Document 3Q7YjOo6rZyoY7o3QzxBXjQ0D

%ii ini she a report found, in Dr. Gardner's desk after his Ocftfoloopetr* 24., 1946. ASosiS'fOs Is Etiology, Patnogenesis and Pathology death, PLAINTIFF'S Is EXHIBIT (Woitf-.oo Asbestosis is a form of pneumoconiosis resulting from prolonged inhalation of asbestos dust. Asbestos, literally "unbumable," is not the naniA of a particular mineral, but is a term applied to a numoer of different minerals, all of them composed of long, parallel flexible fibers. Their structure is unusual because the films are capable of repeated longitudinal suodivision to units of molecular proportions. C Their length varies from a few microns to six or more inches, bone varieties are stirfer tnan others, but many are sufficiently flexible to be spun into yarn and woven on modified textile machinery. Chemi cally, the asbestiform minerals vary, in composition, but all but one of tnem are silicates, l.e., compounds of several different hypothetical silicic acids with varying proportions of magnesium, iron, aluminum and- other bases. Some indication of their .diverse structure is illustrated in the following table, but even this does not tell the whole story for particular specimens from different localities may not exactly conform G to the appended formula. Canadian Chrysotile H4 Mgj SiOy tabbies* PLAINTIFF'S EXHIBIT lAN-OOOZW South African Crocidolite (Blue Asbestos) Ua. Fe---*- (siO3)., - -e #>1i0S3, Anthophylli t e ( Jig. ) SiO^ Amosite (iig. Fe Al) si05 + ?e -- amphlDole (Ha. . Al) di401]L 'drucite ilg. (OH) Pure cnrysotile asbestos is a hydrated silicate of magnesium, Ug.3 (siO^)^. (ngO)^. however,' these elements are .not invariaoly crystallized in tne form of long flexible fibers; under certain 0  October 24, 1S46. ASBESTOSIS Par Etiology, Pathogenesis and Pathology conditions they are combined in massive form to produce the mineral known as serpentine, which is composed of microscopic fibers without the parallsl orientation characteristic of chrysotlle. The massive blue black serpentine, which feels smooth and soapy, is traversed by veins of fibrous chrysotlle varying in width from barely perceptible lines to six or more inches* The fibers run across and not lengthwise in the vein. ^Thus~while Identical in chemn al composition, chrysotlle and serpentine are very different in physical Appearance. Attention is directed to the mineral bruclte, which is often found in the same formations with serpentine and chrysotlle. Bruclte is also fibrous and crystals three or more feet in length are not uncommon. It has no commercial value at the present time for its fibers are hot sufficiently flexible to be used in textiles, out they are capable of repeated longitudinal subdivision. It is unique among asbestlform minerals in containing little or no silica, and for this reason it has been a valuable tool in an experimental evaluation of the action of such minerals upon lung tissue. Industrial Asbestlform Dusts. Expoaire of human subjects occurs in the mines, quarries and mills where the raw materials are procured and processed, in the textile plants where fibrous asbestos is spun and woven into yarn, cloth, brake linings, electrical insulation, etc., and in the use of finely ground asbestos as electrical or thermal in sulation. At tho mines and mills in Quebec there is little exposure to dust of the longer fiber, as the wide vein material is hand cobbed with hammers and packed in bags for shipment. The thin veins and the se> pentine rock is repeatedly crushed to a finer and finer state of Page Z Etiology, Pathogenesis and Pathology subdivision under a system of exhausts designed to remove and save all fibrous elements regardless of their size. Such milling processes are attended by a very considerable degree of dust polution of the atmospher but much of this dust is composed of either very short fibers or nonfibrous particulate maoter. The textile mills, handle long fiber and, before the days of control programs, were dusty places. In crushing the asbestos to open the bund les of vein material, large flocks and some finer fibers were suspended in the air ^for varying periods. The process of mecnanical mixing of the opened fibers with cotton was even mor9 dusty. In the spinning and weaving, the dust concentrations were not as high, but the proportion of fiber of inhalable length was large. Even under the controlled conditions today It Is difficult to apply exhaust systems that will exclude all fioer from the air and, at the same time, not interfere with the manufacturing processes. Reports of dust counts would suggest that the total concentrations in many asbestos fabricating plants were never excessive. Whereas cotints in excess of 100 million particles per cubic foot of air were common in unprotected plants handling non-fibrous minerals, in the asbestos industry counts above 25 million were exceptional. With exhaust systems, counts over 10 million are not common. In view of the fact that asbestosis Is 3till being produced, it would appear thao injury ensues from exposure to lower concentrations of fibrous asbestos than to particulate quartz. On the other hand, it is possible that standard methods of dust collection are not. adequate for sampling air-borne material of fibrous nature. The latter possibility is the subject of current investigation. iC 4 Unfinished report found in Ur. Gardner's desk after hl3 death. October 24, 1946. Page 4. Etiology, Pathogenesis and Pathology Inhalaollity. Experience has demonstrated that most of the particulate matter inhaled into the lungs of man and animals is 10p. or less in diameter. Larger particles are apparently excluded by the protective mechanisms of the upper respiratory tract. In the case of fibrous materials, however, this rule does not apply and fibers 100 and even 200p. in length have been found in the terminal air spaces of human, lungs. In small laboratory animals exposed to asbestos du3t the maximum length rarely exceeds 50 to 60ii. Not every kind of fibrous material la Inhaled with equal readiness; for example, the synthetic fibers of ss wool are apparently too inflexible to pass through the nose, pharynx, trachea and bronchi-v After daily eight hour exposures over a three year period no fibers were detected in the lungs of guinea pigs, rabbits, rats or mice. Localization in the Lunns. Inhaled particulate matter comes to rest tnroughout the terminal air spaces in. all parts of the lungs; inhaled fibers are first retained in . the respiratory bronchioles. These very small tubes are immediately distal to oronchJriLes lined fcy ciliated epithelium. Their own essential lining is a low cuboidal type of epithelium but, as their name implies, they actually function in respiration through lateral alveoli given off as pouches along their walls. Either these pouches, or the abrupt change in the character of the lining epithelium, or the decrease in diameter of three the tube, or perhaps the combination of all/factors is responsible for local retention of the inhaled fibre. _ Only after asbestcsL s is well established are many fibers carried into the more peripheral air spaces. C Unfinished report i'ouna in^yr. uaraaer-s uesit ai^r i--v-ee.*.., , Octooer 24, 1946. Page 5 ASdhbTOSIs Etiology, Pathogenesis and Pathology Tissue Irritation. Inhalation experiments nave demonstratea that the fibrosis of asbestosis begins in the walls of the respiratory bronchioles and spreads from there into the more distal parenchyma of the lungs. The nature of the irritation which produces this fibrosis has been the subject of much speculation and extensive study. This matter is of interest -both from a theoretical stand point and a practical one, as prevention or disease is dependent upon knowledge of its causes. Two hypotheses have been proposed to explain the nature of tissue irritation and resultant reaction. One, based upon experlence witn quartz and other forms of free silica is chemical irritation. Its proponents assume.that the asbestos minerals dissolve in the boay * fluids and that in this process their bases leach away to leave silica in a form capable of irritating tissues. This hypothesis would make asbestosis merely an indirect silicosis. Ine other view to which I now subscribe is mechanical irritation due to tae peculiar physical structure of the Inhaled foreign body. Chemical Theory. If the irritation were chemical, the irritant should become increasingly potent as its particle size decreases. Vi/ith quartz, for example, it has been demonstrated that the smaller A the particles, the more rapid the tissue reaction. In sufficient xi (^quantities, particles of free silica under O.lp. in diameter are < j ^highly toxic and will.kill animals in a few minutes or hours. In the case of asbestos, however, the reverse is true; only long fioera have any specific effect, some years ago we started an inhalation Unfinished resort found in Dr. Gardner's desk after his ueatii, October k4, 1943. Pa~e 6. AoB.faai'Oolo etiology, Patnogenesis and Pathology experiment with call milled asoestos dust in wnich practically all cr the fibers were less than 3(i in lengtn. This was done to produce rapid reaction*as we had witn quartz* so that advanced asbestosis might develop wituin the lifetime of small animals like tne guinea pig. To our surpd.se, exposures to hign concentrations of such dust for 43 hours a week over a three year period produced no~changes visible on gross }s3 i1nspection of the lungs. The reaction was much less severe than we SW ^K'had previously observed in animals similarly exposed to lower concen?a\ tfV trations of unground asbestos (1) containing longer fibers. w If asbestosis is in reality only a silicosis due to the silica component of the magnesium silicate, it would oe reasonable to expect that, like quartz, asbestos would produce its effects in any organ cf any species of animal. For example, injection of fine quartz into extr pulmonary tissues of guinea pigs, rabbits, rats, cats, dogs, chickens, and even tadpoles will produce silicotic nodules. But similar in jections of long or short fiber asoestos nave no such effect. It is possible that cnemical factors may be involved here, for asbestosis bed! do not form in extrapulmonary tissues; in fact, they are not produced even in tne lungs of all species of animals, however, as will be shown later, the formation of tnese bodies does not necessarily parallel tne development of fibrous tissue reactions. If the irritation were cnemical due to liberation of silica in active form, it snould oe possible to neutralize such silica with alumina, as has been done with quartz, but experiment has demonstrated that this does not occur. Injection of particles of 1 to 3ft- Unfinished report found in Dr. Gardner's desk after nis death, October 24, 1946. Page 7 Ab .OS Etiology, Pathogenesis and Pathology quartz suspended in 0.25 per cent amorphous aluminum hydroxide results in simple phagocytosis with nothing even suggestive of the progressive fibrosis of silicosis. Intratracheal injection of similar suspensions of 50 to 60(i cnrysotile fibers in guinea pigs in no way retards the development of fibrous tissue. If anything, the rate of reaction is greater than that to fibers sus pended in physiological saline solutions. Finally, If chemical mechanisms were involved, serpentine, which has the same chemical composition as fibrous chrysotile, should produce the same kind of tissue reaction. But it does not; on in jection into the lungs and other organs of susceptible animals serpentine is an inert material causing only phagocytosis and mild chronic inflammatory changes aoout foci of excessive local concen trations of the particles. The general theory that any silicate can produce silicosis after it3 bases have leached away in body fluids finds no support in experi mental observation. Animal assay of some fifty silicates of different mineralogical groups has failed to .disclose any tnat acts like quarts. A few are toxic and produce acute inflammatory reactions; none causes progressive fibrosis. Only those tnat have unusual physical structure like the fibrous asbestiform minerals, fiorous tremolite, fibrous pyrophyllite and the plate-^like micas provoke tissue fibrosis. Unlike quartz, these minerals exert their specific effects only In the lungs; in other organs, no fibrosis develops within two years after Injection. V> \u- Unfinished report round in Dr. Gardner's cask after nis death. October 24, 1245 Ad ohbTOS lb Etiology, Pathogenesis and Pathology Mechanical Theory. In addition to the negative e viaence tnat prolonged exposure to high atmospheric concentrations of finely ground cnrysotile asbestos will not cause appreciable reaction in animals.' lungs, we nave assayed the Influence of pure asoestlform mineral fibers or various lengths. By intratracheal injection, it has been found that mum tissue reaction is produced in guinea pigs by fibers 20 to 6Q\i> in length; those less tnan 3p. long cause no fibrosis but merely chronic inflammatory changes comparable to the effects of serpentine and most other silicates. Fibers of intermediate size, between 10 and 20|x,are less irritating and scar tissue develops more slowly Tha chemical composition of the florous mineral has little influence; non-siliceous brucite has just as much effect as the silicates like cnrysotile, crocidolite and amosite. One month after a series of three Intratracheal Injections totaling 150 milligrams, all of these minerals in the larger sizes produce a fibrous reaction in the walls and within the lumen of tne terminal bronchioles. Furthermore, such tissue changes antedate by about 6 weeks the development of the so-called "asbestosis" bodies. In the extr.apulmonary tissues of guinea pigs and other animals, the injection of long and short asbestiform fibers causes no fibrosis and practically no asbestosis bodies. However, we nave verified she observation of ------- 8------------(2) that the addition of whole blood facilitates the development of asbestosis bodies, but even when they do form the tissue response Is no greater`than tnat to injected blood alone. Unfinished report round in Dr. Gardner's aesk after his death, Octooer 24, 1946. Page 9 ASObsTOsIa htiology, Patnogenesis and Patnology Asoestosis Bodies. Cook (3) identified these peculiar structures as modified asbestos fibers and established their relationship to the disease, asoeatosis. Later, Gloyne (4) and others described them more minutely and speculated on tne mechanism of tneir development, as- oestosis bodies never occur in nature; they gradually develop after contact with the tissue fluids of the lungs. In guinea pigs this requires a period of 60 to 70 days. In some species like the dog, they do not form at all; in others like the raboit, they develop slowly and in small numbers. In human beings with asoestosis, their number is variable but no correlation with t he severity of the exposure has been possible. The bodies consist of a bright yellow coating upon tne surface of the fibers. Apparently it is first of uniform thickness except at the ends when smooth rounded bulbous swellings occur. Later the coating seems to crack into oeadlike segments, which in turn enlarge laterally, become bulbous and produce very bizarre forms. The yellow coating has the same color as the blood pigment, hemosiderin, and gives the usual microchemicalreactions for Iron. It was proved oy bundina (5) to oe a mixture of Iron and protein. The source of the Iron was for a long time tne subject of consider able speculation and many believed that it was derived from tne mineral However, the development of typical yellow coatings about fibers of iro: free chrysotile and brucite indicates quite clearly that tne host fluid and not the mineral Is the source. This belief found further support when It was shown that the injection of whole blood with fiber would produce asoestosis bodies in tissues other than the lungs. It is ' 'Unfinished report found in Dr. Gardner's desk after his death, October 24, 1345. A33EST0SIO Etiology, Pathogenesis and Pathology Pare 2 Inferred that mecnanical Injury more readily damages the delicate capillaries in the immediate vicinity of individual fibers in the lungs than in other tissues. Furthermore, observation demonstrates the preset of variable numbers of red blood cells within the pulmonary air spaces in early experimental disease. Probably the fibers then adsorb the iror pigments and perhaps albuminous materials from the same source. However such an effect does not occur in the test tube and in tissues otner than the lungs; injection of mixtures of blood and various as best iform miner produces asoestosis bodies only juuu. upon a few of the smallest fibers, usually at the periphery of the mass. The frayed ends of any unopened bundles of asbestos never show any iron coating. The formation of asbestosis bodies appears to minimize further irritation of toe tissue. Attempts to prove this point are not en tirely satisfactory, but most of the evidence points in this direction. Intratracheal injection has demonstrated that fibrosis of the lungs develops before the bodies have formed. Similar Injections of prefomec asbestosis bodies recovered from a human lung have produced no fibrosis in the lungs of guinea pigs. The latter experiment was not entirely satisfactory as the quantity of bodies that could b e recovered was snail and the method of recovering them from the human tissue, antifornin digestion followed by repeated washing and centrifugation, fractured many of them and may have altered their composition* However, when the lung of the injected guinea pig was examined three months after the bodies were introduced, large numbers of variable length were found In the air spaces and no trace of fibrosis had developed. There was soc question whether all of the coating macerial was that derived from the V original human host or.^whether more had been added to broken bodies October 24, 945 Aao^xOala Etiology, Pathogenesis and Pathology . Pare l; trie guinea pig's lung. The do dies were widely scattered instead or being caught in the terminal oroncniolea as occurs after injecting tne fibers themselves, and reaction was limited to phagocytosis. The altered oistrioution suggested tnat tne smootn oulbous ends of the bodies permitted them to glide over tne irregular surfaces of tne bronchioles and be carried on into the alveoli. The same change would minimize mechanical trauma to tne delicate memoranes of the lungs, .'ihetner enough coated fibers of sufficient length to provoke fibrosis were actually introduced is pernaps deDatable, out at least the negative results of this test are in conformity with other evidence. If, as indicated above, the coating of tne fiber resulting in the formation of the asbestosls body neutralizes its irritating properties, progressive fibrosis would not be anticipated.. Experimental ooservatio: confirms this supposition. Groups of guinea, pigs exposed daily to high concentrations of long fiber chrysotile asbestos dust for periods or six months and eighteen months (checkthls) respectively and then allowe to live in normal atmospheres aq long as two years have shown no pro gression of their reaction. The areas of fibrosis did not increase in size as is the case with silicosis produced by quartz..- They tended to become smaller with contraction of the scar tissue and some of the fibrosis resolved and disappeared. 'The same was true of the reaction following three intratracheal injections of various kinds of asbestifor: minerals. Thft permanence of the coating in the asbestos body is a matter cf Interest and pertinent to this discussion.' The evidence is somewhat difficult to evaluate. In old experimental lesions of animals exposed to dust and then removed to normal atmospheres for many months the number of bodies seem to oe fewer than in those sacrificed at tne end ; 4wV v*-w-----m. m -- - -------- -- m " .Jccooer 24, 1^46. ^--__________________________________________________ as BE a T Os La htiology, Pathogenesis and Pathology Page ; . of tne exposure period, The bodies are apparently too large tO' be transported out of the lungs oy the lymph stream for tney are almost never found in the traceobronchial lymph nodes. They might conceivably lose their coating in extrapulmonary tissues, out naked fibers of any length are not detected in the nodes. One nas to infer that tney grad ually dissolve in the lungs and the same must be true of the included fiber, for they likewise are no longer detectable, some doubt is tnrowr on thia deduction by the evidence in one human case reported by Mills (c who has kindly furnished the writer with representative tissue. This . v. and patient died of heart disease, some thirty years after engaging in pros -ie ck etro- pecting for asbestos for an unspecified period. The details of his raohic- 11 v exposure are unknown.. Sections of his lung present small foci of fibrosis, many fragments of asbestosis bodies and large numbers of very thin uncoated fibers. Petrographic analysis of this xaaterial Indicates that ~Unfinisaed report l'ouna in -r. v-ersner' s desk after his death, October 24, 1946. AS3ZSIJSI5 Etiology, Pathogenesis and Pathology Page 12. The histological picture is complicated by the effects of prolonged cardiac decompensation. Since most asbestiform minerals tend to become coated with iron and albumen, one has to assume that these thin fibers have lost their original deposits but did not themselves dissolve over a period of 30 years. Study of more such cases is obviously es sential. At least it may be affirmed that the amount of fibrosis in this lung was not proportional to the quantity of fiber seen in the tissue. Obviously, reaction had not progressed very far and something had stopped continued irritation. Thus, while the evidence is in. places Imperfect, it would appear that the formation of asbestosls bodies is not essential to the develop ment of scar tissue in the lungs and that such reaction probably prevents mechanical trauma. Fibrosis precedes asbestosls body'formation; it does not progress after the bodies have developed. Injection into susceptible animals of bodies preformed in a lung has not produced fibrosis al though the conditions of this experiment were not beyond criticism. Industrial Exposures. Cannot be discussed in detail in this paper. However, there sure a few points that will oe considered for their bearing on the pathogenesis of disease. It would appear that asbestosls is due solely to the fibrous components of the dust in industrial plants and that any particulate matter or finely broken fiber plays little part causing pulmonary reaction. The total dust counts reported from asbestc. plants in various parts of the country a re usually quite low, even where the amount of visible dust in the air seems to b e excessive. 7/hen one attempts to determine how much of the dust from the air is fibrous in nature, the proportions are extremely small. These results would lead UHiiHiSUttU I'SDU* l .w/wiU --X Ui. . wo.A L..B1- 3 UttSA U- wei* iii3~ Utsabxiy October 24, 1346. AoSESTOsIb Page 14 Etiology, Pathogenesis and Pathology one to suspect that either the quantity oi' inha.led floor necessary to ca. use disease Is very small \ or. that our methods of dust colle ctlon are faulty. Studies now in progress suggest that tne electrostic precipitator nay be a more suitable Instrument for collecting samples of air-borne fibrous dusts than the standard impinger that is usea so widely for particulate matter. A most surprising variation in Incidence of asbestosls occurs between the fabricating plants of this country and the mines and mills where chrysotile asbestos is produced in Quebec. In the latter, the atmospheres are generally very dusty and yet not enough asbestosis develops to be* diagnosed upon x-ray examination* men who have worked over thirty years in the plants present films characterized by non specific linear exaggeration with none of the diffuse changes accepted as pathognomonic of asbestosis in other parts of the world. In four autopsy specimens that I have obtained from Quebec mill employees with a lifetime of exposure, there were microscopic lesions of asbestosis but be the disease had not progressed sufficiently to/k ecognizable on gross examination. It is temporarily assumed that much of the dust in the air of these plants is made up of particulate matter for all the machinery 1: designed tocollect and save the fiber, but reject the particles, btucie: are now in progress to compare the relative numoers of fibers and partic." in air-borne dust from these Canadian plants with those of fabricating m: in this country. This study should be of great assistance in d eterainin; whether the observations upon animals will be verified in man. Unfinished report four.d in Dr. Gariner's desk after ms oeazn Octooer 24, 1946. ASBESTOSlb Etiology, Pathogenesis and Pathology Page Pathology. The reaction to asbestos minerals like all others varies with the condition of the lung into which it is Inhaled. Ir the organ is free from infection, either recent or healed, the effects of the dust will be different from that wnere other Influences complicate the picture. In an otherwise normal lung the Inhaled fibers come to rest in terminal bronchioles widely and quite uniformly scattered throughout all parts of the organ. Caught in the walls, these stiff sharp fibers scratch the surfaces of the small tubes as they change shape and length with inhalation and exhalation. Fibrosis results from this irritation, t,:e walls of the bronchioles become less elastic and smooth in contour as tha lateral alveoli are obliterated. As more fibers are inhaled, they are carried out further along the bronchioles with the same effect. Finally, they come to be deposited in terminal alveoli and these in turn are obliterated. The gross picutre of the asbestotic lung almost invariably presen adhesive fibrous pleurisy.- The septa between the lobules are usually thick and fibrous and on section there may be gross areas of dense fi brous reolacement especially common beneath the pleura. In such scar .tissue emphysematous blebs are common and they vary in size from small smooth walled cavities a few millimeters in diameter to large bullae. Elsewhere the parenchma of the lung may appear normal except for grey foci of pigmentation usually located in the centers of the looules. Most of the lung still seems to contain air and crepitation is felt on compression, although an impression of doughy-ness is obtained, and The bronchial/tracheobronchial nodes are pigmented, but normal in size and consistence. - October 24, 1946 Page 15 The microscope in the advanced case reveals a diffuse fibrosis with no particular pattern of distribution that obliterates most, but not all, of the air spaces in a given area of parenchyma. Included in it are islets of apparently normal alveoli and others that are widely dilated and lined by low cuboldal epithelium. _Asbestosis bodies, both free and wholly or partially Ingested by giant cells, are scattered everywhere, but are mcs* numerous in the lumina of still patent air spaces. They are very rare or absent in the thickened pleura and interlobular septa. Only in the early case or as a result of a fortunate choice of sections can one find evidences of the initial fIbrous sleeves about respiratory bronchial nodes.-'The. lymph nodes are filled with phagocytes containing particulate matter, but asbestosls bodies are almost never found and then they are very short- fragments. 'The other organs show no changes.Apparently, as in guinea pigs, the asbestosis body only develops readily within the lungs and they are so large that phagocytes do not transport than! to the regional lymph nodes* Whether the coating never develops about fibers that penetrate the pleura and septa, or whether the coatlhg subsequently dissolves in these locations, is not clear. One suspects, however, that conditions are not right for their formation outside the lungs. The X-ray Pattern of uncomplicated early asbestosis is surprisingly insignificant* Th* lower third of e ach lung field has a. diffuse haziness which tends to obliterate the normal linear pattern*. As the disease pro gresses, the haze increases -in intensity and assumes the so-called "ground glass" .appearance* It also creeps' upward toward the apices, but usually does not involve the supraclavicular regions. In very advanced cases the outline of the heart is obscured by the development of heavy .Unfinished report lounc. is ur. siaruner's cesx alter nia ceawu, pctober 24, 1946. Page 17. radiating bandlike shadows that are apparently the result of pleuro pericardial adhesions. This is the so-called "porcupine heart." The mediastinal shadows are not unusual. Asbestosis and Pulmonary Infection.