Document 82g51vR5Rq4KxdXLwJK470M1a

BIO LO GICAL EFFECTS OF ASBESTOS National Institutes of Health February 1, 1973 Chairman: David Rail, M.D. National Institute of Environmental Health Sciences Environmental Sciences Laboratory Mount Sinai School of Medicine of the City University of New York J. Churg, M.D. E. C. Hammond, Sc.D. A. M. Langer, Ph.D. W. J. Nicholson, Ph.D. I. J. Selikoff, M.D. Y. Suzuki, M.D. Oo Program 1 o Introduction 2. Mineralogy 3. Disease parameters Lung cancer Pleural and peritoneal mesothelioma Gastro-intestinal neoplasms Other neoplasms Asbestosis and pleural changes 4. Multiple factor interactions 5a Pathology 6. Environmental contamination Dose-disease response relationships Sources of environmental contamination Asbestos air pollution Asbestos lung burdens 7. Projections, 1973-2000 Major unresolved problems 8. Questions and discussions I. J. Selikoff, M.D. A. M. Langer, Ph.D. I. J. Selikoff, M.D. E. C. Hammond, Sc.D. J. Churg, M.D., Y. Suzuki, M.D. W. J. Nicholson, Ph.D. A M. Langer, Ph.D. I J. Selikoff, M.D. E C. Hammond, Sc.D. Many of the studies reported are being supported by research program grants from the National Institute of Environmental Health Sciences, ES 00358 , ES 00752 and ES 00792 and ES 44812 Career Scientist Award to A. M. Langer. ( Participants Mount Sinai School of Medicine of the City University of New York. n ,, Jacob Churg, M.D. E. Cuyler Hammond, Sc.D. Professor of Pathology and Professor of Community Medicine. Director of Laboratories, Environmntal Sciences Laboratory. Adjunct Professor of Community Medicine (Epidemiology). Vice-President, American Cancer Society and Director, Department of Epidemiology and Statistics. t w Arthur M. Langer, Ph.D. Associate Professor of Community Medicine (Mineralogy). Head, Physical Sciences Section, Environmental Sciences Laboratory. William J. Nicholson, Ph.D. Associate Professor of Community Medicine (Biophysics). Head, Physics Laboratory, Environmental Sciences Laboratory. Irving J. Selikoff, M.D. Yasunosuke Suzuki, M.D. Professor of Medicine and Professor of Community Medicine. Director, Environmental Sciences Laboratory. Associate Professor of Community Medicine (Environmental Pathology) and Associate Professor of Pathology. h . Outline of Asbestos Mineralogy 1. Asbestos defined: Asbestos is a generic term for 5 varieties of fibrous, hydrated, silicate minerals which possess the following common properties: are separable into thin fibers; are electrical and thermal insulators; may be woven and fabricated into forms easily; are chemically resistant. Mineral Group Serpentine asbestos (1) Amphibole asbestos (4) Mineral Species Chrysotile Amosite Crocidolite Anthophyllite Tremolite 2. Structure: (A) Chrysotile: (sheet silicate) Sheets: silica (tridymite), brucite Curvature Spiral; concentric growth Fibril unit Bundle (B) Amphiboles (chain silicate) Silica tetrahedra (units) Linking of staggered double chains Cation sites (0.40 - 1.40 8 accomodation) Anion configuration Chemical variation Natural occurrence Order-Disorder of cations 3. Chemistry: (structural formula) (A) Chrysotile (X)g(Z^O^q ) (0,0H,F)g MggSi^O^Q(0H)g (B) Amphiboles (W,X,Y)7_g(Z4011)2 (0,0H,F)2 (W0_iX2Y5!(Z8022) (0,OH,F)2for W=0 QX2Y5 Range of Superior Chemical Analyses for Asbestos Minerals Chrysotile Amosite Crocidolite Anthophyllite Tremolite Si02 Ti02 a i 2o 3 Fe23 Cr2 03 FeO NiO MnO MgO CaO Na90 k 2o h 2o 41.8- 42.0 0- 0.1 0.1- 0.5 0.2- 1.3 0- Tr 0.1- 1.6 0- Tr 0- Tr 41.4- 42.8 0- 0.1 0- Tr 0- 0.1 13.6- 14.0 49.47 0.25 0.63 4.15 0. 35.63 0. 0.61 6.57 0.52 0.02 0.20 2.33 to CO \ to 47.6-56.1 0- . 9 0.2- 3.5 9.9-20.1 0- 00- 1.5 0-15.8 0-4.9 4.5- 8.8 0-2.1 0- 3.3 50.1-58.9 0- 1.2 0.6- 8.1 0- 4.5 Tr0-20.5 Tr0- 2.5 17.6-30.8 0.1- 3.5 0- 0.8 0-0.2 1.6- 4.8 54.9-59.5 0- 0.3 0- 4.6 0- 0.5 00- 0.4 00- 0.4 21.7-25.5 11.9-13.1 0- 1.3 0- 0.6 0- 2.3 Outline of Asbestos Mineralogy - 2 4. Associated Trace Mineral Phases: (A) Chrysotile: Serpentine phases (lizardite; antigorite) Magnetite Chromite Brucite (fibrous-nemalite) Talc Magnesite Metallic phases (awaruite) Calcite Olivine, Pyroxenes, amphiboles (B) Amphiboles: Amosite (quartz, Fe oxides hydrated) Crocidolite (as amosite amphiboles) Anthophyllite (talc, chrysotile, amphiboles) Tremolite (talc, "serpentine," amphiboles) 5. Associated Trace Elements: (A) Chrysotile: N i ,C r ,Co,C u ,M n ,Ca (B) Amphiboles: (eg. anthophyllite: A g ,Ba,Co,Cr,Cu,Li,Mo,Ni,Sn, Sr,V,Zr present in > 10 ppm) (eg. crocidolite: Zr,Nb,Th,Ce,Y ,La,Ba,V ,Ni) 6. Associated Organic Contaminants: (A) Chrysotile: Small quantities of oils and waxes (B) Amphiboles: Op to 0.3% oils, waxes, amino acids in amosite and crocidolite from So. Africa 7. Surface Properties: (A) Chrysotile Slightly (+ ) FT1" from surface hydroxyl groups; changes with ph and sorbed material. (B) Amphiboles Moderately (-) , changes with species, sub stitution of cations and sorbed surface material. Also different charge at different sites. General References Deer, W.A., Howie, R.A. and Zussman, J; , 1962, The Rock Forming Minerals: v.2, The Chain Silicates, 329p.; v,,3, The Sheet Silicates, 270p., J. Wiley and Sons, N.Y. Ernst, W.G., 1968, Amphiboles: Crystal Chemistry, Phase Relations and t Occurrence: v.l of Minerals, Rocks and Inorganic Materials, 123p., Springer-Verlag, New York Mason, B . , 1958, Principles of Geochemistry, 310p., J. Wiley and Sons, N.Y. Speil, S., and Leineweber, J.P., 1969, Asbestos Minerals in Modern Technology: Env. Res. v.2, 166-208. Asbestos Disease Asbestosis .This is confined to occupational exposure. .There is considerable individual variation in response. Some workers may be employed in asbestos trades for more than 40 years and still have normal chest X-rays. In others, as little as 1 day of factory exposure (inadequately controlled) will result in parenchymal or pleural disease decades later. .Asbestosis sufficiently severe to be fatal has been seen in our studies in as little as eight years after onset of exposure, but this is most unusual. Death of asbestosis, when it occurs, usually is observed twenty, thirty, forty or more years after onset of work. Three factors generally must be considered in any analysis: Intensity of exposure Duration of exposure Duration from o n s e t o f exposure (Residence time of dust in lungs) .By and large, significant asbestosis is not seen until at least 20 years from onset have elapsed -- the "20 year rule." .All varieties of asbestos can produce disease; whether one type is more fibrogenic than another is uncertain. .Clinical features of note are: Monosymptomatic disease - dyspnoea Restrictive lung function pattern; diffusion defects Fine rales' Finger clubbing Cough and sputum not prominent, except with smokers Tendency to serum rheumatoid factor Cor pulmonale in late stages Incomplete clinical-X-fay-function correlation Symptoms or signs are not useful for "early" diagnosis. X-ray and pulmonary function changes vie for early detection of disease, but years may go by before abnormalities become evident. At present, we cannot predict which workers will suffer early and/or severe asbes tosis. Appropriate predictive diagnostic techniques do not exist. .Pleural involvement is an important feature of asbestos disease. Both localized "plaques" or diffuse fibrosis may occur, and cal cified plaques are often seen radiologically. When bilateral, they are almost pathognomonic of asbestos exposure; even unilateral cal cification is usually reliable for diagnosis, especially when there is no history of tuberculosis, hemothorax, empyema. I Asbestos Disease - 2 .Mortality: in cohorts of asbestos workers studied by us, about 7% of deaths were caused by asbestosis with respiratory insufficiency sometimes precipitated by minor pulmonary infection in patient with limited reserve. Tables (Asbestosis) X-ray changes tend to be extensive after more than 20 years from onset of work. Findings in 1,117 asbestos insulation workers. Onset of exposure (yrs.) Asbestosis (grade) % % -------------------- No. Normal Abnormal 1 2 3 40+ 30-39 20-29 10-19 0-9 121 5 .8 194 12.9 77 27.2 379 55.9 346 89.6 94.2 87.1 72.8 44.1 10.4 35 51 28 102 49 18 35 17 4 158 9 0 36 0 0 1,117 51.5 48.5 366 126 50 Years from onset of exposure 40+ 30-39 20-29 10-19 0-9 Pleural changes on X-ray also are notable more than 20 years from onset of work Number examined Normal pleura Abnormal pleura Fibrosis Calcification 121 28 194 96 77 47 379 340 346 342 65 62 25 36 4 70 67 8 5 0  Asbestos Disease - 3 The cardinal clinical symptom - dyspnea generally obeys the "20 year rule." Dyspnea (degree) U1 0 0 exposure (yrs.) No. Normal Dyspnea 1 2 3 CD i O 40+ 30-39 20-29 10-19 121 52.1 47.9 26 17 16 194 70.6 29.4 35 14 8 77 76.6 23.4 12 3 3 379 92.6 7.4 27 1 0 346 98.6 1.4 50 0 2. Lung cancer Important risk begins as early as 10-14 years from onset of exposure, but results in significant number of excess deaths only after 20 years from onset of exposure. Depending upon the nature of the cohort under study, we have found a 5X - 7X increase in lung cancer. This is the most important cause of death among asbestos workers -- 20% of all deaths are caused by the tumor. All cell types are seen (see Pathology). However, the cancer has seme unusual features in asbestos exposure: 2/3 are lower lobe rather than upper lobe; they tend to be peripheral (main bronchus tumors are infrequent; so broncho scopy tends to have less utility); the pleura is often involved early. Diminished respiratory reserve makes operation less available, and concomitant asbestosis may make radiological diagnosis difficult. The clinical course and prognosis are very much like those in non-asbestos cases. Lung cancer as a result of environmental asbestos exposure has not yet been explored; it may turn out to be even more important, in terms of number of cases, than environmental mesothelioma. It should be noted that adults in urban areas tend to have asbestos fibers in their lungs (albeit many fewer in number than in lungs of asbestos workers). The significance of the presence of these fibers among cigarette smokers in the general population is not now known. Studies are under way to determine if lung cancer rates are increased among family contacts of asbestos workers, among residents of neighborhoods about asbestos factories, and among workers indirectly exposed to asbestos in the construction industry. Rates will be correlated with asbestos lung burden of individuals in these populations. If rates in these groups are elevated, additional approaches will be necessary to evaluate whether asbestos lung contamination in the general public contributes to its lung cancer risk. Asbestos Disease - 4 3. Mesothelioma (Diffuse malignant pleural or peritoneal mesothelioma) Approximately 7% of deaths among asbestos workers are caused by pleural and peritoneal mesothelioma. This is an extraordinary in crease, although the exact amount is difficult to calculate, since the incidence in the general population is not known. In the past, the tumor was so rare as not to be separately coded in the Inter national Classification of Causes of Death. Incidence has varied in general autopsy series from 1:1,000 to 1:10,000. In the American Cancer Society's Cancer Prevention Study, 3 of the first 31,652 deaths were listed as caused by mesothelioma. If we assume the turner was underdiagnosed in the general population by a factor of 2 or 3, then about 1:3,500 deaths was caused by mesothelioma. The contrast with the fate of asbestos workers is striking -- hundreds of times as frequent. To date, the neoplasm has proven invariably fatal. Duration of life is only infrequently longer than a year after diagnosis -- often less. Among asbestos workers, 2/3 are peritoneal and 1/3 pleural. With environmental exposure, pleural tumors seem more common, al though more data are needed before a definitive statement is warranted. Mesothelioma as the result of indirect occupational exposure occurs. It may turn out to be of greater significance, in terms of total numbers, than that associated with direct occupational exposure. In the construction industry alone, some 4,000,000 workers may have intermittent, low-level exposure from the use of asbestos products (taping joints in dry wall construction, carpenters sawing asbestoscement sheets, mixing asbestos cement, sanding asphalt-asbestos tile floors, demolition and waste disposal, etc.) Environmental contamination from factory or mill effluents, or as the result of household contamination by dusts on clothes and shoes of asbestos workers, has been related to mesothelioma. It is not known whether general atmospheric asbestos air pollution (brake lining wear, weathering of asbestos shingles or asbestos cement materials, other end product use) is associated with mesothelioma. Our knowledge may be summarized as follows: Mesothelioma Exposure Direct occupational - extraordinary hazard Indirect occupational - many cases reported Family contact - cases known Neighborhood pollution - cases known General community contamination ? (I Asbestos Disease - 5 4. Gastro-intestinal cancer (stomach, colon, rectum, esophagus) There is a modest increase of gastro-intestinal tract cancer among asbestos workers (2X - 3X). Whether it also occurs as the result of environmental asbestos exposure has not been studied. Two observations may be relevant. 1) Among asbestos workers, asbes tos fibers are present in the bowel wall long after occupational ex posure has ceased. 2) There may be opportunity for asbestos contam ination of food and fluids (filtration through asbestos filters; flow through asbestos cement pipes; talc as food additive) . The signifi cance of these observations is not known. Mortality Data In general, deaths in the asbestos worker cohorts studied may be broadly categorized as follows: Total cancer Lung cancer.............................. 20% Mesothelioma.......... .................. 7% G,, I . cancer.......... ................... 8% Asbestosis 40% 7% The direct occupational risk is associated with current or prior regular work with asbestos. It has been estimated that 1,000,000 in the United States have or have had such experience. While the number of individuals presumed to have indirect occupational exposure (or family contact, or neighborhood exposure) is very much larger, the magnitude of their risk of asbestos-associated disease has not yet been determined quantitatively. The data in the first six tables which follow are derived from the experiences of cohorts of workers with direct occupational exposure and refer only to such groups. Tables 7 and 8 provide some infor mation from 2 series concerning the proportion of environmentallyinduced mesothelioma, relative to those occupationally derived. Table 1 Expected and observed number of deaths among 623 New York-New Jersey asbestos insulation workers, Jan. 1, 1943-Dec. 91, 1931, twenty or more years after onset of first exposure to asbestos. Total Cancer: all sites Lung cancer Pleural mesothelioma Peritoneal mesothelioma Cancer of stomach, colon, rectum, esophagus Cancer all other sites Asbestosis All other causes Total all causes 1943 -1951 1952 -1961 1962 -1971 Total 1943-1971 Exp. Observ. Exp. Observ. Exp. Observ. Exp. Observ. 11.3 28 18.3 57 17.6 104 47.2 189 1.5 13 3.5 23 5.1 48 10.1 84 ** 1 ** 2 ** 5 ** 8 ** 1 ** 3 ** 20 ** 24 4.1 5.7 ** 65.1 76.4 7 5.0 18 3.9 16 13.0 41 6 9.8 11 8.6 15 24.1 32 1 ** 10 ** 22 ** 33 44 89.4 94 78.3 94 232.8 199 73 107 .7 161 95.9 187 280.0 421 Person-years of observation: 3,726 4,406 2,898 11,030 632 members were on the Union1s rolls on January 1 , 1943. Seven died before reaching 20 years from first employment. All others entered these calculations upon reaching the 20-year-from-0nset of first exposure point. Expected rates are based upon age-specific death rate data of U.S. National Office of Vital Statistics from 1949-1967. Rates were extrapolated 1943-1948 from rates for 1949 1955 and for 1968-1971 from rates for 1961-1967. **U.S. death rates not available but these are rare causes of death in the general population. 4" Asbestos Disease i <T> Table 2 Expected* and observed deaths among 17,800 -asbestos insulation workers in the United States, January 1, 1967-December 31, 1971 Distribution by duration from onset of exposure Total Less than 20 years 20 years and more Expected Observed Expected Observed Expected Observed Total deaths 805.63 1,092 178.94 211 626.69 881 Cancer: all sites 144.09 459 26.31 51 117.78 408 Lung cancer Pleural mesothelioma 44.42 ** 213 26 7.03 ** Peritoneal mesothelioma ** 51 ** Cancer of stomach 6.62 16 0.97 Cancer of colon, rectum 17.51 26 2.51 Cancer of esophagus 3.21 13 0.44 All other cancers 72.33 114 15 .36 Asbestosis ** 78 ** 22 37.39 2 ** 3 ** 1 5.65 3 15.00 1 2.77 19 56.97 5 ** 191 24 48 15 23 12 95 73 All other causes 661.54 555 152.63 155 508.91 400 Number of men Person-years of observation 17,800 86,300 12, 681 62,673 5,119 23,627 ^Expected deaths are based upon age specific death rate data of the U.S. National Office of Vital Statistics . Rates for 1968-1971 were extrapolated from rates for 1961-1967. **U.S. death rates not available, but these are rare causes of death in the general population. I Asbestos Disease - 8 Table 4 Expected and observed deaths among 689 asbestos production and textile workers, Jan. 1, 1959 - Dec. 31 , 1971 Total cancer (all sites) Cancer of lung, pleura, trachea, bronchus Lung cancer Pleural mesothelioma Peritoneal mesothelioma Cancer of stomach, colon and rectum Cancer all other sites Asbestosis All other causes Total deaths Observed deaths 72 35 27 8 7 13 17 24 103 199 00 Expected deaths 27.8 + + + + + 5.0 14.4 + + 106.5 134.3 +United States data not available but figure should be only slightly less than 8.4 +United States data not available but these are rare causes of death in the general population. Table 3 Expected* and observed deaths among 933* amosite asbestos factory workers first employed 1941-1945 , and observed to Dec. 31, 1971 Before 1952 Expected Observed Total deaths 69.98 88 Total cancer: all sites 9.81 15 Lung cancer Pleural mesothelioma Peritoneal mesothelioma Cancer of stomach Cancer of colon, rectum Cancer of esophagus All other cancers 1.49 *** *** 1.45 1.56 0.27 5.04 3 1 0 3 2 0 6 Asbestosis *** 3 All other causes 60.17 70 1952- 1961 Expected Observed 108.27 146 18.72 44 3.71 *** *** 1.84 2.61 0.45 10.11 *** 23 0 0 4 5 0 12 7 89.55 95 1962 -1971 Expected Observed 121.24 250 21.63 84 6.21 *** *** 1.29 2.88 0.51 10.74 47 2 4 4 8 0 19 17 99.61 149 Total, 1941-1971 Expected Observed 299.49 484 50.16 143 11.41 ** * *** 4.58 7.05 1.23 25.89 73 3 4 11 15 0 37 *** 27 249.33 314 Expected rates are based upon age-specific death rate data of U.S. National Office of Vital Statistics from 1949-1967. Rates were extrapolated 1941-1948 from rates for 1949-1955 and for 1968-1971 from rates for 1961-1967. **933 men were employed. In 5 cases, ages were not known and these men have been excluded and from these calculations. 877 men were traced to death or to Dec. 31, 1971. 51 men were par tially traced and remain in the calculations until being lost to observation. ***U.S. death rates are not available, but these are rare causes of death in the general population. Asbestos Disease i Asbestos Disease 10 Table 5 Deaths of lung cancer and pleural mesothelioma among 17,800 asbestos insulation workers in the U.S. and Canada, Jan. 1, 1967-Dec. 31, 1971: relation to elapsed period from onset of work exposure. Lung cancer Pleural Mesothelioma Years from on^et < 10 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50+ Expected deaths* 0.48 1.69 4.86 7.55 8.50 6.24 3.53 4.04 3.72 3.81 Observed deaths 0 4 18 25 41 44 23 24 17 17 Ratio '2.4 3.7 3.3 4.8 7.1 6.5 5.9 4.6 4.5 Observed deaths 0 0 2 4 7 4 1 3 4 1 Total 44.42 213 4.8 26 Expected deaths are based upon age specific death rate data of the U.S. National Office of Vital Statistics . Rates for 19681971 were extrapolated from data for 1961-1967. I Asbestos Disease - 11 Table 6 Expected and observed deaths of lung cancer among 876 amosite asbestos factory workers, first employed 1941-1945, and observed to Dec. 31, 1971.* Distribution by duration of employment. Duration of Person-years Deaths of lung cancer employment Number of Men of observation Exp.** Observ. Ratio < 3 months 3-11 months 1+ years Total 256 294 326 876 . 5,869 6,158 6,912 18,939 3 .55 13 3.66 3.58 15 4.19 4.09 45 11.00 11.22 73 6.51 *This table excludes 57 men. 10 died during first year of employ ment, 39 could not be traced after the first year, 7 had prior occupational exposure to asbestos and 1 had employment of uncertain duration. 17 pen of the 876 were partially traced and remained in the calculations only until lost to observation. **Expected rates are based upon age-specific rate dats of U.S. National Office of Vital Statistics, 1949-1967. Rates were extrapolated 1941-1948 from rates for 1949-1955 and for 1968 1971 from rates for 1961-1967. Asbestos Disease - 12 Table 7 Mesothelioma in London Hospital (Newhouse and Thompson, 1965) Total patients............................ 76 Occupational asbestos exposure,... 31 Family contact.................... 9 Neighborhood residence......... . . 11 No known contact.................. 25 Table 8 Pleural Mesothelioma : 232 cases in South Africa Mesothelioma Registry* Exposure history not available.....................22 Exposure ascertained....... ......... . .210 Occupational asbestos exposure.t..102 (48.6%) Environmental asbestos exposure... 76 (36.2%) No asbestos exposure............. 32 (15.2%) *Annual Report 1971. National Research Institute for Occupational Diseases of the South African Medical Research Council, Johannesburg, 1972. Asbestos Disease - 13 Bibliographical Landmarks in Asbestos Disease 1924 1931 1935 1953 1954 1955 19 55 1960 First case report of pulmonary asbestosis (Cooke, 1924). Not fully accepted at first, reported again in 1927 (Cooke, 1927) when case reports elsewhere confirmed the existence of the disease. In retrospect, Parliament had been notified of the hazard in 1906, when Montague Murray testified concerning fatal pulmonary fibrosis among asbestos textile workers. (Departmental Committee on Com pensation for Industrial Disease, 1907). Industrial survey showed high prevalence of asbestosis in asbestos textile factories in Great Britain (Merewether, 1931). Similar prevalence in U.S. asbestos textile industry was found in PHS study (Dreessen, et al, 1938). A case of lung cancer with asbestosis was reported and etiological association suggested (Lynch and Smith, 1935). Despite numerous similar case reports, the possibility of a chance association could not be avoided and the question remained open. An instance of pleural mesothelioma, and one of6.peritoneal mesothe lioma, in association with asbestosis, were reported (Weiss, 1953; Leichner, 1954). Again, these random cases, and others reported elsewhere in the next several years, did not prove an etiological relationship; the possibility of a chance association remained, although the frequent linking with asbestos of this otherwise rare tumor (see Wagner, et al, 1960) was striking. Lung cancer risk of asbestos factory workers clearly established by epidemiological study (Doll, 1955). Careful epidemiological study, going beyond lung cancer, showed U.S. factory hazard as well (Mancuso and Coulter, 1963). Pleural calcification emphasized as radiological accompaniment of asbestosis (Jacob and Bohlig, 1955). Extraordinary incidence in asbestos workers later demonstrated (Selikoff, 1965). Pleural calcification may occur in 50% of experienced asbestos workers against 1 in 1,000 general hospital admissions. Environmental asbestos disease suggested by two brilliant studies. Each took advantage of clinical asbestos ''marker.11 Pleural calcification was found to be common in neighborhood about an asbestos mine and mill (499 of 6,312 x-rayed). (Kiviluoto, 1960.) Numerous cases of pleural mesothelioma reported in asbestosrich area of South Africa. On inquiry, many had had no occu pational exposure but, rather, potential environmental contact (Wagner, Sleggs and Marchand, 1960). This study also did much to establish asbestos-mesothelioma relationship. 1961 1962 1963 1964 1964 1965 1965 1968 II Asbestos Disease - 14 Physiological defect in asbestosis clarified as restrictive dis ease without important obstructive airway component (Bader, Bader and Selikoff, 1961). Experimental mesothelioma produced by intrapleural instillation of asbestos (Wagner, 1962). ~ More recently, this model has been well used to investigate important variables (Stanton and Wrench, 1972). Lung cancer has also been induced (Gross, 1967). Wide environmental contamination suggested by frequent presence of "asbestos bodies" in lungs of routine autopsies (Thomson, Kaschula and MacDonald, 1963). '' ~ This was soon confirmed in many cities of the world. The con cept derived from these observations was that lungs of urban dwellers are regularly contaminated by asbestos. This was dis puted. It had long been known that a number of fibers other than asbestos could also be coated to give similar appearance. It was proposed that, unless one was certain of the nature of the core, non-specificity be signaled by calling these structures "ferruginous bodies" (Gross, Cralley and de Trevilie, 1967). The matter was not resolved until 1971 (See Langer, et al). Asbestos disease described as commpn among insulation workers, drawing attention to the construction industry, which uses 2/3 of asbestos in U.S., and the potential for much wider environmental contamination than that derived from factories (Selikoff, Churg and Hammond^ 1964). Gastro-intestinal cancer found three times as frequent as expected in cohort of asbestos workers (Selikoff, Churg and Hammond^ 1964). Confirmed in later studies. Epidemiological investigations established mesothelioma as a common occupational risk (Selikoff, Hammond and Churg, 1965). Peritoneal mesothelioma was now emphasized in these and other studies (Enticknap and Staither, 1964). Potential significance of environmental asbestos disease highlighted by report of mesothelioma among family contact^ and residents about an asbestos plant (Newhouse and Thompson, 1963). Spectrum of asbestos disease further widened by description of meso thelioma among shipyard construction workers with a history of in direct exposure to asbestos decades before (Harries, 1968). Again, mesothelioma was used as a marker." The problem of can cer as a consequence of asbestos contamination of construction work sites and shipyards (carpenters, plumbers, electricians, masons, laborers., etc.),may turn out to be more important than direct asbestos work (many millions versus hundreds of thousands). Lung cancer as well as mesothelioma may be involved (Fletcher,1972). Asbestos Disease - 15 1968 1970 1971 1972 1972 Multiple factor effect demonstrated. In addition to direct carcino genic and fibrogenic action, asbestos multiplied the lung cancer potential of cigarette smoking (Selikoff, Hammond and Churg, 1968). Asbestos workers who smoke cigarettes have eight times greater risk of dying of lung cancer, as cigarette smokers who do not work with asbestos, and ninety times the risk of men who neither smoke nor work with asbestos. Soils naturally contaminated with asbestos-bearing geological forma tions may expose agricultural populations (Burilkov and Michaelova, 1970) and provide seme measure of "natural background*' of environ mental asbestos contamination. Chrysotile asbestos in lungs of New Yorkers demonstrated by electron microscopy (Langer, Selikoff and Sastre, 1971). Biological potential of such contamination not now known. Asbestos air pollution may be responsible, at least in part, for lung contamination of urban dwellers (Nicholson, Rohl and Ferrand, 1972; Selikoff, Nicholson and Langer, 1972). Air samples, studied by electron microscopy, uniformly showed asbestos present in each of 47 U.S. cities. Levels were well below those of asbestos worksites, however. Environmental causes of mesothelioma stressed by analysis of cases in South Africa (South African Medical Research Council, 1972). 36% of 210 cases were considered the result of environmental exposure to asbestos, 49% were occupational in origin and 15% had no history of asbestos exposure. Bibliographical References 1. Bader, M.E., Bader, R.A. and Selikoff, I.J. Pulmonary function in asbestosis of the lung; an alveolar-capillary block syndrome. Amer. J. Med. 30:235, 1961. 2. Burilkov, T., Michailova, L. : Asbestos content of the soil and endemic pleural asbestosis. Environ. Res. 3:443-451, 1970. 3. Cooke, W.E. Fibrosis of the lungs due to the inhalation of asbestosis. Brit. Med. J. 2:578-580, 1929. 4. Cooke, W.E. Pulmonary asbestosis. Brit. Med. J. 2:1024-1025, 1927. 5. Departmental Committee on Compensation for Industrial Disease. London. H.M.S.O., 1907. pp. 127-128 of minutes of evidence. 6. Doll, R. Mortality from lung cancer in asbestos workers. Brit. J. Industr. Med. 12:81-86, 1955. Asbes Disease 16 7. Dreessen, W.C., Dallavalle, J.M., Edwards, T.I., Miller, J.W. and Sayers, R.R. A Study of Asbestos in the Asbestos Textile Industry. (Public Health Bulletin No. 241) Washington: U.S. Government Printing Office, 1938. 126 pp. 8. Enticknap, J.B. and Smither, W.J. Peritoneal tumours in asbestosis. Brit. J. Industr. Med. 21:20-31, 1964. 9. Fletcher, D. A mortality study of shipyard workers with pleural plaques. Brit. J. Ind. Med. 29:142-145, 1972. 10. Gross, P., deTreville, R.T.P., Toker, E.B., Kaschak, M. and Babyak, M.A. Experimental asbestosis. The development of lung cancer in rats with pul monary deposits of chrysotile asbestos dust. Arch. Environ. Health 15:343-355, 1967. 11. Gross, P., Cralley, L.J. and deTreville, R.T.P. "Asbestos" bodies: their nonspecificity. Amer. Industr. Hyg. Ass. J. 28:541-542, 1967. 12. Harries, H.M. Asbestos Hazards in Naval Dockyards. Ann. Occup. Hyg. 11:135-145, 1968. 13. Jacob, G and Bohlig, H. Roentgenological complications in pulmonary asbestosis. Fortschr. Rentgenstr. 83:515-525, 1955. 14. Kiviluoto, R. Pleural calcification as a roentgenologic sign of non occupational endemic anthophyllite-asbestosis. Acta. Radiol. Suppl. 194:1-77, 1960. 15. Langer, A.M., Selikoff, I.J. and Sastre, A. Chrysotile asbestos in the lungs of persons in New York City. Arch. Environ. Health 22:348-361, March 1971. r 16. Leicher, F. Primrer Deckzellentumor des Bauchfells bei Asbestose. Arch. Gewerbepath. u. Gewerbehyg. 13:382-392, 1954. 17. Lynch, K.M. and Smith, W.A. Pulmonary asbestosis III: Carcinoma^, of lung in asbesto-silicosis. Amer. J. Cancer 24:56-64, 1935. 18. Mancuso, T.F. and Coulter, E.J. Methodology in industrial health studies. The cohort approach, with special reference to an asbestos company. Arch. Environ. Health 6:210-226, 1963. 19. Merewether, E.R.A. The occurrence of pulmonary fibrosis and other pul monary affections in asbestos workers. J. Industr. Hyg. 12:198-222, 239 257, 1930. 20. Newhouse, M.L. and Thompson, H. Mesothelioma of pleura and peritoneum following exposure to asbestos in the London area. Brit. J. Industr. Med. 22:261-269, 1965. 21. Nicholson, W.J., Rohl, A.N. and Ferrand, E.F. Asbestos air pollution in New York City. In: Proc. Second Int'l. Clean Air Congress, Ed. Englund, H.M. and Berry, W.T. Acad. Press, New York, 1971 pp.136-139. Asbestos Disease 17 22. Selikoff, I.J. The occurrence of pleural calcification among asbestos insulation workers. Ann. N.Y. Acad. Sc. 132:251-367, 1965. 23. Selikoff, I .J ., Churg, J. and Hammond, E.C. Asbestos Exposure and Neo plasia. J.A.M.A. 188:22-26, 1964. 24. Selikoff, I.J., Churg, J. and Hammond, E.C. Relation between exposure to asbestos and mesothelioma. New Eng. J. Med. 272:560-565, 1965. 25. Selikoff, I.J., Hammond, E.C. and Churg, J. Asbestos exposure, smoking and neoplasia. J.A.M.A. 204 (2):106-112, April 1968. 26. South African Medical Research Council. Annual Report 1971 of the National Institute for Occupational Diseases. Johannesburg, 1972. 27. Stanton, M.F. and Wrench, C. Mechanisms of Mesothelioma Induction with Asbestos and Fibrous Glass. J. Nat. Cancer Inst. 48:797-821, 1972. 28. Thomson, J.G., Kaschula, R.O.C., MacDonald, R.R.: Asbestos as a modern urban hazard. S. Afr. Med. J. 7:77-81, 1963. 29. Wagner, J.C., Sleggs, C.A., Marchand, P.: Diffuse pleural mesothelioma and asbestos exposure in North Western Cape Province. Brit. J. Industr. Med. 17:250-271, 1960. 30. Wagner, J.C. Experimental production of mesothelial tumours of the pleura by implantation of dusts in laboratory animals. Nature 196:180-181, 1962. 31. Weiss, A. Pleurakrebs bei Lungenasbestose, in vivo morphologisch gesichert. Medizinische 3:93-94, 1953. Multiple Factor Effect i In 1963, a study was initiated of a cohort of 370 asbestos insulation workers, each of whom had begun work at least twenty years before (in deed, 333 had reached thirty years from onset). Previous analysis of the experience of members of this union 1943-1962 had shown lung can cer deaths to be 6.8 times as frequent as expected. It was assumed, with good reason, that these 370 men would have an unhappy experience with lung cancer. It was soon found, however, that there ar asbestos workers and asbes tos workers. Thus, among the 370 men, there were 87 who had no history of cigarette smoking. By April 30, 1967, no death of lung cancer had occurred among them. On the other hand, among the 283 with a history of regular cigarette smoking 24 died of lung cancer, although only 2.98 such deaths had been expected, given their smoking habits. It was not the smoking alon; only three deaths or so would have occurred. It was not the asbestos alone -- the 87 non-smokers had' no lung cancer deaths. The combination of the two had a sharp, multiplying effect. It has been calculated that an asbestos worker who smokes cigarettes has eight times the risk of dying of lung cancer compared to similar smokers of the same age who do not work with asbestos, and 92 times the risk Compared to a similar man who neither works with asbestos nor smokes cigarettes. This cohort has been followed an additional 56 months; the findings re main very much the same. By December 31, 1971, of the 283 men who had smoked cigarettes regularly 41 died of lung cancer while of 87 men who never smoked cigarettes regularly, only one died of lung cancer. We have obtained data in a second far larger study. On January 1, 1967, we registered all members of the insulation workers union in the United States and Canada (17,800 men). 11,656 completed a questionnaire pro viding, among other details, information concerning their smoking habits. Observation of these men through December 31, 1971, confirms and extends our original observations. Of 2,066 men with no history of cigarette smoking, only two deaths (of 73) were due to lung cancer. Among the 9,590 cigarette smokers, 134 deaths (of 596) were the result of lung cancer. Lung cancer is uncommon among asbestos workers who have no history of cigarette smoking; if their risk is increased, such increase is not great. On the other hand, if these exposed individuals do smoke, the risk associated with smoking in general is multiplied many times. Table 1 Expected* and observed deaths among 370 New YorkNew Jersey asbestos insulation workers, Jan. 1, 1963-Dec . 31, 1971 Number of men Jan. 1, 1963 Person-years of observation Total 370 2,520 No history of cigarette smoking ** 87 608 History of cigarette smoking 283 1,912 Cancer all sites Lung cancer Pleural mesothelioma Peritoneal mesothelioma Cancer of stomach Cancer of colon, rectum Cancer of esophagus Asbestosis All other causes Total deaths Expected deaths 15 .74 4.57 *** *** 0.94 2.15 0.37 *** 69.22 84.96 Observed deaths 94 42 5 20 6 6 - 21 53 168 Expected deaths 4.75 1.26 *** *** 0.30 0.69 0.11 *** 22.28 27,03 Observed deaths 15 1 7 2 2 - 5 15 35 Expected deaths 10.99 3.31 *** *** 0.64 1.46 0.26 *** 46.94 57.93 Observed deaths 79 41 5 13 4 4 - 16 38 133 *Expected deaths based upon age specific U.S. mortality for white males, disregarding smoking habits. Lung cancer estimates based upon U.S. rates for cancer of lung, pleura, bronchus and trachea, categories 162 and 163, **Including 39 men who smoked pipe or cigars. ***United States data not available, but these are rare causes of death in the general population. Multiple Factor Effect i to Number of men Jan. 1, 1967 Person-years of observation Table 2 Expected and observed deaths among 17,800 U.S. and Canada asbestos insulation workers, Jan, 1, 1967-Dec. 31, 1971** Total No history of cigarette smoking** History of cigarette smoking 17,800 86,300 2,066 10,163 9,590 46,615 Smoking habits not known 6, 144 29, 522 Cancer all sites Expected Observed deaths deaths 144.09 459 Expected Observed deaths deaths 19.92 33 Expected Observed deaths deaths 79.58 265 Expected Observed deaths deaths 44.59 161 Lung cancer Pleural mesothelioma Peritoneal mesothelioma Cancer of stomach Cancer of colon, rectum Cancfer of esophagus Asbestos is ... 44.42 *** *** 6.62 17.51 3.21 *** 213 26 51 16 26 13 78 5.98 *** *** 0.95 2.52 0.44 *** 2 2 9 1 4 0 4 25.09 *** *** 3.60 9.53 1.80 *** 134 17 29 8 14 7 45 13.35 *** *** 2.07 5.46 0.97 *** 77 7 13 7 8 6 29 All other causes 661.54 555 92.67 36 356.67 286 212.20 233 Total deaths 805.63 1 092 112.59. 73 436.25 5 96 256.79 423 *Expected deaths based upon age specific U.S. mortality rates for white males disregarding smoking. Lung cancer estimates based upon U.S. rates for cancer of lung, pleura, bronchus and trachea, categories 162 and 163. **Included 609 men who smoked pipes or cigarettes. . ***United States data not available, but these are rare causes of death in the general population. Multiple Factor Effect w I Pathology of Asbestos-Associated Disease Asbestos enters the human body via two principal routes: the respiratory tract and the gastrointestinal tract. Respiratory tract Asbestos dust consists mainly of fine, needle-like fibers, ranging in length from a few hundred microns to considerably less than one micron. The dust is easily inhaled and smaller fibers are carried to the most distant segments of the lung -- respiratory bronchioles and alveoli -- where they become trapped. Some of the fibers remain in situ; others are taken up by macrophages and carried into the alveolar septa and the lymphatic vessels, and from there to the regional lymph nodes and to the subpleural lymphatics. Asbestos fibers are able to penetrate into the pleural space; either because they have sharp ends and are quite rigid, or because they are carried by macrophages. Fate of asbestos fibers: Some fibers slowly dissolve at a rate dependent upon the type of asbestos. Some are coated by iron-protein compound and thus probably neutralized. Both of these are very slow processes. In other instances, fibers remain in situ apparently little altered. In either case, asbestos has time to exert injurious effect on the cells of the lung. Its toxicity prob ably depends not only upon its chemical composition but also upon its physical properties (e.g. size and shape of fibers, piezoelectric prop erties) and its ability to concentrate various, often toxic, substances on its highly adsorbent surfaces. Pulmonary fibrosis (asbestosis): Minor degrees of injury can be repaired. Considerable concentration of asbestos is needed to produce widespread irreversible damage. Injury and death of cells and their replacement by connective tissue leads to pulmonary fibrosis. This at first is limited to the septa, but eventually destroys the alveoli and bronchioles while some of the remaining air spaces became dilated. Within the fibrosed areas variable numbers of asbestos fibers and bodies cap be found. The function of the lung, gas exchange, is much reduced. Pneumonia is a frequent and sometimes fatal complication, because of poor ventilation and poor clearance of the affected lung tissue. Plaques represent localized areas of pleural thickening. Though they can occur in various pulmonary diseases, they are particularly frequent in asbestosis and are more often found on the parietal than on the visceral pleura. Right sided heart failure is another frequent complication of severe asbestosis. It is caused by obliteration of a large part of the pul monary vascular tree, leading to pulmonary hypertension and to cardiac overstrain. Malignant tumors: Pathology - 2 Pulmonary asbestoSis is relatively less frequent now than it was 30 years ago, when the danger of inhaling asbestos was less widely appre ciated. However, another serious complication appears many years after asbestos exposure, namely, malignant tumors. The exposure is very often light and limited in time causing only slight or moderate pulmonary fibrosis. However, 20 or 30 years later a large proportion of exposed people develop either pulmonary carcinoma or pleural or peritoneal mesothelioma. Pulmonary carcinoma associated with asbestos exposure has a predilection for the lower lobes (in contrdistinction to the general population where it is more common in the upper lobes), but otherwise it is similar in its rate of growth, mtastass and histologic structure. Pulmonary fibrosis, if present, may mask early lesions and make recognition difficult. It can be demonstrated experimentally that asbestos is a carcinogen, though in the lung its carcinogenic potential is very weak. Of the people exposed to asbestos, only those tend to develop carcinoma who also smoke cigarettes, but the combination of asbestos and smoking pro duces strikingly high incidence of malignancy. (See multiple factor effect data.) Pleural mesothelioma arises from the lining cells of the pleura, the msothlial cells. It is less common than carcinoma, but in those exposed to asbestos it is at least 100 ties as common as in the general population. Smoking apparently has no ffect upon its incidence. Mesothelioma tends to grow along the pleural surfaces encasing the lung in a thick layer of tumor tissue, but it may also invade the lung and produce distant mtastass. It comes in a variety of histologic patterns, the most characteristic of which combines features of carcinoma and sar coma (biphasic tumor). Cells of mesothelioma, as well as the normal msothlial cells, secrete material rich in acid mucopolysaccharides. Experimentally mesothelioma can be produced by intrapleural injection of asbestos. Gastrointestinal tract Part of inhaled asbestos may be expectorated and swallowed, or asbestos may be carried into the mouth by contaminated food on fingers. It can be demonstrated experimentally that asbestos fibers lodge in the walls of the stomach and intestine and may penetrate into the peritoneal cavity. In limited studies to date, no excess of tumors has been observed in the gastrointestinal tract of animals fed asbestos, but in man carcin oma of stomach and large intestine is more frequent in those exposed to asbestos than in the general population. The incidence of mesothelioma of the peritoneum is strikingly increased after asbestos exposure. Meso thelioma can be produced in animals by intraperitoneal injection of asbestos. Peritoneal mesothelioma tends to grow along the peritoneal surfaces, but it also produce's large solid 6r ncxlular masses. Histo logically, it is very similar to pleural mesothelioma. Asbestos Dose-Disease Relationships Only limited data are available on asbestos dose-disease rela tionships. Few dust counts were taken 20, 30, or 40 years ago and those done usually reflected the presence of other dusts, silica, talc, mica, etc., along with asbestos. Materials, pro duction techniques, and control equipment have changed signifi cantly and current conditions cannot be used to evaluate past exposures. Some data, albeit scanty, are available on the asbestos expo sure of insulation workmen and a group of workpeople in an integrated asbestos manufacturing complex. These exposure data, which are only semiquantitative, can be related to ex cellent mortality information (Table 1 and Table 4 of Asbestos Disease section'1 As a result of past occupational exposures of about 10 to 20 fibers (longer than 5p) per milliliter of air nearly 40% of the deaths of these workpeople can be attributed to their work environment. No data are available on the asbestos dose-disease relationship at lower exposure levels. While any asbestos disease present in other than occupational circumstances will be at a signifi cantly reduced intensity, the large number of people at risk give rise to serious concern. In addition to the 250,000 work people directly exposed to asbestos by virtue of their job, 5,000,000 are exposed indirectly in their occupations. Their asbestos exposure may be 10 to 1000 times less than the expo sures which produced the current catastrophic occupational asbestos disease experience. At these lower exposures, if the percentage of deaths related to asbestos is, hypothetically, even 100 times less than direct occupational, 40,000 individuals may be affected. In environmental circumstances with 200,000,000 people potentially exposed, an additional tenfold reduction in asbestos associated disease would still leave 80,000 individuals affected. Dose-response data are urgently required for other than direct occupational asbestos exposures. Analysis of the mortality experience and asbestos exposure of workpeople indirectly ex posed is important. Indirect methods of assessing past air levels, such as the analysis of settled dust, can be helpful in the study of populations environmentally exposed. Autopsy lung tissue burdens of asbestos provide an especially useful method of assessing past exposures. Analytic methods will require electron microscopic techniques. Most asbestos fibers present in the air, even in occupational circumstances, are not visible by light microscopy. In many circumstances, positive identification of single asbestos fi bers can only be accomplished by electron microprobe techniques. Sources of Environmental Contamination Indirect occupational exposures to asbestos have been documented as causative of disease in a wide variety of trades in the shipbuilding and ship repair industry. Mesothelioma is now observed, at an increasing rate; in other than asbestos workers -- in plumbers, welders, electricians, carpenters, pipe fitters, etc. The exposures of these other workmen may come from simply working in the vicinity of asbestos application or from brief periods when asbestos must be removed from pipes or fittings before their own work can be done. Similar exposures are common throughout the construction industry, especially during the past ten years. Since 1960 spray fireproofing of steelwork with asbestos containing materials has produced extensive contamination throughout construction sites with men of all trades exposed.. Over 4,000,000 workmen are employed in the building industry. Their numbers alone create serious concern for their potential risk. A variety of indirect occupational exposures can occur whenever asbestos is widely used. Many electric utility employees are exposed during repairs of boilers or turbines. Chemical plants make extensive use of asbestos insulation material on high temperature pipes and vessels as well as incorporating the fiber into some of their products. For example, in one chemical plant we have seen, the transport of asbestos from a warehouse area, through the plant, to the point of use exposed unnecessarily every production employee. Family exposures constitute an insidious form of asbestos exposure. The dust on workmen's clothing (see Figure le) serves as a ready source of contamination of the employee's home. We readily find fibers of asbestos and other insulation material in the settled dust of asbestos clothes have been implicated in the deaths of wives of factory workmen. Moreover;, children's play clothes washed with a father's asbestos laden overalls are likely to become contaminated with fiber and provide a continuing asbestos exposure to the child. (This cross con tamination of garments has been found to occur during the dry cleaning of a woman's coat containing asbestos fiber.) The magnitude of average asbestos air levels in these family exposures is not known. In fact the variability of the exposure precludes accurate definition. However, these family exposures can be virtually eliminated by proper use of change rooms, shower facilities, and laundry facilities which should be avail able to all asbestos workpeople. At the present time only a limited number of work sites have adequate change roans and few, if any, special laundry facili ties exist in the asbestos industry. Such laundry facilities must, of course, be well controlled as mesothelioma has been found among dry cleaning and laundry employees. Environmental exposures range from ubiquitous, virtually continuous, low level concentrations derived from a wide variety of commonly used products to those iron short term "pathological" uses of asbeistos with extremely high concentra tions of limited duration. Examples of the former are airborne asbestos from the erosion products of brake linings, residence near a factory with inadequate emission controls, asbestos in water systems, and asbestos in beverages and food products. Environmental Contamination - 2 It is estimated that 40,000,000 pounds of asbestos is incorporated into brake linings each year. While high temperatures may alter much of the fiber during use, hundreds of thousands of pounds of asbestos can enter the en vironment annually from this source. Definitive data on the asbestos air concentrations from motor vehicle brake usage are lacking. However, in some very limited studies, asbestos levels two or three times background were observed at sites of extensive braking. Water systems have been found to contain concentrations of asbestos in excess of 10 micrograms per gallon. The source of this water contamination is ill defined but it could arise from geological erosion, rain cleansing of the air, or pollution from human use of asbestos. Asbestos filters have often been used in the food, beverage, and drug industry. Studies in our laboratory have demonstrated that erosion of the fibers from the filters occurs and the products can become contaminated. Some very questionable uses of asbestos that have given rise to significant environmental exposures include the open transport and dumping of asbestos waste, the use of asbestos in paper mache and cement art material which is mixed dry by children, the incorporation of asbestos into consumer fabrics, and any procedure which can generate uncontrolled asbestos aerosols (such as spray fireproofing). Often asbestos exposures occur as a result of fiber contamination of other products. Talc often coexists with varieties of asbestos and the use of cosmetic talcum powders can produce a significant asbestos exposure. In some foreign "talcum powders" the material may contain substantial amounts of anthophyllite asbestos. Industrial talcs, especially, are liable to be contaminated as a major source of such talc coexists with extensive deposits of asbestos. Individuals doing home repairs may occasionally have short term exposures, often unsuspected. Gypsum spackle compounds used to seal wallboard joints or patch plaster often contain asbestos in amounts up to a few percent by weight. The sanding of such material, when dried, can generate high con centrations of asbestos. An insidious such exposure is that to individuals in urban areas whose apartments have been rehabilitated under lead control programs. Here, wallboard is typically installed over the lead contaminated paint. Spackle is applied to the joints and sanded with the result that asbestos dust rather than lead may contaminate the household. Over 3000 uses of asbestos have been documented. Many of these products are produced safely and can be used safely. The production and use of others, however, can easily give rise to significant human exposures. Only constant vigilance by industry, by government, by research scientists, and by consumers will assure their eventual safe use. Asbestos Air Pollution , _io 3 Ambient air^leve^s of asbestos range from approximately 10 gm/m to over 10 gm/m . Thus, asbestos may constitute only 0.0001 per cent to 0.1 percent of the particulate matter present in a given air sample. Moreover, the asbestos found in the ambient air in cludes both micron-size fibers and numerous individual fibrils which may be agglomerated with a variety of other material present in the air sample. These considerations preclude the possibility of quantitative analysis of such ambient air samples by light microscopy, bulk spectroscopic techniques, or X-ray diffraction. The agglomeration of the asbestos with other materials and the presence of many sub light microscopic fibers render light microscopy ineffective. Moreover, the unique identification of small optically visible fibers is not always possible, even using a petrographic micro scope. Any bulk analysis method attempted to date has failed be cause of the presence of the much greater quantity of other inor ganic and mineral material. The only effective analysis method has required the use of electron microscopic techniques and involves the following steps: 1. collection of the air samples on membrane filter paper, 2. low temperature ashing of the collected material to remove the filter material and other organic matter, 3. dispersion of the residue by grinding or use of ultrasonic energy, 4. fixation of the dispersed residue in a nitrocellulose film which is mounted on an electron microscope grid, and 5. scanning at 40,000 X magnification using electron microscopy to determine the mass of asbestos originating from a prescribed Traction of the initial sample. The dispersion procedure has been found necessary as large frag ments of other inorganic material obscure the presence of asbestos which often exists in fibril form attached to other particles. Un fortunately, this procedure allows only the mass concentration to be determined and information on the size distribution of the fibers is lost. One hundred eighty-seven samples from 49 United States cities, collected by the National Air Pollution Control Administration during 1969 and 1970, were analyzed at the Environmental Sciences Asbestos Air Pollution - 2 Laboratory. The following table gives the range of values ob tained from quarterly composites of biweekly 24 hour samples. Chrysotile asbestos content of ambient air samples collected by NAPCA in 49 United States cities. Fiber range ^n No. of samples nanograms/ m__in range 0.1- 0.9 1.0- 4.9 5.0- 9.9 10.0-19 20 -49 50+ 61 102 12 9 2 1 Total samples 187 Results were also obtained from a series of single 8 hour samples collected in New York City by the Pepartment of Air Resources at 12 sites of their sampling network. Chrysotile content of ambient air in New York City by borough Sampling Locations -9 Number of Asbestos air level in 10 gram; Samples Range Average Manhattan Brooklyn Bronx Queens Staten Island 7 3 4 4 4 8-65 6-39 2-25 3-18 5-14 30 19 12 9 8 Sampling about construction sites where extensive spraying of as bestos-containing fireproofing material was taking place shows this procedure to contribute significantly to asbestos air pollution. In some instances chrysotile asbestos levels approximately 100 times "background" were observed. Chrysotile asbestos concentrations near spray fireproofing sites Sampling Location Number of Samples Asbestos ^4ir Level in 10 'g/n> Range Average 1/8-1/4 mile 1/4-1/2 mile 1/2- 1 mile 11 6 5 9 -375 8-54 3.5- 36 60 25 18 Asbestos Lung Burdens Examination of human tissues may provide information as to the in tensity of fiber exposure; fiber type (involving mixed exposure); fiber distribution; and fiber alteration in vivo. The amount of tissue examined in the search for asbestos fibers is related to the degree of exposure (occupationally exposed vs. the "general population," or "non-exposed") and the materials avail able for study. Little material is required for the identification of fibers in tissue from individuals with "heavy" asbestos exposure. Here, histologic sections are quite adequate, However, in cases where small amounts of asbestos are likely to be encountered, bulk tissue will significantly increase fiber yield, greatly reduce time of fiber search, and yield results with increased statistical validity. Histologic sections may be prepared for fiber analysis by a number of methods. The technique selected is based upon the type of in strumentation which will be used in fiber localization and iden tification. The following technique is now used routinely in the preparation of tissues for examination with electron beam instru ments; it is called the carbon-extraction technique (Pooley, 1972; Langer, et al, 1972b). The preparation involves: 1. the ashing of a 5-8 micron thick, unstained, histologic section mounted on a glass slide; 2. impregnating the relict tissue in a water-soluble plastic (po.lyVinylalcohol); 3. "peeling" the hardened plastic, and the incorporated ashed tissue, from the slide; 4. inverting the relict tissue and depositing a thick carbon coat onto the inverted surface; 5. dissolving the plastic from the carbon sheet (which now includes the relict tissue and the inorganic particles), and; 6. placing the carbon film onto appropriate substrates for examina tion in an electron beam instrument (EM copper locator grids are best for this purpose). The bulk tissue technique is the KOH digestion method as outlined in Langer, et al (19^1) 1. Dried lung tissue is digested in a 5% KOH solution while being heated at 90 C for a 4-hour period; . 2 . Several cycles of washing and centrifugation of. the residue are required for the complete removal of digested materials and the KOH; Lung Burdens - 2 3. The residues are then dispersed in triple-distilled water by sonification and a small amount pipetted onto an appropriate electron microscope substrate. 4. After drying, the grid is scanned in a transmission electron microscope at a magnification of 42,000 X. The scan is made across the diameter of the field and the fiber density con verted into mass. The major advantage in using such a method is the concentration of particles from masses of tissue greatly in excess from what one would normally encounter in a histologic slide. The major dis advantages are the time required for a single specimen scan and the instrument commitment to such an analysis. Seme estimates of lung burden have been made. In one study of lung residues obtained iron 28 people who died in New York City we estimated that their lungs contained chrysotile concentrations on the order of micrograms to tenths of milligrams quantities (several hundreds of millions of fibrils). However, that study produced conservative estimates on the basis of technique of preparation (sample loss) and enumeration (direct on EM screen). In another study of 100 additional cases from the "general population," a more controlled procedure produced lung burden estimates which exceed several 10's of milligrams. We have compared these values with those obtained in the analysis of tissues from workmen exposed to asbestos occu pationally. Here the number of fibers per lung is on the order of hundreds of billions, and the calculated mass may be as high as 5 gms/lung. Indirect occupational exposure to fiber results in lung burdenslying between the general population and occupational exposure levels. Sane observations of importance are: 1. Histologic sections are adequate for particle evaluation in cases of intense exposure; however, bulk tissues give best re sults in cases from the general population. 2. Exposure intensities may be qualitatively evaluated in unknowns. 3. Sub-light microscopic fibers far exceed those seen by light micros copy in number in all cases and tissues studied thus far. 4. Asbestos bodies, objects visible by light microscopy and often used as an index of asbestos exposure, only partially and only in some occupational cases reflect the lung burden of asbestos. 5. Chrysotile asbestos is the most common sub-light microscopic fiber in human tissues, most) often occurring in the fibril form. ( References Lung Burdens - 3 Langer, A.M. , 1970, Electron microprobe analysis (study of asbestos fibers and bodies from lung tissue): In Laboratory Diagnosis of Diseases Caused by Toxic Agents, F.W. Sunderman and F.W. Sunderman, Jr., Eds., W.H. Green, St. Louis, Mo., Chap. 14, p. 126-136. Langer, A.M., Rubin, I.B., and Selikoff, I.J., 1972, Chemical character ization of asbestos-body cores by electron microprobe analysis: Jour. Histochem. and Cytochem., v. 20, no. 9, p. 723-734. Langer, A.M., Rubin, I.B . , Selikoff, I.J., and Pooley, F.D., 1972, Chemical characterization of uncoated asbestos fibers from lungs of asbestos workers by electron microprobe analysis: Jour. Histochem and Cytochem., v.20, no. 9, p. 735-740. Langer, A.M., and Pooley, F.D., 1973, Identification of single asbestos fibers in human tissues; In Proceedings Inti. Agency for Res. on Cancer; Biol. Effects of asbestos, Lyon, 1972, C. Wagner, Ed., Paper 19, in press. Langer, A.M., Selikoff, I.J., and Sastxe, A., 1971, Chrysotile asbestos in the lungs of persons in New York City; Arch. Env. Health, y. 22, p. 348-361. Langer, A.M., Baden, V., Hammond, E.C. , and Selikoff, I.J., 1971, Inorganic fibers, including chrysotile, in lungs at autppsy: preliminary report: In Inhaled Particles III, Proceedings of the Conf. Brit. Occup. Hyg. Soc. London, 1970, W.H. Walton, Ed., Unwin Bros., Surrey, England, v. 2, p. 683-694. Langer, A.M., Ashley, R. , Baden, V., Berkley, G., Hammond, E.C., Mackler, A.D., Maggiore, C.J., Nicholson, W.J., Rohi, A.N., Rubin, I.B., Sastre, A., and Selikoff, I.J., 1973, Identification of asbestos in human tissues: Jour. Occup. Med., v. 15, (March) in press. Ehrenreich, T. , Mackler, A.D., Langer, A.M. and Selikoff, I.J., 1973, Indentification and Characterization of Pulmonary Dust Burden in Pneumoconiosis: In Laboratory Diagnosis of Diseases Caused by Toxic Agents., Applied Seminar on Clinical Pathology of Respiratory Diseases, Sunderman, F.W., Ed., in press. . Pooley, F.D. (1972) Electron microscppe characteristics of inhaled chry sotile fiber. Brit. Jour. Industrial Med,, 29, 146-153. Pooley, F.D., Oldham, P.D., Chang-Hyum, Um, & Wagner, J.C. (1970) The detection of asbestos in tissues. In Pneumoconiosis Proc, of the Inti, Conf., Johannesburg, 1969, H.A. Shapiro, Ed.> Capetown, Oxford Univ. Press, 108-116. Timbrell, V., Pooley, F.D., & Wagner, J.C. ,(1970) Characteristics of respir able asbestos fibers in Pneumoconiosis Proc, of the Inti, Conf. Johannesburg, 1969, H.A. Shapiro, Ed., Capetown, Oxford Univ. Press, 120-125. 1 Problems and Perspectives The shipyard mesothelioma question epitomizes the spectrum of difficulties now posed by the asbestos problem. Background: Scientists have been sensitized to look for prior asbestos exposure, however brief, whenever mesothelioma is seen and, conversely, to watch for the occurrence of mesothelioma whenever an individual has had asbestos exposure. This sensi tization perhaps explains the increasing uneasiness with which recent British publications have been received in this country. Starting in 1968, a series of papers has appeared reporting numerous mesotheliomas among individuals currently or previously employed in British shipyards. It is noteworthy that few of these people had been asbestos workers; they had merely been employed in the same yards (as carpenters, electricians, boiler makers, riggers, pipefitters, caulkers, etc.) in which a rela tively small number of other men (generally insulators or "laggers") had been working with asbestos. Their shipyard em ployment had, in most instances, started thirty or so years before the onset of mesothelioma. These British data are of interest to us because their ship building and shiprepairing industry was rejuvinated about five years before ours; 1935 to our 1939-1940, and their mesothelioma experience could presage similar disease in this country. U.S, shipyard employment 1940-1945: Between the two world wars, approxi mately 75,000 men and women were employed in our shipyards at any one time. The vast expansion of the industry in World War II led to rapid growth of the workforce, which reached a maximum of 1,750,000 in the fall of 1943. Altogether, 4,500,000 men and women worked in our ship yards at some time 1940-1945. Given their age distribution in those years, about 3,000,000 are alive. Needless to say, few of these WW II shipyard workers are currently employed in this occupation (which num bers 225,000). They are working at a host of other trades or professions and many only dimly remember the shipyard interludes in their lives, thirty years ago. Shipyard mesotheliomas: As in Britain, mesotheliomas are now being seen in this country in individuals who, in WW II, were employed in one or another capacity in shipyards -- men and women who had worked for six weeks, six months, two years. When lung tissue is examined, asbestos fibers and fibrils are readily found (by electron microscopy), in num bers considerably larger than the relatively scant contamination found among urban dwellers generally. Apparently, the mineral fibers inhaled 30 years ago have remained intact, in most instances, at least. The in dividual's exposure may have been six weeks -- that of the lung parenchyma 30 years. The mesotheliomas being seen are both pleural and peritoneal, with a preponderance so far of the former. As a rule, there have been no X-ray changes of concomitant asbestosis -- it would seem that asbes tos exposure insufficient to result in radiologically evident asbestosis Problems and Perspectives - 2 may still be enough to induce mesothelioma. Cases have been seen in former shipyard electricians, tinsmiths, engineers, riggers, boiler makers, carpenters, laborers, etc. Parenthetically, the U.S. Navy accepts responsibility (in terms of compensation)for cases of meso thelioma among individuals who had worked in its yards in WW II, pro vided there has been no subsequent asbestos exposure, deeming itself the "last employer." These are random cases and it is not known how many are occurring, nor what proportion of the 3,000,000 former shipyard workers will develop mesothelioma. 7% of shipyard insulation workers die of this disease; it is highly unlikely that those indirectly exposed will reach this level, although it is conceivable. Those that occur will be seen over the next twenty years. We have no way at the moment of predicting which individuals will develop mesothelioma, nor have we means of "early" diagnosis (at a time when the tumor is presumably still localized). Therapy has been palliative; cure eludes us. What is to be done? Many groups are concerned with approaches to this asbestos problem, as to others; labor unions, industry, NIOSH, EPA, DOL, for example, are concerned with development of engineering controls, administrative standards and clinical surveillance. Scientists at NIH and elsewhere can augment and extend these efforts, utilizing a range of disciplines from epidemiology to cell biology. 1. Can we inactivate the fibers presently in the lungs of shipyard workers? Can we "defuse" their asbestos lung burden before dis ease supervenes? There are some leads in this regard. 2. Can we develop serological or other means of predictive value? Early diagnosis? 3. Develop understanding of pathogenetic mechanisms, at the inter face between "mineral matter and the living world." 4. Successful treatment of mesothelioma; worthy task for the National Cancer Plan. Progress in these areas will be of value across the whole spectrum of asbestos disease, from occupational groups to environmental exposure, from the asbestos worker to the urban dweller with, currently, asbestos lung contamination. In addition, it is likely that biological concepts of fundamental value will be added to scientific understanding. oo Figure 1 a. An open pit Canadian asbestos mine. b. Ore from the mine showing the fibers of chrysotile. This fragment is about four inches long. c,d. The ore is crushed and the asbestos fibers obtained by air separation in a mill. e. The fibers may be used in insulation material and during application are often divided into their individual fibrils. The workplace and workmen's clothing easily become contam inated . f. The fibers and fibrils readily become airborne. Here they are shown magnified 20,000 times. o ri Figure 2 Transmission electron micrographs of chrysotile asbestos. The main plate figure is that of broken open bundles o f c h r y sotile asbestos. The fibers are observed to be made up of unit fibrils. The insert figure (lower left) shows the mor phological appearance of the unit fibril at high magnification. The uppermost insert photograph with lettered captions shows the range in diameter of both the central capillary and total fibril. The central insert figure shows incipient beam damage of the fibril after exposure to the electron beam. The beam produces a thick coating of dehydroxylated amorphous material. The crystalline capillary wall may be observed to deform with in the encapsulating coat (lowermost figure). All of these features are characteristic of chrysotile. In addition to these distinguishing morphological characteristics, the selected area diffraction pattern of chrysotile (insert lower right) may also be used to uniquely identify the fiber type in both air and tissue samples. Figure 3 Transmission electron micrographs of amosite (one of the repre sentative amphibole asbestos fiber types). The upper figure shows the characteristic morphological features of an amphibole asbestos fiber. The fibers tend to be electron dense and gen erally "straighter" than chrysotile. High magnification view of the fibers (lower figure) shows no internal capillary struc ture. However, on some of the more thin fibers, light and dark banding may be observed across the diameter of the fiber. This is produced by electron diffraction contrast brought about by deformation of layers by the electron beam. Unlike chrysotile, beam damage to the amphiboles is not readily observable nor apparent. The selected area diffraction pattern (insert lower right in upper photograph) although characteristic of the amphibole mineral group is nondiagnostic in terms of unique identification. That is, the diffraction pattern is characteristic of the mineral group rather than any individual within the group. wnisaww V Figure 4 Differentiation of single amphibole asbestos fibers may be made by microchemical analysis with an electron microprobe technique. Plate 1 and 2 show the visual information obtainable with an electron microprobe analyzer. Plate 1 was obtained from a group of asbestos bodies observed in ashed lung tissue. Visualization of the particles was obtained by monitoring the sample current generated as the electron beam swept the sample. a. spacial display of x-ray photons is also possible in this operational mode. b,c. show the two dimensional spacial distribution of silicon and iron K-alpha x-ray emission. d,e. are the sample current and iron x-ray emission at higher magnification. Plate 2 shows the resolution obtainable with secondary electrons in the probe system. Plate 3 shows the normalized K-alpha x-ray emission ratios for the asbestos minerals. The three elements monitored simultaneously are iron, magnesium, and silicon. Each asbestos area is defined by several thousand analyses. The fiber fields are as follows: Amo - 4mosite; Cro = Crocidolite; Ant = Anthophyllite; Chr = Chrysotile; Tre = Tremolite. Each of the amphibole asbestos fibers may be uniquely differentiated on a microchemical basis. Plate 4 shows the asbestos mineral emission fields outlined. Statistical maximum for each field is defined by a circle. The anthophyllite and chrysotile fields contain two areas in which 30% of the total analyses were observed to fall, the squares in each field indicate the statistical average of the iron-silicon-magnesium emission field. The black dots for each field represents a normalized iron-magnesium-silicon x-ray emission for each mineral based on its empirical formula. The arrows from these dots indicate the trend the circle may take if normal compositional variations were to be followed. Figure 5 a. RK: Routine chest x-ray August 3, 1951 shows no abnormality. b. In the early 1950's, had brief episodes of left lower chest pain and slight shortness of breath on exertion. Gradual appearance of some fine linear and reticular fibrosis in the lower lung fields. This x-ray, taken July 2, 1958, shows bilateral infiltration. Unusual occupational exposures were denied; had worked as a machinist and truck driver "for more than twenty years," and continued as machinist. c. Chest x-ray November 14, 1964 shows not only increase in lung fibrosis but also scattered areas of pleural calcifi cation. While diffuse pulmonary fibrosis has a number of potential causes, usually more than twenty years before. Detailed prodding about such exposure yielded persistent denials - until Mrs. K., present at the interview, suddenly broke in: "Yes, Bob, but didn't you once work as an asbes tos weaver in a brake lining plant when we were first married, in 1934?" "Sure, but that was only for six months, and I haven't worked with it since." d. Because of gradually increasing shortness of breath, had to leave work in 1970 and now lives on Social Security Dis ability Benefits. Has no trouble at rest, but cannot mow the lawn of his small retirement house, etc. X-ray June 25, 1971 shows continued progression, the result of 1934 dust still resident in his lungs. 8-3-51 2-58 6-25-71 d 5 Figure 6 a. MG: November 8, 1966. Diffuse interstitital fibrosis was present but not well made out, due to obscuring effect of pleural fibrosis. When localized, and demonstrated tan gentially, it is more obvious, but when diffuse, may be underestimated. b. Death occurred of pulmonary insufficiency. Photograph of lung at autopsy shows markedly thickened pleura, forming a cuirass over the underlying lung. Respiratory function was impaired both by the diffuse interstitial parenchymal fibrosis, and the restrictive effect of the pleural thick ening. Generally, parenchymal disease has the more impor tant effect. c. CD: September 8, 1971. Pleural calcification in an asbes tos worker. No part of the pleura is immune - costal, diaphragmatic, pericardial, mediastinal. Diaphragmatic calcified plaques are characteristic. Plaques, both calci fied or not, as well as diffuse fibrosis, generally involves the parietal pleura. The visceral pleura, although not necessarily spared, tends to be much less involved and adhesions may or may not be present between the two layers of the pleura. Often, the pleural cavity is unaffected de spite the existence of extensive parietal pleural plaques. Figure 7 a. SP,Jr.: December 20, 1972. Localized fibrotic pleural plaque. Currently a bank executive, but had two years of experience as an asbestos insulation worker, 18 years be fore. Such plaques are asymptomatic and, in themselves, result in no functional defect. Their presence has sig nificance only in indicating prior asbestos exposure, with consequent risks. b. HH: Diffuse pleural fibrosis in asbestos worker. c. TM: Pleural calcification in an asbestos worker. The ex tent of such calcification varies enormously. As in this case, it may involve almost the entire parietal pleura. When this happens, it may be difficult to evaluate radio logical changes in the underlying lung. These may be ex tensive, with resulting respiratory difficulty, or may be minimal, with no shortness of breath. The pleural calci fication per se gives little or no trouble and the patient may be totally unaware of it. As with non-calcified plaques, its significance lies in its being an index of prior asbes tos exposure. e. WJ: Tiny calcified diaphragmatic plaque. Asbestos expo sure during employment as sheet metal worker had resulted in diffuse interstitital fibrosis with respiratory insuf ficiency. Radiological evidence of diaphragmatic calcifi cation gave diagnostic clue. 7 . i, Vi! 8 Figure 8 a. MC: Calcified diaphragmatic plaque is seen on flat plate of the abdomen. These often are apparent on intravenous pyelogram, barium enema, gastro-intestinal series, gall bladder series and other roentgenographic procedures. b. ADeV: Normal lung fields on chest x-ray, but diaphrag matic calcified plaque provided diagnostic lead in patient with abdominal disease, demonstrated on laporatomy to be peritoneal mesothelioma. As with pleural mesothelial tumors, primary peritoneal neoplasms may occur following asbestos exposure insufficient to cause radiologically evi dent pulmonary fibrosis. c. RDeP: Fine reticular pattern consistent with interstitial pulmonary fibrosis; had worked six weeks in an asbestos factory 28 years before. d. EK: Extensive reticulation and honeycombing. Although lower lung fields are most heavily affected, no portion of the lung is immune. Asbestos insulation worker. I Figure 9 a,b. JW and FY: Asbestos workers. Lung cancers occurring in as bestos exposed individuals tend to be, as in these x-rays, in the lower lung fields and peripheral in location. Unlike the usual bronchogenic carcinomas, where two-thirds are in the upper lobes and one-third in the lower lobes, the pro portion is reversed. Because of peripheral localization, the pleura is often involved early. All cell types are found. Co-existent pulmonary fibrosis (asbestosis) may ob scure early cancer shadow; critical close inspection of serial films is thus important. K iv i'/ ' 10 11 Figure 10 BC: April 1, 1970. Pleural mesothelioma. Pleural mesothel ioma in an asbestos insulation worker. Tumor characteristic ally envelopes entire lung, including costal, mediastinal and diaphragmatic aspects. Extent precludes successful sur gical approaches. Chest x-ray a year before had shown no evident disease, and right hemithorax of this film still demonstrates no asbestosis. This reflects common observation that mesothelioma may occur as the result of asbestos exposure insufficient to produce pulmonary fibrosis (asbestosis). This observation has led to the unhappy realization that Asbestos Standards sufficient to minimize or prevent asbestosis may be inade quate to prevent asbestos-associated neoplasms, as meso thelioma . Figure 11 a. JLC: May 19, 1967. Chest x-ray taken because of minor ache right lower chest. No striking changes seen. Asbestos worker with 28 years of trade experience. b. Because of awareness of disease potential, observation was maintained. Serial films showed increasing pleural density and thoracotomy demonstrated inoperable pleural mesotheli oma. Film June 11, 1968 shows rapid progression in one year. At present, x-ray surveillance does not afford "early" diagnosis; much more disease is found at thoracotomy than anticipated. c. GH: January 15, 1970. Chest discomfort led to thoracotomy; pleural mesothelioma was found. Of interest was a history of shipyard work as a machinist during the 1930's, in Denmark, and during World War II in the U.S., as an engin eer. Lung tissue obtained at operation showed considerable asbestos. d. Rapid progression is common. X-ray July 16, 1971. Duration of life from time of diagnosis is often 12-18 months, or less. Figure 12 a) Photograph using light microscopy of asbestos bodies, produced experimentally in a hamster lung. Several asbestos bodies of various sizes (4 to 20 microns in length) are recognized in a huge multi-nucleated giant cell. An uncoated thick bundle of chrysotile asbestos is seen at the center of the photograph. One year after intra tracheal administration of chrysotile asbestos. X 1,100. b) An electron micrograph of a longituidinal section of an asbestos body in the cytoplasm of a giant macrophage. Three major structural components, asbestos fibers, elec tron opaque coating substance consisting of ferritin (iron protein complex), and a limiting membrane originating from a phago-lysosome, are shown on this photograph. Note that many hemosiderin granules containing iron particles are accumulated around the body. X 30,000. c) Cross section of a body. A bundle of chrysotile asbestos fibrils with tubular lumens is observed in the center of the body. A clear zone is present between the coating and the limiting membrane. In addition to the intra cytoplasmic asbestos body, extracellular bodies have been observed in aveolar air spaces or in the pulmonary interstitium. Extracellular bodies usually lack any limiting membrane and it is suggested they are released from the cytoplasms of their host cells. X 118,000. I Figure 13 These pictures show various stages of asbestos body formation. a) Five short amosite fibers are seen within phagosomes. The long est phagosome contains several iron particles in its internal space. X 49,000. b) Another phagosome containing chrysotile fibrils is shown. In this case, iron particles are rather scattered around the fib rils. Several hemosiderin granules containing ferritin are recognized around the phagosome. X 53,000. c) A more advanced stage of body formation is illustrated. Numerous iron particles are accumulated within the phagosome. One may call this an "immature asbestos body". X 71,300 It has been suggested that hemosiderin granules can be fused with an asbestos containing phagosome to provide iron-protein complex around phagocytosed asbestos fibers. Figure 14 This photograph indicates various processes of the phagocytosis of submicroscopic chrysotile fibrils. The following steps are demonstrated in the cytoplasm of a macrophage: (a) attach ing of the fibrils to the cell surface (arrow 1), (b) engulfing the fibrils (arrow 2), and (c) incorporating them into intra cytoplasmic vacuoles (arrow 3 and 4). One day after intratra cheal administration of chrysotile asbestos. X 44,200. (I Figure 15 Human mesothelioma cells exhibit striking variability in ul trastructure. However, three major cell types, the epithelial, the atypical epithelial and the mesenchymal or fibroblastic are distinguished. A variety of intermediate forms among these three cell types was recognized. Three major types are demonstrated on these photographs. a) Neoplastic epithelial cells. Two types, a "clear" cell and "dark" cells are distinguished. The former contains multiple nuclei, round mitochondria and a bundle of intracytoplasmic filaments. The latter exhibit well developed rough surfaced endoplasmic re ticulum. The basement membrane is discontinuous beneath a dark cell. X 4,740. b) A neoplastic epithelial cell. This cell is equipped with "intra" and "inter" cellular microvilli. Microvilli formation is one of the most common features in the epithelial cell. X 4,960. c) Atypical epithelial cells. Two tumor cells are lying free in loose connective tissue. They lack polarization, junctional structures and microvilli; however, their internal structures such as mitochondria and vacuoles are quite similar to those of the epithelial cell. X 4,960. d) A mesenchymal or fibroblastic cell. A neoplastic cell of the mesenchymal type is observed at the center of the photograph. It is similar to the fibroblast in its structure and is surround ed by negatively stained collagen fibrils. X 5,600. b), c) and d) were taken from tumor tissue of the "bi-phasic" pattern. '!Y>' ' * * * * T * ' ( L*' & m y ^ ^ m ^ m S e s C & i / E s mmm y .r u]|* 1* B* jM i () f Figure 16 Pulmonary Asbestosis Left Upper: Lung of a man occupationally exposed to asbestos. Cross section of the lung shows many gray streaks of fibrosis particularly noticeable in the lower lobe. Right Upper: Microscopic section of lung showing dense fibrous tissue replacing pulmonary parenchyma and dilated air spaces. Within the fibrosed area there are many asbestos bodies. Left Lower: Left half of the thoracic cavity after removal of the lung. There are many large whitish plaques on the parietal pleura. Right Lower: Numerous asbestos bodies in the lung surrounded by "foreign body" giant cells and by fibrous tissue. The asbestos bodies have the appearance of brown "drumsticks." !1 n i Figure 17 Asbestos Associated Malignant Tumors Left Upper: Cross section of a large whitish mass in the lung representing a carcinoma. Right Upper: Microscopic appearance of the mass showing epidermoid type of carcinoma. Other common types associated with asbestos exposure are adenocarcinoma, large cell carcinoma, oat cell carcinoma and small cell carcinoma. Left Lower: Peritoneal mesothelioma. Part of gastrointestinal tract and omentum studded with numerous whitish nodules. Right Lower: Histologic appearance of mesothelioma showing a typical biphasic structure. Part of the section shows elongated spindle shaped cells and part shows small epithelium-like cells. Figure 18 a. A sample of airborne asbestos in an occupational environment. Here the fibers are shown by light microscopy magnified 1500 times. b. For each fiber visible by optical microscopy many more are present and seen only using electron microscopy. The fibers and fibrils in this photograph are magnified 50,000 times. 16 17 Figure 20 Accurate identification of individual asbestos fibers (air and tissue) can be made using electron microscopic techniques. a. Single fiber of amosite asbestos, and b, The electron diffraction pattern produced by it. c. An amosite fiber (insert) viewed by scanning electron microscopy. The energy spectrum of x-rays produced by electron bombardment of this fiber is also shown. As x-rays of a given energy are produced by a single ele ment, this energy spectrum can be used for semiquanti tative chemical analysis of single fibers and particles. o Figure 19 a,b,c,d. Fragments of chrysotile asbestos found in ambient urban air. The magnification in these photographs is 100,000 times. m () Figure 21 Transmission electron micrographs obtained in carbon ex tracted lung tissues from individuals exposed to asbestos dust. a. Carbon extracted lung tissue obtained from an individual exposed to talc dust. Chrysotile fibers were observed throughout the lung tissue. b. Carbon extracted lung tissue obtained iron an individual indirectly exposed to asbestos dust. Sub-light micro scopic examination of these tissues indicated large num bers of asbestos fibers present. c. Carbon extracted lung tissue obtained from an individual Who was clinically diagnosed as having "interstitial fibrosis of unknown etiology.'1 A lung biopsy was obtained and the tissues examined by electron microscopy. Large numbers of sub-light microscopic fibers of chrysotile as bestos were observed in the tissues. d. A high magnification view of a portion of this tissue. A particle size study indicated their average length was approximately 1500 Angstroms. I Figure 22 Transmission electron micrographs of carbon extraced extra pulmonary tissues. [a-d. These four figures show the kinds of particles observed in the pancreatic tissue of an asbestos worker (with a primary tumor of the pancreas)]: a,b. Chrysotile asbestos fibrils, c. Diatcmaceous earth fragments, and d. Fibrous glass fragments, were observed to be present in the normal pancreatic tissues. Other particles, for example, clays, were observed in the tissues as well. e. Carbon extracted tissue obtained from an ovary in which a malignant neoplasm was present. This tissue was obtained from one of the Tenovus samples forwarded to our Laboratory for analysis. f,g. Chrysotile asbestos fibrils obtained from the peritoneal fluids of an asbestos worker with peritoneal mesothelioma (confirmed at autopsy). Figure 23 a. Spray fireproofing material containing asbestos escaping from a construction site even with tarpaulins erected. b. Asbestos material atop reinforcing steel on a construction site. Such on-site overspray provides a significant source of indirect occupational asbestos exposure in the construc tion industry. c. Asbestos material on the cab of a front loader used outside of a building under construction. Such contamination pro vides a ready source of environmental asbestos exposure to people living and employed nearby. Figure 24 a. Children playing next to a waste dump in Pennsylvania con taining asbestos scrap. The dump is nearly 50 feet high, six to ten blocks in length, and one to two blocks wide. It contains 1,500,000 cubic yards of material. b. The basketball court on which the children are playing is built on waste material that contains asbestos fiber. c. Children routinely play on the dump and occasionally dig for salable buried relics. Several paths over the dump exist that are used daily. d. The dump even encroaches on nearby residences. e. Asbestos fibers from dump waste material found on the basketball court. FABRIC CONTENI 7 2 * REPMCESSU WOOL 2#% TUM nmsm i \ () Figure 25 a. A woman's coat made of 8% asbestos fiber. Brushing or shak ing of the coat creates asbestos dust levels equal to those in factories. Over 150,000 such coats were manufactured of this asbestos containing material. The asbestos was added to the fabric abroad in an effort to have the cloth brought in as asbestos textile product, on which the duty was 6%, rather than as reprocessed wool fabric, on which the duty was nearly 100%. b. Asbestos fibers found in the coat material. c,d. Children constructing a model of asbestos cement. (\ r Figure 26 a. A n asbestos fiber found in a broad spectrum parenteral anti biotic solution. This particular fiber exceeded one milli meter in length. b,c. Electron photomicrographs of asbestos fibers found in two other parenteral drugs. d. A selection of injectable drugs studied for passage through asbestos filters. The asbestos, while efficient in removing bacteria and other undesirable material from the drug solu tion, unfortunately fragments and may erode into the solu tions . o e & t % r WV oo