Document bBjJ9YG4Ejr33XzwmpN75DEK3

n~> -71 -- PLAINTIFF'S EXHIBIT DOW-1558 ST 001(5302 The Locus of Pathogenicity of Asbestos Dust A Theory Paul Gross, MD. Russell A Harley. Jr , MD. Charleston. SC Documented experimental evidence, as well as ttie results of preliminary experi ments. are presented which indicate a re duction in pathogenicity as the polyfilamentous arrangement of asbestos dust particles is replaced by a monohlamentous structure. On the basis of this evidence, it is proposed that the locus of pathogenicity of asbestos dust particles resides in their polyfilamentous structure. A theory based on chemical struc ture became unsatisfactory when synthetic chrysotile, which has the same chemical composition as the natural product, produced no fibrogenic response in the lungs.1 This nonfibrogenic response in the lungs of rats to synthetic chrysotile also de stroyed the validity of the theory that the crystalline character of the asbes tos fibers determined their pathoge sbestos minerals are silicates, nicity. It is to be noted that synthetic A but the pathogenicity of their chrysotile has the same crystalline dusts is unmatched by that of anystructure as the natural product since other silicate, and the fibrogenicttv is it yields the same roentgenographic equalled only by that of crystalline and electron diffraction pattern: and. silica. There has been much specula like natural chrysotile. it also exhib tion regarding the reason for this its a tubular crystalline structure high degree of pathogenicity of the under the electron microscope.1 dust of the asbestos minerals, but The presence of trace metals on the today no satisfactory hypothesis re asbestos particles has also been con mains. sidered a possible cause for their Similar to the theories proposed for pathogenicity.* However, in a recent the pathogenic potential of silica investigation, when neither the re dust, the first theory was a mechani moval nor the addition of trace met cal one based on the notion that in als altered the pathogenicity of as haled asbestos particles tend to pro bestos dust, this theory had to be duce microtraumata by piercing and abandoned 'P. Gross, MD and R.A. impaling delicate lung cells. This Harley, Jr.. MD, unpublished data'. concept proved untenable when the The discovery that, when asbestos dust of fibrous glass' and ceramic is ground to a fiber size less than 5fi aluminum silicate fibers2 were show n long its fibrogenicitv for the lungs to be nonfibrogenic in the lungs. disappears,'1 astounded the scientific community. This finding, subse Submitted for publication March 30. 1973. accepted April 16 From the Department of Pathology. Medical University of South Carolina. Charleston. SC. Reprint requests to 28 Maui Circle. Naples. FL 33940 i Dr Gtomi, quently confirmed.*-7 proved to be an enigma that ultimately resulted in a new concept of the locus of pathoge nicity of asbestos dust. Although the new concept rests 240 Arch Environ Health/Vol 27, Oct 1973 :-c LJC - Locus of Pathoaenicitv/f>r>cc 4 Harley 398354 pauonal physicians and industrial hygienists in plants with relatively few employees. In any well-operated industry, there is a limit of overhead expenditure, but the necessary ser vices of occupational physicians and hygienists can be obtained within reasonable limits, approximately proportional, within industries of comparable types, to the size of the population to be served. Medical-hygienic organizations in the communi ty can be designed to serve all of its industries. In the past, their greatest obstacle has been their failure to sup ply the needed services. The physician practicing occupa tional medicine alone, simply as a physician, is not capable of providing more than general advice and incom plete help in matters of environmen tal appraisal and control, yet these art absolutely essential for .he safety of the employees engaged in certain types of industrial activity. Such a physician should be linked in his oc cupational practice wnth a qualified industrial hygienist, who must have a good laboratory at his disposal, just as the physician requires access to a trustworthy and well-equipped clini cal diagnostic laboratory. The owner or manager of a small industry is loath to employ a private medical-hygienic organization which is tor may bei also employed by his competitor. 'Here, again, the physi cian engaged in the field of occupa tional medicine is not trusted to act as a physician should act. The physi cian in industry is often believed to differ from the one who serves the individual or family, who may be trusted with the most intimate infor mation. If he is not a hireling, he will have to prove that he is not.) Another factor which has hindered the organization of such private medical-hygienic units as are suggested above, is that they would have to be initiated, under present conditions, by physicians whose careers in occu pational medicine have yet to be es tablished. and who must make con siderable capital expenditures with out any assurance of the success of their professional efforts. I know, personally, of several instances of this type in which the economic risk was too great to be assumed. < It seems likely, however, that the stem neces sity of meeting certain governmental requirements on the part of small industries will alter this situation. A factor in this professional dilemma has been that in most states there has been no necessity for industry, either large or small, to meet standards of quality in matters of the health of its employees, and there has been almost no public demand for these standards which, in line with general experi ence and custom, were believed to be unattainable. This situation may. hopefully, be altered in the near fu ture and create such a demand for medical services, in coordination with those of industrial hygiene, as to be irresistible. It would seem that some such demand must be made emphati cally and effectively, if any reason able sort of success is to be achieved in combatting the hazards of Ameri can industrial production. No attempt has been made in this article to provide details of the or ganization of the industrial medical department, or of such a medical and hygienic facility as that envisaged for the small plant. Nor has any refer ence been made to the role occupied by the industrial nurse in either of these situations. These aspects of industrial health units within indus try. or in the private practice of occu pational medicine, are not considered to be of minor concern. Rather, thev are recognized as essential features of the organization which must be dealt with by the individually responsible physician to suit the attendant cir cumstances. The position and func tions of the nurse in industry, for example, while variable, are as well established as are those of the nurse in the doctor s office. They need not be discussed here. On the other hand, the relationship of the physician in industry to the industrial hygienist is a matter which requires repetitious statement. The complementary rela tionship between the physician in industrial practice, and the technolo gist in industrial hygiene, is an expression of the fact that neither individual in the combination can accomplish his task without the help of the other. It is hardly to be sup posed that one man can achieve com petence as a physician, and at the same time, possess the corresponding knowledge and skill to handle the technological problems concerning control of materials and types of ener gy. To protect the health of the people who work in certain industries, the utmost of competence is required of both the physician, and the industrial hygiene technologist. The require ments of the physician s practice, as well as the industrial hygienists, may not be. or may not seem to be. as exacting in some industries as in others. It is nonetheless true that the professional man in occupational medicine or m industrial hygiene will have little difficulty finding problems of human health, on the one hand, and problems of environmental haz ard. on the other, worthy of his great est competence. Eoes'ioois Arch Environ Health'Vol 27, Oct 1973 American Physician/Kehoe 239 398355 lOES'iOOiS uoon an embarrassineiy obvious structural characteristic of asbestos, it is supported by uncontested docu mented experimental findings as well as bv data from some promising pre liminary experiments. The latter, however, require confirmation. Theory and Supportive Data The new ineory :s simply this, the ,ocus of patnoeenicitv of asbestos dust resides in the oolvfiiamentous struc ture of its fibrous particles. Various data support this theory Man-made mineral fibers, m con trast to polyfilamentous asbestos fibers, are monofilamentous. The dust of those monofilamentous fibers fibrous class.1 ceramic aluminum sil icate,- and silicon carbide whiskers') :h3t have been studied have proved to be nonnbroeenic when inhaled or in jected intratracheally Syntnetic cnrysotiie is nonfibrocenic w nen it is injected intratra cheally It is monofilamentous. It dif fers from natural cnrysotiie in that its tubular crystals are discrete and not in ciose parallel apposition to each other, as is the case with the natural product. When a grinding force is applied to asbestos fibers, they tend to split lon gitudinally rather than to fracture transversely. Consequently, asbestos that has been ground to a fiber length of less than 5>u will consist largely of fibers that are monofilamentous. Those Dunaies of fibers still remain ing will be greatly reduced in thick ness and will approach the monofila mentous state. It is the fact that most of the fibers m such finely ground asbestos are either monofilamentous or nearly so. that offers a logical ex planation of its nonfibrogemcity. When asbestos is heated to 1.000 C, its pathogenicity is either lost or se verely reduced P. Gross. MD and R.A Harley, Jr.. MD. unpublished daiac At this temperature, the.fibnls composing the bundles tend to be come fused into unitary structures, le, the fibers tend to become monofila mentous Fig 1). Although chemical changes do occur as a result of the heat, such changes have no bearing on the resulting loss of pathogenicity since it has been shown <with syn- Fig 1.-Asbestos, neatefl tor two nours in an electnc muftle furnace at 900 to 1.000 C. (Left). Chrysotile heated to 900 C. Al though fibrous structure is retained, fibms are obliterated by rounded homogeneities of different density, separated from one another by less dense clefts. (Tod rignt). Crocidonte. heated to 1.000 C. Cloud-like densities and rare factions obliterate fibril lar structure of fibers. (Bottom rignt). Amosite, heated to 950 C. Obvious fusion of constituents in fiber bundles has formed globs of electron-dense material, thereby leaving other portions of fibers relatively electron-transparent (original magnification *41.000). thetic chrvsotile) that the chemical composition of asbestos is not respon sible for its pathogenicity. By cementing the fibrils of asbestos fiber bundles together chemically, it is possible to convert the polyfilamen tous structures into monofilamentous ones. This has been successfully ac complished with various silicates such as those of lead, iron, and mag nesium. The use of other water-insol uble cementing substances, such as those of magnesium and calcium py rophosphate, calcium hypophospnate, and calcium metapnosphate. is con templated. The method has been to suspend finely ground asbestos in a dilute so lution il% to 5%) of an appropriate soluble metal salt (lead nitrate, iron chloride or magnesium chloride). Af ter washing the asbestos free of all excess salt, it is suspended in a 1% solution of sodium silicate. The latter Fig 2.-Chrysotile fibers cemented with lead silicate. Presence of lead silicate indicated by electron-dense stippling within lumen ot the fibms and elsewhere (original magnification X 143.000). Arcn Environ Health. Vol 27, Oct 1973 Locus of Patbogemcity/Gross & Harlev 241 398356 ST004 5 305 r'g 3 - Rat miected mtratracneallv with 10 Tig iron smcate-cementea cnrysotne. touna dead Six monrns later Higniy cellular inflammatory locus surrounds terminal Dronchiole. An occasional giant cell is present, although in adioming region many giant cells were 00served There is early fiorosis (hematoxylineosin. original magnification > 500) reacts with the adsorbed metal salt to precipitate the insoluble silicate. From electron photomicrographs (Fig 2) . it appears that solutes are capable of penetrating not only between the fibrils but also within the tubular lumen of chrysotile crystals. In a preliminary study, the lead sil icate- and feme silicate-cemented asbestos were injected mtratracheal!y into a few rats Their lungs were examined three months after the in tratracheal injection. The predomi nant pulmonary lesion produced by the lead-cemented asbestos was mini mal m character, consisting of promi nent giant cells, few histiocytes, little reticuhn, and no collagen fibers 'Fig 3) . In contrast, the lesions of the same age produced by the unaltered asbes tos consisted of collagen as well as reticulin fibers and histiocytes. Foci consisting of the minimal reaction, as were noted secondary to the "cement ed" asbestos, were not found in lungs injected with the unaltered asbestos (Fig 4). In an in vitro study it was found Fig 4.-Rat died 63 - montns after having been injected intratracneally with 7 mg unaitered chrysotile. Area of collagenous fibrosis is adiacent to respiratory Dronchiole also involved m fibrosis. This fibrosis differs from that in fig 3 as it is more collagenous and less cellular. >e. much more advanced. Granular material m col lagen is brown pigment (hematoxynn-eosin, original magnification x 260). that lead silicate-cemented crocidolite caused only 30% hemolysis of human red blood cells whereas, under identical conditions, the unaltered crocidolite caused 100% hemolysis. Iron silicate was less effective in reducing the pathogenic potential of chrysotile than was lead silicate. The reason for this was a gradual disap pearance of the iron from the asbestos stored in the lungs. However, as ob served in a tall glass cylinder, the iron silicate-cemented chrysotile stains a deep blue color with acidic potassium femeyanide and retains this blue color. It settles rapidly, leav ing a colorless supernatant which remains colorless over many months. Because of obvious inadequacies in these experiments with cemented asbestos, the results can be termed only suggestive. But in conjunction with the other findings, they tend to support the thesis that when polyfilamentous asbestos dust particles are converted toward a mononlameruous state, a reduction in their pathogenic ity takes place. An extensive inhalation study with cemented and unchanged asbestos will soon be initiated, as well as an investigation of the comparative fibrogenic and cancerogenic potential of the poiyfilamentous. versus the cemented asbestos dust injected intrapieuraily. Thus, the documented evidence points to a sharp difference in patho genicity between pol vfilamentous dusts on the one hand and monofilamentous dusts on the other, and to a significant reduction in the pathoge nicity of asbestos dust when its pani cles are rendered monofilamencous either bv grinding or by thermal fu sion of fibrils. Preliminary uncon firmed experiments suggest that a similar reduction in the pathogenici ty of asbestos dust may be accom plished by chemical fusion of fibrils, le. the deposition of insoluble cement ing materials between the fibnis of the fiber bundles. This investigation was supported bv American Cancer Societv Institutional research gram 1N101. References 1 Gross P. et al. The pulmonary reaction to high concentrations of fibrous glass oust Arch Environ Health 20 696-704, 1970 2. Gross P. et al. The effects of a synthetic ce ramic fiber dust upon the lungs of rats AMA Arch Ind Health 13 161-166, 1956 3 Gross P. et ai Problems in the pathology of asbestos is m Shapiro HA *ed> Pneumoconiosis. Proceeaings of the Internatuonal Conference. Johcnnesourg, 1969 Cape Town. Oxford Uni versity Press, 1970, pp 126-132. 4 Gross P, et at Experimental asbestos is The development of lung cancer m rats with Duimonarv deposits of chrysotile asbestos oust Arch Environ Health 15 343*355, 1967 5 Webster I The pathogenesis of asoestosis. in Shapiro HA ied>. Pneumoconiosis. Procrea inga of the International Conference. Johannes burg. 1969 Cape Town. Oxford Lniversi;\ Press, 1970. pp 117-119 6 Hilscher W. et at Zusammenhange zwiscnen Asbestose and Fasertange Saturwissenschaften 57 356-357. 1970 7 Gross P. et at. Asbestos Identification of fibrous particles m lungs J Occup Med 14 757759, 1972. 8 Gross P. et al. The pulmonary response to fibrous dusts of diverse compositions Am Ind Hyg Assoc J 31 125-132. 1970. 242 Aren Environ Health/Vol 27, Oct 1973 Locus of Pathogenicity/Gross & Harley 398357