Document G6y19qEE8NrNKkVbgj8eXqoQn

06/12/02 17:08 FAX 317 735 2283 rNfr-HEALTH SCIENCE J|K '' " " \; .,"" *23w ^ -'? T.- ^-- - " ggjjg- &&iivintnm*ntiil Health Perspectives s. vp- 2S9-5.M. sarj, tiglg Inorganic Particles in Human Tissues and Their Association with Neoplastic Disease' by Arthur M. Langer* @013/017 Ab incnafed jBtrotatetin*l coucar risk is associated with.occupatioiitl exposure to asbestos fiber. Examination of tissue* obtained from octrepubsOjaWy orgxno of exposed workmen dcmonitntas tb presence of asbestos fibers anH.bpdJei': Thifamount of fiber pessent in these tissuse is many macnitvds* lees than encounteredIp tbs lunk&iuiuaa from the same in dividuals. Ingestion of asbestos fiber in some environmental iainacei may approach in magnitude the amount resulting from occupations! exiwsurs- Dlsease'factors are discussed. Inotganic Particles in the Environment and Their Possible Health Effects Recently, there has been concern about the possible long-term biological effects in humans of ingestion of large numbers of extremely small-sized, yet small-mass amounts, of some Specific inorganic particles. These are primarily silicates, either not normally encountered in the ambient environment or those which generally occur at levels not greater than a detectable trace. They find their way into humans, some at significantly elevated concentrations, as con* tam inants. These substances have been shown to produce fatal malignant tumors in animals and are implicated as whole or cocarcinogens in epidemiological studies involving humans. These latter studies have largely been of workmen occupationally exposed to high con centrations of these materials. Some have been associated with increased occurrence of gastrointestinal cancers. These particles may originate from specific sources, such as solid waste discharge of crush ed silicate rock in mining or milling operations, wnieh may contaminate potable water and air 'Maun*. Sinai School of Medicine of The City University of New York, New York 10029 supplies'' (1), or disintegration of man-made products', e.g., pharmaceutical or beverage filters (2). In such instances, silicate particles are inadvertently added to some substance which is directly ingested by humans. This has apparently become more common as the result of modern technology. Silicate particles have even been observed as contaminants in polar ice caps. Mineralogical analyses of ice samples from polar areas have shown an increased occurrence of talc particles with progression in time, to the present/.'ThTs-lfias., been attributed to the in creased usage.-pf talc as an excipient in pesticides. These' small particles have entered the air streams-and have precipitated with rain and snow (S). This may be true for a number of other industrial minerals which have become in creasingly more important and useful with widening applications. For example, our laboratory has examined ice samples from the Greenland poiar ice cap and has found chrysotile asbestos fibers to be present in all samples examined thus far. Concern has been derived from a number of observations: (a) the incidence of cancer of the gastrointestinal tract is rising in the United States: (b) there are some epidemiological studies which have established an association between exposure to specific inorganic particles December 1974 '!ME * \j V P?.!KT ~:VE JH. '2. 5;i0 PM 06/12/02 17:08 FAX 817 735 2283 VNT HEALTH SCIENCE @012/017 and increased gastrointestinal cancer risk;(c)particles accumulate in tissues for the lifetime of the individual; (d) particles may, in some way, interact with other substances in the en vironment to produce a synergistic, mul tiplicative effect; (e) there may exist a zero (5). However, considering the physical extent and mass of this organ, most malignant lesions lend-to be confined to the lower bowel (sigmoid) and the rectum, A question is then whether in creased gastrointestinal cancer in the United States is in any way related to the observed in asbesti ing ne tract. . little a U threshold for particle tolerance in humans, in sofar as c&ncer is concerned, creased silicate contamination of foods, bev erages, water supplies, pharmaceuticals, or any other substance which is directly ingested by Th Gastrointestinal Cancer in the United States humans. It has been estimated that upwards of 335,Q00.. Association between Mineral Particles and Neo men, women, and children died of cancer, of ,all('- plastic Diseases sites, in the United States in 1971 U). Cajiceti'is,,. the second leading cause of death In this couri- -- /"A; Humber of studies over the last 25 years iry, second only to heart diseases. The leading has established an association between occu cause of neoplastic death in men ia lung cancer; pational exposure to 3ome specific species of in females, it is cancer of the breast. Although inorganic particles and increased risk of the second leading cause of neoplastic death in ` neoplastic disease in workers. Workmen expos women was uterine cancer in 1971, colon and ed to asbestos dust (at least five separate rectum cancers were almost equal in number, In mineral species and their chemical ranges) both men and women, over 46,000 deaths from (6-12), hematite miners (hematite dust in the cancer of the rectum and colon were recorded in presence of free silica and other gangue 1971 (Tabic 1). The rate of rectum-colon cancer silicates,-including perhaps asbestos) (IS), talc is increasing, so that it has been estimated that miners and millers (9), miners and millers of before the end of the decade this disease may be uranium ores (H), workmen who process the second most common cause of cancer deaths chromium ores (in), and heavy metal processors in the United States for both men and women. who are exposed to lead, zinc or copper fumes (16) all have substantially increased risk of Fiber Anionite Chrysot ' Two o Approx: occure i r Data i; Data 1 Fiber I Questli Obs tissue: cupati porta; asbest Table 1. Death* (Ton] Cancar in the United State*:- 1971. developing malignant neoplasms. Most of the itself, reported tumor excess tend to be in the thoracic inere; By sex Males Females No. of deaths 183,000 162,000 organs. However, in asbestos exposure, there arc other tumors as well (Table 2). Exposure to eupal amou: magn This Total 955,000 (best estimate) By aile Males, lung1 Males, colon-rectum 53.1.00 22,400 Femaics, bresal Females, uterus (genital) Females, colon-rcecum 30.S0O 25,029 23,600 Table 2. Epidemiological arodlM demonstratiMC an association between expoacre to mineral pariiclas and 1' ' CTeued rik of gastrointestinal cancer.a Study No. men Material used Keul ft!) Selikoff et al. n, iClainfcld et al. <9, 42 Amosite; chrysotile; crocidolite 632 Chrysotiie and insulation 01 Talc; tremolite; snthophyliitc pul mi the d-. such : one n that therm creas to ib nitre: ' 70-e0< of malignant tumor; of the large bo<ei occur in the cecum. sigmoid and rectal region?. Enterline end Kendrick IS) Elme9 and 1.843 Chrysotile (textiles) V :.e Simpaun (10) 170 MUedibur; inyuUtinn IS- Hyperplastic and neoplastic lesions have been found, on scrutiny by light microscopy of ran Novi-house et al. fJ J;1 928 Crocidolite Selikoff et al. (lit 230 Amosite SUggi tabliattlOl- dom autopsy material, to be far more numerous 1 Most of the studies deal with one or more forms of asbes fiber iji and widely disseminated in the bowel, colon and rectum that has been previously reported tos mineral fiber. At least five of ihc major fiber types sre- implicated as being biologically active. disci are t i 230 r* ..'/ED "(ME Jo 'I `.2. 5:03 FV Environmental Health Perspectives ;R:r 'If/,: n11,l,. 5:17V. Dec- i 06-12/02 17:09 FAX 817 70S 2283 UNT HEALTH SCIENCE \Vi @015/017 asbestos fiber leads to increased risk of develop ing neoplastic tumors of the gastrointestinal tract, Difference in fiber type appears to have little affect on relative excess mortality (Table 3), Table 3. Asbestos fiber type And increeecdriik of H&itrointetiaui c*ncei. fiber Amosite6 Chr\'3<itile c No. cases 230 632 Expected 1.6 9.4 Observed 5.0 29.0 ' Two occupational settings utilizing different fiber types. Approximately three times as much gastrointestinal cancer occurs in ImLh groups. 11 Data of Sellkoff et 1. 'izj. ' Dali of Selikoff et al. (7), Fiber Amounts in Tissues and Disease; Important Questions, No Answers Observations concerning fiber amounts in tissues and the occurrence of disease in oc cupationally exposed workmen, raises 3omc im portant questions. One can ask whether asbestos is such a potent carcinogen, in and of itself, that it may be associated with a threefold increase of gastrointestinal cancer in oc cupationally exposed workmen when the amount of fiber in the affected tissues is many magnitudes less than observed in their lungs. This may suggest that tissues, other than pulmonary, are more sensitive to the insult of the dust. Perhaps the gastrointestinal tract is such a more sensitive tissue, thereby, making it one more "target" organ. It may also suggest that there are factors other than the fibers themselves which may be responsible for in creased tissue response. The question arises as to the effects of "organic additives", such as nitroso compounds, and the role they may play m the etiology of gastrointestinal disease. Synergism, for neoplastic development between particle exposure and cigarette smoking was suggested several decades ago (IS), but es tablished epidcmiologically for asbestos and smoke only recently (-25). Multiple interaction of fiber and organic compound increases neoplastic disease risk in a multiplicative manner. What sre the effects of such combinations as particle to particle, particle to gas, and particle to organic phase in asbestos disease etiology? And, most important, does direct ingestion of small amounts of asbestos fiber, in food and water likely less than one observes for the working en vironment, pose a serious threat of neoplastic disease for individuals not occupationally expos ed to the fiber? Does environmental direct inges tion of small amounts of asbestos fiber approach in magnitude the amounts of fiber inadvertently ingested, or migrated, following occupational ex posure? Is asbestos aunique substance with respect to disease? If so, what are the special properties which render it so unique? Is a narrow chemical or physical entity of asbestos within a broader range, the only biologically active member of that series? Although amosite is a narrowly defined mineral entity within the cummingtonite--grunerite series, it has been im plied that all other members of this series are biologically inactive. This appears unlikely because the magnesium member of this series, which alters crystal form slightly, is another amphibole mineral called anthophyllite. Anthophyllite has been shown to be biologically active. Considerations and future Work Future work in the area concerning the biological effects of inorganic particles will have to take into consideration a number of parameters. For example, there is a natural background, and a wide variety of inorganic particles which are normally ingested. Foods contain inorganic components, as well a9 adven titious minerals within the substance itself; some of which have formerly been considered inert. Opal phytoliths have long been known to occur as siliceous parts of plants (22). Their long-term biological activity is known only in animals (23). Potable water may carry large quantities of dissolved and suspended materials which are ingested. Their effects are unknown. The "natural" background of particles in am bient air is only partially known and is con tinually fluctuating qualitatively and quan titatively. The identity of many of the par ticulate components still have to be determined. In addition to these natural airborne materials, particle contaminants and additives in food, water, and beverages add to the body's burden. December 1974 ;-ce:v:D ::ve .ul 12. J3FV. psiiT 06/12/02 17:09 FAX 817 735 2283 CNT HEALTH SCIENCE, @016/017 In addition to characterizing of these par (19). The size distribution of even the larger ticles, one must systematically examine the amphibole fibers is such that this transport may affected tissues. To this date, this has not been be accomplished without size obstacle. A done. We observe in lung tissues of workmen statistical study of the size distribution of that each portion of the lung contains a slightly amosite fibers in the lung of a workman exposed different particle size fraction assemblage. This to dust occupationally, has demonstrated that has not been studied for any of the ex- 95% of the fibers in his lung was shorter than 5 trapulmonary organs. Judging from the ftm in length and the width distribution for fl.'- prevalence of neoplastic lesions in bowel, colon, these fibers was modally centered at 0.15 nm and rectum, one may expect that the accumula size range (21). Even in these cases, the vast tion of particles in the digestive tract is site majority of fibers may easily migrate within the related. The development of proper " tissue ' body. Therefore, asbestos fibers found in the ex- preparation techniques and instrum'erital fcrapulmonary tissues of workmen may have methods of analysis has been achieved to a large ; come to rest in these organs through migration degree (2b). The expansion of this research into and/or direct ingestion. possible etiologic agents responsible, in part, for the development of malignant lesions in the human gastrointestinal tract, is only at the beginning stage. Asbestos Exposure and Neoplastic Disease Asbestos fibers may be easily detected in lung tissues of asbestos workmen (17). These men are generally exposed to highly concentrated dust aerosois so that the inhalation and entrapment We have studied extrapulmonary organs of asbestos workmen by both light and electron microscopy in order to determine the presence or absence of fibrous particles. The results of one such light microscopy study is shown In Table 4. On the basis of this very limited study by optical microscopy, we report that large fibers. those detectable by light microscopic techniques, exist in all extrapulmonary organs examined. However, their amounts are substan Acknov The under niehj from : of fibers in their lung tissues is certain. Many tially less than light visible objects normally en fibers are eliminated from the lungs by the countered In lung tissue from the same, in body's normal defense mechanism. How.eVer, elimination never equals the quantity"'of material which is inhaled. The fate of' these fibers which are removed from the lung may be twofold: they are eliminated from the body or they are removed from the lung, but migrate to other body sites (12--20). Migration may include hematogenous and/or lymphatic mechanisms dividual. Also, uncoated fibers exceed coated fibers (asbestos bodies) by substantial amounts. Using light' visible objects as markers, fibers are observed in extrapulmonary organs, but they are magnitudes less in number than in the lung. We also have examined a number of such ex trapulmonary tissues by electron microscopy. Here also, on the sublight microscopic level, we Anc Dul 0.7; ner Chii N';ci A *,`3 177 W-i itm Table 4. Pretence of asbestos bodies and vuteoated fiber* in lung end extrapubnonery tleaucs of workmen oeeupedoruily exposed to asbeetos dust (light microscopy).* - itjV A 73! . Hai -r.it Lune Liver Pancrees Kidney Adrenal Spleen Case Body Fiber Body Fiber Body Fiber Body Fiber Body Fiber Body Filxr l >99 >99 I 5 2 16 0 47 _ h _ _ O >39 >3!) -- -- -- ___ ___ ___ ___ -- 15 30 3 >99 >99 JJ 4 7 48 1 >99 ___ ___ .___ j >99 >9il 0 1 _ ___ 0 65 0 5 ---- 3 >99 >9!l c 2 2 10 0 60 -- -- -- -- * (VvC tar. "Analyses were made on 175 /im stacks of seven 25 thick tiMue sections. These arc ashed in a loir-tempcrjturt about lo x 10 mm. Counts stopped at 9!) 11 Denotes no tissue available. 232 Environmental Health Perspectives Decs tECElO ".ME__ IH '2. _ 5:93^ wx T'.VE JA`,2. 5:10PM OS /12/02 17:10 FAX 817 735 2283UNT HEALTH SCIENCE a mSt: S tbserved uncoated fibers. Again, as with light nicroscopy, their concentration is significantly .ess than encountered in lung tissues. The obser vation that asbestos fiber may be present in organs which have limited direct contact with the outside environment, by direct ingestion and blood or lymph routes, emphatically demonstrates the ability of asbestos to infect the entire human body. It has been noted ex perimentally that asbestos fiberB are found in liver, spleen, and kidney of experimental animals after asbestos instillation into the lung (1'Jj. Inhalation of asbestos fiber invariably means dissemination of fiber throughout the body, although the number of fibers which may come to rest in extrapuimonary organs may be magnitudes less than one observes entrapped in lung tissues. Acknowledgement The author wishes to acknowledge support under a Career Scientist Award from the NIEHS, ES44812 and under a Center Grant from the NIEHS, ES00928. REFERENCES j- 1 Anonynous, A Preliminary Report on Asbestos in the : Duluth, Minnesota Area. Office of Technical Analysis, j. Office of Enforcement and General Counsel, nlronI mental Protection Agency, Washington, D- C., 1974, I Chaps. 1 and 3 f 2 Nichoiaon. W J., ilaggiore. C. J., and Sclikoff, t. J. ; Asbestos contamination of parenteral drugs. Science y 177: 171 (1972). \ 3. Winilam, H. Grifrin, J., and Goldberg. E. D. Talc in 1 atmospheric dust. Environ. Sci. Teehnoi. I: 923 (1967). t <- Silverberg, E., and Holieb, A. Cancer Statistics, 1971. American Cancer Society Inc. New York, N. Y,, 1972. 5. Hammond, E C. Personal communication concerning onROir.g lenearch at the East Orange V_A. Hospital, j colon and rectum cancer, 1974. . S. Kcal, E E. Asbestosis and abdominal neoplasms. Lancet" 1211 (3, Dec. 1960), 1 " Selikoff. I. Churg, J.. and Hammond, E. C. Asi bestos exposure and neoplasia, J. Amsr. Mid. Aaioc. | 186: 22 (19641 ' 3 Enterhne, P E , and Kendrick, >1. A. Aabcstos dust exposures at various levele and mortality. Arch. : Env.ror.. Health 15: 161 (5967/. 9, Kleinfeld, M, ct al. Mortality among talc miners and millers in New York State, Arch. Environ. Health 14: 663 (1967). 10. Elmea, P. C.i and Simpson, M. Insulation workers "n Belfast 3. Mortality 1940-66. Brit. J. ind. Med. 28: 226 (1971). 11. Newbouje, M-, et al. A study of the mortality of female asbestos workers. Brit. .1. Ind, Med. 29: 134 (1972). 12. Selikoff. I. J., Hammond, E. C., and Churg, J. Car cinogenicity of amosite asbestos. Arch. Environ. Health 25: 183 (1972). 13. Lumy, P., et al, Les opaeites massive* cher les mineurs de fer. J. Franc. Med. Chir. Thoraciques 13: 233 (19S9). 14. Holiday, D. A. Uranium mining hazards, in: Hand book of Experimental Pharmacology. H. C. Hodge, J. N. Stannard, and J. B. Harsh, Eds., Sprwfcet- Varlag, New York, 1973. 15. Mackle, W,, and GrogDrious, F. Cancer of the res piratory system in the United States. Puhl, Health Kepte. 63: 1114 (1948). 16. Breslow, L.. et al. Occupations and cigarette smoking as factors in lung cancer. Am, J. Publ. Health 44: 171 (1954). 17. Longer, A. M., and Pooley, F. D. Identification of single asbestos fibers in human tissue*. In: Proceedings of the International Conference on Biological Effects of Asbestos, Lyon, France, Oct. 2-6. 1972, Bogovski, P., Gilson, J.C., Timbrel!, V,, J.C. Wagner, Eds., LARC, Lyon, Scientific Pub. No. 8: 119 (1974). IS. Holmes, A., and Morgan, A, Investigations into the use of radioactive asbestos in studying the trans location of fibers injected IntroplBuraily into rats. Report Atomic Energy Authority of the UK, Harwell, 1967. ' 19. Kanazawa, K., Birbeck. R, L., and Roe. F. J. C. Mi gration of asbestos fibers from subcutaneous injec tion sites in mice, Brit. J. Cancer 24 : 96 (1970). 20. Westlake. G. E., Spjut, H. J., and Smith, M. K Penetration of colonic mucosa by asbestos particles. An electron microscopic study in rate fed asbestos dust. Lab. Invest 14: 2029 (1966). 21. Langer, A. M., and Macklur, A. D. Distribution of asbestos fibers in the lung o[ an asbestos worker. In preparation. 22. Parry, D. W,, ami Smithson, F. Opaline aHiea in the inflorescences of some British grasses and cereals. Ann. Botany SO; 119 (1966). 23. Baker. G., and Jones, L. H. P. Opal in the animal body. Nature 189: 682 (1961). 24. Linger. A. M., et al. Identification of asbestos in human tissues- J. Occup, Med. 16: 287 (1973), 25. SvIikclT. I. J,, Hammond, E. C., and Churg, J. As bestos exposure, smoking, and neoplasia, J. Amor. Med. Assoc. 2M: 106 (1968). teI017/OI7 December 1974 :ece:/e: 'iM: :a-}. 5: iOFM