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,, -iv^-an r.vc'.y-M'-z.^x-xz;;-e:"r.ri rz:,..yc:^:Dxzy:'ryyziai-yitr~j':-xz-:::x.-: x:rz- Jhrysotile Biopersistence in the Lungs of persons in the General Population and jxposed Workers thur M. Langer and Robert P. Nolan /ironmental Sciences Laboratory, Applied Sciences Institute of Brooklyn College, Brooklyn, New York j burden analysis was performed on 126 autopsy cases of persons who died in New York City from 1966 through 1968. Of the 126 cases, 107 probably non-occupationally exposed, judging by occupational history and asbestos body content of lung. Fifty-three of the 107 cases con>d short chrysotile fibers/fibrils, <5 pm in length, present in 3-fold greater amounts than were found in laboratory background controls. The fiber antrations ranged from 1.8 to 15.7 x 106 f/gm/dry lung tissue, and the proportion of fibers >5 pm in length was only 0.34% of the total iotik- population found. Other inorganic particles present included fragments of amphiboles. In contrast to these data, the lung parenchyma of ns occupationally exposed to asbestos commonly showed the presence of other fiber types, especially amosite and crocidolite, at very much r concentrations and greater fiber length. Any chrysotile present would usually be in fiber bundle form, with both fibers and fibrils >5 pm in th. Comparison of the lung fiber content of occupationally exposed persons with that of the general population showed marked qualitative and ititative differences. Fibers are durable, and are retained in a range of concentrations. Their length and dose, among other factors, which control biological potential are different in the two populations; the risk factors for chrysotile-induced disease are not the same. -- Environ Health rjpect 102(Suppl 51:235-239 (1994) Iwords: chrysotile, crocidolite, durability, retention jrability. Retention, and ^persistence may save the lung but at the expense of Chrysotile asbestos is considered to increased risk of malignancy in other possess low carcinogenic potential because ^persistence of inorganic dust in the lung organs. Pleural drift and mesothelioma of its inherent instability in a biological ` . to be a requirement for the produc indicate that this is biologically important. host, since it lacks both durability and t of chronic disease. Durability, particle Biopersistent, durable, inorganic parti biopersistence (5). Studies using electron ar:i depositional pattern affect the cles may have very low biological activities, microscopy showed some magnesium loss fllity of scavenging cells to intercept, causing for example, benign pneumoco from the chrysotile structure, detectable jtagoc, tize, and sweep breakdown prod nioses. Chest radiographs obtained on only for relatively thin fibers {6,7). By > out of the lung parenchyma. workers occupationally exposed to barite using radiolabeling, chrysotile has been '. If a fiber is not broken down within a (/), tin oxide in the absence of free silica shown to degrade in vivo (5). Electron agolysosome, translocation may only (2), zircon dust (zirconium silicate) in the microscopy studies have also shown what crease lung retention at the expense of refractory industry (3), and dust in iron appears to be fibril disaggregation from the cumulation at another tissue site, foundries (4) show a profusion of opacities fiber bundle, as well as some thinning of rsistence in the host is preserved. For with little or no clinical disease. the fibril wall, within the phagolysosome aeral fiber, especially the amphibole stos varieties, the mucociliary escalator* I, Table 1. Asbestos body content of standard aliquots of pulmonary tissues obtained from 3000 persons who died in New York City, 1966--1968^; present study population and case distribution for TEM assay. paper was presented at the Workshop on rsistence of Respirable Synthetic Fibers and nerals fheld 7-9 September 1992 m Lyon, France, AML \wishes to acknowledge the efforts of collUes who participated in various portions of this ' vhile at the Mount Sinai School of Medicine: YAshfisey, R. Fuller, A. Mackler, S. Perlowitz. Dr. A. I, I. Rubin and Dr. A. Sastre. Special recognition is to AML's late colleagues who also collaborated, ing keen interest and often brilliant insigbt into , problem; Drs. Victor Baden, Carl Berkley, E, ^Cuyler Hammond. Joann Schwartz, and Irving Selikoff. Funding support is acknowledged from OSPHS EC-00160: USPHS UI-00440; Career Scientist "ward (AML), NIEHS, ES-44812. Address correspondence to Dr. Arthur M. Langer, ironmental Sciences Laboratory. Applied Sciences :itute of Brooklyn College, Brooklyn, NY 11210. [efephone (718) 951-4242. (718) 951-4793. Fax (718) "1-4438. Sex Total cases scanned Male % Female % 1971 1029 (% of population) 3000 Number of cases selected from each category for present study (%) 3 From Langer etal.()6|. (%) cases by sex Asbestos bodies found in scan Positive cases by sex 0 1-4 5-14 >15 n % (65.7) (34.3) 958 (48.6) 593 (57.6) 802 (40.7) 392 (38.1) 152 (7.7) 40 (3.9) 59 1013 (3.0) 4 436 (0.4) 51.4 42.4 (1000) 1551 1194 (51.7) (39.8) 192 (6.4) 63 1449 (48.6) (2.1) 32 57 18 19 126 (25.4) (452) (14.3) (15.1) (100.0) pvirc mental Health Perspectives 235 m LANGER AND NOLAN Table 2. Occupations of 25 persons whose tissue aliquot contained no asbestos bodies. Age at death' Sex Principal occupation(s) 45 M Handyman 53 M Bartender 75 M Porter 46 M Factory worker (appliances) 50 F Stock broker 80 F Office secretary 79 F Housewife 76 F Housewife 76 M Dress manufacturer 68 M Presser; tailor 47 M Paint factory 58 M Shipping clerk; messenger 83 M Salesman 84 M Asphalt laborer 63 M Pastry chef 56 M Office clerk; salesman 62 M Porter; elevator operator 50 M Foundry worker 68 M Waiter 75 M Salesman; clerical 54 M Restauranteur 80 M Restaurant worker: porter 69 M Restaurant worker; roofer 71 M Bus driver 50 M Butcher 'Average age at time of death 64.6 years (13.4). (9,10). Animal studies have shown that chrysotile is effectively eliminated from the lung after exposure by inhalation (11). These data, and more, have led some inves tigators to conclude that "chrysotile disap pears from the lung," i.e., it lacks biopersistence. The implications of such a statement regarding carcinogenicity are obvious. If chrysotile is neither durable nor retained, the likelihood of its exerting a lasting or chronic biological effect is signifi cantly diminished. However, the study of human tissues shows that sometimes, even many years Table3. Occupations of all 19 persons whose tissue aliquot contained 15ormore asbestos bodies. '| Number of asbestos bodies Age at death' Sex Principal occupationlsf ' >99c 63 M Pipecoverer ' >99 55 M Welder-shipyard >99 65 M Elevator operator1' >99 72 M Plasterer >99 51 M Electrician, shipyard >99 59 M Pipecoverer, insulator 92 73 M Carpenter, shipyard 52 67 M Laborer, shipyard 42 72 M Electrician, shipyard 37 64 M Truck mechanic 35 40 M Painter, shipyard 32 48 M Plumber 29 62 M Plasterer 29 73 M Pipefitter 28 58 M Laborer; carpenter 20 72 M Longshoreman; porter 19 56 M Laborer, construction 17 57 M Laborer, construction; longsnoeman 17 64 M Painter ''Average age at time of death 61.6 years (+9,4).6 New York State death certificates record last employment only if dece dent was still actively working. Certificates frequently state "retired." Most data from interview with next-of-kin. `Count stopped at 99 to comply with program format. `'Last employment as shown on death certificate. No interview was avail able with next-of-kin. All cases are male. after cessation of exposure, chrysotile fiber is encountered in lung tissues, and occa sionally at exceedingly high concentrations. Trace amounts of chrysotile have been reported in lungs of persons in the general population (12), and high concentrations in lungs of some occupationally exposed workers (13). This study explores the phe nomenon of chrysotile persistence in human lungs. Materials and Methods During the years 1966 to 1968, 7 lung specimens, obtained from selected anatom ical sites, were removed from each of 3000 persons who died at one of three hospitals in New York City: Mount Sinai Hospital, Manhattan: Veterans Administration Hospital, the Bronx; and Elmhurst General Hospital, Queens (14). The specimens were collected for a study involving the quantitative determination of asbestos bod ies and uncoated fibers, visible by light microscopy, in the lungs of these people, and its possible bearing on morbi-l'-v and mortality. In addition to autopsy :tocol, clinical records, occupational histor:.s, and a complete personal profile was known for each case. Similar studies had been done in urban areas elsewhere (15,16). These studies (17--20) showed a strong correlation between the presence of both asbestos bodies and uncoated light-visible fibers with sex (males greater than females), Table 4. Chrysotile detected among 126 cases studied by TEM. Number of chrysotile 0 fibrils/fibers counted N xP Exposure categories by number of asbestos bodies found 1-4 5-14 >15 N xf N xf N xf Total chrysotile N'xlO5 f/g/dry <9 10-27 >28 Total 5 34 10 43 10 19.3 20 20.0 17 ' 17572 ' r 27 113.4 32 3188 57 3504 1 1.0 8 15.0 9 94.1 18 970 3 4.7 5 20.0 11 1345 19 1594 19 <0.58c 43 0.64-17 64 >1 79' 126 Chrysotile>5 pm 1-5 pm <1 pm N 7 100 3081 <y N l%l N i5i>l N (0221 (3.14) (96.64) 6 151 3347 1017) (4311 (9552) 11 136 823 n.131 (14021 184 85) 28 463 1103 (%) 0(1.76) (29.05) (69.19) N Total 52 850 8354 9256 'xf = average number of chrysotile fibers/fibrils found among cases (N). ; These values were converted from length of the object on the viewing screen, at a particular scan magnifica tion. to pm. ; Limit of detection is 0.064 x 105 f/g/dry lung (64.000 fibers). : Range of positive cases. 179-1574 x 10 - f/g/dry lung CHRYSOTILE BIOPERSISTENCE It was decided to make a more detailed examination of a number of cases, using transmission electron microscopy (TEM). Bulk tissues from 126 cases were subjected to complete alkaline digestion, from which the particles were recovered by centrifuga tion. Aliquots of the dust suspension were transferred to grid substrates and examined by TEM. Twenty-eight specimens were analyzed with an RCA 3G microscope with a magnification x31,000, and the remain der with a Hitachi HU11E-125 micro scope with a magnification x42,000. The asbestos fiber that was counted was identi fied as chrysotile on the basis of morphol ogy and structure. Amphibole fibers were presumably also present but could not be identified. The study population, selected on the basis of asbestos body content, occupation, and personal history, is shown in Tables 1--4. Results %if figure 1. Chrysotile recovered from an occupationally exposed worker's lung (A), with fiber displaying characteristic structure (B), and from the lung of a person in the general population (C). Scale in (C) is approximate for (A) as well. The 18 pm2 area represented in (Al is about f/625th the area of an entire grid opening. Compare this chrysotile concentration T'.Witf) that in (C). with the fibrils shown counted in an opening of 11 236 pm2. The numerical difference of chrysotile con >' (sntradon is about x 20.000 and a mass difference in excess of x 1 million. These illustrate the opposite outliers of , '/thrysob.'s exposure. 3ge (prevalence and amounts increased - with age), and occupation. The overalT v asbestos body distribution is given in Table 1. These studies clearly indicated that asbestos bodies, and the accompanying fibers With diameter <1 pm, were not uniformly ^distributed among the general population ,,,-ut rather along an exposure continuum, in which most of the group had experienced lit tle or no direct exposure to asbestos. They would provide a reliable tissue burden benchmark for ambient air exposure, against which the chrysotile levels found in persons subjected to workplace exposure to asbestos could be compared. Chrysotile biopersis tence, across a range of exposures, may be explored utilizing this material. The completed study showed that the general population dying in New York City between 1966-1968 experienced a wide range of exposures (Tables 1-3). The greatest concentrations and highest preva lence of asbestos bodies occurred in males, especially workers in occupations involving asbestos-product use or installation. These included pipe-coverers, shipyard workers, and general construction workers (Table 3). Two plasterers are listed among the occupations (when) plasterers in New York City sprayed asbestos-containing fireproof ing on steel structures during building con struction. Most of the cases were not occupationally exposed. These included women and white-collar workers, who made up an important proportion of the category without asbestos bodies. At least some chrysotile fiber was found in the lungs of 124 of 126 persons in the study, but it was decided to recognize that there was a background level. This was set at the highest level found on "control" grids, nine fibrils in nine fields (one per field opening of 11,236 pm2 area). In 19 of the lungs studied, the fibril count was <9. Setting the statistical population at approx imately three times this value, at 27 fibrils, there were 64 (50.8%) statistically positive cases out of 126 (Table 4). There are three important caveats: First, the background level observed varied in these two tissue populations so that the highest value, that reported in the 1971 study (72), was used for all cases. Second, some of "the <9 cases" included short fibers, not fibrils, suggesting a "real" expo sure had occurred. Third, four of six cases 'alum 102, Supplement 5, October 1994 237 LANGER AND NOLAN vvich >99 asbestos bodies had almost no chrysotiie in their tissues, and the two oth ers had only modest amounts, slightly more than three times the background level. Virtually all the chrysotiie in nonoccupacionally exposed persons was composed of short fibrils, most <1 pm in length, with the modal class between 0.2 and 0.5 pm (Figure 1C). The asbestos bodies in the occupational group were characteristically amphibole fibers. However, it should be noted that many occupationally exposed workers had lung burdens the chrysotiie contents of which indicated intense, pro longed exposure {12,20), being several orders of magnitude higher than the gen eral population. The chrysotiie fibers were much longer also (Table 4). Most of the chrysotiie fibers/fibrils observed in this study were <5 pm in length. Only 52 of 9256 (0.56%) chrysotiles observed were longer (Table 4). There was a trend, however, which sug gested that the lungs of individuals with, apparently, occupational exposure to asbestos contained more chrysotiie, fibers/fibrils > l to 5 pm, and > 5 pm in length (Table 4). The quantitation of the chrysotiie levels in the 64 positive cases, counting all fibers and fibrils, including those <1 pm in length, gave values between 1.8 and 15.7 x 10" fibers per gram of dry lung tissue. The values for remaining 62 cases ranged from below the detection limit, 0.064 x 106 fibers per gram of dry lung tissue to 1.73 X 106 fibers per gram (Table 4). The highest chrysotiie levels found did not correlate with asbestos body content nor with occu pation. The highest "general population" level of chrysotiie >5 pm in length, was about 1.7 X 101' fibers/g of dry lung tissue, in an 80-year-old male. His exposure source remains unknown, and his cause of death was coronary heart disease. In this study, amphibole fiber (presum ably, based on morphology and diffraction character) >5 pm in length was restricted to individuals who were occupationally exposed. Discussion and Conclusions The presence of chrysotiie in lung tissues indicates durability, retention, and host, biopersistence; and the trace amounts found in the general population are pre dominantly short fibrils. Rare outliers were found. Only in lungs of some heavily exposed workers were high chrysotiie con centrations found; in these instances they appeared to be long unaltered fiber. The present study supports the tissue assay guidelines used in our laboratory, which exclude fibrils less than 1 pm in length from analysis, since they appear to repre sent nonoccupational exposur.. Chry50t-i <: fiber elimination most certain! . . ;curred' ' all cases, but in proportions tha- ould q be estimated. " Chrysotiie asbestos had been detected I in the lungs of 50 of 83 persons (60.2%V known to be exposed co asbestos either inf their occupation or as bystanders 0f exposed occupation or in the households of asbestos workers {13,21). The highest chrysotiie exposure was calculated at 7790^ X 10* fibers >1 pm in length per gram off dry lung tissue (Figure JA). The meaof value, for all 50 cases, was calculated as 715 x 106 fibers >1 pm in length per gram of dry lung tissue, and the proportion of long ) fibers in the asbestos varied between 5 and 50%. Analysis of selected fibers showed' preservation of both chemistry a..; 1 struc ture. It would appear, therefore chat in occupational exposure co chrysotiie not only are doses higher, but the proportion of long fibers is greater than in the chrysotiie to which the general population is exposed. The biological activity of chrysotiie may depend on its durability and persis tence, but the influence of the other fac tors--fiber length and dose--clearly affect the asbestos-disease risk {22,23). For this reason, the general population is not at the same risk as those that are occupationally exposed. REFERENCES 1. Pancheri G. Su alcune forme di pneumoconiosi particularmente studiate in Italia. Tio pneumoconiosi e baritosi. Med D Lavoro 41:73-"'(1950). 2. Pendergrass EP, Pryde AW. Benign pneumoconiosis due to tin oxide. J Indust Hyg Toxicol 30:119-123 (1948). 3. Harding HE. The toxicologv of zircon. Br J Ind Med 5:75-76 (1948). 4. Vorwald AJ. Pratt PC, Durkan TM, Delahant AB, Bailey DA. Siderosis: A benign pneumoconiosis due to the inhalation of iron dust. Indust Med Surgery 19:1 "0-180 (1950). 5. Beger PJ. Cber die Asbcstosiskorperchen. Virchows. Arch Pathol Anac 290:280-353 (1933). . 6. Langer AVI, Rubin I, Selikoff IJ. Electron microprobe analysis of asbestos bodies. In: Pneumoconiosis. Proceedings of an International Conference. Johannesburg, 1969 (Shapiro HA. ed). Capetown:Oxford University Press, 1970:57-69. ~. Langer AM, Rubin IB, Selikoff IJ, Poolev FD. Chemical characteri zation of uncoated fibres from lungs of asbestos workers by electron microprobe analysis. J Histochem Cvtochem 20:735-740 (1972). 8. Morgan A, Holmes A. Gold C. Studies of the solubility of con stituents of chrysotiie asbestos in' vivo using radioactive tracer tech niques. Environ Res 4:458-464 (19"1). 9. Suzuki V. Churg J. Structure and development of the asbestos body. Am J Pathol >>:--9--10-- 11969). 10. Suzuki Y. Formation of the asbestos body: A comparative study with three types of asbestos. Environ Res 3:10~-- 118 (19"0). 11. Wagner JC. Berry G. Skidmore JW, Timbrell V. The effects of the inhalation of asbestos in rats. Br J Cancer 29:252-269 (19_4). 12. Langer AM. Selikoff IJ. Sastre A. Chrysotiie asbestos in the lungs of persons in New York City. 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Demonstrath'-'s of asbestos bodies: comparison of available technique In: Proceedings of the 2nd International Conference on Bid ;ical Effects of Asbestos (Anspach M, Holstein MH, eds). 1968:22 - ;9. 18. Schwartz J. Langer AM. Technique of removal and analysis <: sin gle fibrous particles from human lung tissue. Proceedings or the 2nd International Conference on the Biological Effects of Asbestos (H Anspach, H Holstein, eds). 1968:8-12. 19. Berkley C, Langer AVI, Sastre A, Arneson A. Electron microprobe analysis of asbestos bodies. In: Proceedings of the 2nd International Conference on the Biological Effects of Asbestos (Anspach M, Holstein H, eds). 1968:12-22. 20. Langer AVI, Baden V, Hammond EC, Selikoff IJ. Inorganic fibers, including chrysotiie, in lungs at autopsy: preliminary report. In: 238 Environmental Health Perspectives CHRYSOTILE BIOPERSISTENCE Inhaled Particles, III. Proceedings of the Conference of the British Occupational Hygiene Society, London, Vol 2 (Walton WH, ed). London:Unwin Bros, 1971 ;683--694. Langer AM, Nolan RP. Fibre types, concentrations, and diseases among persons exposed to asbestos in the Uniced States. (Submitted for publication) 22. Browne K. Asbestos related malignancies and the Cairns Hypothesis. Editorial. Br] Ind Med 48:73-76 (1991). 23. Langer AM, Nolan RP. The properties of chrysotile asbestos as determinants of biological activity. Accompl Oncology 1: 30-51 (1986). 02. Supplement 5, October 1994 239 Biopersistence of Respirable Synthetic Fibers and Minerals Volume 102, Supplements October 1994 NATIONAL INSTITUTES OF HEALTH National Institute of Environmental Health Sciences