b i r t h th r o u g h a l i f e t i m e o f 73 y e a rs , an approxim ate av erag e lif e tim e in th e U nited S ta t e s . Thus, in e q u a ti o n s (6 ) and ( 7 ) , t * 73 y e a r s and d * 0 .0 0 0 4 o r 0 .0 0 2 . In e q u a ti o n ( 6 ) , Tq * 73 a n d i n e q u a t i o n ( 7 ) , t(j * 0 t o a c c o u n t f o r c o n t i n u o u s exposure. Because eq u atio n s (6) and (7) a re lin e a r in the dose u n it d, one can im m ediately o b ta in from T able 7-2 li f e tim e r i s k s a t o th e r co n tin u o u s (from b ir th ) en v iro n m en tal ex p o su res by m u ltip ly in g by th e a p p ro p ria te dose f a c t o r . F o r e x a m p l e , l i f e t i m e r i s k e s t i m a t e s a t 0 . 0 2 f i b e r s / c m ^ a r e 10 tim es h ig h er than the e stim a te s a t 0.002 fib e rs/c m ^ . V E. 212 TABLE 7 - 2 . E stim ated In d iv id u a l L ife tim e R isks from a C ontinuous E xposure to A sbestos a t 0.0004 F ib ers/cm ^ (a M edian Dose) o r 0 .002 F ib e rs/c m ^ (a High D ose)a D isease Lung can cer^ Lung can cer Lung c a n c e r Lung can ce r M esotheliom a E x p o su re Group M ale sm oker Female smoker Male nonsm oker Female nonsm oker A ll Estim ated Ind iv id u al M edian Exposure (0.0004 fib e rs/c m ^ ) L ifetim e R isk x 106 High E xposure (0.002 fib ers/cm ^ o O CM 64 (0 to 23 (0 to 110) 320 (0 to 1 ,5 0 0 ) 120 (0 to 530) 6 (0 to 22) 29 (0 to 130) 3 (0 to 13) 15 (0 t o 6 6 ) 9 (0 to 350) 46 (0 to 1 ,7 0 0 ) a L ife tim e assum ed to be 73 y e a rs ; ex p o su re o c c u rs from b i r t h . Lung can cer r is k s a re c a lc u la te d w ith c * * 1.02 o r an ex cess r is k o f 2 \ per ( fib e r/c m ^ )y r, e stim a te d from n in e s tu d ie s w ith v a rie d r e s u lts . M e s o t h e l i o m a r i s k s a r e c a l c u l a t e d w i t h c = 2 . 5 3 x 10~ a n d k * 3 . 2 , e stim a te d from fiv e s tu d ie s w ith v a rie d r e s u l t s . See a ls o e x p la n a tio n s in te x t. ^Sex d iffe re n c e s fo r lung cancer r is k a re due to d iffe re n c e s in lung cancer background r a t e s a s s o c ia te d w ith sm oking p a tt e r n s , o c c u p a tio n a l e x p o su res, and o th e r fa c to rs . cRange o f e s tim a te s . The low er lim it o f 0 is alw ays p o s s ib le i f lin e a r e x tr a p o la tio n o v e re s tim a te s r i s k . See a ls o te x t below . The e s tim a te s in T able 7-2 w ere based on th e fo llo w in g fiv e con sid eratio n s: Exposure le v e ls . A m ix o f indoor and o u td o o r m easured exposure le v e ls was used to s e le c t th e m edian v a lu e o f 0.0004 fib e rs/c m ^ and the h igh v alu e o f 0.002 fib ers/cm ^ as th e re fe re n c e le v e ls . Use o f th e li n e a r m odel. The m odels used by th e com m ittee a l l assume low -dose li n e a r i ty and, as such, produce h ig h e r e stim a te s o f ris k a t low d o se s th a n w ould be o b ta in e d w ith o t h e r m o d e ls. However, b ecau se th e o c c u p a tio n a l d a ta do n o t r u le o u t low -dose l i n e a r i t y , the com m ittee b e lie v e s th a t th ese e stim a te s do not unduly o v e rs ta te the r is k s . C ount-m ass c o n v e r s io n . The c o n v e rs io n o f a m b ie n t f i b e r m ass m easurem ents to an e q u iv a le n t number o f f i b e r s was b ased on m easurem ents I 213 0f mass and num bers o f f i b e r s in th e w o rk p la c e . The co m m ittee r e a l i z e d , how ever, t h a t th e num ber o f f i b e r s in am b ien t a i r w ould be much g r e a t e r because th ese fib e rs tend to be sm aller than those in the w orkplace (see Chapter 4 ) . D epending on th e t o x i c i t y o f sm all f i b e r s , th e r is k s could be g r e a t e r o r le s s th a n th o s e c a lc u la te d in t h i s c h a p te r . I f th e p resen ce of long f ib e r s is n e c e ss a ry fo r a to x ic re s p o n se , r is k s would be low er. Model d ep en d en ce. The r e s u l t s o f th e m eso th elio m a m odel depend very h e a v ily on th e v a lu e o f k. This acco u n ts fo r th e la rg e range of e stim ates fo r m esotheliom a. I t is assumed th a t th is dependence on k among w o rk e rs h o ld s f o r th e e n t i r e p o p u la tio n th ro u g h o u t a l i f e t i m e . I f the dependence is no t as stro n g ( i . e . , a low er k v a lu e ), th e low er end of the ran g e w ould a p p ly . I f th is dependence is as s tro n g ( i . e . , a h ig h e r k v a l u e ) , th e u p p e r bound may be m ore a p p r o p r i a t e . C hildhood e x p o su re . The m odels used fo r e x tr a p o la tio n fo r both lung c an cer and m esotheliom a a re based on th e assum ption th a t a u n it dose o f e x p o su re (m easured a s f ib e rs /c m ^ > 5 ym lo n g ) in e a r l y l i f e is eq u iv alen t in its in tr in s ic carcin o g en ic p o te n tia l to a u n it dose in la te r l i f e . I f c h ild re n a re more b io lo g ic a lly s e n s itiv e th an the w orker group, th e r i s k per u n it dose w ould be in c re a s e d . R e su lts from s tu d ie s o f exposure to o th e r m a te r ia ls in d ic a te th a t c h ild re n a re o fte n more s e n s i tiv e th an a d u lts to a g iv e n d o se , even when e x p re s se d as d o se/body w e ig h t. The r i s k e s tim a te s and ra n g e s shown in T able 7-2 a r e th o s e th e com m ittee c o n sid e rs m ost re a s o n a b le . Because o f th e u n c e rta in v alu e o f k and the s e n s iti v it y o f e q u a tio n (7) to i t s v a lu e , the range of e stim a te s i s m u c h l a r g e r f o r m e s o t h e l i o m a t h a n f o r l u n g c a n c e r . Two c o n c l u s i o n s can be drawn from th e e s tim a te s in T able 7-2: For nonsm okers, th e lif e tim e r i s k fo r m esotheliom a from non o c c u p a tio n a l en v iro n m en tal exposure to a sb e s to s is h ig h e r than fo r lung can cer. For sm okers, how ever, the r is k s o f lung cancer are s u b s ta n tia lly h ig h er than fo r m esotheliom a, because o f the m u ltip lic a tiv e in te ra c tio n o f sm oking and a s b e s to s e x p o su re s. In d iv id u a l li f e t im e r i s k e s tim a te s fo r lung ca n c e r from n o n o c c u p a t i o n a l e n v i r o n m e n t a l e x p o s u r e s t o 0.0004 fibers/cm^ a r e m u c h lower th an th e r is k s observed fo r sm oking. The b a s i s fo r th e c a l c u l a t i o n s in T able 7-2 is d is c u s s e d in d e t a i l in th e fo llo w in g two s u b s e c tio n s . C a lc u la tio n o f th e Lung C ancer R isk E stim ates in T able 7 - 2 . C alcu la tin g lif e tim e r i s k e s tim a te s from e q u a tio n (6) in v o lv e s th e n o tio n of r e l a t i v e r i s k u p t o tim e t , d e s i g n a t e d h e r e a s RR. From e q u a t i o n ( 6 ) , t h e RR f o r l u n g c a n c e r b y a g e t c a n b e s h o w n a s f o l l o w s : 214 I(t,d ) I0 (t) (8) * cu m u lativ e lung c a n cer m o r ta lity by age t a t dose d b a s e lin e c u m u la tiv e lu n g c a n c e r m o r ta l it y by age t - c*(T 0d ), where (Tgd) * to t a l d o se -y e a rs fo r th e exposed group and c* is a co n stan t th a t depends on the c o h o rt. For a g iv en stu d y show ing an in c re a se d r e l a t i v e r i s k fo r lung can c e r, c* = (1 + P /1 0 0 ) , (9) where P is the p ercen tag e in c re a se in [2 p e r ( f i b e r s / c m ^ l y r ]. S ch n eid erm an values o f P fo r nine d if fe re n t w orker summarized in T able 7-3. lung cancer r is k per u n it dose e t a l. (1981) p resen ted the c o h o r t s . The r e s u l t s a re V alues fo r P in T able 7-3 range from 0.06 (Study 8) to 9.1 (Study 1 ). The h ig h e r v a lu e e s t a b l i s h e s th e u p p e r end o f th e ra n g e g iv e n in T able 7 -2 . The z e ro v a lu e fo r th e low er end o f th e ran g e in d ic a te s th a t th e low -dose l i n e a r a p p ro x im a tio n in e q u a tio n (3) may o v e r s t a t e r i s k . The m edian v a lu e fo r P in th e s tu d ie s shown in T able 7-3 i s P * 1.1 (Study 7 ). This v a lu e , rounded upward to 2, was used in o b ta in in g th e e s t i m a t e s f o r l i f e t i m e l u n g c a n c e r r i s k i n T a b l e 7 - 2 . To c a l c u l a t e t h e s e e s tim a te s , i t was n e c e s s a ry to know o n ly th e b a s e lin e a b s o lu te r i s k s fo r th e a p p r o p r ia te s u b p o p u la tio n s . The b a s e l in e c u m u la tiv e in c id e n c e r a t e s o f lu n g c a n c e r f o r th e fo u r su b g ro u p s in T ab le 7-2 h av e b e e n e s tim a te d by Schneiderm an e t a l . (1981) as fo llo w s: m ale sm okers * 0 .1 1 ; fem ale sm okers * 0 .0 4 ; m ale nonsm okers * 0 .0 1 ; and fem ale nonsm okers * 0.005. T hus, u s i n g 22 a s a v a lu e f o r P, th e l i f e t i m e r i s k o f lu n g c a n c e r fo r a male smoker is (0 .1 1 K 1 + P/100) - (0 .1 1 )(1 + 0.02) * 0.1122. (10) The in c r e a s e d l i f e t i m e r i s k a t t r i b u t a b l e to a s b e s to s ex p o su re a t 1 fiber/cm ^ fo r 1 y ear is 0.0022, i . e . , 0.1122 - 0.1100. At the am bient exposure o f 0.0004 fib ers/cm ^ assumed in Table 7-2 and fo r a 73-year lif e tim e ex p o su re, th e in c re a se d lif e tim e r i s k o f lung c an cer 6 .4 2 x 10~^, i . e . , 0 .0 0 2 2 x 0 .0 0 0 4 x 73. R ounding t o two s i g n i f i c a n t f i g u r e s g iv e s th e e s t im a te in T ab le 7 -2 f o r m ale sm o k ers. The o th e r c a lc u la tio n s in th a t ta b le were d eriv ed in a s im ila r fash io n . is When d e s c r i b i n g th e u s e o f th e p e r c e n t a g e s g iv e n i n T a b le 7 - 3 , S ch n eid erm an e t a l . (1981) comm ented t h a t th e low p e r c e n ta g e in c r e a s e s r i s k in S tu d ie s 3, 6, 8, and 9 p ro b ab ly r e s u lte d from s e v e r a l f a c to r s . In Study 3, fo r exam ple, th e s u b je c ts w ere r e t i r e e s o ld e r th an 65. in 215 TABLE 7 - 3 . E stim ated In c re a s e in Lung C ancer R isk p e r U nit of Exposure to A sb esto s3 O- ,, X /2J Study N o . __ O ccupation of W orker C ohort A sb esto s Type Percent Increase in Lung C ancer R isk per ( fibers/cm 3)yr R eferen ce 1 Insulation A rao site m anufacturing 2 A sbestos C rocidolite, product manu- ch ry so tile, fa c tu rin g and am osite 9.1 1.3 m ales 8.4 fem ales 3 A sbestos A m osite and 0.3 m anufacturing ch ry so tile; some c r o c i d o l i t e 4 A sbestos C hrysotile; 1.1 p ro d u c t manu some amos i t e fa c tu rin g and c ro c id o lite 5 T extile C hrysotile p ro d u c tio n 5.3 6 T extile C hrysotile p ro d u c tio n 0.07 e a rly em ployeesb 0.8 la te r em ployeesb 7 Insulation m anufac tu rin g C hrysotile and am osite 8 M ining C hrysotile and m illin g 9 M ining C hrysotile and m illin g 1.7 0.06 0.15 Se idm an t a ^ . , 1979 Newhouse and B e rry , 1979 Henderson and E n terlin e, 1979 N icholson e t a l . , 1979 D e m e n t e_t al_. , 1982 P e to , 1980 S elikoff e 1979 , McDonald and L i d d e l l , 1979 N icholson e t a l . , 1979 a A d a p t e d f r o m T a b l e 4 i n S c h n e i d e r m a n e t _ jal_ , 1 9 8 1 . ^ E arly em ployees began work b e fo re o r d u rin g 1950. a f t e r 1950. L a te r em ployees began work 216 S c h n e id e rm a n e t a l . s t a t e d t h a t th e i n v e s t i g a t o r s may th u s hav e m isse d a sb e sto s-re la te d ""3 e a th s o c c u rrin g a t e a r l i e r ag es. In Study 6, the d is e a se r a te s fo r w orkers em ployed e a r l i e r were low er th an those em ployed l a t e r who w ere fo llo w e d f o r s h o r t e r p e r i o d s . The d is c r e p a n c y h as d im in is h e d as more d a ta have a c c u m u la te d . The s u b j e c t s in S tu d ie s 8 and 9 were m ining and m illin g w orkers whose exposure p a tte r n s were q u ite d i f f e r e n t from e n v ir o n m e n t a l a m b ie n t a i r e x p o s u r e s . T h ere i s a l s o some e v id e n c e t h a t many lung c a n c e r c a s e s w ere m isse d in S tu d ie s 8 and 9 because of com peting causes of d eath a t e a r l i e r ages. Thus, Schneiderm an e 1 . (1981) concluded th a t th e range from 1.1 (Study 4) to 9 .1 (S tu d y 1) is th e m ost r e p r e s e n t a t i v e o f t r u e v a lu e s . The v a lu e o f P = 2 used in the c a lc u la tio n s in Table 7-2 f a l l s n e a r the bottom of t h i s r a n g e , b u t i s w i t h i n a f a c t o r o f 5 o f t h e t o p o f t h e r a n g e . I f we use P = 5, w hich is th e m iddle o f the ran g e, the lung c an cer r is k e s tim a te s in T able 7-2 would be m u ltip lie d by a f a c to r o f 2 .5 . C a l c u l a t i o n o f M e s o th e lio m a R is k E s t i m a t e s . To c a l c u l a t e th e lif e tim e r is k w ith e q u a tio n (7 ), th e numbers c and k must be d e te r m ined. Then the life tim e r is k L a t d = 0.0004 fib e rs /c m 3 , assum ing t = 73 and t g = 0 ( c o n t i n u o u s e x p o s u r e fro m b i r t h t o ag e 7 3 ) , i s L = c(0.0004)(73)k. (11) To a p p ly t h i s e q u a t i o n , c and k m u s t be e s t i m a t e d fro m e p i d e m i o l o g i c a l s tu d ie s of o c c u p a tio n a l exposures to a sb e s to s. Each study must be s t r a t i f i e d by d u ra tio n o f exposure ( t - t g ) to e stim a te th ese p a ra m e te rs. Most o f th e fo llo w in g a n a ly s is is s im ila r to th a t of P e t o ejt a_l ( 1 9 8 2 ) . F i r s t , l e t u s c o n s i d e r th e c h o ic e o f k . As n o te d e a r l i e r , when P e to e jal. (1982) f i t t e d e q u a tio n (7) they obtained the eq u atio n l ( t ,d ) k = 3 . 2 +_ 0 . 3 6 ( s t a n d a r d e r r o r ) . to the d ata of S e lik o ff e t a l. (1979), = b ( t - tg)32f w i t h b = 4 . 3 7 a n d I n e q u a t i o n ( 1 1 ) , t h e r e f o r e , we in i ti a ll y use k = 3.2. M o d ificatio n s using d iffe re n t values fo r k w ill give the range of e s tim a te s fo r d 0.0004 fib e rs/c m 3 in Table 7-2. F o r d = 0 .0 0 2 f i b e r s / c m 3 , we r e p l a c e 0 . 0 0 0 4 w i t h 0 . 0 0 2 i n e q u a t i o n (1 1 ). W ith k * 3 .2 , P eto e a l . (1982) a ls o f i t t e d fo u r o th e r d a ta s e ts to o b t a i n f o u r v a l u e s o f b i n t h e e q u a t i o n l ( t , d ) = b ( t - tg)3,2. The v a lu e o f b i s s p e c i f i c to e a c h w o rk e r c o h o r t and d ep en d s on th r e e numbers: d (th e average fib er/c ra3 ex p o su re), l (th e average le n g th of ex p o su re), and t - t g (th e average tim e sin ce f i r s t ex p o su re). These v alu es are g iv en in Table 7-4. In a d d itio n , Table 7-4 c o n ta in s the e stim ates of c th a t are a p p ro p ria te fo r eq u atio n (7 ), based on the c o r r e s p o n d i n g e s t i m a t e o f b g i v e n b y P e t o e t aJL. ( 1 9 8 2 ) . W h e n e x p o s u r e is not co n tin u o u s from tim e of f i r s t exposure (tg ) to th e age o f o b se rv a tio n ( t) fo r th e se s tu d ie s , the r e la tio n s h ip betw een b and c changes from c = b /d to 4 .5 6 b/d 1 - [ 1 - Z / (t-tg)]3 * 2 * (12) 217 TABLE 7 - 4 . E stim ated C onstants fo r E quations (11) and (12) fo r Five S tudies study b x 10 da fa t - t 0 a c x 10( S elikoff e t a l . , 1979 Ncwhouse and B erry, 1976 P eto, 1980a,b Hobbs e t a l . , 1980 Seidm an e t a l . , 1979 4 .3 7 4 .9 5 2.94 5 .1 5 4 .9 1 15 12.5 1 6 .5 NAb 35 15 24 6 31.5 14 22.5 NA NA 1 35 1 .3 9 3.67 0.85 NA 7 .2 2 a E stlm ated from d a ta g iv en In T ab les 4 and 10 o f Schneiderm an e t a l . (1 9 8 1 ), u s in g e stim a te d m edian v a lu e s . The p ro d u ct d f from colum ns 3 and 4 above Is th e estim ated cum ulative exposure In (fib e r/c m 3)yr o f th e i r Table 10. b NA n o t a v a i l a b l e . The f a c to r 4.56 a d ju s ts from o c c u p a tio n a l exposures a t about 1,920 hours p e r y e a r to en v iro n m e n ta l ex p o su res a t 8 ,760 h o u rs p e r y e a r. A ppendix G p ro v id es th e m athem atical b a s is fo r eq u atio n (1 2 ). Table 7-4 giv es the v a lu e s o f th e c o n s ta n ts fo r each stu d y in w hich P eto e t a l . (1982) estim ated b. To o b ta in th e e s tim a te s f o r m esotheliom a a t th e dose o f 0.0004 fibers/cm in T able 7 -2 , e q u a tio n (11) i s used w ith v a lu e s fo r c from Table 7-4 and k 3 .2 . In T able 7-2 th e life tim e r is k fo r m esotheliom a a t d * 0.0004 fib e rs/c m ^ i s 9 p er m illio n . T his is c a lc u la te d from e q u a tio n (1 1 ) w ith c 2 .5 3 x 10" , th e m edian o f th e ra n g e o f th e c v a lu e s In T able 7 -4 , and k 3 .2 . The h ig h e s t v alu e o f th e ran g e in T a b l e 7 - 2 a t d 0 . 0 0 0 4 u s e s e q u a t i o n ( 1 1 ) w i t h c * 7 . 2 2 x 1 0 " , t h e u p p er v alu e o f c in T able 7 -4 , and k 3 .8 , o b tain ed from 3 .2 + 1.65 x 0 .3 6 . The s e le c tio n o f 3 .8 as th e v alu e fo r k is based on an a p p r o x i m a t e u p p e r 95% c o n f i d e n c e l i m i t f o r t h e e s t i m a t e o f k . T he l o w e r lim it i s tak en as 0 , w hich i s alw ays a p o s s ib le low er l i m i t , e s p e c ia lly i f th e low -dose lin e a r assum ption in eq u atio n (5) o v erestim ates the individual lifetim e risk . 218 P eto (1982) recommended u sin g a k v a lu e o f 3 .5 fo r r i s k assessm en t p u rp o s e s . As an ex a m p le , he e s tim a te d t h a t th e r i s k o f m e so th e lio m a f o r c h i l d r e n e x p o s e d f o r a 6 - y e a r p e r i o d ( a g e s 12 t o 1 8 ) a t 0 . 0 0 3 fib e rs /c m ^ would be one in 100,000. N ich o lso n review ed a d d itio n a l d a ta , in c lu d in g d a ta on o ld e r w orkers up to age 80, and d eterm ined th a t a k v a l u e w o u ld b e 5 . S c h n e id e r m a n et^ 1 . ( 1 9 8 1 ) u s e d k * 3 . 0 . F o r th is stu d y , the com m ittee used a v alu e o f 3 .2 . A lthough n e ith e r e x i s t i n g d a ta n o r b i o l o g i c a l th e o r y can p ro v id e v e ry much g u id a n c e on the value of k, i t s value is very im portant in p ro je c tin g the life tim e r i s k s o f m e s o th e lio m a from a s b e s t o s e x p o s u r e s . T a b le 7-5 show s how life tim e r is k v a rie s from the v alu e o f 9 p er m illio n fo r se v e ra l v alu es o f k . A lso shown a re r i s k e s t i m a t e s f o r o t h e r v a lu e s o f c . The r e a d e r can e a s ily c a lc u la te the r e s u lts fo r o th e r values of exposure. O ther au th o rs have a ls o e stim ated the ris k s o f m esotheliom as. E n te r lin e (1983) d e riv e d a li f e t i m e r i s k o f 100 p e r m i ll io n by u sin g c u rre n t re p o rte d r a te s of m esotheliom a, an assum ption about the r e la tiv e c o n trib u tio n s of nonoccupational and o ccu p a tio n a l asb esto s exposures, and o th e r f a c t o r s . T his e s tim a te c le a r ly r e l a t e s to p a s t exposure to v a r y i n g l e v e l s o f a s b e s t o s . S c h n e i d e r m a n e al_. ( 1 9 8 1 ) e s t i m a t e d life tim e r is k s fo r m esotheliom a to be betw een 800 and 5,000 per m illio n fo r a cum ulative exposure of 1 (fib e r/c m 3 )y r . These e stim a te s c o rre s p o n d to l i f e t i m e r i s k s o f 23 to 150 p e r m i l l i o n f o r 0.0004 f i b e r s / c m 3 f o r 73 y e a r s . As m e n tio n e d a b o v e , t h e s e i n v e s t i g a t o r s e f f e c t i v e l y assum ed k = 3, b u t t h e i r e q u iv a le n t c was h ig h e r th an th a t used fo r the c o rre sp o n d in g e s tim a te s in T ables 7-2 and 7-5. TABLE 7-5. Sensitivity of Estimates for Lifetime Risksa of Mesothelioma to Values of k and c \k cX 0.85 x 10-8 2.53 x lO"8 7.22 x 10-8 Lifetime Risk Estimates x 106 , Using k Values from Various Studies Peto et Peto et This Study Schneiderman This Study al., 1982 This Study al., 1982 (low) et al.. 1981 (middle) 7middle) (high) (high) Nicholson, 1983 2.6 3.0 0.2 1.3 3.2 3.5 3.8 4.0 5.0 3 11 41 97 7,000 0.7 4 9 34 120 290 21,000 2 11 26 96 350 820 60,000 All estimates are derived from equation (11), L * c(0.0004)(73)k , where L " lifetime risk at a continuous exposure to 0.0004 fibers/cm^ for a lifetime of 73 years. Note: This table demonstrates that the risk estimates are extremely sensitive to changes in the value of k. I t The Use o f 0 .0 0 0 4 F ib e rs/c m * and 0 .0 0 2 F ib e rs/c m * a s th e M edian and High N o n o c c u p a tio n a l E n v iro n m en tal E xposure L e v e ls . The l i f e t i m e ris k e stim a te s g iv en in Table 7-2 a re based on an assum ed continuous environm ental am bient exposure e q u iv a le n t to e it h e r 0.0004 o r 0.002 f i b e r s l o n g e r t h a n 5 vim p e r c m * o f a i r b r e a t h e d . T h e c o m m i t t e e b e lie v e s th a t 0.0004 fib e rs/c m * i s a re a so n a b le assum ption f o r a median p o p u la tio n exposure le v e l and th a t 0.002 fib e rs/c m * i s a reaso n ab le high exposure le v e l (c o n sid e rin g o n ly exposures from b re a th in g am bient a i r c o n tin u o u s ly ). These assu m p tio n s a r e d is c u sse d below . The e f f e c ts of noncontlnuous high exposures a re d iscu ssed l a t e r in th is ch ap ter. T ab le 7-6 sum m arizes some e n v iro n m e n ta l a s b e s to s sam p lin g d a ta p ro v id e d by N ic h o ls o n (1 9 8 3 ) . To c o n v e r t from m ass m easu rem en ts (ng/m*) o f a ir b o rn e ex p o su res to f i b e r c o u n ts (fib e rs /c m * ), th e com m ittee u sed th e c o n v e rs io n f a c t o r o f 30 ug/m ^ f o r 1 fib e r/c m * . ( S e e C h a p t e r 4 o f t h i s r e p o r t , S c h n e i d e r m a n e_t a l . , 1 9 8 1 , a n d C o n s u m e r P ro d u ct S a fe ty Com m ission, 1983 f o r f u r t h e r e x p la n a tio n .) The d o se -re sp o n se d a ta u se d in th e c o m m itte e 's r i s k e s tim a te w ere tak en from m easurem ents o f exposures in th e w orkplace, w here th e f ib e r s tend to be lo n g e r th an th o se in am bient environm ents n ot clo se to m ajor so u rc e s o f a s b e s to s . As d is c u s s e d i n C h ap ter 4, th e r e w ould t y p i c a l l y be ap p ro x im ately 2,000 f i b e r s p e r nanogram in w orkplace a i r ; in rem ote a r e a s , how ever, th e r e would be a p p ro x im a te ly 70,000 am b ien t f i b e r s in a n anogram . To c o n v e r t m ass i n th e w o rk p la c e t o a m b ie n t a i r , t h e c o m m itte e used th e number o f f i b e r s lo n g e r th a n 5 y n t h a t would be found in th e w orkplace when th e w orkplace m ass eq u ale d th e rem ote am bient f i b e r m ass. The d o se e s tim a te i n num bers o f f i b e r s w ould be a p p ro x im a te ly 35 tim e s g re a te r (7 0 ,0 0 0 /2 ,0 0 0 ) i f th e a c tu a l s iz e s of f ib e r s in am bient a i r were c o n s id e re d . I f we assum e t h a t a l l f i b e r s a r e e q u a lly p o te n t, th e n th e r i s k e s t i m a t e s w o u ld b e c o r r e s p o n d i n g l y h i g h e r . On t h e o t h e r h a n d , f i b e r s iz e a p p a re n tly a f f e c ts f ib e r potency, b u t th e ap p ro p ria te adjustm ent fa c to rs f o r f i b e r s iz e a re n o t known. Table 7-6 in d ic a te s th a t m edian c o n c e n tra tio n s in outd o o r a i r have r a n g e d f r o m 0 . 0 0 0 0 2 t o 0 . 0 0 0 7 5 fibers/cm-* i n s e v e r a l s t u d i e s ( s a m p l e s e t s 1 t o 8 ) ; t h e i r m edian i s a p p ro x im a te ly 0 .00007 f ib e r s /c m * . The o b serv ed m edian in s id e rooms w ith o u t a s b e s to s i s 0.00054 (sam ple s e t 9 ). In rooms w ith a s b e s to s s u r f a c e s , th e m edian i s 0.0006 fib e rs /c m * (ran g e o f m edians fo r sam ple s e ts 10 through 14, 0.00006 to 0.00405 fibers/cm -*). I f th e s e th r e e m edians a r e w eig h ted by assum ing p erso n s spend appro x im ately o n e -fo u rth o f th e ir tim e o u td o o rs, fiv e -e ig h th s of th e i r tim e in d o o rs in un co n tam in ated room s, and o n e -e ig h th o f t h e i r tim e in a s b e s to s-c o n ta m in a te d room s, a re a s o n a b le e s tim a te f o r a m edian p o p u latio n exposure i s 0.0004 fib e rs/c m * . The com m ittee a l s o u se d 0 .002 fib e r s /c m * f o r a h ig h continuous exposure in i t s c a lc u la tio n s f o r Table 7-2. o b tain ed by u sin g th e m edian o f th e 90th p e rc e n tile s in each exposure su b categ o ry . For o u td o o r a i r , th e m edian value of T his v a lu e was Table 7-6 fo r i s 0.0003 220 TABLE 7-6. Summary of Environmental Aabaatoa Expoaure Sample* Sample Sets 1. Paris air No. of Samples Measured Concentration (ng/m3)________ 90th PerMedian centile Equivalent Concentra tion (fibera/c3)b 90th PerMedian centile 161 0.7 3.2 0.00002 0.00011 Keference Sabastien et al., 1980 2. Paris (outdoor control) 3. Outdoor control samples, for U.S. schools 19 31 0.7 5.2 0.00002 0.00017 0.9 9.8 0.00003 0.00033 Sebaatien ct al., 1980 Constant ct al., 1982 A. Air of 48 U.S. cities 5. Air of U.S. cities 187 127 1.6 6.8 0.00005 0.00023 2.3 7.8 0.00008 0.00026 Nicholson, 1971 U.S. Environmental Protection Agency, 1974 6. Air of five U.S. cities (outdoor control sample) 7. New York City air 34 22 6.7 31.9 0.00022 0.00106 13.7 42.9 0.00046 0.00143 Nicholson et al., 1975, 1976 Nicholson et al., 1971 8. Air 0.5 mile (0.8 km) from asbestos spraying 17 9. Air in U.S. schoolrooms with out asbestos 31 10. Air in Paris buildings with asbestos surfaces 135 11. Air in U.S. buildings with cementitious aabestos 28 12. Air in U.S. buildings with friable asbestos 54 13. Air in U.S. schoolrooms with asbestos surfaces 54 14. Air in U.S. schools with damaged asbestos surfacing materials 27 22.5 82.6 16.3 72.7 1.8 32.2 7.9 19.1 19.2 96.2 62.5 550 121.5 465 0.00075 0.00275 0.00054 0.00242 0.00006 0.00107 0.00026 0.00064 0.00064 0.00321 0.00208 0.01833 0.00405 0.01550 Nicholson et al., 1971 Constant et al., 1982 Sebastien et al., 1980 Nicholson et al., 1975, 1976 Nicholson et al., 1975, 1976 Constant et al., 1982 Nicholson et al., 1978 Adapted from Nicholson, 1983. t*Based on conversion factor of 30 ug/n>3 1 fiber/cm3  221 fib ers/cm 3 ; fo r indoor uncontam inated a i r , i t is 0.002 fib ers/cm 3 ; and fo r in d o o r a s b e s to s - c o n ta m in a te d a i r , i t i s 0 .0 0 3 f i b e r s / c m 3 . The same d i s t r i b u t i o n o f o c c u p a n c y o v e r tim e was u s e d to a r r i v e a t th e 0 .0 0 2 fibers/cm 3 fig u re fo r a high exposure le v e l. Risk Assessments for Special Subpopulations T ab le 7-2 show s l i f e t i m e r i s k e s t im a te s f o r p e o p le who a r e ex posed throughout th e ir liv e s to le v e ls o f e ith e r 0.0004 o r 0.002 fib e rs/c m 3 in am b ien t a i r . The p red o m in an t r i s k is from m eso th elio m a, b u t lung c a n cers a ls o c o n tr ib u te to th e r i s k , e s p e c ia lly fo r m ale sm okers. For exposure p a tte rn s th a t a re d if f e r e n t from th o se assum ed, life tim e r is k s c o u ld be h i g h e r o r lo w e r . The f o l l o w i n g a r e t h r e e i l l u s t r a t i o n s o f how life tim e r is k s could be d e riv e d fo r such s p e c ia l p o p u la tio n s. C h ild re n Exposed in A sb e sto s-C o n ta m in a te d S c h o o ls . The com m ittee e stim a te d th e r i s k fo r p erso n s exposed from b i r t h to age 73 y e a rs to en vironm ental le v e ls of 0.002 fib e rs/c m 3 (as assumed in Table 7-2) plus an a d d itio n a l r i s k from a 1 0 -y ear exposure (from ages 6 to 16) in an a sb e sto s-c o n ta m in a te d schoolroom fo r 6 h o u rs d a ily , 200 days per y e a r, to 0 .0 2 f i b e r s / c m 3 (550 ng/m 3 , th e 9 0 th p e r c e n t i l e in T a b le 7 - 6 ) . The e q u iv a le n t co n tin u o u s d a ily 10-year ex p o su re is ap p ro x im ately 0.003 fib e rs/c m 3 , i . e . , 0.0 2 x (200 x 6 )/(3 6 5 x 2 4 ). U sing e q u a tio n (6 ), the l i f e t i m e r i s k o f lu n g c a n c e r fo r a m ale who e v e n tu a lly becom es a smoker i s 0 .0 0 3 x 10 x 0 .0 0 2 2 , o r 66 i n a m i l l i o n . T h is r i s k r e p r e s e n t s an a p p r o x i m a t e l y 20% a d d i t i o n t o h i s a m b i e n t l i f e t i m e r i s k o f 320 i n a m i l l i o n (0 .0 0 2 x 73 x 0 .0 0 2 2 ) , f o r a t o t a l o f a b o u t 390 in a m i l l i o n . For such an in d iv id u a l, th e schoolroom exposure adds r e l a ti v e ly more to th e r i s k o f m e s o th e lio m a , a s shown b elo w . U sin g e q u a tio n s (G4) and (G5) in A ppendix G fo r th e l i f e t i m e m eso th elio m a r i s k , L, a t t * 73 fo r an e x p o s u r e o f l - 10 y e a r s s t a r t i n g a t a g e tg * 6 a t th e d o se l e v e l d , th is r is k can be c a lc u la te d from th e form ula: L c d { l - [ 1 - l / ( t --t g ) J k ) ( t --t g ) k , w ith d = 0 .0 0 3 , Z - 10, t - tg = 73 - 6 = 6 7 , and k = 3 .2 . life tim e m esotheliom a r i s k becomes T h is L * c ( 0 . 0 0 3 ) { 1 --[ 1 --( 1 0 / 6 7 ) J 3 * 2 } ( 6 7 ) 3 , 2 * 8 4 5 c . If c is the m edian v a lu e o f Table 7-4 estim ated life tim e m esotheliom a r is k , 21 x 1 0 "6 . ( i . e . , c * 2.53 x 10"), the L, from th e 1 0 -y e a r e x p o su re is T his r i s k i s th e n added to th e b ackground r i s k o f 46 x 10" in Table 7-2, g iv in g a life tim e m esotheliom a r i s k fo r th is su b p o p u latio n o f 67 x 10". I f a m i l l i o n p e o p le had r e c e i v e d su ch a p a t t e r n o f e x p o s u re s , a b o u t 67 m ig h t be e x p e c te d to d ie o f m e so th e lio m a . In t h i s exam ple, th e c o n tr ib u tio n to to t a l r is k from th e schoolroom s is le s s th an th a t o f th e lif e tim e exposure to the low er c o n c e n tra tio n s o f a sb e s to s e s tim a te d fo r th e am b ien t a i r . However, i f th e v a lu e fo r k in E q u atio n (7) were h ig h e r th an 3 .2 , the s ig n ific a n c e o f th e schoolroom exposures r 222 w ould in c r e a s e b ecau se o f th e s tr o n g e r dependence on tim e s in c e f i r s t exposure. For exam ple, i f k * 3 .8 , the h ig h e s t v alu e used in T able 7-2, the lif e tim e m esotheliom a r i s k w ould be 910 x 10"^ . I f k w ere le s s th an 3 .2 , th e c o rre sp o n d in g lif e tim e r i s k fo r m esotheliom a would be le s s th a n 67 x 10- ^ . These c a lc u la ti o n s show t h a t c h ild h o o d ex p o su res to a sb e s tifo rm fib e rs m ight c o n trib u te n o tic e a b le life tim e m esotheliom a ris k s to those so exposed. A F e m a l e N o n s m o k e r i n a R e l a t i v e l y A s b e s t o s - F r e e E n v i r o n m e n t . An exam ple of a perso n in a lo w -risk group is a fem ale nonsm oker exposed to an a v erag e le v e l o f 0.0001 fib e rs /c m ^ . T his ex p o su re le v e l would n o t be to o u n lik e ly fo r a p e rso n exposed p rim a rily to r u r a l in d o o r and o u td o o r a i r , sin c e 0.00002 fib ers/cm ^ is th e low est m edian v alu e fo r a l l th e outdoor c ity read in g s in Table 7-6. Then, th e c a lc u la tio n s in T able 7-2 w ould le a d to a m esotheliom a lif e tim e r i s k o f 2.25 x 10"^ (9 x 10~ d iv id e d by 4 ) p lu s a lu n g c a n c e r l i f e t i m e r i s k o f 0.73 x 10' The l i f e t i m e in d i v id u a l r i s k f o r such a p e rso n w ould be 3 x 10"6 fo r both types o f can cer. A M ale Smoker L iv in g in an A rea C ontam inated w ith High L ev els o f A s b e s t o s Who i s A l s o E x p o s e d t o H i g h I n d o o r C o n c e n t r a t i o n s . As a n example o f a h ig h - r is k p erso n , c o n sid e r an urban m ale smoker exposed to 0.003 fibers/cnr* fo r o n e -h a lf th e tim e and 0.018 fib ers/cm ^ fo r the o th e r h a lf . This p a tte r n is based on th e assum ption th a t th e s u b je c t spends o n e -h a lf o f h is tim e in indoor environm ents w ith a high asb esto s c o n c e n t r a t i o n ( s e e sa m p le s e t s 13 an d 14 o f T a b le 7 - 6 ) a n d o n e - h a l f e it h e r in h ig h ly co n tam inated o u td o o r environm ents (see sam ple s e ts 7 and 8 of Table 7-6) o r in indoor environm ents a t th e h ig h end o f the d i s t r i b u t i o n fo r rooms th a t a r e n o rm ally n o t co n tam in ated w ith a sb e s to s (see sam ple s e t 9 o f T able 7 -6 ). Thus, h is c o n tin u o u s averag e exposure would be a p p ro x im a te ly 0.01 fib e rs /c m ^ , i . e . , 0 .5 (0 .0 0 3 ) + 0 .5 (0 .0 1 8 ). T h e re fo re , m u ltip ly in g th e second colum n o f T able 7-2 by a f a c to r o f 5 (0.01 * 5 x 0 .0 0 2 ) w ould g iv e th e in d iv id u a l lif e tim e r is k s fo r such a p e rs o n as 1 .8 x 10" ^ f o r th e two form s o f c a n c e r ta k e n to g e th e r (230 x 10"^ fo r m esotheliom a and 1,600 x 10"^ fo r lung c a n c e r). This life tim e r is k is th e a d d itio n a l in cu rred r is k a ttr ib u ta b le to the nonoccupational environm ental exposure to asb esto s and does not include th e r i s k in c u r r e d by th e sm oking i t s e l f . The p o r t io n o f th e a d d it io n a l r i s k a t t r i b u t a b l e to lung c a n c e r is c o n s id e ra b ly h ig h e r th a n i t w ould be fo r a nonsmoker ex p erien cin g id e n tic a l a sb e sto s exposures. COMPARATIVE R IS K ASSESSMENT M ethods The g o a l o f co m p arativ e r i s k asse ssm e n ts is to d eterm in e w hether th e fib e r exposure in q u e stio n p re se n ts r i s k s -- in term s o f to t a l number and se v e rity of e ff e c ts per year in the U nited S ta te s -- th a t are about the same, c o n sid e ra b ly m ore, o r co n sid e ra b ly le s s th an th o se a ssessed