Document DkmvqzYgYN930BdnK52eg9M5

FILE NAME Brakes BRK DATE 2002 DOC BRK145 DOCUMENT DESCRIPTION Journal Article - Malignant Mesothelioma and Occupational Exposure to Asbestos A Clinicopathological Correlation of 1445 Cases Ultrastructural Pathology 55-65 2002 Copyright '2002 Taylor & Francis 0191-310223 12.00+ .00 < Taylor Francis @ healthsciences Malignant Mesothelioma and Occupational Exposure to Asbestos A Clinicopathological Correlation of 1445 Cases Victor L. Roggli MD Anupama Sharma MD Kelly J. Butnor MD Thomas Sporn MD Robin T. Vollmer MD Department of Pathology Durham Veterans Administration and Duke University Medical Center Durham North Carolina USA Asbestos exposure is indisputably associated with development of mesothelioma However relatively few studies have evaluated the type of occupational exposure in correlation with asbestos fiber content and type This study reports findings in 1445 cases of mesothelioma with known exposure history 268 of these also had fiber burden analysis The 1445 cases of mesothelioma were subclassified into 23 predominant occupational or exposure categories Asbestos body counts per gram of wet lung tissue were determined by light microscopy Asbestos fiber content and type were determined by scanning electron microscopy and energy dispersive ray analysis Results were compared with a control group of 19 lung tissue samples Ninety percent of the cases occurred among 19 exposure categories Median asbestos body counts and levels of commercial and noncommercial amphibole fibers showed elevated levels for each of these 19 categories Chrysotile fibers were detectable in 36 of 268 cases All but 2 of these also had background levels of commercial amphiboles When compared to commercial amphiboles the median values for noncommercial amphibole fibers were higher in 4 of the 19 exposure groups Most mesotheliomas in the United States fall into a limited number of exposure categories Although a predominant occupation was ascertained for each of these cases there was a substantial overlap in exposure types All but 1 of the occupational categories analyzed had background levels of commercial amphiboles Commercial amphiboles are responsible for most of the mesothelioma cases observed in the United States Keywords mesothelioma asbestos fiber analysis occupation amosite tremolite chrysotile The association between mesothelioma and_ prior asbestos exposure is undisputed A wide variety of occupational and environmental exposures have been implicated as the source of this exposure In the past insulation workers and shipyard workers were exposed to high levels of asbestos dust and decades later were found to have a markedly elevated rate of mesothelioma Bystanders working in the vicinity of those directly handling asbestos products were also found to be at risk In addition household contacts of asbestos workers and those living in the vicinity of an asbestos manufacturing plant also developed mesotheliomas 1-3 Such studies have led to the Durham Veterans Address correspondence to Victor L. Poggli MD Department of Pathology Administration and Duke University Medical Center Durham NC 27710 USA conclusion that mesothelioma may be related to brief level or indirect exposures to asbestos Although numerous reports document mesothelioma risk associated with particular exposures there are relatively few studies that have examined the distribution of occupations in a mesothelioma cases Otto reported categories in 71 patients with large series of the occupational asbestos mesothelioma and 37 spontaneous or idiopathic cases 4 The Australian Mesothelioma Register provides biennial reports on the occupational categories of the mesothelioma cases collected by the registry in Australia 5 It is difficult however to find detailed analyses of lung mineral fiber content in a series of mesothelioma patients that also contain detailed information regarding occupational or environmental exposures to asbestos We have previously shown that amosite asbestos is the most common fiber type identified in the lungs of 55 56 V. L. Roggli et al patients with mesothelioma from the United States 6 Furthermore there is a significant correlation between lung fiber burden of asbestos bodies and commercial amphibole fibers with duration of exposure to asbestos 7 For equal durations of exposure individuals who directly worked with asbestos products have a higher lung burden than those who were indirectly exposed i.e. bystander exposure and shipyard workers have on average a higher burden than shipyard workers The present study extends these observations by examining exposure information in more than 1400 cases of histologically confirmed mesotheliomas In 268 of these cases the exposure information could be correlated with the results of tissue mineral fiber analysis MATERIALS AND METHODS The consultation files of one of the authors VLR were reviewed for all cases of mesothelioma for which information was available regarding possible exposure to asbestos The diagnosis of mesothelioma was based on the gross distribution of tumor histologic pattern and the results of immunohistochemical studies as previously described 8 In some cases histochemical stains and ultrastructural studies were performed when indicated Information was also obtained regarding the age sex primary site of the tumor pleura vs. peritoneum smoking history presence of pleural plaques and calcification and presence of histologic asbestosis 9 10 Patients were classified into one of the 23 exposure groups shown in Tables 1-3 Industries with known asbestos exposure are listed in Table 1 occupations in TABLE 1 Mesothelioma Cases by Industry Shipbuilding U.S. Navyb Construction Insulationd Oil and chemical Power plant Railroad Automotive metal Asbestos mfg. ,, Papermill Ceramics Single 203 91 99 92 78 50 37 24 33 34 7 6 Multiple 86 84 35 11 10 10 16 27 10 5 0 0 Total 289 175 134 103 88 60 53 51 43 39 7 6 Includes joiner shipwright rigger sandblaster shipfitter electrician painter and welder bIncludes merchant marine seamen Includes construction worker laborer carpenter painter dry wall plasterer Includes pipecoverer insulator asbestos sawyer asbestos sprayer Includes auto mechanic brake repair worker brake line worker Includes steel aluminium and iron foundry workers furnace worker potroom worker Includes asbestos textile asbestos manufacture asbestos plant worker TABLE 2 Mesothelioma Cases by Occupation Pipefitter Boilermaker Maintenance Machinist Electrician Sheetmetal Other asbestosd Single 159 81 75 62 59 17 23 Multiple 28 31 15 27 22 5 0 Total 187 112 90 89 81 22 23 Includes welders Includes boiler worker boiler maker boiler mechanic boiler repair- man steamfitter Includes mechanical engineer Includes millwright brick mason bagging machine operabagger asbestos worker not otherwise specified Table 2 and occupational exposures in Table 3 The occupations listed in Table 2 are distributed across many of the industries listed in Table 1. For example pipefitters may be employed in shipyards oil refineries power plants etc. Many individuals worked in more than one of the categories indicated in the tables However for purposes of analysis an attempt was made to place patients in a predominant category where the most intense exposures based on previous analyses from our laboratory were likely to occur e.g. insulators or shipyard workers When more than one category of exposure occurred these separate exposures were recorded as well When available data were also collected regarding the duration of exposure for each of the categories indicated in Tables 1-3 Fiber analyses were performed on formalin or paraffin embedded lung tissue specimens by using previously described methods 11 Lung tissue was processed for digestion by using the sodium hypochlorite technique The residue was collected on ...m pore Nuclepore filters For light microscopic analysis the filter was mounted on a glass slide for asbestos body quantification Filters were counted at a magnification of 400 and only bodies with typical morphology and thin translucent cores were TABLE 3 Mesothelioma Cases with Nonoccupational Exposures Household contacts Building occupants Other Environmental Single 6705 6705 6705 6705 Multiple 3 1 0 0 Total 89 18 46 5 Includes architect baker bookkeeper businessman computer consultant driver dry cleaning business dye and press setter elevator repairman forest service furniture co grinder hairdresser jewelry repair Kent smokers landscaper industrial manager minister no known exposure nurse policeman pressman professor resident construction salesman salt cake and carbon plant operator school administrator silica plant and pattern shop status postradiation /chemotherapy telephone installer textile worker tire manufacure Mesothelioma and Occupation 57 counted as asbestos bodies 12 Results were reported as asbestos bodies per gram of wet lung tissue AB The detection limit for a 0.3 sample size is approximately 3 AB For cases in which no asbestos bodies were detected in the sample the value was recorded as less than the detection limit for that sample For scanning electron microscopic SEM analysis the filter was mounted on a carbon disk with colloidal graphite sputter with gold or platinum and examined in a JEOL 6400 scanning electron microscope at a screen magnification of 1000 and with a screen size of 22.7 x 17.3 cm Fibers 5 ...mor greater in length were counted by using a protocol in which 100 consecutive fields or 200 fibers were counted whichever came first Fibers were defined as particles with an aspect ratio length to width of at least 3 and roughly parallel sides The concentration of fibers for each case was calculated based on the fiber density i.e. per mmon the filter surface times the effective area of the filter divided by the weight of the lung sample that was analyzed The results were reported as total asbestos fibers coated and uncoated 5 ...mor greater in length per gram of wet lung The detection limit for a 0.3 sample size is approximately 440 fibers For cases in which no asbestos fibers were detected in the sample the value was recorded as less than the detection limit for that sample Fiber types were determined by using a combination of fiber morphology as determined by SEM and elemental composition assessed by energy dispersive ray analysis EDXA Fibers were classified as amosite crocidolite tremolite anthophyllite actinolite or chrysotile as previously described 11 For purposes of analysis amosite and crocidolite were grouped together as commercial amphiboles AC Tremolite anthophyllite and actinolite were grouped together as noncommercial amphiboles TAA The proportion of each fiber type and the total asbestos fiber concentration were used to determine the tissue concentration of AC TAA and chrysotile for each case All other fibers were counted as nonasbestos mineral fibers NAMF For cases where no fibers of a particular type were detected the value was recorded as less than the detection limit for that case The results of fiber analysis for the mesothelioma cases were compared with 19 controls from our laboratory with macroscopically normal lungs no evidence of asbestos disease and no history of asbestos exposure For statistical analysis we used the log rank test to explore the relationship between age of diagnosis as a time of failure and industrial exposure and the Cox proportional hazard model for the final analysis of age We also used Kaplan plots to illustrate age effects We used a general linear model to relate the logarithmic transformation of fiber counts to industrial exposure and fiber counts below the detection limit were arbitrarily set at half the detection limit We used analysis of variance for exploratory analysis of continuous variables and square tests for analysis of categorical variables We used logistic regression analysis to relate binary variables to other independent variables Finally all P values were for sided test and all analyses were done with PLUS software MathSoft Seattle WA RESULTS . : A total of 1445 cases of histologically confirmed mesothelioma were retrieved from the files of one of the authors VLR These included 1322 men and 123 women The median age for the entire group was 67 years range 17-94 years The site of origin was the pleura in 1309 cases and the peritoneum in 136 cases The histologic types included 698 epithelial 442 biphasic and 292 sarcomatoid cases For 13 cases information was not available regarding the specific histologic pattern of the tumor Information regarding smoking was available in 1112 cases 830 were smokers or smokers and 292 were nonsmokers Information was available regarding the presence or absence or pleural plaques PPP in 778 cases Plaques were present in 608 cases 78 Information regarding the presence or absence of asbestosis was available in 577 cases Asbestosis was present in 135 cases 23 Exposure Categories Cases were classified into the 23 exposure cat- egories indicated in Tables 1-3 The industry with the largest number of cases was shipbuilding followed by U.S. Navy construction industry and insulation industry each of which included 100 or more cases Table ) Among the 12 industries listed in Table 1 an exposure in some additional occupational setting was noted in 26 of the cases The occupation with the largest number of cases was pipefitter followed by boilermaker Table 2 Among the 6 specific occupations listed an exposure in some additional occupational setting was noted in 21 of the cases The nonoccupational group with the largest number of cases was household contact of an asbestos worker Table 3 Among the 4 nonoccupational groups an exposure in an occupational setting was noted in % of the cases Two of the categories were fairly nonspecific with other asbestos Table 2 including several occupations for which there were few cases in any one subgroup and other Table 3 including a variety of occupations with no known exposure to asbestos In addition the building occupant group is known to be associated with tissue asbestos burdens that are oftentimes indistinguishable from background levels Among the 4 cases with environmental or neighborhood exposures only 1 was from the United States When these 4 groups are excluded the remaining 19 categories 12 industries 6 occupations and 1 nonoccupational exposure accounted for 94 of the 1445 cases of mesothelioma included in this study Two of these exposure categories often have been considered as level exposures These include household contacts of asbestos workers and environ- mental neighborhood exposures There were 89 cases that were household contacts of an asbestos worker 58 and 10 of these had an additional occupational exposure to asbestos Of these 79 were women with an average age of 59 years There were 4 cases with environmental exposure to asbestos All were men with an average age of 67 years None had any additional known exposure to asbestos Three of these cases were from a region of Turkey where there was intense environmental exposure to actinolite The fiber burdens in these 2 groups are discussed below Gender Exposure Duration and Age Over 90 of our cases of mesothelioma occured in men In some occupational categories all were men Table 4 These included insulators railroad workers power plant workers steel workers brake repair workers boiler workers electricians and machinists A large percentage of the women with mesothelioma occurred in the household contact group which as noted above consisted of 79 women The building occupant group included about an equal number of men and women The median duration of exposure to asbestos is also provided in Table 4 for those cases where this information was available For most categories the median duration was 2 or 3 decades with ranges as short as 1 V. L. Roggli et al month to as long as 56 years Shorter duration was observed for shipbuilding U.S. Navy asbestos manufacture and building occupants The former 2 are related to large numbers of workers with shipyard employment or navy service limited to World War II bringing down the median value for these groups Shorter duration for asbestos manufacture may have been related to the very dusty environment with many workers quitting after a relatively short period of employment 12 Table 4 provides the median and range of age for each category of exposure A log rank test demon- strated that there was a significant relationship between the age at development of mesothelioma and type of industry or occupation square 112 P < .0001 Table 5 provides detailed results of a Cox model analysis for the relationship between age and the key industries or occupations that had unusually high or low hazard rates In the table the relative hazard rates column HR provide the key result Whereas values of HR above 1 the reference for remaining undesignated cases indicate a higher hazard and younger age for developing mesothelioma values of HR below 1 indicate a lower hazard and older age for developing mesothelioma For example the highest relative hazard of 2.19 occured in those exposed in a nonindustrial TABLE 4 Age Gender and Duration by Exposure Category Age Industry Shipbuilding U.S. Navy Construction Insulation Oil and chemical Power plant Automotive Railroad metal Asbestos mfg Papermill Ceramics Occupation Pipefitter Boilermaker Maintenance Machinist Electrician Sheetmetal Other asbestos Nonoccupational exposure Household contacts Building occupants Other Environmental 69 38-91 67 38-84 66 39-85 59.5 37-78 70 45-89 68 39-81 64 31-83 74 45-94 71 44-81 64.5 48-86 68 51-77 64.5 40-79 71 38-91 67 39-86 70 39-88 68 47-87 69 48-83 70 52-76 60 45-84 59 25-93 45 17-78 63.5 28-78 67 39-68 Values represent median with range in parentheses b Ratio of men to women in given group Values represent median duration of exposure in years with range in parentheses Note NA not applicable Fb 37 55 96 All men 40 All men All men All men All men 6.8 2.5 5 61 All men 89 All men All men 19 All men 13:67 9 27:11 All men Exposure duration 10.5 1 mo yr 9 3 mo yr 30 1-46 26 1 mo yr 30 6 mo yr 30 2-50 23 3-50 30 2-47 31 5 mo yr 8 7 mo yr 35.5 13-42 30 17-52 29 6 mo yr 21 6 mo yr 28 2-56 17.5 1-51 28.5 1-49 27.5 1-43 27 5-40 20 1-45 14 1-26 NA 28 18-38 Mesothelioma and Occupation 59 TABLE 5 Cox Model Analysis of Age of Development of Mesothelioma Variable HR SE P value Nonindustrial Insulation Pipefitters Rail workers Duration Female 2.19 1.33 0.66 0.52 0.99 0.70 0.134 0.110 0.129 0.162 0.002 0.143 4.8 10 .010 .0010 5.9 10-5 2.3 10-10 .014 Note Here HR is the relative hazard and SE provides the standard error for the regression coefficient which can be calculated as log HR setting i.e. household contacts building occupants or other nonindustrial exposure This result implied that this group experienced mesothelioma at an earlier age Workers in the insulation industry also experienced a higher hazard rate but pipefitters and railroad workers had lower hazard rates All these results were controlled for duration of exposure and female gender because both were covariates in the analysis Interestingly longer duration was associated with increased rather than decreased age at diagnosis and after controlling for category of exposure female gender was associated with a lower hazard and later age at diagnosis The P values listed in the table provide the significance for the effect of each variable or group on the hazard for developing mesothelioma Figure 1 illustrates these results further 1.0 0.8 Free Tumor 0.6 i ry of 0.4 Probailty 0.2 00 0 T T T U 20 40 60 80 Age years FIG 1 Kaplan plots of the probability of being tumor free versus age in years Here age at diagnosis was treated as a failure time Curve 1 provides the plot for pipefitters and railroad workers curve 3 provides the plot for those in the insulation industry and those with nonindustrial exposure and curve 2 provides the plot for the remaining groups of occupational exposures In the figure are 3 Kaplan plots of the probability of being tumor versus age Curve 1 combines pipefittes and railroad workers who had the lowest hazards and developed mesothelioma at the oldest ages Curve 3 combines those with nonindustrial exposure and those in the insulation industry and this group developed mesothelioma at the youngest age Curve 2 is for the remaining cases Tumor Location Pleural Plaques and Asbestosis Approximately 90 of our cases arose in the pleura The other 10 arose in the peritoneum The highest percentage of peritoneal mesotheliomas occurred among insulators and absestos manufacturing plant workers Table 6 In each of these groups the ratio of pleural to peritoneal tumors was about 2 In the remaining groups this ratio ranged from 8.6 in construction workers to more than 50 in shipyard workers The low ratio of 1.8 in building occupants suggests that mesotheliomas in this setting are at or near the background rate of occurrence for these tumors TABLE 6 Site Plaques and Asbestosis by Exposure Category Site pppb Asbestosis Industry Shipbuilding U.S. Navy Construction Insulation Oil and chemical Power plant Automotive Railroad metal Asbestos mfg Papermill Ceramics Occupation Pipefitter Boilermaker Maintenance Machinist Electrician Sheetmetal Other asbestos Nonoccupational exposure Household contacts Building occupants Other Environmental 52 54 8.6 2.1 82 17 8 38 9.3 2.2 6 0 144/177 81 12/57 21 14/41 34 64/75 85 36/46 78 23/27 85 8/12 67 20/24 83 15/16 93 21/24 87 5/6 83 1/2 50 37/132 26 4/37 11 6/35 17 34/59 58 5/29 17 3/16 19 0/12 % 2/17 12 3/11 27 1/17 65 1/5 20 0/2 % 50 30 26 22 74 20 5 103/119 87 60/74 81 45/56 80 32/44 78 33/40 83 9/11 82 2/6 33 20/83 24 11/46 24 7/35 20 4/28 14 8/30 27 1/7 14 0/5 % 4.3 1.8 8.5 4:10 20/35 57 3/7 43 11/24 46 0/1 % 3/38 7.9 0/10 % 2/21 9.5 0/1 % Ratio of pleural to peritoneal tumors Number of cases with plaques divided by number of informative cases percentage Number of cases with asbestosis divided by number of informative cases percentage 60 V. L. Roggli et al When information was available regarding the presence or absence of parietal pleural plaques PPP it was found that a high percentage of cases did in fact have plaques Table 6 Chest radiographs and even computed tomographic CT scans are somewhat insensitifvoer the detection of PPP so cases where PPP were not mentioned in the radiographic reports and were not observed in surgical specimens were considered to be uninformative Although logistic regression analysis demonstrated that there was a significant association between category of exposure and the presence of PPP P = .0015 these categories explained just % of the noise in the data and it was difficult to identify particular categories associated with PPP In general workers in insulation pipefitting and steel had increased prevalence of PPP and those in nonindustrial situations had lower preva- lence of PPP On the subset of 199 cases with asbestos body counts logistic regression analysis demonstrated that the prevalence of PPP was closely related to log asbestos body counts P < .0001 In this subset of cases industrial category explained an additional 11 of the noise in the data with a P value of .044 Having accounted for the effect of fiber burden the auto industry seemed to have an increased prevalence of PPP but the variance associated with the remaining exposure categories was too great to reach any conclusions about the remaining categories of exposure Neither exposure duration nor gender was significantly related to the prevalence of PPP When information was available regarding the presence or absence of asbestosis it was determined that a relatively low percentage of cases had histologically confirmed asbestosis Table 6 Among occupationally exposed individuals the percentage of cases with asbestosis ranged from % of glass and ceramic workers and friction product workers to as high as 67 of asbestos manufacturing plant workers Asbestosis was rarely observed among patients with mesothelioma and nonoccupational exposures None of the environmental exposures or building occupants had asbestosis but asbestosis was confirmed histologically in 8.3 of household contacts of asbestos workers Logistic regression analysis demonstrated that although the category of exposure was significantly associated with asbestosis P .0001 there was no pattern of one category or another that could be identified as having either a high or low prevalence of asbestosis Furthermore when the burden of asbestos bodies was accounted for by including log asbestos body count in the model the industrial category was no longer associated with the prevalence of asbestosis In other words the influence of industrial category on prevalence of asbestosis appeared to be mediated entirely by differences in fiber burden Lung Fiber Burden Analyses The results of tissue fiber analysis for each of the exposure groups are summarized in Table 7. The median asbestos body count in each of the 23 exposure categories exceeded our normal range of 0-20 AB except for 2 categories automotive brake repair workers and building occupants The industry with the highest median asbestos body count was the insulation industry and the occupation with the highest count was pipefitter Analysis of variance demonstrated that the category of industry or occupation was significantly related to the number of asbestos bodies P < .0001 to the number of commercial amphibole fibers P < .0001 to the number of noncommercial amphibole fibers P < .0005 and to the number of chrysotile fibers P < .0001 Furthermore much of the industry occupational differences were due to higher fiber levels in the insulation industry coupled with lower fiber levels in 3 industrial groups those with nonindustrial exposure those in the auto industry and those who were machinists This is illustrated in Figure 2 which provides box plots of the natural logarithm of fiber counts in these 4 categories versus an other group of all remaining cases Simple visual comparison shows that the pattern for fiber counts is roughly the same for all 4 types of fibers and general linear model analyses demonstrated that after controlling for gender and duration of exposure the associations between fiber counts and these 4 industrial groups were significant P values ranging from approximately 0 to .02 with one exception level of noncommercial amphibole fibers in the nonindustrial group P > .1 The predominant fiber type identified in each of the categories was commercial amphibole mostly amosite with some crocidolite except for 4 categories automotive brake repair workers household contacts building occupants and environmental neighborhood exposures Table 6 In these instances noncommercial amphiboles mostly tremolite with some actinolite and anthophyllite predominated over commercial amphibole fibers Chrysotile fibers were detected less frequently and for 7 categories were not detected at all Nonasbestos mineral fibers were present in all groups in roughly similar amounts Further analyses were performed on the 12 exposure categories for which there were at least 10 analyses within the category Figure 3 Commercial amphibole fibers were present in concentrations that exceeded the background level in all 12 categories ranging from 57 other to 100 insulators of the individuals in any one category Noncommercial amphibole fibers were also present in excess concentrations in all 12 categories ranging from 13 maintenance workers to 68 shipyard workers of individuals in any particular category However the percentage of individuals in a category with elevated levels of noncommercial amphiboles exceeded 50 in only 2 categories shipyard workers and electricians Chrysotile was present in excess concentrations in 9 of the 12 categories not in pipefitters construction workers or other ranging from % to 23 of the individuals in any one category In none of the categories was chrysotile found in elevated concen- Mesothelioma and Occupation 61 TABLE 7 Lung Fiber Burden Analyses in 268 Mesothelioma Cases gma ACb TAAb Chrys NAMFb Industry Insulation Asbestos mfg Shipbuilding Power plant Construction metal Oil and chemical U.S. Navy Railroad Automotive Papermill Ceramics Occupation 20.1 0.12-1600 4.1 0.9-322 1.08 0.006-436 0.34 0.013-21.9 0.19 0.002 83.5 0.48 0.13-2.3 0.27 0.018-2.8 0.17 0.002 4.4 1.49 0.005-5.7 0.02 0.003-1.5 NA 3.05 246 0.81-11900 33 14-755 23.9 0.24-2150 18.8 0.92-200 14.7 0.48-268 8.4 2.3-129 4.9 1-39.3 4 0.54-202 38.6 2.95-48 1.4 0.12-17.3 NA 28.2 5.19 1.11-19.7 6.7 1.7-90 4.56 0.026-79.8 3.84 0.73-2 4.6 0.48 15.7 2.6 0.49-6.6 2.4 0.67-6.9 3.3 0.98 17.1 9.68 8.85-27.3 2 0.24-9.8 NA 3.4 2.06 0.87-124 66.5 43-90 4.8 0.91-11 7.71 1.19-14.2 0.55 0.48-0.6 ND ND 3.1 2-4.3 ND 2.1 0.72-2.18 NA 1.1 11.6 2.24-19.7 27 3.2-54.1 10.3 1.18 138 6.2 2.4-19.5 6.3 0.6 85.2 6.4 0.49-23.9 6.4 1.3-22.7 8.3 0.58-27.6 17.7 5.13-33.8 1.4 0.34-18.5 NA 6.8 Maintenance Pipefitter Boilermaker Machinist Sheetmetal Electrician Other asbestos Nonoccupational exposure Other Household contacts Building occupants Environmental Reference casesd 0.4 0.013-15.9 2.2 0.006 174 1.68 0.24-8.6 0.1 0.002-1.8 0.78 0.4-0.83 1.4 0.006-6.3 1.53 0.1-3.9 0.043 0.001-11.5 0.13 0.002-14.1 0.002 0.002-1.1 0.7 0.005-8.2 0.003 0.002-0.022 24.3 0.32-316 24.2 1.05-49.4 21.3 4.14 149 19 0.98-48 6.2 0.6-34.1 5.5 2.3-94.5 33.6 2.0-33.7 3.9 1.02-54.9 3.4 0.45-116 0.87 0.38-43.8 ND 0.6 2.54 1.8 0.63-17.1 5.2 0.98 19.2 8.49 0.78 24.2 15 2.9-27 5.8 4.1-7.4 5 0.51-45 3.54 0.66-17.3 2.3 1.05-43 5.2 0.98-22.4 2.3 1.1-4.1 158 1.7-455 0.6 0.17- 1.2 1.19-1.26 ND 1.45 1.44-1.45 ND ND 5 1.6-10.4 ND 0.92 1.8 0.64 ND 0.6 2.54 6.4 1.3 18.5 10 0.85-31.7 7.3 1.84 19.1 5.1 0.49-34 11 7.4-18 6.7 3.1-54 4.0 2.4-45 6.5 0.48-28.1 9.3 0.24-14.6 4.9 1.5-36.8 5.1 3.1-14.5 0.6 0.17- microscopy Asbestos bodies per gram of wet lung tissue 10)as determined by light Values shown are medians with in " Fibers 5 ...mor greater in length per gram of wet lunglung tissue ^ 10as determined by scanning electron microscopy raanndgeenerpgayrednitshpeersseisve ray analysis When Values shown are medians for cases where fiber fiber type was detected with range in parentheses ranges are not shown only one case had detectable levels of indicated fiber type detected Tissue was available for fiber analysis in only one case of ceramics plant worker dNinteen cases with normal lungs no history of asbestos exposure and no evidence of asbestos related tissue injury at autopsy Note AB asbestos bodies AC commercial amphiboles amosite + crocidolite Chrys chrysotile gm gram of wet lung NA no tissue available for analysis NAMF nonasbestos mineral fibers ND none TAA noncommercial amphiboles tremolite + actinolite + anthophyllite trations in more than half of the individuals in that category Two of the categories deserve further comment Household contacts of asbestos workers had tissue asbestos burdens that were similar to the median value for some occupational groups For example the median asbestos body count of household contacts 130AB 130AB was of the same order of magnitude as construction workers 190 AB Hence household contacts have tissue asbestos burdens that are on the average equivalent to mild to moderate occupational exposure 14 15 Wives tended to have higher lung asbestos burdens than daughters or sons In contrast the median asbestos body count for automotive brake repair workers was within our normal range In many of these cases the tissue asbestos content was completely within the limits of background In those cases with an elevated tissue asbestos content excess commercial amphibole fibers mostly amosite were invariably detected Lung burden analyses in automotive brake repair workers reflect either a normal range tissue asbestos content or elevated commercial amphiboles 11 17 To further examine how the prevalence of plaques and asbestosis related to fiber burden we used a logistic regression model to relate prevalence to the fiber burden of commercial amphiboles The analysis demonstrated that both plaques and asbestosis were closely related to the natural logarithm of commercial amphibole counts P < .0001 ) and the result allowed us to fit these relationships with 2 equations one for the probability of plaques Pplaq and the second for the probability of asbestosis Pasb If we symbolize the logarithm of commercial amphiboles as Lca then 1 PplPapqlaq = 1 1+ 3.36 - 0.393 * Lca 1 PaPassb b - 2 2 1 + 30.2 12.4 ^ Lca Figure 4 shows how these 2 compare over the range of Lca found in our cases Clearly this plot demonstrates that piques appear at lower fiber burdens 62 Asbestos Bodies 14 4 tissue tissue 4 = = 10 : 10 gm count 8 4 count count 9 4 fiber . fiber Log 4 : Log 0 pany Other T:v : . : Rete Non ; A | : : Insul _ | : Auto Mach 2 ap a+ gs 2 50 87 oS 0 ^' g Commercial Amphiboles Il ] oo. : : : = > : : Other Non Insul Auto Mach V. L. Roggli et al Commercial Amphiboles Chrysotile ) tissue 12 tissue tissue tissue 10 | gm count count 8 count fiber 6 4 fiber LogLog wt } } : og * : : . ae Other : | Hy | . * : : ay Non : : : : i Insul - _ _ Auto I Mach 12 12 tissue tissue tissue 10 tissue 10 gm count 8 count count fiber fiber fiber Log Log _ eed . | by Other | ey I Non Insul Auto Mach FIG 2 Boxplots of fiber burden for asbestos bodies upper left commercial amphiboles upper right noncommercial amphiboles lower left and chrysotile fibers The vertical axis provides the fiber burdens in log number per gram and each plot provides the details for 5 industrial or occupational groups nonindustrial exposure Non insulation industry ( Insul automobile industry Auto machinists Mach and all remaining groups Other The results inside the solid dark box provide the range from the 25th to 75th percentiles and the white bars indicate the median value The more distant brackets and lines above and below the solid boxes provide the full range and most peripheral values than asbestosis Asbestosis begins to become prevalent when the commercial amphibole fiber burden exceeds 22000 per gram of tissue Lca By contrast at this level of amphiboles already 64 of cases have plaques Thus plaques are a sensitive marker for lower levels of fiber burden and asbestosis does not occur until much larger fiber burdens As a result of the above relationships among occupationally exposed individuals the percentage of mesothelioma cases with asbestosis remained low at around 20 until the highest exposure category insulators was reached At this point the percentage increased to more than 60 of cases with histologically confirmed asbestosis These findings indicate that there is a much higher threshold of asbestos exposure for asbestosis than for PPP and this threshold is uncommonly met about 20 of cases for most exposure categories The above models and equations suggest that with increasing fiber burden all will eventually get asbestosis DISCUSSION The current study extends our previous observations regarding mesothelioma and asbestos exposure by examining a large series of cases for which information was available regarding the patient's occupation or other exposure to asbestos We have found that 94 of our cases had exposures in one or more of 12 different industries 6 occupations or 1 nonoccupational exposure Exposure in more than 1 category was a common finding observed in at least 26 of the industrial categories and 21 of the occupations The most important nonoccupational exposure was as a household contact of an asbestos worker The duration of exposure was typically on the order of decades although we made no attempt in this regard to distinguish between intermittent and continuous exposures It could be argued that these cases are not representative of the types of exposures occurring in mesothelioma cases in the United States since more than 90 of them are medicolegal cases Therefore it is of interest to compare our exposure groups with those obtained by the Australian Mesothelioma Surveillance Program 5 The latter is a survey of all mesothelioma . cases in Australia and therefore does not suffer from any medicolegal selection bias The top 14 groupings are shown arranged from greatest to least number of Mesothelioma and Occupation 100 90 80 70 60 50 40 30 20 10 i 63 CHRYSO TAA -- -- -- FIG 3 Histogram showing the percentage of cases in each category with elevated lung fiber burdens for commercial amphiboles AC noncommercial amphiboles TAA and chrysotile Categories represented are those for which at least 10 cases with lung analyses in the given category were available HHC household contact cases in Table 8. Carpenter would be included in our construction industry as would laborer Waterside would be included in our shipbuilding industry and plumber is included in our pipefitter occupation Finally asbestos dwelling is equivalent to our building occupant category and brake lining to our automotive industry It can be seen that with the exception of mesothelioma cases related to working in the Wittenoom mine in Australia the major categories of exposure are remarkably similatro those noted in our series of cases More than 90 of our cases occurred in men reflecting the predominance of males in those occupations and industries most commonly associated with asbestos exposure Women predominated among household contacts of asbestos workers related to the laundering of work clothes by the spouses of workers occupationally exposed to asbestos 15 16 The median age for most groups was the seventh or eighth decade consistent with the long latency period for the development of mesothelioma and initial exposure during adulthood 8 Exceptions to this included household contacts and insulators The former is due to exposure of some household contacts during childhood The latter suggests the possibility of an inverse relationship between dose and latency for mesothelioma In addition pipefitters and railroad workers were significantly older Figure ) The latter may be due to the fact that most railroad exposures occurred prior to 1958 i.e. during the steam era The highest percentage of peritoneal mesotheliomas occurred among workers involved with the manufacture of asbestos products and insulation workers Table 6 The percentages however did not reach the level reported by Selikoff et al in which the ratio of peritoneal to pleural tumors among insulators was 3 1 2 Insulators and asbestos plant workers also had the highest lung asbestos fiber burdens which is consistent with the observation that on the average peritoneal mesotheliomas are associated with higher doses than are pleural mesotheliomas 7 The observations are consistent with a model in which the pleural and peritoneal mesothelial cells are equally susceptible to the development of mesothelioma and the probability is in turn related to the dose At sufficiently high exposure levels the dose to the peritoneum is high enough that the probability of a peritoneal origin approaches that of a pleural origin 18 Pleural plaques were found in a high percentage of cases 78 of informative cases for the whole series 64 V. L. Roggli et al 1.0 Figure 4 In contrast asbestosis was observed less commonly 24 of informative cases for the whole series again with evidence for a dose response Figure Asbestosis 4 These findings are consistent with our prior Asbestosis Asbestosis Asbestosis Asbestosis Asbestosis | Plaques 0.6 Plaques Plaques Plaques Plaques of 0.4 of 0.4 Probability Probability observation that pleural plaques and mesothelioma require less exposure to asbestos than is typically associated with the development of asbestosis 11 The results of fiber burden analysis are consistent with our prior observation that amosite is the most common fiber type associated with mesothelioma among U.S. workers 6 Furthermore the present study shows that amosite predominance extends over Probability Probability 0.2 Probability Asbestosis most occupational exposure groups Figure 3 consistent with the widespread use of containing insulation products in these industries in the past 0.0 0.0 0.0 T 4 T TT Lf T T T 6 8 10 12 14 16 However among nonoccupational exposures noncommercial amphiboles predominated Table 7 Chrysotile was infrequently identified in any exposure group consistent with its tendency to break down into smaller Commercial Amphiboles fibrils that are more readily removed from the lungs 19 FIG 4 Plots of the probability of either observing pleural plaques or asbestosis on the vertical scale versus log commercial amphiboles found per gram of tissue on the horizontal scale The lines provide a graphical picture of the results of two logistic regression equations see equations 1 and 2 one for the probability of observing plaques left curve as noted and one for the probability of observing asbestosis right curve as noted Environmental or neighborhood exposures appear to be a very uncommon cause of mesothelioma based on our observations The 4 cases we studied in this category included 3 from the southern Anatolian region of Turkey that were exposed to high levels of tremolite and actinolite in the local environment The only U.S. case we studied had a fiber burden indistinguishable from background Similarly exposure to asbestos as a building occupant is also an infrequent cause of mesothelioma Among the 6 cases of building occupants for which a fiber analysis was performed 3 had a modestly elevated content of noncommercial amphiboles and 3 had levels indistinguishable from background The finding of low levels of noncom- lending further support to the proposition that a high mercial amphiboles is consistent with an exposure to percentage of our cases are asbestos related predominantly chrysotile asbestos in this setting 21 B same: Furthermore there was evidence for a dose response with a higher percentage of plaques observed with Only 1 occupational exposure group contained on average more noncommercial amphibole fibers than increasing levels of commercials amphibole fibers commercial amphibole fibers This was the category of automotive brake repair workers In this group fiber burden analyses performed on 11 cases showed either an elevated amosite content or an asbestos concen- TABLE 8 Australian Mesothelioma Registry Report Carpenter Wittenoom laborer Navy Asbestos mfg Shipbuilding Railways Boilermaker Power plant Waterside Plumber Asbestos dwelling Brake lining Fitter turner Single 187 189 150 100 99 79 89 77 76 70 62 66 58 51 Multiple 33 25 27 43 33 53 36 40 39 8 13 626 626 16 Total 220 214 177 143 _ 132 132 125 117 115 78 75 72 70 67 Source From 5 tration indistinguishable from background Workers in this category frequently were exposed to asbestos in other categories as well Table ) and none had asbestosis Table 6 Among 15 workers exposed to brake dust who also had plaques 10 had additional exposures in jobs or industries where commercial amphiboles predominated and 3 additional cases had elevated commercial amphiboles in their lung tissue samples Lung tissue was not available for analysis in the other 2. These findings are consistent with our prior observations of brake repair workers with mesothelioma 11 17 22 and with the nature of brake dust which contains low levels of short chrysotile fibers 23 These observations in combination with a negative case control study 24 indicate that brake dust is unlikely to cause mesothelioma Another group of interest is individuals exposed to crocidolite fibers from smoking Kent cigarettes the micronite filters of which contained crocidolite for a Mesothelioma and Occupation 65 year period during the early 1950s 16 We have performed fiber analyses on lung tissue samples from 4 such cases For 3 of these smoking Kents or pretending to smoke Kent cigarette butts as a child was the only known exposure to asbestos these cases are included in the Other category in Table 3 One case that also had an exposure as a household contact had low levels of amosite in her lung samples None of the 4 cases had detectable crocidolite Based on these analyses smoking Kent cigarettes seems to be an unlikely cause of mesothelioma Nonasbestos mineral fibers were found in roughly similar amounts among each of the exposure categories Table 7 These include talc silica rutile aluminium silicates metallic fibers apatite and manmade mineral fibers 11 25 26 There is no evidence that these fibers contribute to the development of mesothelioma 27 A possible exception is refractory ceramic fibers which have produced a high rate of mesothelioma in inhalation exposure studies and have been associated with the development of pleural plaques in humans 28 29 These fibers have a greater biologic persistence than most other manmade mineral fibers 30 We have identified refractory ceramic fibers in lung tissue samples from 6 patients with mesothelioma and in 2 cases they were the most frequent fiber type identified In both cases however commercial amp- hibole fibers were also present in excess amounts Insufficient information is presently available to implicate manmade mineral fibers including refractory ceramic fibers as a cause of mesothelioma in humans 31 REFERENCES 1. 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