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In the Forum ST006I292 A Is Short-Fibered Asbestos Dust a Biological Hazard? Paul Gross, MD, Charleston, SC Contrary to the determination that the Inasmuch as asbestos fibers smaller finer the quartz dust, the greater Its than 5/i tend to remain airborne pathogenicity; the pathogenicity of the finest asbestos dust has been shown to be negligible. It has been the finding of research labo ratories In Germany, England, South Af rica, and the United States that short-fi bered asbestos, dust, le, less than 5p In length. Is Incapable of causing fibrosis or cancer. This finding. In conjunction with the failure of different laboratories In the longer than the larger ones, they have a greater chance of being inhaled. Furthermore, although the anatomy of the respiratory tract tends to pre vent the intrusion into the airspaces of all but a few of the larger sus pended particles, this deterrence does not extend to the smallest particles. The latter very readily enter the air United Kingdom and In this country to dis spaces with the inspired air. Some of cern abnormalities following prolonged the short asbestos fibers may settle asbestos feeding to rats, should lead to the abandonment of the present concept that maintains that mesotheliomas and gastrointestinal cancers arise from the In gestion of asbestos dust cleared from the lunge. These negative results should also al lay the alarm that has been raised as a re sult of the finding of ultramlcroscopic on the alveolar surface by sedimenta tion, whereas the smallest fibers, behaving almost like gas molecules, contact the alveolar membrane by diffusion. What is the potential of these ex tremely fine submicronic fibers to produce disease? Is their potential mineral fibers In certain beverages and greater than that of optically visible drinking water. fibers? Is the behavior of submicronic asbestos fibers as opposed to that of larger fibers similar to that of the fi- brogenic effect of very fine quartz By short-fibered asbestdS dust is meant that which has a fiber dust as compared with that of the same weight of coarser quartz par- length of less than 5p. Although fiticles?1-' bers of this size usually constitute a These questions take on added im very small fraction of the weight of a portance in view of the commonly dust cloud, their numerical prepon held hypothesis that mesotheliomas derance over the larger fibers may be of the pleura and peritoneum arise by manifold. the transmigration of fibers to the pleura and peritoneum, respectively. Submitted for publication Sept 19, 1978; ac cepted Jan 30, 1974. Prom the Department of Pathology, the Medi cal University of South Carolina, Charleston, SC. Reprint requests to the Department of Pathol ogy, Medical University of South Carolina, 80 Barre St, Charleston, SC 29401 (Dr. Gross). In the case of abdominal mesothe liomas, it is assumed that the as bestos fibers cleared from the lungs are swallowed and then migrate through the intact intestinal wall to the peritoneum, there to initiate the development of mesotheliomas. So far as ability to penetrate into and trans migrate across the intact intestinal wall is concerned, once again it would appear that the submicronic fibers would be better able to accomplish this feat than would the coarser fibers. Originally, the question of the pathogenicity of the short-fibered as bestos dust had relevance only to people occupationally exposed to as bestos; but more recently short as bestos fibers have been found in cer tain beverages and city water, in ambient community air, and ir. the lungs of city dwellers.3-4 Con sequently, the relevance of the above question must now extend to entire urban populations. However, lest un due alarm be raised by the last state ment, it should be pointed out that in city dwellers no disease has been found that could be attributed to the presence of submicronic asbestos fi bers in the pulmonary tissues. Nei ther has there been documentation of an increase in abdominal cancers in the general population, in spite of the fact that in many cities and smaller communities drinking water has been and i3 now transported in asbestos- cement pipes. At the International Conference on the Biological Effects of Asbestos held in Dresden in 1968, Klosterkdtter3 found that both chrysotile and crocidolite, ground to an average fi ber length of less than 5p when in jected intratracheally or intraalu'ominally, produced no fibrosis. The Arch Environ Health/Vol 29, Aug 1974 Short-Fibered Asbestos Dust/Gross 115 ST0D6I 293 pulmonary response consisted only of a macrophage reaction. In contrast, longer fibers of the same asbestos re sulted in fibrosis in both .regions. At the same conference Timbrell and Skidmore" reported the results ob tained in rats and guinea pigs ex posed to equal concentrations (by weight) of short-fibered amosite (90% of the fibers <4/i long) and long-fi- bered asbestos (45% of the fibers >4/i long). They concluded, "minimal reac tion has been observed to short fibres but a marked reaction has been ob served to the longer fibres." In the following year, Webster' reported that monkeys inhaling finely ground crocidolite (fiber length <5/i) also showed merely a macrophage reac tion in the lungs. In 1970, Hilscher et al* showed the chrysotile or crocido lite, when ground to a fiber length of <3/i with a microtome and injected intraabdominally, produced no fi brous adhesions; whereas the same asbestos with greater fiber length did cause dense fibrous adhesions. In 1971, the Johns-Manville Re search Laboratory prepared for us chrysotile asbestos ground to a fiber length of <5/l We injected this dust intratracheally into 10 rats and were able to confirm that such short-fi bered asbestos could induce no more than a macrophage reaction (unpub lished study). In 1973 Smith et al* re ported that hamsters injected intrapleurally with chrysotile ground to a fiber length of <l/i developed no pleural cancer, whereas hamsters in jected intrapleurally with longer chrysotile fibers did develop such can cers. Recently Wright (private com munication) disclosed that in his labo ratory short-fibered asbestos injected intratracheally also failed to elicit a fibrotic reaction. Maroudas et al" have concluded that, "Particles (min eral fibers) smaller than 20/i in length induce neither growth in vitro nor mesothelioma in vivo." Thus, these reports from different laboratories are unanimous in finding asbestos that has an average length of < o/i is devoid of pathogenic poten tial. This included not only the fibrogenic potential5 ' " but also the can- cerogenic potential.* " It may be argued, that when as bestos is ground to a very small fiber size, either in a ball mill or a hammermill, much of the energy is converted into heat and the heat may change the chemical structure of the fibers. To continue this argument: since, strictly speaking, the fibers so altered may no longer be asbestos, the bio logic "inertness" of such "altered" as bestos need not necessarily apply to fine asbestos dust that has not been heated to a high temperature. This argument is rendered void by the following facts: 1. The short-fibered asbestos of Hilscher et al* was found to have maintained its fibrous structure after the grinding process. 2. Smith et al* prepared short-fi bered asbestos as an aqueous slurry. This obviated excessive heat. 3. It has been concluded that the chemical structure of asbestos does not determine its pathogenicity since synthetic chrysotile is devoid of path ogenicity." The latter has the same chemical and crystalline structure as the natural product. Therefore, the mere process of grinding with the as sociated heat production does not ac count for the lack of pathogenicity of the finely ground asbestos. However, by fitting together some newly de rived experimental findings, a theory has recently been formulated regard ing the locus of pathogenicity of as bestos dust that does offer a reason able explanation for this lack of pathogenicity." There is, however, one laboratory that reported that short-fibered as bestos is tumorigenic. Pott and Friedrichs" and later, Pott et al" maintained that 100 mg of chrysotile with a fiber length <3/i injected into the abdomen of rats caused the devel opment of cancers. Nearly 80% of the tumors were sarcomas-mostly fibro sarcomas. The character of the tumors pro duced by this technique should have given the authors pause for reflec tion; not only because rats will pro duce fibrosarcomas secondary to in jected or imbedded materials known to be biologically inert, but also be cause subcutaneous fibrosarcomas are very common spontaneous tumors in aging rats. An indication of the ease and nonspecificity of such tumor pro duction in rats is demonstrated in the first" of the two above-mentioned pa pers when the authors list a betterthan 60% tumor production with mag nesium hydroxide and a 55% tumor production with fibrous glass! In con trast, they reported only a 40% tumor production with chrysotile. This lower tumor production was doubtlessly re lated to a high mortality caused, in turn, by the exceedingly high dosage of materials injected (100 mg). The employment of unrealistic dos age, of inappropriate routes of ad ministration, and of inappropriate animal species (all three "sins" were committed by the above authors) to achieve positive results has recent ly been adequately discussed by Dr. H. E. Stokinger." When asbestos is ingested, it is the ultramicroscopically-sized asbestos fi bers that are assumed to be respon sible for the development of mesothe lioma by virtue of their alleged penetration and transmigration through the intact intestinal wall. The failure of short-fibered asbestos to induce mesotheliomas when, in jected intrapleurally* " makes the above assumption highly question able. Unpublished data from differ ent laboratories (David B. Clayson, University of Leeds; L. M. Swin burne, St James's Infirmary, Leeds, England; and John M. G. Davis, In stitute of Occupational Medicine, Edinburgh) in which rats were fed as bestos intimately mixed in their food, indicate complete failure to induce tu mors or any other kind of abnormal ity by these regimens. (A joint paper describing these investigations from the different laboratories is in prepa ration.) As one example, the following ex periment may be cited: ten weanling male rats were placed on a finely ground basal diet containing 5% by weight of chrysotile asbestos. Five litter mates were pair-fed with the same weight of food as the experi mental rats had consumed on the pre vious day. This regimen was contin ued for 21 months. At the end of this time, the weight curve of the as bestos-fed animals was not signifi cantly different from that of the pair- 116 Arch Environ Health/Vol 29, Aug 1974 Short-Fibered Asbestos Oust/Gross ST006 I 294 fed controls. The animals were killed 21 months after the initiation of the feeding period. At autopsy, no gross abnormality was found in either group of animals and microscopically no tumor or other gastrointestinal le sion was observed." It is to be noted that in previous studies, the first asbestotic lung cancer death occurred 16 months after the initiation of the dust exposureand the first asbestotic pleural cancer death in rats oc curred 17 months after the intrapleu ral injection of asbestos dust." It is of interest in this connection that the dose of fibers in the intesti nal tract of the asbestos-fed rats was astronomical compared with the dose of fibers that is likely to be swallowed daily by a person occupationally ex posed to asbestos dust-and he, in turn, would have an astronomically greater dose of fibers than the dose of fibers ingested daily by an urban dweller drinking a beverage or water containing mineral fibers. The uniformly negative asbestos feeding results should cast some doubts on the tenability of the con cept that peritoneal mesotheliomas and an increased prevalence of gas trointestinal cancers arise in occupa tionally asbestos-exposed people from the ingestion of asbestos fibers cleared from their lungs. There must, of necessity, be some other explana tion! Although not an asbestos-feeding study, a recent report purports to demonstrate that the presence of as bestos in the intestinal lumen results in the penetration of asbestos fibere into the blood stream and organs throughout the body, inclusive of the brain." The writers injected the as bestos into the stomach by means of a syringe and needle, thereby ignoring the probable opening of vessels in the path of the needle track and the pres ence of injection! References 1. King EJ, et al: The action of different forma of pure silica on the lungs of rata. Br J Ind Med 103-17, 1953. 2. Hatch T, Kindsvatter VH: Lung retention of quartz dust smaller than one-half micron. J Ind Hyg Toxicol 29:342-346, 1947. 3. Gross P, et ai: Mineral fiber content of homan lungs: A comparison of the counts obtained from the lungs of people of Pittsburgh, Pa, with those from the lungs of people of Charleston, South Carolina Am Ind Hyg Assoc J 33:A162, 1971 4. Gross P, et al: Lymphatic transport of fi brous dust from the lungs. J Occup Med 15:186189, 1973. 5. KlosterkOtter W: Experimentelie Untersuchungen liber die Bedeutung der Fsserlange ftlr die Asbestdbroee sowie Untersuchungen liber die Beeinfluasung der Fibrose durch Poiyrinylpyridio-N-Oxid, in Biotogische Wirkungen da Asbestet: Internationale Kmfercm, 1998, Dresden. Berlin, Deutsches Zentralinstitut far Arbeitsmedizin, pp 47-51 6. Timbrell V, Skidmore JW: Significance of fibre length in experimental asbestoais, in Biologieche Wirkungen da Aebeetee: Internationale Konferenx, 1988, Dresden. Berlin, Deutsches Zen tralinstitut fUr Arbeitsmedizin, pp 52-56. 7. Webster I: The pathogenesis of asbestoais, in Shapiro HA (ed): Pneumoconiosis: Proceedings o/ the International Conference, Johannesburg, 1989. Cape Town, Oxford University Press, 1970, pp 117-119. 8. Hilscber W, et al: Zusammenhlnge Zwischen Asbestose und Faserilnge. Natunoissenschafien 57:356-557, 1970. 9. Smith WE, et al: Biologic differences in re sponse to long and short asbestos fibers. Am Ind Hyg Assoc J 33A162, 1971 10. Maroudas NG, et al: Fibroblast anchorage in carcinogenesis by fibres. Lancet 1:807-809, 1978. 11. Gross P, Harley RA Jr The locus of patho genicity of asbestos dust: A theory. Arch Envi ron Health 27:240-241 1973. 11 Gross P, Harley RA Jr. Asbestos-induced intrathorade tissue reactions. Arch Pathol 96:245-250, 1973. 13. Pott F, Friedrichs KH: Tumoren der Ratte nacfa i.p. Injektion faserformiger Staube. Naturvissenschaften 59:318, 1971 14. Pott F, et al: Tumoren der Ratte nach i.p. Injektion von gemahlenen Chrysotil und Benzo (a) pyren. Zb Bakt Hyg I Abt Orig 155:463-469, 1971 15. Stokinger HE: Sanity in research and eval uation of environmental health: How to achieve a realistic evaluation (in seven commandments). Science 174.-662-665, 197L 16. Gross P, et al: Problems in the pathology Of aabestoaia, in Shapiro HA (edh Pneu moconiosis: Proceedings ofthe International Con ference, Johannesburg, 1989. Cape Town; Oxford University Press, 1970, pp 126-131 17. Gross P, et al: Experimental aabestoaia: The development of lung cancer in rata with pul monary deposits of cfaryaotile asbestos dust. Arch Environ Health 15:348-355, 1967. 18. Pontefract RD, Cunningham HM: Pene tration of asbestos through the digestive tract of rata Nature 243:352-353, 1978. Rebuttal In looking through "Biological Ef fects of Asbestos" (Ann NY Acad Sci 136:87,1965) I find one paper by Holt, Mills, and Young that says very small asbestos particles do cause fibrosis in the guinea pig lung. In the published discussion, no one challenges this re sult; one discussant, Ian Webster from South Africa agrees with it, and Gilson quotes it approvingly in his fi nal wrap-up. At least in 1965, ultramicroscopic asbestos particles were believed to have fibrogenic po tential for guinea pigs. George W. Comstock, MD The Johns Hopkins University School of Hygiene and Public Health Hagerstown, Md I reply that Paul Holt used the same make hammermill to commi nute his asbestos as I used. I fully agree with his statement that a high proportion of the particles to which he exposed his guinea pigs was too small to be seen by the light microscope. The more important aspect of Holt's statement is the long fibers were present in the dust cloud. Hav ing seen his set-up, I was impressed by the high density of the dust con centration (unmeasured!) to which his guinea pigs were exposed. The dosage of long-fibered (optically visible) particles must have been enormous whereas the dosage of submicronic fi bers (those visible only with the elec tron microscope) must have been as tronomical. Holt's finding of many optically visible fibers in the lung sections of his animals as pictured in his illustra tions and of many asbestos bodies at test to the plentiful dosage of long fi bers. This undermines his claim that "Fine dust particles, too small to be seen under the light microscope, will produce asbestosis in the guinea pig " The determinant(s) of asbestos tox icity is not known and I make no claim to such knowledge. However, in this article, I point to one aspect of asbestos dust which is not associated with pathogenicity. By "submicronic" is meant some thing invisible with the light micro scope but visible with the electron microscope. This generally means a particle <0.25^ in thickness. Although the vast bulk of fibers that have been ground to a length <5p are submi cronic, some would be thicker than 0.25p and therefore, optically visible. Perhaps, it would be best not to spec ify "submicroscopic" and speak only of "short" fibers as defined in the opening sentence of the report. Paul Gross Naples, Fla Arch Environ Health/Vol 29. Aug 1974 Short-Fibered Asbestos Dust/Gross 117