Document DGZOw0LqMyenyZrZyjw7by26N

P ITTS B U K PLATE GLASS COMPANY PLAINTIFF'S EXHIBIT LJ-7S general offices ONE GATEWAY CENTER. PITTSBURGH 22 PA May 25, 1962 Mr. Karl Baumler, Vice President Pittsburgh-Corning Corporation Ijth Floor Dear Mr. Baumler: The enclosed are the articles nentioned when sending you the other material on asbestos. The library came through and I feel that you now have ample reference material about asbestos and its effects. Please advise if there is anything further we can obtain for you. Yours, CCRtpg Enclosure of* -s^dhedtodid ttNNETH M. LYNCH, M.D., Charleston, S. C y* While the asbestos industry may date its beginnings back into antiquity and while the condition now known as asbestosis may have occurred through a long period of time, the industry as we know it is new. and the health hazard related to it is of recent knowledge In fact, the term asbestosis was not entirely acceptable as recently as about 30 years ago. while up to that time any thought of ill effects of occupational exposure to asbestos dust tended to confuse the resulting disease with osis. Parenthetically, perhaps it is pcrm.ssihle to express an opinion that before we have finished with the study of the class of pulmonary disease attending exposure to dust in'industry the whole chapter will need to be revised. It is within the time of experience of some who are still concerned with the study of cer tain unsolved problems in the subject that there has been established this distinct vari ety of pneumoconiosis. During the same period, and probably largely because of dis closure of the hazard, there nave been im provements by the industry to protect work ers, so that, so far as my observations go, the atmospheric conditions in asbestos mills are greatly different from the conditions of 30 or more years ago. Even though improve ments have been made and although knowl edge of the course of the disease has come largely from examination of workers whose President, Medical College of South Carolina. Read in the Symposium on Occupational Disr--e of the Lungs, sponsored by the Massachusetts cal Society in cooperation with the Institute ot Industrial Medicine of the New York 'University --Post-Graduate Medical School, Boston. Oct. 28, 1953. employment went back into the very dusty conditions of earlier times, it should not be assumed that the hazard has -been eliminated. Harmful asbestosis is still occurring. Asbestosis is the product of the inhalation of asbestos dust in sufficient amount and dur ing a sufficient period of time; but under working conditions, either now or formerly, there is no uniformity in degree of disease among workers, even under similar ex posures. Apparently come persons in a group working in the same environment will be severelv affected, while others will l>e less affected, and some will esea)nr harm, and this for reasons unknown Furthermore, the lime required for similar quantitative exposures to produce like grades of nshe.-tosis apparenth varies with individuals. While in our efforts to establish protection of the health of industrial workers we have set tip certain standards concerning atmos pheric dust concentrations, these arc of a general nature rather than specific, and may have given a false sense of security. '1 he verv dusty atmospheres surrounding the workers in this as well as in certain other industries under former conditions would certainly he more harmful than the relatively clean environment to be found in a presentday careful operation, but we may need to establish something more than merely the particle counting and measuring practices now in vogue if wc shall have dependable safety controls. The particulate matter in as!>cstos-plant dust is composed of broken fibers of crystal line silicates. When inhaled, most of it is expelled, but the quantity of fragments of lengths up to 100^ or more that may reach the terminal respiratory units is remarkable. As compared with the material deposited in the lung in silicosis and in certain other con ditions of occupational connection, this ma- 185 ISDl 'STKIAL ItliALl l< ;. 'A- .; .a.*;;v.A\ .n*!;,,Y7 V . T'-TJwj, : '-,v ;-J; \ v v",,. ;v,,s? VSV,- Y v / ^ v v*',`7,'-V-*?'', "-'I<';` ,i." ->.. v>~ t .-> ***> Pig ). --.\'ln''t(i'i> 1 klie> iii >imiiiiii cnnri-nlrau rcilmid Irmn a plHiioiiiicrugrapli. X /Ox terial apparently exerts physical rather than chemical influence. At least it now appears that while tree silica i> in a crude sense chem ically poisonous to living tissues when <le(K)silcfl within them asbestos crystal irngments may traumatize living tissues by their physical (jualities. Hence the present belief that it is the larger particles that <lo the dam age here, as contrasted with the harmful ellects of the smaller particles in silicosis. It is titling to that conception that, possibly bv a protective mechanism, the asbestos frag ment remaining in the lung becomes envel op'd by foreign-lxidy giant cells and covered by a smooth coating. apparently of colloidal bin. 2.--tirade III fibrosis, with ashestosis Ixxlics. phagocytes, and black granular pigment in reduced alveoli; reduced from a photomicrograph. X 280. 186 nature and of tissue fluid or cell origin. Thi process transforms the naked asliestos crystal into a golden or brownish object of a varicH of architectural sltaps, called the asbestosis body. This characteristic IkkIv i> formed in the alveolus of the lung. It may le found in the sputum of a subject with asltestosis. as a confirming diagnostic finding, and in tinfluid extracted from the lung. I'.ecause "t their size, comparatively few- a-liestosi' lxxlies. and only the smaller one', may le trans|x>rted in the lymphatic system to lie rlejxjsited in lymphoid deposits within the lung, while still fewer reach the hilai or medi astinal nodes. The limitation of physical opprtunity for entry of the asbestos fragment into and transportation by the draining lymphatic* seems to explain another characteristic dit fercnce Ik-1 ween silicosis and ashestosi*. The small free particles of silica readily jK-netrate the aveolar walls and lung tissues, aided or unaided by phagocytes, and are mainly de posited ill the lymphoid d<-|*its along the drainage system, thus setting up focal reac tion and characteristic nodular fibrosis, whereas asbestos fragments stay mainly where they land in the alveoli, particularly in the vestibular areas of the lobules, so arousing a more uniformly distributed reac tion and usually nonnodular or diffuse fi brosis. although there is evidence that they may penetrate the tissues also. As alveoli become obliterated and the lung architecture becomes distorted, the asliestosis Ixidics liecome embedded in fibrous patches amt masses, to remain of much the same appnr ance indefinitely, although in the older scar* there appears to be some change in them and they may then absorb the basic-staining dyes. Just what conijioses the first part of the reaction to asbestos fragments deposited in alveoli is subject only to deduction at the present. If we assume the primary effect to be from physical injury firaumatisrn) of alveolar linings and septa, we may assume fluid accumulation. It may constitute the first or acute reaction, and that fits \vith the physi cal evidence of increase of lung fluid that clinicians find in asliestos workers early in I ATHOLOGy or ASHESTOSIS Fig. .V--tirade JV tihrnsi* of Itmg in alc't>M<, wit It n-hc'in-b Ivxlu' ami granular material in alveolus ami fibrous ana. X 2WV .ncir exposure. cvin before there is evidence of fibrosis. it is also consistent with the earlv "ground-glass" changes in mentgenographic lung fields. As tin- condition progrcsse:--ordinarily through years of continued exjKisure--and while alveolar fluiil may coiitiiiiu' to accom pany the giant cell and colloidal envelopment of the fragments of asbestos crystals as long as fresli de|>ositinM continues, permanent change in the form of fibrosis takes over and proceeds. This lihrosis is essentially the same as will occur from any relatively innocuous hut irritating presence of solid foreign ma terial located within living tissues. There is some evidence that it may he halted by re moval from exposure to continued asbestos inhalation, but after its formation it cannot l>e expected to be reduced, and when it has reached a disabling grade jhe disability may he expected to be jx-rmanent. In the advanced stage it causes respiratory embarrassment and finally circulatory difficulties resulting in increased right heart burden. 1 be gross condition of the hmg. as seen in an autopsy service where asbestosis may be encountered, of course, varies with the grade of fibrosis. While that condition tends to lie consistent with the degree and duration of exposure to the dust, the causative e.\|Kisure and the- resulting fibrosis do not al ways agree. Merely the fact that a |ktsoi, has worked in an aslx-stos plant does not justify an assumption that he ha- ac<|uired asbestosis of a clinical grade. In some of our cases the finding of small numbers of asbestosis lxidies in tile alveoli Fig. 4. - - Advanced (Iratlc I\ asliestosis: oblit erating hyaline librosjs. INDUSTRIAL HEALTH wa> merely incidental. The lung in such an iu-taiice exhibits nothing else of that coninvtion. 1`sualiv tlx- occupational story re veals tbat the jHTson worked in an asbestos |ilant |>erhaps even for several years but sitme time previously. Merely for recording pur- we have designated the condition as iradc 1. Grade II is also an incidental finding. It means an estimated thickening of alveolar Malls and perivascular fibrosis, neither being remarkable, together with asbestosis bodies in alveoli and scattered through the fibrous framework. The lung of that grade may be -omewhat coarsened in texture but may not appear grossly abnormal Grade HI is associated with definite respir atory difficulty, but tip to this phase apparcntlv progress of the disease may be halted bv removal from exposure, and the condition remains in status quo. It is not per sc a fatal state. The anatomical grading is based iqion nutopsv examination when death has oc curred for another reason. The lung in this case is of coarsely honeycomb fibrous tex ture. nonclastic and distended. This quality is general, although not entirely uniform. J'articularly in the upj>er parts there are patches of distorting indefinite scarrings, and there is a grayish marbled cast on section. The pleura may be thickened and adhesions may be found, but in some instances it may be quite normal. Grade IV is the advanced phase which will terminate fatally on its own account if some other death-dealing condition does not inter vene. The subject Irecomcs increasingly, and finally absolutely, disabled in respiratory and circulatory functions. The lungs in this final phase are i ;h. coarse, inelastic, fixed in expansion, g; h marbled in appearance, and general'. : ut irregularly, in an extreme state of fil-rotis induration. Various distorting scarrings oc cur. particularly in the upper parts. Although such scarrings are patchy rather than nodu lar. they sometimes resemble, lioth grossly and microscopically, the lumps and nodules of silicosis. The pleura may l>c thick, even cartilaginous in toughness, and the cavity partly or entirely obliterated, but not inevita bly. Inasmuch as pleural fihrosis is not in variable. it appears that its occurrence i- as a complication and not as a part of tb< pri mary disease. 188 i pj, &t)iSabifitly in s^ileilod *\AJorb monary icrS KENNETH W. SMITH, M.D., New York JONH* tE4h 'uTI iS "! ii rWUP. OTJMiF"' fibers can be found in pajier, wallbu.ird, shingles, pipe covering, floor tiles, brake linings and brake blocks, cements, putties, Asbestosis has been descrilicd in detail in and plastics. numerous published articles and texts. While It should be noted that the facts presented it is true that cases of far-advanced asbestosis here apply to those persons who have liccn may have severe pulmonary disability, rela- exjiosed only to' asbestos fillers and to no tivelv few of the people exposed to the filler other dusts. As previously indicated, industry develop the -disease. 1 hereforc, it is the today is finding many new uses for the fillers intent in this paper to mention asbestosis when they arc mixed with other dusts. It only briefly and then to outline various other is an established fact that when asbestos pulmonary disabilities seen anions asbestos fibers are mixed with silica, diatomaccous workers. earth, or other potentially toxic dusts, the The word "asbestos" is generally used to describe several fibrous magnesium silicates which arc different in their chemical compo sition and physical properties. The most important types o! fillers are chrysoldc. amosile. crocidolite, amhophyllite, actinolite, and tremolile. Total world production of all fibers last year amounted to slightly more than 1.500.000 tons. Approximately 95% of the fibers produced were of the chrysotile pulmonary changes resulting from the inha lation of these mixtures arc not typical of asbestosis. The x-ray pattern may he differ ent. the clinical course changed, or the sus ceptibility to intercurrcnt infection increased or decreased. Thus, in making a diagnosis of (iccupationnl pulmonary disease, it is highly important to obtain a detailed occupa tional history, so that asbestosis, silicosis, or mixed pneumoconioses can he differentiated. varietv. Sr/c criicidTilitc. and 2r-r amosite. 1 he statements and observations reported Deposits of various types of this mineral are here concern several thousand men and ' found in many countries, but the largest women employed in the asbestos industry mines are located in Canada and Africa. in Canada and the United States. In this Asbestos fillers arc highly resistant to heat and acids. They have great tensile strength and large surface areas. Itecause of these properties as well as their filamented struc ture, industrial use of these fillers through out the world is increasing. The textile in dustry has used them for many years to produce blankets, clothing, threads, ropes, tapes, braided tubing, and filters. In recent years, however, there has been an increasing use of asbestos in the insulation, building, and friction-material trades. In addition, the industry the various mining, milling, and manufacturing operations create some dust containing asbestos fillers. Jf the fibers up to J>Qp in length are inhaled continually in sufficient quantities over a period of several years, a typical pulmonary fibrosis will develop. It has been demonstrated that this fibrosis is due not to the chemical but rather to the mechanical action of the fibers.1 The asbestos fibers are deposited in the terminal bronchioles, initiating a tissue response which coats the fiber and eventually produces what is known as the asbestos body. This appears Recorded for publication April 7, 19S5. to be a defense mechanism of the lung. Nu Medical Director, Johm-Manville Corporation. merous asbestos bodies can be found in the 198 / *t -{ UU.ro,VARY DISABILITY IN ASBESTOS WORKERS rout::" :>f persons who have had only short .cv.d rgotcic exposure to the dust. These, j-.- .-sr.r. uc healthy and have no demonstra ble rig;u. or symptoms of asbestosis. There* it ctr.'.s more appropriate to use the t.rri 'Ve!;;::os" bodies rather than "asbestc:::." toriics, signifying exposure to the fibers 111 rot necessarily indicating disease. If in: casing quantities of the fibers are.*. Cv/..tiiv.:i;.ly inhaled, the tissue reaction pro gresses, and a generalized, diffuse fibrosis gradually appears throughout the lower lobes of the lungs. With additional exposure, this T . ! > -w -I-- iii ...... * ; . v\V . . *. riA* .i , , .** \ 1 `' iA I l Fig. 2.--Moderately advanced asbestosis. ated with this disease, which may account for the "ground glass" pattern which has been used to describe the typical x-ray picture. In moderately advanced, or second-stage, asbestosis (Fig. 2), the infiltration has in creased but still is confined to the lower lung fields. The "ground glass" pattern is Fig. 3.--Far-advanced asbestosis. Fig. 1.--Early asbestosis. fibrosis will spread to the other lobes, even tually causing respiratory embarrassment and finally cardiac failure. The pulmonary fibrosis resulting from prolonged inhalation of asbestos fibers will pro-luce s. typical x-ray pattern. In early, or first-stage, asbestosis (Fig. 1), the x-ray shows a fine, diffuse, homogeneous infiltra tion throughout both lower lung fields. It should be noted that this infiltration is bi lateral, that it is generalized at both bases, and that the nodular conglomerate patterns of other pneumoconioses, such as silicosis, not seen in asbestosis. There is a consiucrablc amount of pleural reaction associ- * - -'.f'v * H : . , - .. * t . -' v. \.-1 -r-; - . *. % * . . * 1 .i - > i , . * .\ \f , . >.* -* v v -irvY-`* , -i*.- 1 - .* *5 / " * > ;,C'. t. ' ------ ", . - i ; r * . .* -- 199 A. U. A. ARCHIVES OF INDUSTRIAL HEALTH more apparent, and the heart borders are becoming indistinct or shaggy. There is some irregularity of the diaphragmatic outlines and beginning obliteration of both the cardiophrcnic and the costophrenic angles. In far-advanced, or third-stage, asl>estosis (Fig. 3), the infiltration still is homogeneous and bilateral, has spread to the middle and possibly the upper portion of the lung fields, but the apices remain clear. The cardiac out line is almost completely obliterated, as are the domes of the diaphragm and the costo phrenic sulci. With this picture in -mind, it is advisable to reiterate the observations of many physicians, namely, that the x-ray pic ture should never be used to estimate the presence or the extent of impaired pulmonary function or disability. Matty cases with x-ray evidence of third-stage nsbestosis have been known to carry on their usual work and live fairly comfortable lives for several years. On the other hand, no case of definite disabilitv has been seen unless there was the typical x-ray pattern. There is no typical clinical picture for nsbestosis. The disease is insidious in it> onset and slowly progressive with continued inhalation of the fiber. There is a gradual increase in cough and expectoration, some anorexia and weight loss, then slowly in creasing dyspnea. Cyanosis and clubbing of the fingers arc rare findings. There is evi dence that asbestosis will not progress after exposure ceases, but this seems to be true only if the worker does not develop an inter current pulmonary infection. It will be shown that asbestos workers are not predisposed to develop more intercurrent pulmonary infections than are found in other workers. However, when an acute pneu monitis develops in the presence of an estab lished asbestotic fibrosis, the infection is slow Jo heal, relapses are frequent, and the patient may be more susceptible to subse quent pulmonary infections. While it is true that the disease is slow and insidious in its onset and that people with advanced asbestosis may lead relatively normal lives, eventually the heart begins to fail, and death from cor pulmonale rapidly follows. 200 Gregoire * has rejxjrted that pulmonary function studies on asbestos workers have shown that the chief physiological problem is that of a "tight" lung. The vital and maximum breathing capacities are lowered, expansion of the lung is difficult, and arterial oxygen saturation of the blood is diminished in some cases, indicating an impairment of gas transfer through the lung. Diffuse ob structive emphysema, so commonly seen in silicosis, is not apparent in asbestosis. These pulmonary function studies are of importance in the proper diagnosis of pulmonary fibrosis and the estimation of pulmonary disability. Of more importance is the fact that these tests can often help the clinician in directing the treatment of the case. Unfortunately, there are too few persons who are properly qualified today to carry out- these tests and interpret the results. An x-ray survey was made of one group of 708 employees working in an asbestos mill where the ore was dried, crushed, sep arated and graded, packed, and then shipped. Operations in this plant required the em ployees to rotate through various jobs; hence it was impossible to relate any x-ray changes to a particular job or to a specified dust concentration. At the same time it could be assumed that all members of the group had Ix-en exposed to varying concentrations of the dust. The chest x-rays of these em ployees were divided into three broad groups: (a) essentially normal lungs; (b) marked linear exaggeration (P-2) but no typical pattern of asbestosis, and (c) def inite asbestosis. Tabic 1 shows that of the 708 employees studied 649, or 9\fo, had normaJ x-rays. This is of interest because 204 employees, or 29% of the total group, had 10 or more years of service, and 2 men actually had worked more than 40 years in the dust. Table 2 indicates that 52 of the 708 em ployees showed a marked increase of all peri bronchial markings, although none had defi- Gregoire, F.: Pulmonary Function Studies in Men Exposed for Ten or More Years to Inhaiaticn of Asbestos Fibers, read before the Seventh Sara nac Symposium, 1952 (unpaWishecfjL / 'JLMONARY DISABILITY IN ASBESTOS WORKERS Table 1.--Employees with Normal X-Rays Zxpotun. ................................................................... X-* M Employ*!, #o.................................................... !W >*1 10-H `W M ** ** *'-*4 * **** *. 4(M` 1 <;u' 1 nite asbestosis. Inasmuch as the majority of these men had essentially normal x-ray films early in their employment history, it is assumed that most of the later increased lung markings were associated with their subsequent dust exposures. Further indica tion of the length of exposure necessary to develop x-ray changes is seen when it is noted that 69% of this group had 10 or more years of exposure. Table 3 shows that of the 708 employees 7 had developed definite x-ray evidence ot asliestosi.-. These men exhibited various stages of pulmonary involvement, but all were working steadily at their accustomed jobs with no signs of disability. It is of interest to note that none had developed x-ray evidence of asbestosis with less than 20 years of exposure. Frequentlv it has been stated that it takes iron) 5 to 10 years of exposure to develop a>l>estosis. The survey reported here con cerned mill employees. It is jxtssiblc that other operations might have different expo- sores with other disease experience. Factors which might influence this experience are not only the length of exposure or the concen tration of du-t in the air but also the fact that there is probably an individual suscep tibility to thi- development of pulmonary fibrosis. Medical literature has given considerable attention to occupational pulmonary disease, but very little has lxren reported on the oc currence of nonoccupational respiratory dis ease among those employed in the dusty trades. The following survey was made in order to determine the incidence of non occupational respiratory disease in another group, of 1561 men and women, working in the nsliestns industry. A review of absentee records indicated that no valid conclusions could l>e obtained from this source. localise the reason for absence was given by the employee himself. Sickness often was used as an excuse to rover short absences for a variety of personal reasons. It then was decided to study the claims submitted for sickness and accident insur ance. All employees in the survey participated in a plan operated hv an independent insur ance company. Indemnification was made only after the nature of the illness had been certified hv the treating physician. The study included claims submitted over a three-year period tor such illnesses as the common cold, -inusitis. pharvngilis. grippe, brnnehiti'. pneumonia, asthma, and pleurisy. Occupational respiratory diseases and pul monary tulierculosis were excluded in the report. * Table 4 shows that of the 1561 employees in the survey group there were approxi mately equal numbers in dusty and nondusty occupations. < )f all claims filed for respira tory diseases. 459c were for employees with dust exposure. Clinical observations for many years had given the impression that a dusty occupation in itself would not predisjio.se a person to more nonoccupational respiratory disease than would a dust-free job. This survey shows that the rate of disease over Table 2.--Employers with P-2 X-Ray Readings Exposure, yr.......................................... ................... 1-4 SO 1014 1.V1P Employee, no........................................................... 5 11 S 10 II Sn-v can !j-ip 4 1 1o1 Table 3.--Employees with Asbestosis Exporure. yr............................................................... 1-4 S- 10-14 1H SOl4 *>-S4 lb-M 40-44 4V48 xiployc**. Bo........................................................... 0000(10100 201 A. M. A. ARCHires OF INDUSTRIAL HEALTH a three-year period was approximately the same in the two groups. In addition,, there was no appreciable dilTerence in-the duration of illness in either ('roup. Anipial experiments and clinical observa tions have shown that asliestosis docs not predispose a person to the development of pulmonary tul>ereiilosis, nor does it ajj^ravate an apparently healed tuberculous lesion. In two isolated one-industry towns in the Province of Quebec where asbestos was mined and processed, the incidence of tuber culosis over a period of many years was no greater than in other isolated towns with comparable populations hut without a dusty Kip. 5.--Ktcclriui micropraph. amosite asbes tos: y 4000. than that ainmi); the general population of these mining towns. Conflicting ojiinions and different re|xirts make it extremelv difficult to confirm or dem conclusively die causal relationship of asbestoMs and carcinoma of the lun^. Too often a common conclusion is drawn from observations and experiences with different racial groups, livim; in different parts of the world under variable socioeconomic condi tions and working in diverse occupational exposures. To these variables should be added the fact that there are various types of asbotns libers. trade;f In addition, the incidence of tuber culosis aiming aslie-tus workers was lower Kip i> --Klcctrim micropraph, crocidolite asbes- 1 (; X 40iK). T Parrot. P.: Personal communication to the author. Taiu.i: 4.--A nn...-, ii/'iilimiiit Disctur l-.x/`crirncc tula! n>. ................................................. Kinplnypr* with !ut fxpt^urr................................ Krnplnyr^^ *f(h nt* l( ...................... for Uiry .............................. 1'Jnlni- fur posure tory H***-*^ 11H 1u*t ex 0lm ftr rri|*lrtorjr lih no duat exposure .................................................................. 1/^1 0U7 J7 1J 16 Avtrxxt Jfnjrih of lia^nr** lih tuM expoftire, vk......................................................... SJ Averxce Wnplh of twnrr with no rtuxX rxponurr, wk..................................................... 1,1 202 PVI.MDNAkY DISABILITY IK ASlUiSTOS Il'Okklikk Badollel $ has rejiortcd that there arc several different types of asbestos fibers used by industry today, and these fillers have different physical and chemical properties. Figures 4, 5, and 6 arc enlarged electron micrographs of three types of fillers used most commonly in industrial processes. The Jong, soft, and silky chrysotile fillers arc found chiefly in Canada, while the amosilc and crocidolitc fillers which arc shorter, stiffer, and brittlcr come from Africa. Canadian experience with a-lic-tu-is Ims lieon limited to. the chrysotile liber. The ma jority of industrial processes in the I'niled Stales use this fiber, hut in recent tears there is increased use of the amosilc and crocidolitc tiliers. The British and I'.urojictm industries use greater quantities of these harsher libers. Therefore, in trying to clarile the causal relationship of asbestosis and bronchogenic arcinoiua. many variable facts should be icarly identified, especially the type of liber used and whether or not other dusts were present in the industrial and environmental atmosphere. Sl'M M AKY Respiratory disease experience among several thousand male and female asbestos workers in the l nited States and Canada i- rejHined. < h` all workers oxjrosed to the pliers, verv few develop asliestosi*. Xsliestosis is insidious in onset and pro gresses slowly with continued exjvistire, causing respiratory emliarrassmcnt and cariliac failure. X References ' and ,t. Physiologically, asliestosis is the problem of the "tight" lung. Kxpansion of the lung is difficult, and there is impaired gas trans fer through the lung. Diffuse, obstructive emphysema is not common. There is a typical x-ray pattern which can not lie confused with other pneumoconioses. An x-ray survey of 708 employees in a milling operation showed that the majority had normal x-ray patterns, that 10 or more vears of e\|Hisure were necessary to pro duce x-ray changes, and that no cases of asliestusis were found who had worked less than 20 year- in the dust. The incidence of noiioccupatinunl respira tory disease wa- not increased, nor was the illness more prolonged among worker- ex posed to asliestos dust than among uoucxjKised workers. Asliestosi.- does not predispose to jhc development of tuberculosis, nor docs it aggravate an apparently healed lesion. There are several reasons for- different opinions expressed concerning the relation ship of asliestosis and bronchogenic carci noma. Difference- in asliestos fillers are noted. 'REFERENCES 1. Vor'valil. A. _F; Durban. T. M.. awl Pratt. P. C.: ExiK-rinirntal Studies of Asbesto-i-. A. M. A Arch. Indust Hyp. S : 1 --13 (Jan.l 1951. 2. Badollet. M S.-. Asbestos: A Mineral >A Unparalleled Properties. Canad. Min. & Metal. April. 19-1. ,t. Badollet. M. S.`. Asbestos Fibers: Productioil and U-afrr. Uanad. Min. & Metal. Aug., 19iJ. Some dinicat Obierualioni ofSl'ibeiloiii in Wkne and ffiilt 'Worlert PAUL CARTIER, M.D., Thttford Mines, Quebec, Canada eases have been diagnosed by rocntgcnnlogv. ami 33 of these 121 cases have liecn con ' ' V ^.. Iti'' t 'r * r V 1 Instead of giving I he usual clinical descriptinu of aslicstosis as niciiliuncd in (lie pro firmed by the pathological study of the lungs ; so we can say that 33 cases have been diag nosed by x-ray .and histological inlerprcta. tiimi. The remaining seven cases bas e been gram. which description may seem to many diagnosed by pathological study only, having a mailer of personal impression and there been missed on the reading of the standard fore controversial, I prefer to brim: to your chest films; hut it is important to add that attention a series of remarks ami comments these seven cases tire cases of minimal asbes collected during nn nine rears of medical toses. \\ it bout going into a too long discus super-vision of some 4fXK) asbestos mining sion of the effectiveness or the superiority workers. of roentgenology over histo]>ath<.iiogv or l'roin PM5 to 1954 the annual medical and x-ray examination of the asbestos work ers. along with the histological study of 58 vice versa lor making a diagnosis of asbestosis. I should like to adti the following re marks. autopsy case'-, permitted the detection of 128 \\ e have to admit that the roentgenologi cases of ashestosis; 40 of the patients are cal interpretation might fail to delect cases already dead- and autopsies have been per formed and 88 are still living. Table 1 gives the age-group distribution and the classificatjoii by decree of ashestosis in the 128 cases. Yon mav see that there are /2 eases ot minimal. 5e cases ol moderate, anil 21 cases of advanced ashestosis. The age distribution indicates that 10 workers arc 7(1 years and over--one worker with far advanced ashestosj- is 84 years of age and still living--and (ifi workers arc (>0 years am! over. ol minimal ashestosis, hut from persona! ex perience and from repeated contacts with tjardner, Sampson, Robert, Bristol, Yorwald, and Pratt, 1 can sav that no cases of ashesto sis of clinical importance have been diagnosed by the pathologist without having been de tected anteriorly by the roentgenologist. I do not know whether a similar statement is true for employees of the asbestos textile industry, where apparently the x-ray pat tern of ashestosis is fainter than the one found in the asbestos mining industry. I'irsl. it seems indicated to explain how the diagnosis of ashestosis has been made in thoc 128 cases. One hundred twenty-one A second comment is about the wide discrepancy in the appreciation of the degree of nsliestosis by different pathologists. In a few instances, cases which looked like mini TTu-llVirtl Industrial Clinic. mal ashestosis to one pathologist have been Read in the Sym|>sium on Occupational Dis eases of the Lours, sponsored by the Massachusetts Medical Society in cooperation with the-Institute of Industrial Medicine of the New York University-- Post-Graduate Medical School, Boston, Oct. 28. 1953. classified as advanced asbestosis by another pathologist. With the increasing number of autopsies for old employees and with the recent use of the lung biopsy and the lung resection in asbestos workers, we may assume 204  A ' N1CAL OBSERVATIONS OF ASBESTOSIS Tabu. 1.--Thetjord Mines Survey, 1945-1953 literature. Nevertheless, briefly, I want to Distribution of 118 Caaa of Aabtaloala by Me Oroupr aod by launoity review these causes of death, trying to investi gate the part played by asbestosis in the Act Oroupa, Tr. death. lilntmal aibtaloala Uodtrat* asbestosis Advaoctd libealotit Total 36-49 to to-M Mi 84 $ 10 tnd 6-70 Ovtr Total 11 n> l 11 ii t4 u 0 6 10 t t 81 -- ---- ---- -- *2 40 31 16 188 It is true that 12 cases, or 30% of the deaths, were caused by an evolutive tulierculosis; this incidence may seem too high, but knowing that a more complete statistical analysis of all the employees in the asbestos industry made in 1950 did not reveal a higher that there will be more instances in which pathologists will differ in opinion among themselves and will not agree with the roent genologist in the estimation of the amount of asbestotic fibrosis present. This lack of agreement is very confusing in any medical study, but it is still more confusing before a compensation board. For practical purposes, it is of great im portance that a solid roentgenological classi fication of the cases of asbestosis. correlated with the histopalhologica! findings, be recog- d and accepted by all those concerned i this problem of asbestosis, because the chest film must be considered as an essential criterion in making a diagnosis of asbestosis and, notwithstanding the limitations of the chest films in some exceptional minimal cases, this tool remains more objective and more adequate than any other presumptive criteria. Table 2 shows the seven main causes of death in the 40 cases of asbestosis that have been autopsied; 12 patients have died from evolutive tuberculosis, 5 from coronary thrombosis, 10 from cardiovascular diseases, incidence of tuberculosis than in a control group or a severer evolution of the tuber culosis, this rate of 30% is not in itself suf ficient to establish a causal relationship be tween asbestos-dust inhalation and tulierculosis. Considering the second cause of death, coronary thrombosis, it is difficult to explain how a minimal or a moderate asbestosis could contribute to the formation of a throm bus in the coronary circulation, and, conse quently, I am inclined to estimate these five deaths as not related to the factor asbestosis. The third cause was cardiovascular dis eases. It is not so simple to say how many of those employees have died from their' cardiovascular disease and how many have died from their asbestosis. The fact'that most of the employees who have died from cardiovascular diseases were 60 and over and the fact that statistics men tion that 65 to 70% of the imputation of the same age arc also dying from cardiovascular diseases should be taken into consideration before arriving at a conclusion. 4 from cor pulmonale, 6 from bronchogenic carcinoma, 2 from bronchopneumonia and bronchiectasis, and the last one from cancer Tablf. 2.-- Thclftird Mines Sur-.ey, 1945-1953 Causes of Death In a Series of Fort/ Ca*** of Aabcsloal* of the brain. In reading this Table, the first question which comes to mind is: To what extent is this enumeration of causes of death ditferent from a similar enumeration for a comparable group of employees from another industry? Unfortunately, I do not know whether there is a marked difference, and I did not have the opportunity to discuss this Table with ' physicians or to compare it with a v -*ar one which mav exist in the medical VlDlmal Asltes- tosts Kvolutive tuber* ciiIoaJ* j Coronary tbromboi*ls 1 Cardiovascular diseases 3 Cor pulmonalo 0 Droorhojreolc earcluoina 3 Broofhopocumoolt and broDchle*. tails 2 Other cause Total --1 n Xndcrata Advanced Ashes- Aahea* toals to aii 80 40 43 1s 13 00 ._0 0 17 Total It t 10 4 1 40 205 i, >1 53 i ' *, fi IXIHSTMAL HEALTH In a few Underline cases in which it was difficult to appreciate clearly the role played by tle aslie.stosis and the role played by the cardiovascular jathologv, the different car diologists consulted were of the opinion that, unless the asliestotic fibrosis is extensive enough to produce jKithological or clinical signs of right heart failure, it is impossible to tel! with some certainty that the fibrosis Iras contributed appreciably to the death, especially if there are evident signs of ad vanced degenerative diseases. In practice, this group of employees with cardiovascular diseases and a minimal or a moderate degree of asl>estosis is Incoming a serious problem as far as the compensation aspect is concerned. Without too much im. agination and from the findings of an in1 creasing muni ter of autopsies on old emj ployees, we can assume that there is a large unknown number of employees who have a i minimal amount of asliestosis and who. most likely, wall later on also present a cardio vascular disease. Then, unless definite cri teria are developed to estimate objectively the harm produced by the asbestosis and the harm produced hv the cardiovascular process, obviously tho-e crises will remain embar rassing t<* appreciate correctly both by the L-clinician and by the compensation hoards. I have purposely separated from the cardiovascular group the four cases of cor pulmonale, liecause these four deaths seem quite evidently related to the presence of asliestosis. There are also the cases ot two other workers who although they died from bronchogenic carcinoma and asbestosis showed evident signs of right heart failure. Therefore, we can say that in six cases of asbestosis cor pulmonale developed ami the patients died from their asbestosis. The following group of six eases of bron chogenic carcinoma present a special interest. \\ ithout going into nnv discussion of this r problem of jxjssible relationship between ' asbestosis and pulmonary carcinoma. 1 just want to say that there are also seven other patients with bronchogenic carcinoma among the employees who did not have asbestosis. "Moreover, a general statistical survey of all employees in the industry docs not seem to indicate any statistical evidence of a causal relationship. Therefore, the part played by the asltestotic fibrosis in (iroup 5 remains questionable. The two patients who died from broncho pneumonia and bronchiectasis most likclv died from this pathological process rather than from their minimal asbestosis. The last patient died from cancer of the brain. in summary, in my personal opinion, six patients quite obviously died from asbestosis, and the other 34 developed a lesion which could very well be considered as the cause of Table 3.--Thelford Mines Survey, 1945-IV53 Clinical Status of EInhty-Elght Living Patients with Asb^stot'ls t i (M H i ......................................... MiliJ symptom*................. Moderate symptom*........ Severe symptom*.............. Wlnlniul .1*1#**iosi* a; II s 2 >lodcr#i^ Advanced A*!-*- Ar tosi? tus:? 43 32 93 25 Total............................ 3" IS 13 death, although we do not know the role played by the asliestotic fibrosis. Table 3 gives the clinical status of the K's living patients with asbestosis. !u anah/mg this Table. 1 have to admit that we cannot be too certain of the classification of the cases of asbestosis into minimal, moderate, and advanced, because there is a significant dis crepance between the roentgenological and the pathological classification. I lure the da-sitication is based on a roentgenological appre ciation. and likclv the histopathological classi fication would he different. A second important reason why this I able may look highlv questionable is that it is quite impossible to evaluate clinically the respiratory function of a group of employeewhen a large proportion of those employeeare 60 years of age and over and w hen they present at the same time other disease- that may impair the respiratory function to the same extent that asliestosis might do. Obviously at that age there are many factors other than asbestosis which could 206 C7-/.V influe these patient ing mo ""iy yT'f Vitl to prov statuadvanc 59 as! without fir-r tw Tor relation the cli a better employ the role This that too data, weight. To sui a serious CL1MCAL OBSllKl .ITJOXS 0J: .ISlili.S'l OM.s influence the cardiorespiratory function, and these factors could explain very well why 10 patients with minimal asliestoxis are present ing moderate and severe symptoms while 5 'with advanced ashestosis have no clinical symptoms. With all its limitations, this Table seems to prove at least one thing, that the clinical status of 30 minimal. 4 moderate, and 3 advanced cases is good and that a total of 59 asbestotic emplovees are able to work without any discomfort--1 mean those in the first two groups. For the remaining 29 cases, no good cor relation lietween the degree of ashestosis and the clinical status has liven found. There is a better correlation lietween the age of the employees and the clinical status, showing the role played by the age. This Table may also demonstrate indirectly that too many similar tables giving clinical data, such as cough, expectoration, and weight, cannot prove too much. To summarize, I lielieve that asliestosis is a serious disease in some instances, but more frei|Uently it remains a disease which can Iktolerated ipiite well for many years, even without appreciable symptoms, as long as another serious disease does not supervene to cause death. ()n the other hand, in practice, this dis ease may look more serious and cause impor tant medicolegal problems il a too scientific medical concept or a too lilieral social inter pretation is accepted by the medicolegal pro fessions. lalnir and compensation lnidies. As a matter of fact, if the least amount or a minimal amount of asbestotic hbrosis is interpreted as ashestosis. "occupational dis ease," and. more so, if the compensation (wards decide to apply the aggravating factor clause, notwithstanding any effective dustcontrol program, the problem will remain unnecessarily serious for many years to come. The combined effort of pathologists, physiopathologists. roentgenologists, cardi ologists, and clinicians is needed to orientate any research program and to bring answers to the many unknown aspects of ashestosis. i sc'.1" *; votmtim*.- w 207 Archives of Induslrial Hygiene and Occupalinat_ Medicine Volume 3 JANUAnY 1951 Number 1 OofvMcin, JOjl. r tiii Akuiwii Mfirja Ahociition EXPERIMENTAL STUDIES OF ASBESTOSIS ARTHUR J. YORWALD, RK.D.(Poih), M.D. THOMAS M. DURKAN AND PHILIP C. PRATT, M.D. SARANAC LARI. N T. ASBESTOSIS is a form of pneumonoconiosis resulting from pro- longed inhalation of asbestos dust. The name "asbestos," literally "unburnable," is not that of a specific mineral but is a term applied to a number of different minerals whose characteristic feature is a structure composed of long, parallel, flexible fibers. This structure is unique because the fibers are capable of repeated longitudinal subdivision to units of molecular proportions. In length the fibers vary from a feumicrons to 6 or more inches (15 or more cm.). Some varieties are stiffer than others, but many are sufficient!)- flexible to be spun into yarn and woven on modified textile machinery. The asbestos minerals are silicates of variable composition and belong to the serpentine and the antpdiibole groups. Listed below arc the more common varieties. Amphibole group: actinolite, amosite, amphibolc, antbophvllite. crocidolite and tremolite. Serpentine group: chrysotilc. The bulk of the asbestos of commerce is chrvsotile, 3Mg0.2Si03 2H.O, uluch is mined on tins continent principally in the Thetford region of the Province of Quebec, Canada, and in Vermont. Crocidolite and amosite also arc used commercially but in much smaller amounts. Chrvsotile occurs as veins in serpentine, a mineral of similar chemical composition, which exists in massive form and is made up of microscopic fibers without the parallel orientation characteristic of chrysotilc. The massive, bluish black serpentine, which is smooth and soapy to the touch,, is traversed by veins of fibrous chrysotile varying in width from a barely perceptible line to 6 (15 cm.) or more inches. The fibers run across the vein and not lengthwise with the formation. From the Saranac Laboratory of the Eduard L. Trudeau Foundation. This series of studies o: asbestosis, initiated at the Saranac Laboratory more than twenty years ago by the late Dr. Leroy U. Car.bier, director of the laboratory, was neariy completed a; the time of his death in October 19-!5. Although parlia! reports and ir.formj! reviews of some of the experiments had been giver, from time to time by Dr. Gardner, this paper p,resents for the first time a complete survey of the entire, experimental investigation. 1 2 IS'DVSTRI,\L HYC1EXE ASD OCCITAI IOX.4L MEDICINE Attention if. directed to the mineral brnciic. MgO.H..O. which is ollin found in the sanie formations with serpentine and chrysotile and ritav be fibrous in structure. Except for thr manufacture of magnesium, brucitc lias no commercial value at present because its fibers are not sufficiently flexible to be used in textiles, hut they arc capable of repeated longifudirtaj subdivision. Unlike other asbestiform minerals, brucite is not a silicate, and for this reason it has been a valuable tool in an experimental evaluation of the action of fibrous minerals on lung tissue. EXPERIMENTAL ASHESTOS1S For many years studies 1 have been carried on at the Saranac Laboratory in an investigation of the cause, nature and development of asbestosis. The present paper is devoted to experimental asbestosis, Fip. 1.-- Human asbestosis (P-36-1 <). The photomicrograph reseats a bronchi ole f rip lit center) with a smooth muscle bunchc at its inferior margin and wr.h an extensive zone o: collagen deposition largely obliterating the surrounding alveolar structure. The biack loci are macro pnag''.' containing incidental pigment. Asbestosis bodies arc present but are not apparent at this magnification (X 2lrj). and in it are described the experiments made on animals with various kinds of asbestos dust. Another report, to be prepared and issued at a future dale, will be concerned with human asbestosis and will cover the health aspects of workers who have been exposed to asbestos dust in an industrial environment. Although in man asbestosis is a chronic disease with diffuse pulmo nary fibrosis which requires years to develop, it is possible to reproduce 1. fo) Gardner, L. U., and Cummings. D. E. : Studies on Ex . urimcnlil Pneumokomosis : VI. Inhalation of A'bestos Dust, lls Effect u;o n Primary Tuberculous Infection. J. Indus:. Hyg. 33:65 and 92, 1631. (o) Gardner, L. U. : Chrysotile Asbestos as an Indicator of Subtile Differences in Animal Ti.sucs, Am. Rev. Tuberc. 45: 762, 1942. fORU'ALD ET AL.--STUDIES OF ASDE.^TOSIS 2 in one or more species of animal characteristic tissue changes which are similar to tlie lesions of human ashestosis (fig. 1). Since the life span of the experimental animal i> relatively short, it is not possible to produce the characteristic lesions in animals under conditions identical with the usual industrial environment. Consequently, to obtain a complete evalu ation of the tissue response to inhaled particulate and fibrous material, it is necessary to accelerate the reaction by employing higher concentralions of dust than would ordinarily he encountered it: industry. While conditions of exposure are thus different, the information yielded by animal experiments is invaluable in furnishing a letter understanding of the reaction of the human organism to inhaled asbestos dust. Expr.KiMr.xTAi. Mtritons For investigating the tissue reactions of experimental animals to the various asbestos minerals, two types of technic have been employed. namelv. the inhalation method and the mjiction method. In inhalation experiments, groups of animals--up to 'ICO or more guinea pigs and sometimes smaller numbers of rabbits, cats. dogs, rats or mice -- arc kept for eight hours a da} in a cubical dust room. 8 ft. (2.5 M.) in dimension, in winch a cloud of asbestos dust is maintained by a rotating paddle in a dust hopper,1' At intervals during the experiment a few animals arc killed and the tissues examined to determine the nature and the extent of the dust reaction. Some animals are exposed tor periods up to three years. The injection experiments arc used to determine in as short a time as possible whether or not a particular Gust has a potential capacity to produce inflammatory reaction when in direct contact with tissues of the body. The method involves injecting the dust, either dry or suspended in fluid, into the animal by the intravenous, the ir.trapcritonca!, the intratracheal or another route. Long term inhalation experiments furnish information on which great reliance is placed when estimating the degree to which a dust might constitute a respirators' hazard to industrial workers. Even though an atmospheric Gust .may be potentially dangerous, as indicated by injection experiments, only inhalation procedures will reveal whether the cost can be inhaled, pass the natural dciensc barriers of the body and reach, the pulmonary tissue in quantities sufficient to cause damage. Injection methods are useful, however, because they make certain that contact occurs between the dust particles and tissues and because the}' allow accurate estimation of the dosage and of the potential capacity of that dose to produce reaction. The intratracheal method is particular!} valuable when one is dealing with fibrous minerals like asbestos, since it permits observation of the effect of the fibers on pulmonary tissue. ' Tissue Suscxmnu.iTv Unlike free silica, asbestos does not produce specific effects m all organs oi all species of animals. The comparative data presented in table 1 arc based on completed observations and therefore diner slightly from a preliminary report.lh Fine quartz introduced into various organs 1 i ! i i : ; ! ; ; ; ; . j i j : ! | j ! ! I j I 1 1 4 INDUSTRIAL HYGIENE AND OCCUPATIONAL MEDICINE of various animals (guinea pig. rabbit, rat. mouse, cat. dog, chicken and even tadpole) eventually will produce silicotic nodules but at different rates. Similar i-ntroduction of long fiber asbestos has resulted in a fibrous reaction in the lung and. to a lesser extent, in the peritoneum but not in other organs of the guinea pig, the rabbit, the eat and the white rat. In our experience the lungs ot the clog and the white mouse failed to respond with fibrosis, although Schuster : has reported such changes in a dog that lived in an asbestos-fabricating plant. This variation in species and in organ susceptibility is yet to be accounted for 1; it is presumed that in the susceptible animals the greater reaction of the lung to asbestos, far exceeding the reaction of other organ tissues, is due principally to the greater mobility of the lung. Peculiar Characteristics or Assestos Experience has demonstrated that most of the nonfibrous dust particles inhaled into the lungs of man and animal are 10 microns or less Table 1.--Reaction lo Lone Finer Chrysolite in Lungs of Sion and Other Species cj Animal SjV'cici Man.......................... G.noca pif.............. pAl-til..................... CM.......................... W hilf r 1.1............... hile m(*ulc....... p.C.......................... Modf of Iipoiurf IcbtlalloJnhalfitior rifJ JoKMion JohcilitioO and thKCl'on Johkltticb ai,4 lDhtiet,oriacidlrtjr<Uo3 Inhalation JoJfctloL Flbroiii <4 J-r 4 -44 0 0 Abticf( R<x3>ci R u in ? r o u < Mode:aUDunierouf Rare tod atypical Rare aid atypical Vcryrarr Rare and aljplta! Rod* * 1 he iymtroJj 0 to 4 + refer to tbr C'c^ee of tinue rtactloo. in m.iximum dimension. Larger particles apparently do not gain access to the lungs, because, first, large panicles settle in air so rapiciv that few remain suspended in the atmosphere breathed and, second, large particles are more effectively removed by the protective mechanisms of the upper respirators- tract. In the case of fibrous materials these factors have less influence and fibers 100 and e\-en 2CO microns in length have been found in the terminal air spaces of human lungs. In small labora tory animals exposed to asbestos dust the maximum length of fiber found in the lung rarely exceeds 60 microns. A large proportion of nonfibrous particulate dust inhaled into the lung is found in the terminal air spaces (alveolar ducts, atriums, alveoli) in all parts of the organ; in contrast, inhaled asbestos fibers are first discovered in the respiratory bronchioles. These small passages are immediately distal to bronchioles lined by ciliated cpithcliu m.* Their 2. Schuster, N. H.t Pulmonary Asbestosis in a Dog, ). Path. E Eact. 34 (pi. 2):751, ]931. * 3. Yorvsald. A. J.: Variations in Individual Susceptibility to Industrial Dusts Inhaled into the Lungs, Am. Lev. Tuberc. C2: (13) 13, 11750. 4. Miller, W. S.: The Lung, Spring field, lib, Charles C Thomas, Publisher, 1937. / VOXU'ALD ET AL.--STUDIES Of ASBESTOSIS 5 own essential lining is a low cuboical type of epithelium but, as their name implies, they actually function in respiration through lateral alveoli distributed along their walls. Eitln-r these alveoli or the abrupt' change in the character of the lining epithelium, or the small diameter of the respiratory bronchiole, or the combination of all three factors is responsible for retention of the fiber at this site. Only after asbestosis is well established are appreciable, numbers of fibers seen -in the more peripheral air spaces. Further explanation is required to clarify this observation. Rate or Tissue Reaction to Asbestos Fibers The affected tissues react much more rapidly to asbestos than to quartz dust. For example, .in rats receiving asbestos fibers by intra tracheal injection fibrosis of a characteristic type is visible as early as one month after injection; for quartz dust the latent period is two months or more. Tims, the development of nodular fibrosis due to inhaled silica lags behind the deposition of dust to a greater extent than docs the evolution of the diffuse reaction to asbestos. This results in a difference in the degree of progression which, follows termination of exposure to dust. For example, on discontinuance of exposure tiic nodules of silicosis become larger, to a limited extent, for a considerable period of time, whereas the fibrosis oi asbestosis increases for onlv a short time. Subsequently, the ashcstotic fibrous tissue contracts; this process often distorts the adjacent pulmonary tissue and may, as a result, progressively interfere with cardiorespiratory function. Asbestosis Forms The pccuhsr structure known as the asbestosis boclv or `'curious body" is a specific concomitant of asbestosis.5 The tvpica! bodv is a golden ycliow, beaded or haustrated rod. which may be either straight or curved (fig. 2). Often one or both ends are bulbous like a dumbbell. The bodies vary considerably in length, and dimensions up to 250 microns have been recorded. ]t is believed that asbestosis bodies are inhaled fibers on which pro tein and iron pigment of tissue origin have been deposited.6 * *G* i*oyr.c 5b observed reproduction of these bodies in guinea pigs nine months after subcutaneous injection of fibers rendered free of iron. The bodies arc abundant in man and in the guinea pig (table 1) but are much larger in the lormcr, probably because the iarger-sized air passages admit fibers ot greater dimension. In guinea pigs they form after about 70 days 5. Gloync. S. R. : (c) The Formation of the Aslxrstosis Boev in the Lunf;, Tubercle 12:u9S. 1931; (b) The Asbestosis body, Lance: 1:1331, ]932. (c) Gard ner vod Cummings 6. Lynch. K M . and Smith. V/. A.: Aslcst>'sis Bodies m Sputum and Lung. J- A. M. A. 95:659 (Aug. 30) 1950 Simson. F. V/., and Sirachan. A. S.: Asbestosis Bc-dics in the Sputum : A Stud;' of Specimens from 50 Workers in an Asbestos Mill, J. Path. L Bad. 2-3 ;], 1931. Gardner And Cummings 11 Gardner.:b GJoyr.e.*# 1 6 /A DUST RIAL UYGIESE AXD OCCUPATIOXAL MPDICISE of contact will) the tissue. In cats, rabbits and mice a few of the fibers show an atypical costing after much longer residence in the lungs. In rats the bodies are rarely seen, and in dogs none could be found. Although the evidence is incomplete, it appears that the formation of the asbestosis body prevents the fiber from damaging the tissue. Many of the points mentioned above will be elaborated on in subsequent para- Fip 2--A. Irunsn ashcstosis bodies This collection c; ashcstosis iiodies ".as found in the lung stirnui in figure 1. The usual venations o: sue anc connguranon are represented ( >; -tCO). B, guinea ptg ashcstosis tody. This one is similar to some of those shown in A (x -100;. * graph-. dealing with the actual experiments. Fc: presentation our investigation is divided into two sections, otic dealing with inhalation experiments and the Other with injection experiments. ( .. VORWALD LT AL--STUDIES Of- ASiW.STOSIS 7 INHALATION EXrtl'IME N T5 > Four large scale inhalation cxpcrimcnts have been conducted in this laboratory with various forms of asbestos ilust. In each of these invest!-' gations, more titan 160 animals were used, and the cNpcrimcr.ts were carried on for periods ranging from two to more than five years. The four kinds of asbestos dust employed am designated as King's floats, short fiber, 100 per cent ball-milled, and long fiber asbestos dust. Kinc's Floats Asblsios Dost The first inhalation experiment conducted at the Saranac Laboratory with asbestos dust was begun in 1928. Animals inhaled the dust for Table 2.--Chrmicol Ar.clysis oj Asb'stoJ Pujlmp Moterioh Type Of Atbcnot SIO: FfjOa AbOi Cf:0 MnO Cft*) Wk'O K*iO K:0 COi lroi-' tlOD Toi* Tola] Kluc* floili............. short fitxr.................... Loot fiber.................... 39.3-J 3T.2T 1S.40 fc.M fr.C3 1.0 S 3: 0.7& * Cll * 0 0? 00$ O.c: O.fi 0.31 l\ `A ISf-C <0 It OK 0,00 0-30 0.06 * 0.9S 0.57 12.; )<. K.oo r.M 100.1! W.7d Xol dfUrmlo'd. TaFLE 3. -- Fcfrcorcf'k\C .4'.o!\SiS oj rld'CStO! DusixnC .Vn/fric/j Kinc'f fict ts : TIk irT-roxInM'- cc'-poptlof). On sr ] on p n Iclr* (e x rrp c r f.ry fc*i.lr) frnill?: than 10 nvirrorii and rcporird pr: errtnrr ot-iatPrj irorr. parncif foiMf. cOry*otur K, Krprr.im*' *0. mirnniif i:. r r Lone b. talc ]?, otr.e: miner* I' i For cnryrotilc, fiptrr up to 2u0 ELicroc* lone inci-idcd. Shc>;t fiber t: The pta:r:. nl. ln-lcr* ?'nr hull milk!. contatrrc! a p*r pcndmiDce of flhrot;* rhryjonJe inti pijt) f nor.f.l ;ol ) f <: ,r*~.: TLr ti'M' Mnmr rc:n;m< itm-, 1? *a; chrjtoi.lc F'"rp',nn.`>f Sb. maenrnte 10. c^eriz oruciit j. oWtrr :r.i;,r:lb, meiudme Cclomlu. t c t id o)He *d<3 tremoiitc, !i. Lodc I: The rr.jtrru! ror.'.-Mh4 principally of the fibrem* mm'-ral ebr y:-r.t !k ShirxK of noncpa:fttrd finer* 0 to IS ;:..cron* In C'Ciuftr; tnd up \ 0 >0 tn.crori In Jcnpin rre prr*rr.;. T.'.r t pprox ima t e r orn ;-o*1'-cn fit p^rru.iacf v* rk'ry*oii,< p^c 1 !nr lb. rr&c- Delitr 5, britr.tc C, otr.cr rnnerM*. T.pgr upirh verc cairttc and rnioritic izC micaceous mineral*, 3. Ooly a iracc of quarti ckKnrd. The ftDft!yis of the Ktnc'r floet* nt'rrlo(, made t-y Dr. C. S HhrfMit Jr.. Of b'arrard Cr.i vf .< 1: y. ht* f.pcD rrporuc ei*r).rrr (}{;:: .`>l''.Jt, and V.ir.umi, C. R.: Tf.e M:otralorx of A*hcMos LjlM. J JdOjK L'jr L Toxirol. 17: N.'. IV-) t For the 5hort fiber asf*T5i05 art.-'. i`.f iocc fiber *hcH0J Ihr p^irocrcph'C aoalyr't *es lupj'lrmrnled *Hh x-ray Clfiracuoa t x arr.io ft 1100. periods up to 33 months. Some guinea pigs with six and nine months' exposure lived for an additional three years after cessation of their exposure. A preliminary report '* presented observations after 29 months of exposure. At that time observations covered a period of only 2yd years and the conclusions as to the ultimate effects of inhaled asbestos dust were provisional. Those conclusions are substantiated by results ot the completed study, which is reported as follows. jComfoJi/iou end Atn:o.sfkcrit Concentration the Dust--The d'.itlir.g ma tc r :;.l. a commercial variety of asbeslos known as Knit's heats, was composed oi short fibers, ranplng in Icnph from 1 mm. to J micron or less, anri cf particles which also varied in sire. it was obiamcd from the T'neliord. Quebec, plan', of the Asbestos Corporation of America, and analyses (tables 2 and 3) rcscal that the amount of fibrous chrysotile v.as only 14 per cent, a rather low value. I 8 tVDUSTRlAl- HYGIENE AND 0CCITAT10NAL MEDICINE Impinger sampl's taken soon alltr Ihc experiment was juried indicated that llte dust concentration was at f.tsl quite iow, the average dust count being onlv 6.0 million j>articIc per cubic foot of an b> lire standard iiglit field lechr.ic and 05 million for particles and fibers greater than 10 microns. Alter the inhalation experiment had been unJer way ior about two )ears, the speed of the routing paodle in the dusting machine was increased and for the remaining 10 months of the experi ment considerably more dust was dispersed into the atmosphere. The average dust count of impinge.' samples collected after this change was 537 million by the usual light licit] method and 1.6 million for particles and fibers larger than 10 microns. It is probable, however, that the true values of the dust concentration were higher than the counts given in this paragraph. The impinger samples for the Kings floats experiment were collected in water, but later studies * have shown that count- of impinger samples of asbestos dust taken in water are not reliable. Ethyl alcohol instead of water was used as the collecting fluid in all subsequent experi ments . l re\i Cc v. I TxSLt 4.--J'niiimc'y cj Inhalation r,'cn men: Kmc'j Floats Asbestos Dust Natut< of Ln <r;=cc: I>ut crpo#ur< contiguous tfcroupoout life Ih)i loll ,y pro looted rcfiUcnct li iiorrrinl iir Tur>c:eu!ou< Ir.fccuo o ' a*. start of c'iis t r> i-ofurc Contro.s to ipfcctio i: so dust rxl-ur-ure Tuberculous nf*ctir>: : a fie' T' :po. of dust e\r,c,`ur<_. tber. ru'idecee In oorrr.il mr ConifM* to InWclio \: do dust ex* puturc An in. Bis Ni PUTfi pips 9 ;i'omu U Til} lb cu'or* v r Zb ru ne* pie* J Jtt-lr.l 1 rabbit i0 tuton t'-C* Z3 ruler* pip* i: p u; b e a pip 11 pUiDCa pips >51 x irr.urn 11 0 1. S u. r "w v 1 nun Afi-T hot t hi 1'UM i x t*c<ure. I Xf o y.o 33 0 IP 0 C0 e 26 9 3? e 30 l li ^ J 36 0 0 lb 1 uJ Li Type! p'-nbroncMola: C broa'.i b fur Jfl moo: /orriro bod* brooebiUf Little or do reaetioD NoDprorr<rs#i\< r^roi? NobprocitSMxe CDroJif ALisorptiod of forrifD body reart'OD Tentporary prr.r** * <'UL of Id lectlor,, tollo*r Ji r.ftl nc v,:n n;*;osi li^ai.rip i-y rfoIu;io:. (uie r x cr ptlcr.) Zo li No appreciable Inerto** ID f \i*C( p ' P * I to luf*crcciou` iDfr-ciiGG; heai.Dj *ru\ `uror. 0 IV t e i:cp by rc*o)utioD 'Tne p'..ini`B me' um Irticn'.! vitr, lov Tt.-ul.-nrc R; ttrair: ot tubrre-r Carious. 1 TOIr tract iIk -urvixcl j>c:*c-cf icltoaizc tcl'-cirou. Kc-uhs of the investigation, briefly summarized in table -R show that inhalation of Kit g's flr-ats asbestos cus: produced a typical peribronchiolar fibrosis in guinea pigs b it -not ir. rabbits or rats. Re-iehon in Normal Cumec Pies --Guinea pigs infilling this dust for periods up to 33 months had a characteristic fibrosis CKtcurri.ng in conical patches about the respiratory bronchioles. During this exposure the peripheral alveoli were not involved. The particulate elements of tne dust were transported through the lymphatic system to the bronchial nodes, causing no significant reaction in either site; Ihc fibrous elements remained fixed at the points of original localization and were seldom detected in the lymph nodes. Af'er exj-osure of approximately a year a small amount of cellular reaction had teen produced about many respiratory bronchioles (fig 3.4). As more dust was inhaled, it continued to accumulate in the same location, and later stages of the disease (fig. 5 P) consisted of extensions of the original lesions. Apparently, the inhaled fibers we:e caught m the jocket-bbte alveoli that are given off from the lateral w;l!s of the respiratory bronchioles There they 7. Fulton. V>'. B.; Hou::. R L. ; Dt-ciey. A . and Mathews, J. L.: Asbeslosis: ]. The Collection and Counting of Asbestos Dust .'encountered in Asbestos Fabri cating Plants. Special Bulletin 37, 5"cnn.sy)va:iia Department of Labor and Industry, Harrisburg. 1934. I VORH'ALD LT AL--STUDIES OF ASDESTOSIS 9 were phagc.>cytosed, and man) of them were carried into the wall I y migratory Cel'*.. Mononuclear leukocytes attracted to the area caused an appreci able thicken ing of the bronehiolar wall. After 16 months a delicate fibrosis made its apj>carance. he process evolved gradualls, and the numl>er of fine intercellular collagenous "Tubers steadily increased. As this fibrous deposit contracted, it partially closed and Fig. 3.--King's floats inhalation experiment' A. lung of a guinea pig with 12 months' ejeposore. It includes a respirators tronchioic, at titc icit, brandling and becoming an alveolar duct, at the right Note the accumulation of cells in the wall o; Inc bronchiole and in adjacent alveoli (X 130). D. lung of a guinea pig with 2S ruontns' exposure The fieid includes a bronchiole, at the center, witn peribronchial fibrosis cxicr.c.ng into the waiis of adjacent alveoli. Note the cufioical epithelium lining these alveoli. This ;s the so-called "adenomatoid'' appearance (X 200). distorted the alveoli, and with this change the alveoli !>ocamc lined with cuioidal cells. The result was an adenoma-like ap[-carancc which frequently accompanies r I li l : \i 10 lS'Dl'STKlAl H Yd EKE AKD OCCUFATIOKAL MEDICI SE chronic pulmonary inflammation resulting (rcrm many causes. Willis descried a similar struciurc in the ]ungs ol guinea pig:J inhaling silicon carbide. The longer asbestos exposures resuhed only in more thickening of the walls of the air spaces, largely due to an increase in the amount of fibrosis. The fibrous tissue always remained cellular and (ailed to show the hyaliniiition characteristic of silicosis. j ; < i ( 1 i f Archil j Oc<` Fig. A.--ICing's foals inhalation experiment: A, lung of a guinea pig with six months' dusl exposure (oliosscc! by .to months' inhalation oi normal air. The reaction is rather slight. but distinct fibrosis is present (X 2CO). Note that 28 months of continuous exposure (fig 3 a) produces much mote extensive reaction. />, lung of a guinea jug cx[-osed*to the asnestos dusl for nine months and living thereafter ir, normal air lor 3/ months. The reaction shown is more than that in A but much less than the reaction in figure 3B (X 200). 8. Willis, H. S., and Erutsacrt. F.t Tumor-lile Structures in the Lungs of Guinea Pigs Artificially Exposed to Silica Dust, Am. Rev. Tul-crc l/t2LS, 3928. 1 v I--Ksnrf Y'KTF'x*- i I'ORll'ALD ET AL.--STUDIES OF ASBESTOSIS 11 Asbestosis bodies (fig 2B), first seen in the lungt of the g"uine: pigs llut had inhaled dust for about two months, be-came more numerous and more distinctly jegmer.ted with increasing exposure. The reaction produced in g-uinea pigs exposed for six and nine months did not progress significantly during a subsequent period o! 3S and 37 months when the animals lived in a normal atmosphere (fig. 4). Between eight and II months after exposure ceased, the cellular reaction in the lung had be-en completely replaced by thin strands of fibrous tissue. At later periods the scar tissue was less in amount, but In the last animal killed, 37 months after discontinuing dust exposure, some fibrosis was still visible. Reaction in Guinea Pips Injected unth Tubercle Bacilli at the C*njf( of Dull /nJiclotip'i.--Of the gtoup of AO g-uinea pigs infected with attenuated tubercle bacilli. Ri strain,' at the time that dust exposure was l-cpun, 31 died or were killed before the completion of two years of the exposure and were reported in the paper by Gardner and Cummings '* Seventeen of these died from inlcrcufrent pneumonia. Briefly, the results were as follows: Ten revealed some evidence of spread of the tuberculous process (fig. 5 A) ; in 6 of these it was confined to the lungs, and in the other 4 the abdominal viscera also were involved Extension of the injection was first seen after seven months of dust inhalation, during the next 20 months more than half of the animals showed actively spreading tuber culosis, and in 3 of them small unties had deve'.ojvcd- During the last eight months no animals exhibited arty evidence of active infection although in half oi them the healed fibrous scars of previous spreads were obvious. The scars were morj extensive than is characteristic of either tuberculosis or asbestosis alone The nine animals which were still aiivc after two years of dust exposure were killed a! intervals during the following year. In lour of them the primary foci of infection were healed with fibrosis and even calcification, and there was no evidence of progrcssicci (fig SB), fn the remaining five the tuberculous foci showed evidence of bas ing previously spread locally ; in four of them, by the time of autopsy, the fcci were healed, with excessive fibrosis ; in the fifth animal there was a generalized chronic tuberculous pneumonia ir. one lobe, and in the other lubes there were isolated primary tubercles, which were still active but had not spread Rcoction in Guinea pigs Infected tntfi Tubercle Bacilli After Establishment of Asbestoses.--Twelve guinea pigs, after inhaling King's floats asbestos dust for 26 months, were infected with tufercle bacilli and then removed to normal air. Six of these animals died within seven weeks, five from intercurrent nontui-crculous infection. i he remaining six animals were killed at intervals up to 14 months after infection. The subpleura! tubercles were no more numerous in the dusted animals than ir, the nondusted controls, but a considerable number were found m the depths of the lung about foci of asbestosis. The tuberculous component of the Combined reaction showed only slight local extension about lesions in the lungs and tracheobronchial lymph nodes. Caseation was found in tubercles 1 / months Old, but by S'/s months it had completely disappeared, leaving only scar tissue. Foci of fibrosis still persisted in the last animal, which was killed 14 months alter infection. Reaction m Rabbits.-- Rabbits ex;>osed to the asbestos dust for perirxfs up to 19 montiis showed a foreign body type of reaction of low grade, but no fibrosis Although their lungs contained particuiale elements of the dust, fil-ers were not present. Tridicating that the upp-er respiratory mechanism of the rabbit is adequate, to exclude fibrous foreign bodies. Two rabbits, after inhaling dust for six and 19 9. Steenkeu. V.-.. Jr., and Gardner, L. U.: Ki Strain of Tubercle Bacillus: Its Dissccialion and Virulence of Variants in Normal and Silicotic Guinea Pigs, Am. Rev. Tubcrc. 14:51, 1946. T- , "1 I f Tiv Tf. i a - ^ s - II 1 :i ; i. ' i: t 12 ISDUSTRIAL HYCIESE ASD 0CCUPA710SAL MEDICISE months, lived in normal air (or more than two years. At autopsy neither animal showed any evidence of cellular reaction or fibrosis in the terminal bronchioles, nor were lbs re any asbesiosis bodies. ` A/ochon in H'hitr Eds--All the rats had acquired an infection, resulting in the formation of pulmonary abscesses, before they came to autopsy. Apparently, so much heavy mucus obstructed their bronchi that very few fibers could have entered li ii i i' s Arc'.-.i' Oc v. I 1M 1 < . t \ Ii '* I Fig 5.-- King's heat inhalation ejeperirr.ent : A. lung of guinea pip infected with K, tut>crcic bacilii and then excd to dust for 2-t .months. A bronchiole is shown just clove center. Surrounding it is some collagen deposition, together with tyj'ical epithelioid cell mfiitrati.m c: the wall Mete the lack t>f encapsulation and the peripheral epithelioid ceil pr.eumon.a, which illustrate a spreading tuber culous process (X dtO). B, lunp of a guinea pip infected u :tii R, tui-erdc bacilli and then tar posed to dust for 3S month.s. Note the subpieural distincti) encapsulated casrcnis kCjs, the calcification at the right border of trie iesicn ar.d the absence of criis in adjacent alveoli, all of which illustrate a healing tul^rculous process (x2C0). . 1 * I'ORH'ALD ET AL.--STUDIES OF ASDEST0SI5 13 \Stlr lungs. In a feu. of the rati, an occasional asbestOMj body was discovered, tut there was no fibrosis. This phase of the experiment was considered unstretesstui- .Summery end Interpretesion oj 1 nhdalion ExperimerJ ziith King's nplorJs Dust--The findings in the experiment with King's floats dust can be summarized under two headings: 1. Effect of the inhaled dust on norma] animals. The King's floats dust caused a characteristic peribronchiolar fibrosis in guinea pigs hut not in rabbits or rats. The fibrosis did not increase significantly in extent after the dust exposure was discontinued. 2. Effect of the inhaled dust on tuberculosis in guinea pigs In guinea pigs infected with attenuated tubercle bacilli and then placed in the dust room, the results were more variable than is usual in an experi ment of this type. A few animals showed no sign of progression of the infection; in most of them there was evidence of temporary progression with subsequent healing; in one animal the tuberculous process remained active to death. In contrast, when guinea pigs after being infected are exposed to quartz dust instead of asbestos dust, the infectious process continues to progress and eventually causes the death of the animals. On the other hand, infected animals exposed to a harmless dust like iron oxide do not show any progression of the infection.'0 Guinea pigs infected with attenuated tubercle baciih after the termination of two years' asbestos dust exposure did not snow progressive disease. The only modification of the infection was in its localization, a few bacilli being retained in the peribronchiolar fibrous tissue, with tubercles forming there in addition to the usual tubercles beneath the pleura. In view of the variability of the results, the unusual nature of the .sponse and the high proportion of deaths due to intercurrcnt pneu monia, it is felt that on!}' tentative conclusions as to the influence of asbestos dust on the course of tuberculous infection are justified by this experiment. Short Fjfep, Asbestos Dust Since hazardous dusts like quartz are most effective in producing fibrosis when the particles are 3 microns and less in size, an inhalation experiment was performed to determine whether this condition is true for asbestos dust. It was thought that a short fiber asbestos dust consisting almost entirely of fibers and particles smaller than 3 microns would initiate an accelerated tissue response and produce an advanced reaction in a shorter time than did the King's floats dust, which con tained fibers from 1 mm. to 1 micron and less in length as well as much particulate matter. Ccm(-os\Un onA. A1 mo s [ tim( Corse t nlr a : von oj ! n t Dvjl.--The dusting material for this experiment was (he remains of fit<rs collrclcd ir, dust bins of an asbestosfibricating plant after a carding operation and screened to pass 203 mesh Since 10. Vorwald, A. J. ; Pratt, P. C.; Durkar.. T. M.; Delnhant. A. B., and Bailey, D. A.: Sidcrosis: A P.cr.ign Pneumoconiosis Due to the Inhalation of Iron Dust, Indust. Medct Surg. 1V: 170. 19S0. Tr fT tr T I i \ 4* i i t ` * :: I A: )< INDUSTRIAL HYGIENE AND OCCUPATIONAL MEDICINE the material ai received contained many long fibers, it was ground in a sire) ball mill to reduce practically all the particles to 3 microns or Jess in sire. When used alone in the standard dusting machine, this finely ground asbestos tended to pack in the hopper, and it became necessary to mix one volume of the unground materia) with three volumes of the ground to generate a satisfactory dust cloud It is pertinent to mention here thjt the addition of the small quantity of ungrour.d asbestos was unfortunate, because it confused the interpretation of results. The comporition of the rhort fiber asbestos as received is disclosed by the chemical and petrographic analyses given in tables 2 and 3 Samples taken before and after grinding yielded atcut the same values cn analysis, indicating that there was no contamination from the mill or loss of water content. The dust concentration varied during the experiment, the light field counts for atmospheric samples collected inside the animal cages with the impingcr apparatus nngnng from SJ million to 183 million. The average of counts was 130 million for the first year of the experiment, 13-t million for the second year and 1*0 million (or the third year. Sire-frequency measurements of air-floated dust from inside the cages at a magnification of 1.3CK) X revealed a great preponderance of fine particles, nearly TaBLE 5.--oj 1 r.hci^t\0n Exf'rrimcr.t tihth Short Fiber Ajbejloj Dust Kiturt of Eipcrlmect rxnt tXTonJM eoottooouj ibrocxhool Ule Animal* 46 ruinet pin IS t>U Jf cat* 1 I ibblll X>jH exi*orJrr by prolocted lo Dorcnil atr 1? tulDf plf* leal* J T* bblt Wtrlcua Hail- b U rv t 11 mum Attrr Inin Lx ITjU Lxpo* urt r*o*urt. Ho. Ho. U0 r. 0 n 0 47 * c to li' 31 u c: e FfMdlU Rate of fetrMoD about tbr umf / Id expert tnrzi *U0 Kmc t float? !> noi but rxieot of it.TOltrrrmnt er) cueb ir-st Cbaractenmc patmri of peribronchiolar Cbro*!?: do ut*''iO`if bcKjirt Fut-t>u:il T'aMlOr, 0 3 1J" ho b:o*.> p-p-ro fros'it; of afwofar riL ci)elfDlnk- after i0 doc m j* exi'eaure I'ToeT'^?!ion after remonf from dj*l dokiht Iu> --neither clearly ttiabhtbrS do: <2cLnu<ly C 2 0 <! C ( d Fame lor coctlouous eibocrp to continuous espoiurt; eTkjehct of aJit nt rr ne* *too AfU: 13 morltif tht *Ttf ciporfd to HO crul bnii rr.11Ir-J I't-utO' t Tt* fraction rn procatty Cur to loot Ot-crr to tt.t uacround matrrlal vtiifti lo ptoduc* a i at!r tactory duel cloud. retied v|tb the ground iiheiUx dun 90 per cent cf the particles seen being smaller than 3 microns. It was estimated that approximately 1 per cent oi the dust was in the form of fibers greater than 10 microns in length. Four species of animals--guinea pigs, white rats, cats and rabbits--were used in this experiment. The results of the dust exj>05ure. summarized in table 5. are presented in greater detail below. Reaction in Gnincc Pegs.-- Eighty guinea pigs were originally placed in the dust room, but 21 of them were latet eliminated from trie experiment and killed because of enlargement of the cervical lymph nodes thought to be due to intcrcurrent infection of the upper respiratory tract Oi the other 59 animals. ^6 remained in the dust room until they were killed or died at periods up to 3-t months, and 13 animals w-crc transferred to normal lir after being exposed lo the dust for 20 months. The type of tissue reaction provoked by the inhaled short fil-er aslxslos was essentially the same as that already observed in the c_\perimcnt with King's floats asbestos. The rate cf reaction also w as approx Irr.atciv the same, but the extent of involvement was 'cry much less After 1C to 2d months of exposure only a very few small foci of reaction. v,hich generally required microscopic examination for detection, had been produced in the guinea pigs. wT v~ VORU'ALD ET AL.--STUDIES OF ASBES7 0S1S IS Only after ex[>osurcj had continued (or approximately one year was there an appreciable tendency (or duet-containing phagocytes to gather it.to dumps. By J6 months phagocytes had collected alout the walls o( a few of jhe respiratory bronchioles which revealed a little proliferation or infiltration of mononuclear cells. There were also some mulllnuclcatcd cells, but they were of the inert, foreign body type At 20 to 24 months the cellular clumps were sometimes quite prominent, and sometimes changes in the epithelium resulted in the adenoma-like or 'adenomatoid" appearance (fig. 3 B) previously described in the section review ing the experiment with the King's Reals dust In most cf the subsequent members of the series the reaction remained cellular, but a few exhibited pronounced development of fibrous tissue. In these few members of the series the col lagen was pale in color and tenuous, with no appearance of being hyalinized. Diffuse chronic pleurisy was present in a lew animals without evidence of pul- TaBU 6.--Analyst! o/ Lunos o/ Ciumrc Figs After Prolonged Inhalation oj Short Fiber Asbestos Dust Expo*urr to In/it. Mo. Period Is Sorrn t) Air, Mo. /mount of A t h. r,f of Dnrd Luor 7oU) HOi. d. ot Dtyc Luor Toll! SlOi. % O f Alb Dut Exposure CoDttDuou* Durloc Life 6.tt o.ti t! n 4 jxS c *c { 6.If C-b-4 jo. n 10 le 10.M 6 o: o <; P.K U 0 4 70 0 <3 v.o? 4.06 0-1*3 10.60 to i K 0 `5 It (6 t.lZ O.K) 14.07 u i r. 0 7 5 .50 0.7f 14 4? 14.10 X i 5.35 0.K 37. n C.So i.t; 19.46 31 o *6.05 0.75 o.to 11.37 15. U Dull Expoiurr roIio*ed by I'rolonfnj ftcMdeccr Ic Normil Air to t 6.10 6.11 G.4* o .y. p.y.t 7.16 to 10 ft.n 3* o c: 0 34 10-tl 6.61 4.n 0.25 6J1 to 6.16 0 V. 6.0) it: V.Z2 < TWut R*4ftlOD * t+ i+ 4+ 4+ 1+ 1+ s+ * Ttv irmt'o].' trfrtric-c the tl-suf rrecuoL' Id rsch frrour of tulnrs p!r rrermat merely the retelire rterrec ot reaction, nnrloc Iron, (q o-.* tfons tUe) to < -r (Hie msilmum tor IM* ei r-eri rr.ee l). Tfie r-U noo-Mp? ppij odIj vn.-.lo this ikI.Ic *y mbol* Id other it Mm. c.douI t/e compart-d vltp monary intection. This suggests that pleurisy may be a specific concomitant of aslrcstosis, but the evidence is not adequate to establish this [Kjint. The reaction of the tracheobronchial lymph nodes was more pronounced than in the previous experiment with King's floats asbestos, prohahiv t<causc more fine particles had been transported to the nodes in animals inhaling `hod fiber asbestos The nodal reaction was essentially an increase in reticulum, rather than a fibrosis, with the original cells hemp preserved between the thickened reticular hirers. In the group remosed to normal air alter 20 months' inhalation of oust, progresSion of disease was not definitely demonstrated, but neither could it be absolutely disproved, owing to the variability of the response m different animals The rcacim-os. from mild to severe, occurred sporadically and l-ore no relationship \o the length of time after cessation of exposure. The differences were attributed lo variation in individual susceptibility. This view received sup;K>n frerm the chemical analyses (table 6), which revealed comparable amounts of ash and silica in lungs with uidely drfTerent amounts of tissue change. For example, the ash i r <( f 4 > Pfu 1 x ( i t t (v i 1 i t I'ORU'ALD ET AL--STUDIES OP .iSPLSTOSIS 17 alvrohr ducts in which the walls o( the associated air spaces were scrv thicl:. owing to swollen collagen framework. Connective tissue and Fool-Iiirlschow sky silver preparations revealed complete loss o( capillary bxf locally. Ou'side the collagen was a thin laver of epithelial cclis. This did not resemble the adenomatoid change characteristic of guinea pig ashestosis Near the lesions the air spaces were filled with phagocytes containing gray to yellow particulate dust and a rare, long, naked asbestos fiber. Careful search failed to reveal even a suggestion of an tibei'.oiil body. Picuriiy wu absent. T-hc tracheobronchial nodes showed com pact focal collections of monocytic cells at 12 months and. at 20 months, some diffuse thickening of the reticulum. In a few rats there was definite fibrosis along the margins of the node, extending into the mediastinal areolar tissur. Results of chemical analyses made on the white rats are given in table 7, and the average values have been recorded in table 8 fut comparison with similar values for rats inhaling other dusts. It will be noted that the values for asbestos are lower than those for quartz or chert but approximate those for the gypsumquartz mixture, in which atmospheric agglutination tended to reduce the amount of dust inhaled. This condition prevailed even though the atmospheric concentra tion of asbestos dust was essentially the same as that of the quartz, was one-halt that of the gvpsum-quartz mixture and was onc-fiilh that of the ferruginous chert Since the values for asbestos are low, it mignt be inferred that the total quantity of that dust actually inhaled was small or that it had teen eliminated irom or efjssolved within the lungs Evaluation of these ]>ossibiiitics is not feasible on the ba-sis of the observations derived from this study. Rcochon i>: Cots.--Twenty cals were used in this inhalation experiment with the short fiber asbestos. Eighteen were kept in the dust room continuously until pxt to death, the exposure period ranging from one month to ncariy >1 months The other two were removed to normal air after a dust cx|osurc of 31 months; one of these was killed five months, and the other 2-t months, later. In general, the tissue response was confined to microscopic f"Ci of fibrosis, which were in the walls of groups of suhplrural alvcoii rather than in the peribronchiolar areas. In one animal the change was extensive enough to he visualized on gross inspection of the section Only in the animal with the longest exposure--months--did the roentgenogram reveal definitely abnormal shadow; A roentgenogram, made after 30 months revealed no abnormality ; after dp months, a faint mottling could be delected throughout both lungs. At autopsy, nine months later, there was only microscopic fibrosis in the subplcura! zone plus heavy lymphocytic infiltration about small bronchioles. Ashestosis bodies were rare. On prolonged search a few yellow atypical bodies, smooth and without haustrations, were found in two animals exposed for more than a year. Rcoction in Rabbits.--Eight rabbits were exp-osed to dust for periods extending from one to more than five years; the last animal was removed from the dust room and left in norma! air six months before being killed There was never enough pulmonary fibrosis to be detected gross!), and there was no chronic adhesive pleurisy. Microscopic evidence of alveolar wall thickening was firs! detected in one animal after about three years of exposure and was seen in all five animals examined thereafter, including the one removed to normal air. One animal that died of paralysis after nearly four years of exposure exhibited a reaction visible on gross insj-eclion of tissue sections The possibility of pulmonary infection in this animal could not be excluded. In another animal chine two years later the fecal fibrosis was not nearly as obvious or as advanced. Areas of involvement, which were largely visual.zed because of phagocytic reaction within the air *naccs. tended microscopically to become more fibrous with the passage of time, hut there was never much encroachment on the lumen of tor spaces and the structure of the Jung was preserved. Asbcstcsis bodies were not delected in rabbits that died early in the experiment hut were seen in all animals that had been exposed to the dust for more than three years. I I I. ;1 1 i: _____ *i :1 Arc)! / *I T 16 INDUSTRIAL HYGIENE AND OCCUPATIONAL MEDICINE nd silica values were quite similar for three animals living in dust 20 months and then in normal air (or 14 months, yet the tissue reaction was severe in one animal, mild in another, and only doubtful in the third. The formation of asl<slosis bodies was at first cjctremely limited in both groups. After five months' exposure only a very rare short body could be found, usually inside a cell. Some of the finest intracellular particles were surrounded by yellow deposits having the same color as-lhc asbestosis body One year's exposure had per mitted an accumulation of many longer fibers, a numler of which were coated and teen as typical asbestosis bodies Most cf there were rtill ihort enough to be partially or entirely within phagocytic cells. By the twentieth month and thereafter they Taile 7.--Analyse! of Lunas of White Rots That Hod Inhaled Short Ether Asbestos Dust Duration Of tlKrare, Jdo. o t 4 Amt o[ A9h. Sc of I'necJ Luce 2.9 4.3 ?. 36 43 39 2.4 '3 3 3.6 29 l:.t 33 se li Totil 6tO.. q of l>nJ Ludc 0 00 0 fO - o (' 0 (O 0 ,fi 0 (C 0 CO o.c* 0.13 0 Cv 0 06 0.05 o. 3: o.cfl Tont PIG:. Of AftC 00 on 00 00 00 0.0 0.0 !1 li 11 11 !.J I0 a r>ur Hoc of Lri-> vure. ko. 6 Ajot of An^. *2? Of Inlrd Lunc *5 >< IP 16 6 11 4A l*' f < 10 < 6 L1 64.75 Toitl fctC-:. V. Of Luof oo: 0 03 o.w or* c ie 0 15 0.17 0.16 C.l? C 15 0.15 0.12 Totil 6lO:. ^ O f Aftfi M 1.5 1.1 I1 6.5 1.4 4.0 4.2 Jf 3.3 11 t.6 borDial roDtroli (do dust exposure). I Taulz B.--Avercge l'clues of Ash end Total Silteo for Luncs of ll'hite Rets Inhaling Parians Dusts for I'ortous Periods (Lungs Only, li ithout Included Lymph Nodes) Amt. ol A*h, rrj r r------------- Uon Fhort of Ex Fit>rr po rur*, Aftl*ft- Ho. to# Quirtr 1 13 4.3 1 14 4.6 6 16 7.1 1 16 4-6 10 4.0 7.6 at IrrJrj Lung TotalfcIOi. ' G y tim* Ft rru Cur.ru f :nou> iifx CNcri turr f hert r u.cr A ft l-rt- tot. 9 :.p 0 OP 1.9 2 6 O.W 9.9 3 4 0.0ft v.t* 3.6 0.15 14.1 4.1 0.15 Quirtr 0-61 0.51 !W 1.44 4.40 Priest Lure Gro'um- r< o r t Frrru- Cu *: li Fiber flnou? Xi i x Aftt*ft- Cten IUTC toft 0.250.22 0 Cr C 07 16 2.6 l Aj 0.11 1 ft 1 40 0 72 3.9 6.OP 0.23 i: QuirU n.7 n.i 41.5 29 4 K6 G y p un.Fe rru- Quftru t ILOUI Mix Cbert ture 3.9 2.6 l.C to U 4 3.4 20.5 4-3.T V.l C.T were relatively numerous although still rare in comparison with the findings in the King's floats experiment. Reaction in While Rets.-- Seventy - three while rals were exposed to atmospheric short fiber asbestos dust for periods up to 32 months During the first 10 months animals were killed bimonthly and for the remainder of the experiment at less frequent intervals. Up to eight months the dust cells were widely scattered and existed in foci only sporadically. Reaction was limited to occasional slight thicken ing of the septums about small accumulations of dust cells. At 10 months there was a suggestion of early fibrosis i:\a few rats, but the change was so slight that it would probably have leer. overlooked without the clump of Cust cells which attracted attention to the area Only 10 animals were cxjKrscd for from 12 to 32 months. In each of them tlie lungs contained minute foci of well defined fibro'is distributed like that of asl-estosis but with.out asbestosis bodies. The lesions, visible only at a magnification of 130 diameters or more, consisted of patches along A ST g I IF INDUSTRIAL HYGIENE AND OCCUPATIONAL MEDICINE ,5'tttriiiii/rv ond / nlrr f-retclton o' I rtkclalton Ex fcrunc n! U`.tk Short Fiber Asbestos Dus!.--The original purf>osc of the experiment was to evaluate the role of short asbestos fibers`in the pentsis of asbestosis. It was felt aho that if the tissues reacted more rapidly .and more extensively to short fiber asbestos than to King's floats there would be a basis for believing that the action of asbestos is in part, at least, a chemical one as postulated for quartz. This experiment, in which the tissue reaction was slower and less extensive than that in the previous experiment with King's floats dust, indicates that the capacity of inhaled asbestos fibers to produce fibrosis is determined primarily by factors not chemical in nature. Of the four species exposed in this experiment, only the guinea pig and to a lesser extent the white rat responded with characteristic peri bronchiolar fibrosis. The cat reacted with atypical subpleural fibrosis and the rabbit with only slight parenchymal fibrosis. BALL-MiLLca Asnr-sros Dust In the inhalation experiment with short fiber asbestos dust a small quantity otTunground short fiber asbestos was mixed with the ballmilled product in order to generate a suitable dust cloud. When that experiment failed to produce an accelerated tissue reaction, in com parison with the response initiated by King's floats, it became apparent that the biologic activity of asbestos is not increased by a reduction of fiber size. Thus the possibility arose that the tissue reaction observed was. due solclv to the relatively few long fibers of the unground asbestos and that the short fibers of asbestos had no more than a very ;r,significant role in the production of asbestosis, a concept not in accord with previous experiments concerning pncumoriorcniosis. Consequently another inhalation exjvcrimcnt was started in which only ball-milled asbestos was used. Composition end A One s Core r r. ire non cl the Dust.--T'nt dusting materia! was the hall-milled. short fiber asbestos used ir. the previous inhalation experiment, but ungroun! materia! was not mixed with it Owing to the tendency of the materia! to form small spherules which prevented much of the fibrous portion from floating out of the dusting machine, the dispersal of the dust was not entirely satisfactory. Therefore, after an initial seven months of operation, steel wire brushes were attached to the inside surface of the hopper and to the rotating paddle 10 disintegrate the spherules and release the filers. Tins arrangement gave satis factory results and was used fer the remaining 21 months of the experiment. The comjosition of the raw asbestos used is shown in tables 2 and 3 Petro graphic and x-ray diffraction examination of atmospheric dust, collected in the dust room with an electrostatic precipuator after the installation of wire brushes, indicated that about IS per cent of the air-suspended material was chrysotile, and aleoul 60 per cent, serpentine; of trie balance, magnetite comprised 10 per cent, brucile 3 per cent, quartz 2 per cent and.other minerals 10 per cent. During the seven month period before the wire brushes were used, the chrysotile content of the atmospheric dust was somewhat lower than IS per cent, but reliable values were not obtained. The dust concentration during the first seven memths of the experiment was about 103 million particles per cubic lcot of air. After the wire brushes were VORWALD ET AL.--STUDIES OF ASBESTOSIS 19 insulhd. the dust counts were higher, and the over-all average for the remaining 21 months was about ISO million. Size-frequency studies of atmospheric duM collected inside the animal cages revealed that nearly 99 per cent of the components suspended m the air could be classified as dumps or particles; only about 1 to l.S per cent was fibers. One third to one half of the fibers were longer than 10 microns, indicating a concentration of long fibers of about 0.B million. This figure is about one-half the estimated value of M million for the short fiber experiment Guinea pigs, rats and mice were used in the inhalation experiment with the 100 per cent ball-milled asbestos dust. The results are summarized in table 9. Reaction in Guinea Pigs--The experiment was started with 300 guinea pigs. As the dust exposure proceeded, there were 39 accidental deaths. 32 of these being due to pneumonia in an epidemic. The 61 pigs remaining exposed to the dust were Willed at intervals during exposure, except for 16 guinea pigs transferred to. normal air after 28 months of dusting. For the first year of exposure practically the only reaction to the dust wis the presence of scattered phagocytes and an occasional minute asbestosis body. At 16 and 20 months no gross response was visible on the tissue section, but microscopically peribronchiolar foci of inflammatory cells T>LBL 9.--Summary cf I nh-alation x/Vnmfn/ u\th Asbestos Dust per Cent B(sll-t4\lied Nature of El pertinent I>y?t uperure con tinuous throufhoot Ul Dut exposure lotk*ed by prorrfidtoc< lo Donoi) ilr a_d: c". ill H rutnei rift 40 M U mice 1C fUlD* l plfl M l i tm u zn M111- 6ut Tit *1 mum After Taj it Ex poiurc, Dut Expo sure, Mo. Mo. ReruUi ?4 0 No epprerlAMe pulnoc* r j reaetloa JO 0 No rurpfflion ot i: 0 No lufkCHioo o! ist*!ie!x cs 12 ElbroJifi typical of irPertOMF prucot 1C mo. *ficr txporure crtt-tC Id is imousl to be riilble rro*'!y: Toe! could be r?D micro^opiciUr *t 1 mo. *od rr.o. Alter tcrmlm Hod of exposure could be seen. At 2-t months (fig. 6/1) there wj; still no change large enough to be seen with a hand lens, although microscopic examination revealed ccilular accumulations about terminal bronchioles and many mpre asbestosis bodies, chiefiy within cells. The lungs cf animals exposed for the full ousting period of 2S months and afterward living in norma] air for two months revealed the changes described above and also very slight peribronchiolar fibrosis. For exposed animals living eight months in norma! air the findings were similar, but at 12 months three of four animals showed grossly visible characteristic peribronchiolar fibrosis with adenomatoid change (fig. 6 c?). The tracheobronchial nodes were essentially normal until cx;osurc had been continued for more than a year and a half. Animals killed at ]2 months and at 16 months revealed a few minute collections of phagocytes containing particles but practically no fibers large enough to be reccpnired as such. After 20 months of exposure many monocytes filled with yellow granules were present. At 30 months there had been a slight increase in reticulum but no fibrosis. Ko further changes occurred in the nodes. Asbestosis bodies were not seen in the nodev, of any of the guinea pigs. M mute asbestosis tLies were observed in the lungs as early 2s three months after exposure t<gan, but they did not become numerous until 16 months had elapsed. The bodies were snort auid practically a!! v.ere intracellular, although at 20 rhonlhs. some were long enough to project beyond the cell borders. It is 20 INDUSTRIAL HYGIENE AND OCCUPATIONAL MEDICINE im[>ortant lo note that in the later month? of ex;>osurr there was a distinct increJse in the number of 1 or.^ fibers, up to 70 micron* in length. in the lungs with the formation of charade 1 ssltc long asbcslosis,bodes Chemical analyses (table 10) of the lungs revealed that considerable dust had been retained in the lungs. After 24 months of continuous exposure the average r- lV '.v - A -v` \ - '* "Cv..-. -T A- V n 2*-XAk\\ ' JC'-?t ^ - c tA. V >V- . Va h;* ~ - " j/ / . ' V '' vl, k; > VK~ A 2N" /a., `"'A , :"bi. * / , H / re*x* > - (A': ^v y VA cp * r* r- r'.KjN, s v) ^\-x-^ \V. r `a 'X' v' V. Arc'.:. C f ie 0--Hall-millet! asbestos inhalation experiment: A. lung of a guinea pig with 22 months' r:u`t exposure. A bronchiole i< shown at the center, w-.t.n a slight accumulation of phagocytic cells but without the formation oi coiiaper. ( X 2&j). />, lung of a guinea p:r with 2S r.ionth*' rijet cx;o*ure and then iff months' inhalatic.n of norma! air. J he rr.icir.n is much iir-c ih.at shewn in A. but there is a slight deposition of collagen, nicst apparent at trie len (x720). value for total silica, per cent of ash, was 25 37. the average value of 12.32 (table 6) for aa fiber asbestos dust. Tins should be contrasted with months to ihi. short r nx--*r VORWALD ET AL.--STUDIES OP ASBLSTOSIS 21 In view of the high values for silica obtained with the animals exposed to 100 per cent ball-milled dust, it is important to note that their pulmonary re';>onsc t was much less than that of animals txjoted lor 2-1 month; to the short fiber abcstos in the previous experiment. This again indicates that the biologic activity of asbestos inhaled into the lung is not increased by a reduction in sire of the fibers. A'cec/ioii it li'kite Ratj and Mice--In thi- experiment 40 rats were exposed for periods up to 20 months and 24 mice for periods up to 12 months. ' In neither pccic> did even a suggestion of asbestosis develop, and reaction was limited to phagocytosis of inhaled particles by widely .vattered dust cells which remained free in air spaces or were transported to the tracheobronchial lymph nodes. No aslxotusis bodies were found in the rats, but in the mice there were a very few (null, nonliaustrated forms within phagocytes. Taslx 10.--Analyses oj Lvncs of Guinea Pi-ls Esposrd to Dust in 1 nkalctwn E-tfcritnn.t u-ith JC\< per Cent Bc'l-Muled Asuestos Dust Z_xpu'urf 10 bull, Uo. Period to Nor1 AL'. )tio. Amt. of Art., cf Drird LuSf To:*) F!Oi. o! I'rirxj IxiDf Tot*) S. ^ of Att) TImik f\e*euos Du* t ). x p o rur e Codiicuou* tnjrloc Life < fi on f"1 0 4 X C.:-0 ;.co 4. 0.?( b oo 0 10 4W 4 iO fc.Cu on _ o.: * o.u 4 tO 7.40 32.0: 0 M/j o.:o 3:4: 0 to: o.r? e.as t 0J4 0 t0 fc 10 L t* 1.02 or 8 o 0.? 7.51 7. < T 7.t; 0 0 i.is o.:: h.w 0 5 fo i.n rc.16 J! 0 tu 1.45 0 It c b.4fj t.o; j i: l.U 1*.M ji ri 5.(o i.n Z2 f*0 0 5 ID l .:b Si Cl i: !< ft 0 tX i.V, l.f-5 i.:i T7.O0 21.70 rr Dui t Expoturr Follo*-e<I bj ProIoncfO fccufdrnc* Id Norm*) AJr 1 7.Si tt: 1 :: C3 i.:4 + *i-b i a. 0 fA on 12.W 34.Jk ts li C li s.n 0.F4 13 0M 1: 41 2+ The eymltol; ixnntr me tlfnir metl-an In mch group rfprwrnl mmly t h* r c t * 11 t drrrrr c! mcMon. i.snr.r Irom 0 lo y: (qur<: .c-cbr ) to 1 * ttnr ri.vmorr. ta tr.l; crprrfmeM 1. The rrlitionitsf;* pply 0CJ7 xithln tr<le i.blc and c.udoi be tompi.-rd with irmbols Id other tit-ire. Summary cud I uter pr eicG.or. oj Inhalation Expertmant ii-itk ]00 per Cent Do!l-MH!ed Asbestos Dust.--The tissue reaction observed in this experiment was not as intense as that in the previous investigation with short fiber asbestos. The reaction was slower in development and less extensive even though more airs: accumulated in the lungs. Since there were fewer fibers longer than 3 microns in the material used in this experiment, the results tend to confirm the interpretation made in the summary of the previous short fiber experiment that the reaction is r,ot primarily chemical in nature, and to supf-ort the impression that reduc tion in size of asbestos fibers does not increase tiic biologic activity of asbestos inhaled into the lung. 22 INDUSTRIAL HVC1ENE AND OCCUPATIONAL MEDICINE The finding of long as.bcsfos.is bodies in animals that had inhaled the ball-milled material is an example of the difficulty of completely eliminating long fibers from a large volurcc of asbestos as required for an inhalation experiment. In regard to the progression of the tissue reaction after the animals had been removed from the dust, observed in this experiment but not in the others, the following-interpretation is offered: When the reaction is well developed at the termination of exposure, the contraction of the fibrous tissue obscures any progression that may have occurred; in this experiment, however, since the reaction observed was less mature, its subsequent progress was more readily apparent. Long Fiber Asbestos Dust Since inhalation of short fiber and of 103 per cent ball-milled asbestos dust did not result in acceleration of the tissue reaction in comparison with that produced by King's floats, the hypothesis that short fibers of asbestos were of minor importance in the etiology of asbestosis was given added support, and attention was directed to the view that the long fibers were of primary significance in that etiology-. The King's floats asbestos used in the first inhalation experiment had a rather low content of fibrous chrvsotile and contained considerable serpentine and other impurities Therefore, it was decided to conduct a new inhalation experiment with a purer form of chrysotile which would be richer in long fibers. Car.fosition orA AI m Psp h c r tc C one c<'trct<pr. c( :hf Dull.--The dusting material employed ir. tlm investigation was obtained from an ast-eslos fabricating plan;. Samples of several varieties of long finer asl-csto* dust were firs' submilled to the Saranac Laboratory for examination, and one of these, wh.ch was low in magnetite and chromite and had a fibrous content estimated to be about 75 per cent, was select! d as most suitable Steel wire brushes fastened to the inside surface of the hopper and to the rotating paddie as in the pieecding inhalation experiment, were used to open up the bundles of asbestos and liberate more fibers into ihe almospne re. The composition of the long fiber asbestos u^cd is indicated by the chemical and petrographic analyses given in tables 2 and 3. Analyse of air-suspended material from the dust room disclosed that about 60 per cent o: the long fiber dust was chrysotile and about 20 per cent serpentine ; as already noted, the composition of a similar air-fioatcri sample of ball-milled, short fiber dust was 15 per cent chrysolite and 60 per cent serpentine. The dust concentration as revealed by impingcr samples tahen inside the animal cages was much lower than the concentration for the experiments with short fiber or hall-milled dust. For the first year of the experiment with long fiber asbestos the aicragc of the light field counts was 32 million particles per cubic fool of air: for the second year. million; for the third year, 39 million, and lor the fourth year, -13 million. The size-frequency of atmospheric samples of the long fibei asbcttr.s dust and of the L"ll-rr.illcd dust is shdan ir, table 11 Loth samples were collected with the electrostatic precipitator. It will 1< noted that there uas far more fibrous material in the long fit<r dust. Guinea pigs, cats, rats and mice were employed in this inhalation exjvcrimrnl The results, summarized in tabic 12, are Ccscrit-ed in greater detail below. VORU'ALD ET AL.--STUDIES OF ASBEST'aSIS 2J Feecliom in (Tvtnro Figs--The experiment wii started with I M guinea-pigs.' Alter exposure hid been carried on lor a year, a severe cpidert>: o( pneumonia arose in the dust room and about one third ol the animals died or were killed. To replace them, 38 more guinea pips were added to the surviving greup. Histological examination revealed lesions in the lungs alter eight months o( dust exposure, consisting of cellular connective tissue atout the terminal bronchioles (fig. 7 A). At 12 months there were adenomatoid changes in the adjacent parenchymal areas, and by the sixteenth month (fig 7 B) definite fibrosis was present in these areas as well as around the bronchioles. The. fibrous lesion could be seen nuacroacopieally at 20 months. From this time on the reaction increased in extent and in the amount of collagen, and by the thirty-fourth month, it had fanned out T/tSiX II.--Sise-Fregiuney c/ Atmosf-beric Long Fiber one 200 firr Cent BellMilted Asbestos Dust Collected Inside Cooes Type of Aitxitoi Loaf 6b................... BiU milled ................. Gri-lDs. *ac J'lprrt. C4 <3 HIctodi Go i so e 5 10 U IcroDi 1.1 4.6 > io H IcrODl 0.0 00 < 10 Hjcfodi r> .8 0.6 > 10 Clumr*. Hkrooi 6 7 1.0 0.6 1.2 Ton) 100 J(X) fr,TaBLE 12.-- 5uir,mo -V Ol Ir.r.C.lot ion f- i inth Long Fiber Asbestos Dust Ni1 ure of x I < r 1 it tz t Dust exrorurr codtisuoui Lbroucb out lilt Dust exposure Jol Jo* rd t; pro Jot-ffd reMdcnct Id doidi] ilr Anlir *ls IK pulor* plfl 4 Cl U 50 r*u 50 mice l! ruiifi pir* 9 ruiori pip* 1 CtU Mil! mum Pjp t x ;*c turc. id o Kii'-rrum Eur e: r ij AI Lpr - Pun r r*o iurt, Ho Rp-ulU 0 Definite Cbrosi* In 16 mo <: 0 Slow |j dfxrlop'-E Tbrorls fWt fppd it 24 rrc is 0 .Virkrd ;*crlt'roDcbioUr f.bTo*!e Ant rccd it 24 mo is 0 Plmilttj rescilop: do Thro?:? to 14 C^irlnc of Icf. t. m-r e t o* j rnclioo abd definite contrectioD o! fibrous 11r u c *1 9 C'rinnr of lnfi.s:nm*torj ruction *nd ltpM co:;;8ctioD o( Cbrour tlrruc n U Sbr.Uir to continuous exposure rroup; rurrr-`tic>r. of prcrmrlon Id one of the two laixtis considerably into the parenchyma (fig. .-?) The lesions were rather sharply localized and the extensions from different bronchioles showed no tendency to fuse, even in animals exposed for the maximum period ol three years. Although the intrapulmonary reaction sometimes reached the pleura, there was no involve ment ol that membrane. Emphysema was not detected at any point. Some thicken ing of the larger bronchi with a chronic inflammatory infiltration was revealed, but it was considered no more than would be produced by a similar period ol inhalation of any dust. In guinea pigs exposed to the dust lor 20 months and then removed to normal air, there was a marked tendency for cellular inflammatory reaction to clear. This effect, accompanied by contraction ol the fibrous tissue, resulted in a diminishing size Cl the local lesions. None ol these animals, killed at various periods up to 14 months after exposure, revealed lesions as large as those in the group killec"at the end ol the 20 month exposure [ecriod or those in animals which remained in the dust room for more than 2l> months Fourteen months after oust ex;*osurc ceased, the foci in lour ol the sit remaining guinea pigs were so small that they were visible only with a hand lexis (fig. 8 B). 2i INDUSTRIAL HYGIENE AND OCCUPATIONAL MEDICINE i In the group tipo'e;1 {or 2? months and thert transferred to a norma! atmosphere * the response ".as quite sirnilar to that in the 20 month exposure animals mentioned j aliovt. Small foci wnt always visible on gross inspection of sections of all 'j jpuinca pigs of the 27 month aeries, but in no instance was there evidence of the i reaction. : Arch I o'( v.- I i Fig. 7.-- Long filer aslcstos inhalation experiment: A, lur.g of a fumea pig with eight months' dust exposure. The broncmolc at the center already snows an accumulation cii phagocytic ceils, and there is a slight depositor, of collagen. Com pare with figure 6 A. showing Inc reaction to bail-nulled asbestos after 2-1 months (X 2M). B, lung of a guinea pig w ith 16 m nths' dust exposure- Again note a bronchiole with its surrounding reaction, consist.ng oi r.brosts and ader.r-m.atoid change Col lagen dc;osition is now seen in the walls of adjacent alseoli. a: the right (>; 2CO). In the tracheobronchial lymph nodes reaction was first visible at the J.ird month of exposure. By the eighth month (.atciics of cellular connective tissue K4., X '*r T IP VOKU'ALD LT At --STUDIES Of ASBESTO'^IS 25 bcfjn to appear in the medulla, and by the fourteenth month men of the node hid been replaced by cellular connective tissue. This picture, which resembled jhat in early silicosis, persisted to the end of the eJt|>eriment. Some animals showed, ,s j variant, heavy sheets of diftusel) distributed moncicytes and large active giant Cells, but there was never any necrosis or hyaline formation. The spindle-shaped Ftp. B.-- Lon;; liber asbestos inhalation experiment : A. lung of a guinea pig with 24 months' dust ex;'.sure. A bronchiole is seen a: the lower center; the larpc area above it represents the involvement of alveolar walls Compare with figure 7 and note the increased extent of reaction ( >; 2CO). B, lunr 01 a guinea pip with 20 months' duM exposure and then 14 months', hvtr.p in normal air. 7 r.e reaction is rrntialiy hire that show n in figure 7 B : The bronchiole at trie right center ts surrounocri by fibrous tissue with adenomatoid cluaj-tpe at the right, There ts residual starring in the walls of adjacent alveoli at the )e!t. it is apparent that no progression has c*ccurrcd (X 2CO). dcw cells were yellowish from fine pigment granules that stained for iron. No fibers or asbestosis bodies were seen. Arch 0 V t( i 26 IKDI'STFIA* HYGIENE ASD OCCUPATIONAL MEDICINE Although asl<s'.9sis todies were found in the lung as early as one month after txjosurc began, they were rate and turd to f\nd At fvt months more wen visible, chiefly coiled inside giant cells, and at eight months many todies Tabli 13--AnolysfJ cl JLvnpj cl Guinea Pics Exposed to Dust Experiment uvfh Long Fiber /{sbestos Dust I nXcJaficn trpoiur* to Duit. Uo. Period It Normal' AU, liO. Amt ot Aah oj Drtac Lwtr Total 8. *V o! Lusr TotaJ 8'Oi. % o! Alb Tt**u fc*-iCUOL Doit Eipoiur* CodUduoui Dunac UI. 4.15 0 04 1.10 I 0 4.33 o.to 111 < -37 0.04 0.03 0 4.45 0 cs IM J 0 4 46 0 06 i.n 4 0.00 l^C 4.35 0 06 ' 1-10 s 0 4.35 0 (3 1.13 4.61 0 tc 1.46 4.-7 0 05 1.76 t 0 4 G3 o :: ! 47 S.C>5 o c* 1.77 I .r! o.io I 0 4 tK 4.34 o o> o.cr i>? 1 ->5 4 4 5* cm JX> n 0 6 c: CM 4.tv 6 ic CM fc.t*? * ! VS CM 11.70 36 t.7 3 it 0.53 0.3l 1: zj> 10 Pi I-*- 3W 0 43 n :: 10 3 3 55 C 4? o s: n 03 14.0? 1+ 3 4! 0 35 1C 15 u 0 s.s: or? id 3 + 3 4r' o r- 11-51 n 0 3.7 4 oa 13.15 S+ J 03 0 3T 10 fo so J.C3 0 31 11.:: j.SS C ?4 c 10 4+ J.Fo * 0 6 6m u 0 f 6 70 0M ::.47 4+ 1 4 .10 0 *7 9n 16 0 ! :'< 0 \5 1:. rO 4 *- r>ut F.rporurt Touted by Prolonrer'. peiMcnev Id Norma) Air lM 0 43 11.:: JO o 3 60 ,3 iS 0 <r 0 1: 13 03 14 s? t+ 1 C^> to 4 ! - 50 10 \ 4 16 } 4.30 c:: 0.17 0.14 or: 7.13 s.so 5.7-5 5 07 t+ 14 J 6.01 JO 14 ! sw 17 0 J1 3S..4K0 0n 0.16 0 .y> 0 <a 4 IV 3. Of 11.61 13.16 4 I4 ?.K 0.3] 8.60 *7 S 1 :.s< 0.15 t u 14 17 t 3.IP [ !.JS 0M OM 7 77 14 r i s r. ( t:i> or? C.73 ! >: 6.31 14 The rjnnhoW averacinr ihp tlv'j? ma'tlo- Ir rreh rrour r?t'rrftt tt-. rer tb' rfUHn drrrrr ot rra;t!ra. TarfiDc from 0 to ^ t. c> r.n M to 4- {tt*r n m knurr tor tMi m-rl- in'M). Tr-r rr la t'or-i ?*:pi a,T)y cmiy HUiln ir.li taMr and caCDOl t< eonparreJ rJib jymLOli Jo Mhfr lit-ifi. writ free in connective tissue. They Income fairly aouncant 2S exposure con tinued, although in some later animals the asbeslosis bodies were only mc-derately numerous. It is important to note from analyses of the lungs (tabic 13) that even though the tissue response at ar.y given period of lime was much greater in the guinea VORH'ALD ET AL.--STUDIES 0I: ASDES7 OSIS 27 pijj of this experiment than in those exposed to either short fiber or ball-milled c-sbestos, the amount of mineral matter in the lung ash was much less. Ktaclion in Cals.-- Four cats inhaled the long fiber asl-estos du>; for periods of U, 25. 33 and <2 months, respectively, and were immediately killed. Two other tats, after being exposed to dust for If months, lived in a normal atmosphere for an additional 2< months. Fourteen months' exposure w.as sufficient to produce cellular accumulations 01 phagocytes around terminal bronchioles and -peripheral arterioles together with compact collections of similar cells in the tracheobronchial lymph nodes. At that time there were no typical asbestosis bodies, but smooth, pointed, yellow fibers were seen very rarely. With continued exposure, up to <2 months, reaction in the locations noted progressed to the formation o! cellular con nective tissue which made well defined sheaths absut the respiratory bronchioles and arterioles, marked lymphoid hyperplasia and lymphoid infiltration of bronchiolar walls (fig. 9). Typical asbestosis bodies were nut formed, although there was - v. rJv. jr ~ri ' vj t.1 -.r./ys:. ;s f >- i -* V'-/ > -'T,. -X- t 'V\V:r X' '-V* .. I Jri "h ov^-. ^ ^ tZ >.SV-r^-V ... * < * e -U - T- N-V * *t ** V-'.-T'di ` '' f. r.V4 ,4 ' ,\v- ,C >-,S y \ ^ - S' : : , . rv;Tr'--J:r lVu'k 9 \v;. >'>4^ . 't: JUV-'j - x*>\-nlC.aw'X* x-i -- '-1 \ \v ^ A Fig. 9.-- Long fiber asbestos inhalation experiment: Lung of a cat wiih 42 months cust exposure. Two bronchioles are shown with adjacent cellular reaction and collagen deposition (x2O0). an occasional fiber, smooth, yellow and ;>ointed. Pleurisy was not present. The reaction was similar in location to that in the guinea pigs, but fibrosis was much slower in development. Roentgenograms of cats made after exposure periods of 25, 33 and 42 months, `respectively, failed to demonstrate evidence of pulmonary lesions. Recclxow in Reis.--Although 20 rats were placed in the dust room, many died from pneumonia and were not suitable for study. Five animals, of winch one was exposed for 19 months and. four for 25 months, were free from pulmonary infection and offered a basis for tentative conclusions. In the 19 month animal, the reaction was ju beginning. All four animals killed at 25 months showed a well market! jcihronchiolar fibrosis After a Jong search, only two small, smooth as;*cs!osis bodies were found jn the 19 month animal and none was found in the 25 month animal, j hus these animals exhibited f.hrosis without asbestosis bodies or fibrosis accompanied by only a very in^Tguent asbestosis body. Arc < ' i ' ' 2S INDUSTRIAL HYGIENE AND OCCITA1ICNAL MEDICINE Reaction In Mice.--Out of 20 while mice used in :his exf>erimrnt, J] lived a vtjr or more in dusl and died or were killed wilhoul inowinj; an appreciable define of pulmonary infection. The reaction to. the inhaled dust was limited to phago cytosis by mononuclear cells. Usually these were widely scattered through the air (paces: a limited number were grouped about the terminal bronchioles, producing some thickening of their walls. There was no suggestion of fibrosis. Numerous asbestosis bodies' were observed in animals killed late in the experi ment. Thus these animals exhibited asbestosis bodies w ithout -fibrosis. Smntnerx ond Interpretation o| Inhclabon Ex periment u-.lfi Lor.g Fiber Asbestos Dust.--The purpose of this experiment was to evaluate the importance of long fibers in the tissue response to inhaled asbestos. The results, in comparison with those of previous investigations, indicate strongly that long fibers are chiefly responsible for asbestosis. Thus, the reaction in guinea pigs developed earlier and became more extensive in this experiment than in previous experiments in spite of a smaller conccntration of atmospheric dust and a lower mineral content of the lungs. Furthermore, typical peribronchiolar fibrosis was produced in cats, although in a previous experiment with short fiber dust peribron chiolar fibrosis did not develop in this species. The'cause of the cellular f.brosis in the lymph nodes of the guinea pigs is not clear. ]t did not occur in otiicr inhalation experiments with asbestos. INJECTION EXPERIMENTS Since the inhalation experiments reported above strongly suggested that long fibers of asbestos are the significant factor in the causation of asbestosis, a scries of injection experiments was inaugurated wherein the dosage and the length of the fibers cbuld be controlled more precisely. Also, by the use of controlled dosages, the relative capacities of various asbestos minerals to produce reaction could be compared. ]n these injection experiments, guinea pigs, rabbits, rats and dogs v.ere used, and the mineral dust W3S injected by the intratracheal, the intraperitonca! and the intravenous technic, but not all the technics were used for each species. For the purpose of simplification the findings in each scries of tests, except for dogs, have been condensed and reported in tables, to which reference will be made later. In the case of dogs, only one test was made, and since the findings were negative, no detailed report is included. ExrrRiMiNTs Using Intratracheal Tech vic As the asbestos minerals do not cause typical advanced fibrosis in extrapulmonsry tissue, the intratracheal tech.mc is the preferred way of introducing fibrous oust into tiie ex;>crimen-.al animal. In this method the dust suspension is injected by means of a special needle or catheter deep into the trachea, from which it flows into the lungs. Comparison oj Fibrous and Won fibrous Dusts.--To demonstrate that the ability of asbestos to produce fibrosis resides in its fibrous character, the scries of injection experiments reported in table 1-4 were p-erformed. yr^- y r '.T/W-t M.--Coitiforijcn cl Reactions to Chrysolite ond Serf'C^fno Injected 'J JntroJrocheolly ;.**arr: >'.arh aMroal va riven an IntratrarUal InJr-ctlOD of 0 j re. of a i |t cml iu*pen*loe ot lh T*o rek* later iOotrer im II* r Inlcruoe r*wn. Tola' unownl ol Coal IriJrctfO * iO fn{. Animal* med: Six {roup* of 9 ruloea p*f* r^rh (one {four for r*rh tyt*e of dual). yrtlo>\* ( vhlcb animal* er killed: Ooe or t*o aolmala id each {roup at I, l, i, &M aod U month* fur U#t lojKduo. ji-rparailon of dull: (ball milled) uohe*ted. n:i niiiirx) for J.H6 hr.^drvd tod Ip ifiti niftMif. O.ry*onk (bill tnlHrrt) Irnhrd: half znlUnd chrjaoiilc hraifil lor * hr. it aioul 700 C., thee m i;iU mortar Z or 3 rms rhD'Oliic (flbrou*} unbfted: Ground In acat' mortar to p* P*1 me*h. t*hrr*otlio (ftbroui) Ifnlted: XOmeih material heated lor C hr. at tout "(O C. Ko further { fill.Hoc. Serpentine (balJ mtUod) unseated: hall milled for l.fps hr.. tiried and rrfrouod In irate mortr. Serpentine (bill mined) bill rnUled aerpeutioe heated lor 2 hr. *l it'out 7C*. C., ihco {round Id afale mortar I or I am. Mineral Chry*otilr (bill milled; UOhea ted C'hryaotllc (bi N milled) IpOlU'd Chy*otlle (fibreu*) uebf a.ted ChryiOtll (fibrou*) Jrolled Gerpcotlne fbi'J mfbed) cobcitod ferf<ctinr (hiL* mill'd) trolled Stic Of Duit Particle* S talCTODf IDd IPW I micron* od k*f t>'jO alcrooi a pprox. H>-IS) mlcrooi approx. 3 tuleror.i aod kii S ntlcrooa aod Jeai RmiMt Grlcdlny d**ftrojrd cepa-lty to ratif f.bro*l*. At 1 mo CODMd'iiMr InSimmiioo olnn a nd erllolar proMfrra Hod and locallialton of duM partiek about hrooehl ole*; it T mo.. only a very riirhi proli for a lit c reaction; at 0. fri nd 1? mo.. "My eraiterc| M'nll mononiK !* a r phaforyte* At 12 m* , a ( microscopic patrhrp of Ihlo alveolar al! tl'^irnmc ^ Ith omr ad t non a i od chaDC' Jo portion ol jit abuu'.n;; on lh\eWmvd brooehl. bo l-odi'r orn. Frariioo limitr-uJ to Urc< forrirr. body ciarU rcib *!ihoul pICKfUCtlOO Oi ODfOUa A dlMloet f.broyl?. Reaction L'w'alij^rl to connective tia*ue aboui trrm:rial bronriiiol^: l;itlc lifnn lhoe< CXoDtract'.no cau*rd a `knom r i oid apr^aranee of air iptccr fiven ofT dir'-liy from terminal bronchiole* Rcaciion trra brrimr nnalirr vllh prorre-*i of time no Ct rcr!on*. Inrc'lvod No chronic plru;i'> even it po.r.t* abutltnc In: r a pulmon a * y chanirr. At 1 me cor.tldcr a ti e Ibflamniatory rd'rua aid Ion of crUuJar pr oil ler a t Ion ; at ! jno cli rr.arkol rHIuicr proliferation and fibre*:* occurrlnp foceHj abo' t rc*piratory bmnchioir* Thia reactmn declfpi1 tx'li-rr a*i-'iio*lf ldn fiad formed and var aa I'hin^l m that produce) !) 1 yr. Intiaia- tlon of aa-J?tof di*t At fj mo, reaction ir5* e*teo:vc than at 2 mo., apparently du* to rontfaruon of fibroj? tiaaue; a3l*f*to*ir tod.l-* ere af'undant. At rno.. fraction rliil lra exirrore, confined to the Immediate Tlrlotlj of tf*e nnall leirrunal bronchiole*. here the rear tlaauc *at Quite dee%e and a l^omLny hyaline In rhar aeter. f-oniMImn It ver, obliterated the tronehioic. Art*cftOM* bodtef bad krotnr scarce At \2 mo., the *dl dcreloiol r-cril*rc*r e Jna] end In r a brnnrhJal edeno matold area* of fibror'* hr d prodorrd C0D*ldcabie di- torlton. ifore penpher illy *err patrh^a of pneumorltlj vliJi eorlnopbtlk Infiltration, aomr of hich a> t*em{ traDfformed, Into fibron- tUnr. The**< erern^d to l*e pre- curaor* of tfic localire*-!. ritfiu*-r pa lobe* of tfilo alreolar *aU Cbrorlf aerr e)3e*brre Reaetloo Unli^ to lar^f fr-rrlcn bpdy riant relU *ltfioul prolt fer a t loo. Utatlr.j: the fiben. 'filch made thern brittle, destroyed their capacity to produce ilfolflcact rr action. l>uet relatively Inactive. At 1 and Z mo . alrr.ple phayo cyio*ta ithoul prob feratlon; at 6 mo., co charge eierpt j*c>f*ltilr lymphoid c*l! Infiltration; at f-, mo.. * allfht elironlc j>neirnon!t t>; at 12 mo., only a little porumonUU *:tbout #Ji:rer;ion of Duel xeiatlecly Inactive. Reaction tm-Ltuiiy me a rne a for unheal'd aeri^otlne. With JrrdUiJ 'rj^ntloc. Irvi Undeory for dual to l* tinW to brunchlal oodca. 30 INDUSTRIAL HYGIENE AND OCCUPATIONAL MEDICINE Fig 10.--Comparison of reactions provoked by injected long fiber and ballmilled asbestos dusts: A, lung of a guinea pig which iour months before had received an intratracheal injection of long f.i-rr asfestos dust. Note the peri bronchiolar accumulation o: cells with collagen oe;-osinon. The bronchiole chiefiy involved is in the midst of the reaction (x 3lO). B, lung of a guinea pig which four months Iciorc had received an intratracheal injection of bail-milled asbestos djttt. A btonchtoic is shown at the right In contrast with A, note that only a lew cells have accumulated afoul the bronchiole and that collagen deposition is absent (v ?l0). VORH'/iLD ET AL.--STCD1ES O/ ASFF.ST0S1S 3! The tests were made with long fiber chrysotilc, unhealed, and with chrysotilc that had been ignited to destroy its flexible structure or ball milled to reduce the length of fiber to 3 microns and less. At the sanfc time control tests were made with serpentine, which lias the same chemical composition as chrysotilc but is nonfibrous A review of the findings reveals that only the unheated, long filler chrysotilc produced typical peribronchiolar fibrosis and that ball-niilied material containing only fibers less than 3 microns in length failed to cause fibrosis (figs. 10 and 11). Fibers subjected to ignition also had lost their capacity to cause serious tissue damage Ignition produced important changes in the chrysotile fibers, among them being loss of water, an alteration from a flexible to a brittle structure and possibly other changes. Expcri- ~'\r> `c V .. f ( ' XJ Z- Xy ' C-- " . v>- x- .1 W L . . ` \>, r4 . p l?> fiy -d y V-'-, r.*'-v si 'r* J YV v_ a' f.*rT-i*v w- * j - l * r yy r:< v._*vVnS -S\' v ' v. * *\ \ N X y- A ^ 1 r Ji \ \ Fig. 11--Serpentine injection experiment: Lung of a Guinea pig that had received an intratracheal injection of this oust four months before. A fcror,chicle is shown at the left center. The phagocytic ceiis exhibit little predilection for the bronchiole and collagen deposition is absent (x 200). mental studies concerning this observation will be reported in a separate publication. Comparison oj Marions Lour/ Fiber Dusls.-- Some very interesting findings arc >i. closed bv the results of the experiments recorded in table 15. First, all the long fiber asbestos minerals tested, with the exception of anthophyllite, produced typical fibrosis. The characteristic peri bronchiolar reaction caused by three representative long fiber asbestos minerals--chrysotilc. amositc and crocic'olitc--is shown in figures 10 d and 12. Why anthophyllite behaved differently from the other usbestos minerals is not entirely dear. Second, with the mineral brucitc, which is not a silicate but is a fibrous form of magnesium hydroxide, a characteristic fibrosis like (4 I i i i 1I i i i )i I ! Arch l l l Il T/JiU IS.--Camfe'iion c! Reotlipr.s lr I'c'inuj Lcnf Filer Duste Injected Jntrotrcc neclty lKeaff: To Injection* of 0.1 n o! i f prr ml tu[^Diop fl*to ! ***** epari, Tol*J do** * b0 mj. Ablmal* v. 7 rom ( to P guinea plpa lor each dual. Juried* wt whlcL animal* were kill's! L'amllj at 1. 4. I aod K moctha ilur Ul lojecUoo. fciec ol dual partkka. fwparated ec Ihii moat fct*n were (rom 30 to to mkrooa loog. Xi Inert] RfuU Cbryaolflc (Tbetlord) C'hryoi tif (a;Uom : low Iron ftnml; ars* tt.Oij AjnOiltr 4>CKddc>l|lf (7io.hr it ) CTC^ioolUr (6. Africa) AxthophyDIte Trrr.oll tc Bruelte OJ** *00! Diitlnrt Additional Information fleet oppoalw chrywoll* (fibroui) UObnUd, In l b It )i. eaerior> tiruitllr ldKikal ltt that In TbMIord chryeothe Hoth f.hrot aod *l*'-toJ *Oflir j.rcvinrnJ wi*h #n fontncl/ *rry rJiilf Iron. ribrom* c^'riirreil e p.upi <r,tMn terminal brorrMoir* aod t| f.nrr dcporlu i iwrJpher) KPirnni O'-vMoi*-.) txIciit/iio>n bod* vn Ktn #o d *$ In cellular Muir well formed 11 on* month Utth k^, f.brou* ilMiir rontrariref tnd occupied nmlt'-r irri but *a more drhv*. Adenomatoid rhifirn motiif \v tho*e *nh ThMforC chryeotile !'icu:i*y limited to lmnM.#ir rlnnitf o! early reaction about arraa ol Rjn'itr JorttizMion Ail^Monr l*rdie* fornmd but *rrr If*. At l mv iltr* Injection. minute lor! of mocunuciea: proliferation about hroncbmlr* acd In mu of itMcela*!' l 1V mo. heavy per n-ronrh tola r pairnc* 0! ftbroi* ofteo *Kh pcpMIrrj proiei-imr* ptrilally clonnp lumen of bronchiole; Kfrrnmiloid appearance marked: connective tieue Traction iheiwed hMTt roliar^n but no h y a Mr. z e tior.; at C mo., minute Joel of veil nnlurnl f.brour about hrnnr hioir*: at C mo., mature a*lelol* f.hroM with fvMrner of e or. t r a r linn ; r o~>* idT a bli chror.le rOMmonti i vlih Infiltration nf lymphorrie* and r omc.pr..i* At ^ mo., am all ir.tr a- broncMolar A'*roua plus* ' nli loe of mot* dcnntf Abrowa at ienph<r7 *T7ptral Atro\'. crvrtotirnnrhinfiU* and r*ribrnnrhioiUI vlth formatloe of atypical a (> 1 (lr |.(.cl ^ Hm'Uitinn of \ 9 lcrari before alh mo. alley ln;erilor. vri) t.t tth mn prral't aftrr Kth mo KeaPtion at 1 mo h*vy erdrf-rnorhio'..P` and j>erii>ronehioi!i > alrxadj ihovlnp Aiifon* minin' af^.,v`tni and At.ro* uh aome neero at lie of ma^irf Inr a'.I: a t tr.n cl At 4 mo hr ary. widely aratirr^d tndolironrhuiMl* and r'n'.rr.nrf.n.iiti t.n* Ar-rcm*. * Uh m a: * defor mity of f<roni'iiif.ir* r.d '. h an a denom a t (cd *p;^trar\rt At 7 and 10S mo., fenriirin m lunp emiiailr tf,'" *amr a* a*. * mo At 1. mo., f or I of fhrovi* endo'.rone hiofr.* md o^r'dircrrl'r lit l tfli larre. run more cVmv rear ti'm^ an j inorr deformity o! *.ror.fh.l tu'-e# t*ut do ciIcd*Iod luto. or aUirctajiv of. i^ripbcral paTDfhyma Advanrrd f.urnu* endohr or.rh ol` t i? and i^rf^roneMoMU 7Vadn<3 ar>*r. !op* Nodi'-* z*ot*d at mo At } no., nr'.j Anrou* endohronrhioinia ard pfrlbronrhlollti*. many riant mil* and aom* iy m i-oor y; ;f reaction. At i mo . rrraK rrra> of md(`f-r one MolU l erattr-d thre-uenouf th* Ju-r: rcllultr Ahro*.. At 5 and 1? mo. area* of broncMolft l rmallrr t*eeau*< of rontranion of <1en*r me., rr.araed lymphoeyllc Id.'J- trat.on a*:d adnromeloid : I'^ur.rr. Ty p.r al bjvirm! Aor(>u p n <* < " r one p mf It P and y^: ibronchloli 11 rrodured bj 0 5^ aurpeo^fon (1 ct lota! d^1*); rrort ac-mal* would not i( i^;p umal t*~ys rj* r-^n/lon J'lhroi* *fi; drvplop'd rcforc *}rto*i^ bc-di^ peer. At < mo . vrji drrrt(..p(i P.orou* i'f one t..oi .t i with 1 rri pr.o'-y t r ar.-j leint rrlb and e dr.'Ki.fi told c-iunro At * mo. lyp-raf broorhiobtr* r of Quite a? ftt.'nnu or a* brae.'y Al-rou* a* with a .;,7c r u* |*<`n.Jon. otf>'TvKc the ar.mr Many d'-'-plj etunnd Abrr* w;,-. a re.nd proporiloo of bat)*! rated e`be-tni* bo !>r` At JC mo., heaey f.r.mua t.rot.ehiolitb. more p^rfbronrhioim* and < ndnbrr.nr moot i<. with lymphoeylra and flaot crJJr; Trry marled edroomaiokJ appparahft. Lyrr rbor y t *r Ir.Attrafion and riant rr!l but no rhrpi A Terr few atypical r>r*toO be*. be At ) mo , many eretumd U-r> c' in 1 r a i.r r nr hmi a r dut wjtfirut jntuitf )r>"e 5:: a t lor.. iyrv.pbrrTi't tr.Attralton of wall* and a frv plan! o-Ii* At f and 1C rr>o.. lltlb mdMire of du*t: a 1p hronfMc-1'* ID'! bronrtn wflh plant ce/Jp In adjacent aJrecf- aod wfth Jjmphocytfc InAltraUon of rlii. pihroaij about t'ronrhlob* At 1 mo., area* c? d-!t JoeabiatloD with col lapse Of alieedi end Infiltration with amte (off t m m. a tor r r'-lK. marro phapea nod pient fell*. V.'ithin tte area err a f*1* f^*el of fibrou? tl*ue and nmnornu* arri* ef hyi'-'rtror.h y of afreolar r pit helium. Many bron* rbloW parked with Ai--r* At 4 mo.. rr:rt! apN'aranr** of Wion uneharif'-d; pleura elirbily tl.^rned over hrary loe a l:r a t ion* of d*jt An ore air-t. a 1 rrrnrnird aat*etr"i f'CeJy At i mn . many lo*l of fit>rrr In bronehlok end alTerder .ImM* ho rubber r'-artion 1* 7--forr: auo, mine 1(^1 afiov.si dbtiret eofiarrn drp^.Mtfon At IC ar*d 15 mo.. rraet/OD K lw-fore witii fibrrl about brr.neh.oI*-* mrrr aui'erent f--rau'e* of coo- Irartlor* and 'Wrraec of lr ft t mmi 1 ion C.Ibo: r*il* prominent. Pleura inarVe^ly Inxcdred. Tyr-leal fibrnu* endobrnor Mo'll i* end jv*t fb r r>r,"h'o)l t U like rcartion to mineral*. At 1 me. rTi*nl\r endr.i.rr'irhiobtl* end i-rtnion- flur*] *. will, riant e-SI d'f'*e fbrnii* |r>op` *U`i.n brotirhlolei and olluJar Ahro*l *N-uit llmm. a d' - r n a l r. 1. ' fbar.re pr'^enl At ? mn . brary Inr r a bior.rbinle r an.1 r*7r.i-ior-'.h-r-la r f.hr'* prr-diif.np r.urW-d drlorrr.itT with fl.*lf'*;*-n ot tui--* a;--f Mlnrreime nf *nrmund>nc air epr,n-*; Af-ro`i pale v 11 hem* hy e Hni/a t lor. ut with f'w nurir; r,o ne-i(,"< T^pi cal a*l*^tr,! t**'? ' e^m At 4 nd 5 run.. |!t|i' ene.r.ce; Tt-rcu* tl^u* eontrartlrr At b*- rr.t dene f'l-rnr* hton<h,n|ii 1* with aet<eto*la bodies. No i'lr',iny No rnt'^C'ion to e ur rot nr. r.p lunp. Ko f.hrftal* within a yea: At 1 mo., r.o rrartfer. fr*`dr hrooeMol**! In al air rpaP*** clump* r, J pieni ^il* pa'-knl with Ar.e eplfu'pe of pla w;u. 1 y mpta < t \ :e Ji. A.: ? a l mr, ni e.tjer*r.t w;:*; no *breio*!e fod>aAt l mo., reaellrn le*a inter*/- tl an at 1 mo ; fair !md riumpe of e*0Djrated giant phapo<*te* cnr-talomp ep>rule ard particle* of tlaeal no rndobtonchill* At 4 er>d f mo. reaction anil din.iobM.rp At 11 mo., foe*' 1 p * * f meumor. \ ! with n<* f.t-ru*** or f ru'obroDC bit it. mcrfJe fat/ iuini*n of rmooth Iron atalnlnp Cbr;*. 12 VORW'ALD CT AL--STUDIES OP ASPFSTOSIS 33 that produced by the asbestos minerals was obtained (tag. 13 A). Since the brucite used contained only 0.90 per cent silica as an impurity, it is obvious that a siliceous component is nut an essential factor in the development of asbestosis. /-N s' ** ~ -*7'*X* ~ ^ -^7 a- >r` ;cv k T-- \ s.-.i '`.v;: - r,* :vl: '' -* .*' w-r:' t, >A < . `r '`'.''i'v" ` V.- V-''''- '-Vi ^y^'vr-A'W^AA-yA-.-.! y. a * r 7- ;v**:;vyy;j. fy' ;c;TTax''n -'l-'s' '-'' <r.. :-r>..*.avt-vvfaiv ; _ 3- Zc-:.1c ? ' f 1t 1 r> 1 Z fi '.'a'1 c1- ->v' - * -x_ V V,; , ; V # / T--> sC_ Sr. V y --ox<A t- b\' /r -- - ^ N '.V ^V Aw'. ^C-" 1 : yS -* .. .-7 A. ''' ' Z'S&*.v&A'.'-'Acay-' ( , -Vw { X > S !v7 V ;'.r> V-^sbf- V' ;^ r-vy/7r-.;^/ ^ 0 :'.A -> 7; fvy^t( J-- .V; - . p i /JybAtv/ 7ov7r::> ^ * ^ -N>1- r-7^X7-*T*.r{.^^ ' - ^ l!--, _ f C ,, ... *_ I v'-'V^ -r .5;:-;' V ' *^7;v.-r ; v ;1 ^B <r7vY -r :i Fig. 12.--Ar.iosiic and :idolitc injection 1 x;crimcnls : A, long of a guinea pig (our months alter an intratracheal injection oi amositc The in rcaciton exhibits pronounced accurnuia tion c-f eel's and collagen deposition (X 2(\'). B, lung of a guinea pig lour months after an intratracheal injection of crc>cibo- litc- As 111 A. pc: tbroncluolar accumulation of cells and dc;osmon of collagen are shown (x2M). ' Third, no fibrosis resulted from the injection of fdass wool fibers (fig. 13 b'), even though glass wool resembles asbestos in TliiiilN cf \ S. idowever, there arc fundamental dincrenccs. A glass wool fiber 3 microns 34 INDUSTRIAL HYGIENE AND OCCUPATIONAL MEDICINE in diameter is a solid rod which in short lengths is fairly rigid, while an asbestos fiber of the same diameter is a bundle of extremely fine filaments which impart to the fiber a high degree of flexibility. It would seem that this structure and the associated flexibility are important factors governing the capacity cf a mineral to produce peribronchiolar Arc' Ftp. 13.-- Brucite and plass wool injection experiments : A. limp of a (puinca nip which four months before had received an intratracheal in; ret tor, ct brucite. Even with this nor,siliceous fibrous rr.:;crai theie is peribronchiolar accumulation of ceils and deposition oi coflapen sirmiar to '.ha: shown in A and 3 of fipurc 12 (X 200). B, lunp nt a pumra ptr which four months l-riotc had receded an intratracheal injection of plats woo!, "i w o hroncholcs ate show:;. otic in cfi-s section and the other in longitudinal section Below the latter is a '.hick-wailed blcod vessel The bronchioles are without reaction and can l-e considered norrr.al tor comparison with oilier fipurcs. Glass awl fibers arc present in this field but cannot be seen at this magnification {X 2M). . . . VORWALD ET AL --STUDIES OF ASDES1VSIS ' 35 fibrosis. Experimental studies concerning this observation will be ' reported in a separate publication. / ' TaBLC 16.--Companion ej Reaction} Produced b) Long Fiber a>ji Short Fiber j Jrjcird JntraJrctfltfolly pouff: T*o JaJfCUoci I C.fr ec. of a fr per col iuipcpiIod cI*cd two dor* vai frO Of. iput jLrlCDiU uk^: SLr iroupa of r\Kea jHfi. it arfcJcb cBtmaU er kflMj; J, J, C, fS% *o<J 31 tnodth afUf lfijccUoD. ToIaJ XllDtnJ Eire of IaiiI Particle* ReauJU Cbry aoUW Bone .".Ur, A dlatmrt f.brol* Refer Vo tbnovlU (fibroua) ud- (Tbct ford) 30 60 micron* Eborl Ct-er. bea'-Kf In tapir 1 So Refer v> cbryaotlle Cb*-^ trilled) uotxatod $ micron* nd )f/j to table U iJDOllU Bods Coer, Il>6> dlCTODJ Typ'r*! f'brcn* rndobroocbioliti* and perlbrobcblolltU. hr'. Cl lo I* Sir 15 Ebort Ct-er. R/kCt'On brnit/d to ph a;or y ioir with Irmphoryllr lr:l JO liatu-p of lOrr.1 'Uv Short fit-cr.r pacled IhilO* AOd ItAI tvohen j-n*roc>c-f locrc* ooe# lrc~c. aome coaled lo form typxai a*ly n-p bodies At J mo. alter ic)rc- tloo. a Ut oil can t r : n r d fnorj s.ie: f'ant relit: pod phaforyt*? wcf xithtc rr fparc* and bad i,ot mirraird u. vn!i< At < mu, free r \ : r arc..-jla r f.Sn bad p:*'-'1. them* !tri hurdihii ii**ue. where tnrrf v* rtterakc prcd.1rra:ion o! lymphoid cei'f add memo' j ic a hut no Soro*'* Ai ( mo toreirr body readier. with e(.>r.,r pr>rurr>cr.!'Ji, Fie bronchiolitis. TyP'cal a jirrxru CroeldollU Loot l<r. Ad\*or^f fif.rou* ci'do.nr one inoitln and p^rlbrObcMo- (BoJria) ' micron* Ebon. r.;*:. i;;i* F.rfn ic- tab'c 1^. Ko fifxoM* At l mo., air fpaerr corr.prf*ted and JO L2ic:ODI u>d larrcif fili^*! with r . * r. i rriw {er*0'l vjtn dost r.efdxt bfAtt't ir. *: i r a tref uijh ntc:c'r>:n and lympf*- old ceb* At i no, a m o d cr e l ? decree ol re`Icier isf.'tre Hort oJ r5*i. mnl; fits; re,is part'd Ub <3il eplcu*r? At G ar.d f- - rno.. mac<-* cl ciant eel':, tor.rdofrni pa;;icier, in rent!: b:or.cn; out not lo rr P:r&l or y tr o: e f* c> .* ; Brnehr: ezr* idtfy cm- terfd In tennoei air ipurr* Sur^rout atw:`to.`le bod'^. So mhct1";* in conrectiTf ti`fue So endo bronchial proMrre ;ion. At )I no., mtny ece.urred irr.a'l ri'oncyyfn pae^rfi with du*l No cr.dchror* tMn* So j--r.ptic: 11 r.brofis. lo lymph node, eiicht Teliculo*!?; do f.-r'-Ms. Ablbopb jLjU boza fiber, Lynrphc-ryU: In f.lt: a : !cr. and ^laot cclif tut do drfiolle 2a-.`0 micron* fpffi*.B Refer to Jj. Ebon fib::. 3 miCTODI So fioro1 ? ar,d preictireily to tkHoiF t*ocfiAt 1 mo., local eol',vt,c-tf ol dun-r.iifd rr.orocptc< end a abd ku Ifv r'a hi rr He: at -J mo.. omf edcncmatO'd cp.trtf.'lal reaction; at f rnc , nmpi^ porcrr.cr.tlis w'.fh Phapo c.nf''n of fhort f:f''Tf. at 11 rno., I * c i.; r. * and fharpiy )ocal<:fd eci'^tir-n* of dc*l cJ( ipfidr air iparm* alnnut tfrrr.ir.al ar`c:iolr-j Reactinn in a!U limited to lymphoid e<<l ir re t fon. So dr, real*. Jn lymph node. reactioD limited to ehebt promiofnet of reticu lum. Trcmoliu Lone f.t-cr, Fibroma about bron^hloie*. Refer to table 15 SO micron* Ebon tt-.t, Elmplc torcirn body r^actloo. So arute Inf. a mm a t too. 50 micron* So a reumul a t irn of Cud In or about Ifrm.'.na! btotv Dd )rji chlokf. Sc- rndc nrot.rbitiA At 1 mo., accturrd mill fla r>t erf.'* nd coi*id:rM<- JnMt;:on ol lihrct valla *tf> moncyy'.ea ar.d JamphoM rrii*. At < mo., little eherr# nerp'. more r*-lluitr lnf.it r a tloo of eoh- nnrtlrp 11`ruc. At f rno.. lymphoid iu f.'tr a t ioz and thieWnlnr of ah at-oui eome t*ul rot all terminal bronc-Voie*. Bructw Bone fi.ber. T'yv'-cal f.f.rojB * ndr t ro-ic r.loll t le icd pcrftroDchto.'flJ* r.lcroo* l'*f rrart.ro io 'i'(HC1' minera!* Rrl**: to tat.r 15. Ebon f.:/r Jrert t.T;* of r^'cirn At 1 mn 11 u r Ir.f^xi oh, rrr.ali lt (made by moM'jUB wicriy >r attrrr-d tnn-ui;h a.r rparr-; |<v-u i m:Mbc loor of e;orcir*! v`.t*. iyn.rhoid !r. f . i r a t.c n of rorr.rre#rd I fii-cri * :n. a.';;-arr t So cr 6 Ol-t cr.r n 111 rranicn tt ;h rv 1Ur ;*olire- th r y * o i b *. At 1 t'O. r c a r .: c u i rr. 11 a r to that at 1 i m*c) rr-o.; tji*'rai l.^toi| P'-o.-b rern At l! rno . emtli eJuTT.pi of Icariitr C.jfl f*fii p f. a a oe j tr# . no fibroei*. So fraction In lymph r.tyjc* Comparison oj Long Fiber end Short Fiber Dusts.--\Vi:h quartz dust it has been demonstrated that the smaller the particles the more i i i i J6 ikdvstri.il hlcieke akd occcpatiosal yr.DiasE intense is the tissue icaction and that particles larger than 3 microns in diameter cause little reaction. In the # case of asl<stos, how, e_ ver, the reverse is true and aj>pr,rcrtly only long fibers have any speem: effect, as was suggested by the inhalation experiments. This is confirmed by the data of table 16, in which a series of tests with fibrous minerals is reported. When the injected dust consisted of fibers 20 to 50 microns long, all the fibrous minerals tested except smthophylhtei as noted in the preceding section, produced fibrosis; when the material was prepared by first grinding the fibrous dust until the length of fibers was reduced to 20 microns and less or, in some cases, to 3 microns and less, none of the injected dusts caused fibrosis. These results diner from those of King. Clegg and Rae,11 who reported the production of. reticulosis comparable to the experimental silicotic nodule in rabbits receiving monthly intratracheal injections of 100 mg. of Rhodesian asbestos fibers, 15 microns long, and tiic produc tion o: diffuse interstitial fibrosis in rabbits receiving similar injections of short fibers. 2.5 microns in length. Wc believe this dose, especially in the long term rabbits, is highly excessive. In our exfenments the dosage was kept low in order to minimize untoward reactions which might obscure the peribronchiolar type of fibrosis which characterizes early human asbestosis. Exrtxi.Mt.vrs Using Jntra vrvous Technic The experiments summarized in table 17, in which the intravenous method of injection was employed, show that the asbestos minerals are far different from quartz in their action on tissue. It has beer, repeatedly demonstrated that intravenous injection of quartz particles 3 microns and less in diameter will cause a typical tissue reaction with the development of hyalinized fibrotic lesions in extrapuimonary sites, such as the liver and the spleen. Asbestos minerals, however, on intravenous injection generally produce only an inert type- of reaction, as is revealed by the results given in the table. The reason for the early deaths in the experiment with chrysotilc particles is not clear. ExnxiMtvrs Using 1 NTRArr-Ri-roNnAi- Technic The results of injection experiments with the intraperitoneal technic are given in table IS. It will be noted that the long fiber dusts produced a fibrous reaction while dusts composed of particles 3 microns and less in size caused only an inert type of response. These experiments indi cate also that the fibrosis initiated by the irritation of asbestos fibers is not rcstiicted to the lungs, as was formerly assumed, but can be pro duced in the peritoneum as v.eli. ot her experiments l win; asuestos minerals A number of additional experiments were conducied to throw more light on specific phases of the asbestosis problem. 11. King, E. Off;.":. J. 'S , .ini! Kac. V. M.: Ehrcl of AsVsios. and of Aslicstos and Aluminum, on Lungs of hi!.bits, Thorax 1: lFo, If-tO; abstracted, IndusL Hyg. Digest, 19-w, vol. 11 (Feb.), no, Z3-t. T A n !.r. 17.-- S u m m a ry o f In je c tio n p .r p e rtin e n ts b y In tra v e n o u s T e c h n ic 37 VORII'ALD ET AL--STUDIES OF ASBES7 0S1S 39 P*CJTLcn\T Acnos' or Aluminum CourouNi'- Whcn colloidal aluminum hydroxide had been added (o a suspension of long fiber chrvsotilc prior to injecting this sns]>cnsion intratrachcally into rats, the aluminum compound chd not prevent the irritation of tissue due to chrysolite. If anything, the acute inflammatory response evoked by the injected fibrous mineral was accelerated. One month after the last injection of the dust suspension the bronchiolitis was becoming fibrous. King and his associates also found that aluminum failed to protect pulmonary tissue from the irritation caused by asbestos fibers 11; in their experiments metallic aluminum was used instead of the hydroxide. Foaxiatiox or Asntstosis Bonir.s The iron in the coating of the asbestosis body appears to be derived from blood or tissue elements and not, as has been suggested, from the mineral fiber. After two kinds of chrysotilc were injected subcutaneously into the groin of a guinea pig--one kind containing 2 per cent and the other 0.2 per cent ferric oxide--the asbestosis bodies were equally numerous at both sites of injection and showed no difference in their reaction to prussian blue, the reagent which stains iron. This finding is in agreement with that of Giroux." Tissur. Reaction to Asbestosis Boi>ies Asbestosis. bodies recovered from human lung tissue and injected intratrachcally into guinea pigs failed to produce a fibrous reaction. The nt3lcria! for injection was obtained by digesting with sodium hypochlorite solution the lur.g tissue removed at autopsy from an asbestos worker. The asbestosis bodies could be seen in the guinea pigs for at least a vear after injection. This experiment shows that the asbestosis body has a rather resistant coating which is not destroyed by moderate hypochlorite treatment, which may be maintained in vivo for a year or longer and which renders the fiber incapable of producing fibrosis. It thus appears that the coating is a protective mechanism. This thought was expressed by Beintker as earl)' as 193-1." THEORY OF IRRITANT ACTION Two hypotheses have been proposed to explain the tissue irritation and reaction caused by asbestos fibers: the chemical and the mechanical. In the chemical theory, which is based on experience with quartz, it is assumed that the asbestos minerals dissolve in the body fluids and that in this process their bases are leached away to leave silica in a form capable of irritating tissues. According to this hypothesis asbestosis is merely an indirect silicosis. Several facts make the chemical theor.' untenable: Intratracheal injection of brucite fibers, which had a silica 12. Giroux, M.: Amisniosc experimental : valcur pathognemonique du "corps d anv.antc," Laval nic'd 8:239, ]9!3. 13. Bciniker, E. : t.'t<r die Asbestosiskorpcrchen : Berner true gen ru dcr Arbeit von Bcgcr, Virchows Arch. f. path. Anat. 283:527, J93-1. <0 INDUSTRIAL HYGIENE AN D . OCCU P AT ION AL MEDICINE content of only 0.90 pxr cent, caused typical fibrosis like that produced by the asbestos minerals; free silica particles increase in potency as the particle sizr becomes less, but asbestos fibers shorter than about 10 to 20 microns are relatively innocuous; aluminum hydroxide neutralizes the irritating effect of quartz but not of as'nestos; serpentine has the same chemical composition as long fiber chrysotilc, but it produced only an inert type of tissue reaction; there i a wide range in the chemical composition of the minerals which do cause asbestosis (table 19). In view of this evidence it seems more likely that asbestosis is caused by an unusual mechanical irritation due to long asbestos fibers, this irritation being related to the peculiar filamcnlcd structure of the fiber and the associated flexibility, which are possessed by no other foreign body studied. Thus, ignition of chrysotilc fibers changed their structure and made them inert, although the same fibers, before being heated, would have produced fibrosis (table 14). Further support for the theory of mechanical irritation is that asbestosis occurs in an organ of high mobility --the lung--and that a fibrous reaction can be produced by injecting FJbrou* lllncrtU Arooiltc............................. Amphibolc...................... Auihoi'hjUUc................ Brxjcite............................... C*iT7*oUlc........................ CrocJdolitf...................... TrtrsoUlf......................... EiO. 4C.13 46 <'A ifc.Ki otc x.y. b* 99 Sr..TO TaBUE 19.-- AnC.'ysfJ c'j fl.Sr.TuJ }! I nrrcU Tc :0. 4.00 os: 6.7e :.jj )c.:r *-> TcO *#c n.d: 0.36 4.59 AliO. ** 3,oo ioo C.ZZ 0.46 0.S4 L01 0.S6 C0 ^ ixr. izz: 0 *< OfH O.CTi 0.*o 444 UrO CJS t9.ro :: ia iN` 3-v6 17.7 > * N..0 0.12 on o.s: 0.P1 o.rJ 6.97 6.7* K.o % 0.50 0.K C.ifc O.lt 0 c* C-17 O.I lrcUloa Lots < HU c. > 10A 0. %% 0.6-5 e.r 1.60 o.n 4 06 0.5o 5S.W 4 JO J4.W 0 C? i.to 0.M 1.78 Tput 99;; 97 77 w i; *k 90 65 wr asbestos fibers into the peritoneum, where th ere is also a degree of mobility, but not by injecting them into other cxtrapulmona ry organs such as the liv er. the spleen and subcuta ncous tissue. COM PLICATIONS The experimental investigations with asbestos minerals were con cerned primarily with the effect oi the dust on norma) tissue, but some attention was given to other phases, such as susceptibility to infection. The only experiment in which the effect of asbestos dust on a pulmonarv infection was Studied was the first inhalation experiment, carried on with King's floats dust. It is unfortunate that, owing to the lack of adequate facilities at that time, infection studies could not be made in the other inhalation experiments also. Sl'SCTTTimUTV TO T UfiCBCt'UiVS Inflctiov * The development of a tuberculous process initiated at the beginning of exposure to dust, and also of a tuK-reulous infection superimposed on an established asbestosis, was describ'd in preceding sections of this paper. It may be staled that asbestos when classified according tc the effect of a dust on tuberculous infection would be placed below an active I'ORU'ALD ET AL.--STUDIES OF ASBESTOSIS 41 (Just "like quartz but above an inert dust such as iron oxide. In animals infected with attenuated tubercle bacilli, quartz causes the infectious process to progress until the animal dies nf tuberculosis. Inert dusts have no effect on the infection, and the lesions usually heal and the disease disappears. Asbestos dust is in a different category. In the experimental investigation, when the fibrous dust was being inhaled dur ing the evolution of the infection, there was spreading of the tuberculous process for a lime, but usually the stimulus for continued proliferation of the tubercle bacilli was not sustained, the progression was arrested and healing followed. Ir. guinea pigs infected with attenuated tubercle bacilli after being exposed to asbestos dust for slightly more than two years, progressive disease did not develop. The only modification of the infection was one of localization, a few bacilli being retained in the fibrous terminal bronchioles and forming tubercles there, in addition to the usual foci beneath the pleura. Such tubercles healed in a few months. S U S CXrT1E! L! TY TO NoNTL'SCRCULOUS INFECTION There was no specific experiment concerning the effect of inhaled asbestos dust on nontuberculous infection, lirtcrcr.rrcnt pneumonia was rather common among animals exposed to asbestos dust, the frequency in guinea pigs exposed in the four inhalation experiments ranging from 16 to 39 per cent. This incidental evidence suggests the possibility of an effect of asbestos dust on nontubercuious infection. Nevertheless, since such epidemics are not uncommon in inhalation experiments with other dusts and even m the colony of norma! animals, it is felt that the .inhalation of asbestos dust does not exert a significant effect on the susceptibility to nontuberculous pulmonary infection. COMMENT AND SUMMARY Owing to the vast amount of data included in this investigation, it seems most convenient to summarize and to state as concise!)' as possible the various observations which emerged from the experiments and to follow each with a brief resume of the evidence. A. Various species of animals, including the guinea pig, the rat and the rabbit, but not the mouse and the dog. develop peribronchiolar fibrosis of the lung similar to human asbestosis after being exposed by inhalation or intratracheal injection to long cnrysotile asbestos fibers. Both inhalation and injection experiments provide ample support for this statement. Figure 8 A reveals the cellular fibrosis that occurs in guinea pigs following inhalation of long fiber asbestos; figure 9 shows the fibrosis caused in the cat by inhalation of long fiber asbestos dust. Similar but less extensive fibrosis occurred also in rats and rabbits (table ll. Mice and dogs failed to respond. This variation in response of different species to identical dust exposures is still to be accounted for. B. Long asbestos fibers arc essentia! in the production of the peribron chiolar fibrosis; short fibers are incapable of producing this reaction. <2 IKUVSTKtAL ill CIEXE ASD OCCVI'ATIOS'L UED1C1SE Jnhal iti'n experiments with asbestos dust suggest, and intra- Uarli'-.il nij'-' ti'.n ex|.>:rinvnts confirm, that peribronchiolar fibrosis is i '- by 1.' -nMar-. between 20 and 50 microns in length but not by ja.rtii l s t.bort'-r limn 20 mirrons ftabic> 10 and 18). This indicates ili.ii ill* ii.iiiMM'iin l> .; i!i oi fib'-r )!o- -' s.in^ ib' capacity to j.r'xluce the ly|i'al |.- i ibi be ,1m librn'.i'. in animals F som<: where between 20 and '.U> mi< J'iiiiio d .indi'-. havr not b'-cn carried oi>t to determine tin- ii|i|.< r limit at i ifit iivc hin t length Jt appears, however, that that limit will lie determined by the inhalability of the fiber. C. The mode of action of the loaf; asbestos fiber in the production of asbeitosis is primarily mechanical rather than chemical in nature. The evidence for this conclusion has been reviewed in a preceding section, page 39. The flexible ^lamented structure of asbestos fibers plays an essential pan in the irritating action, since the solid, inflexible fibers of glass wool do not produce fibrosis (fig. 13 Z>). D. Typical experimental asbestosis was produced by the inhalation of an atmospheric suspension containing an average of 13S million asbestos particles per cubic foot of air by light field count, of which less than 1 per cent consisted of fibers longer than 10 microns. In the inhalation experiment with 1CX) per cent bali-miiled asbestos dust containing 0.6 per cent of fibers longer than 10 microns ftabic li) a; least th;.: ar. arm. *.-hcric concentration o: as:>tr.o; cur. rtimer.---- less than 1 million pG.6 per cent X 13S mi'.hon j r.bers longer than 10 microtis per cubic foot oi air is capable of producing experimental nsbcsnvb in cranea nigs. The a cra.nl loner lur.a. r; ccnrcntrar.cn of long til ers ncccssara to produce asbestcrsis in animals cannot be estab lished from these studies. E. The duration of exposure requited to develop the pulmonary reaction to inhaled asbestos cus: is inversely proportional to the concentration of long fibers in the atmosphere ; as the concentration is increased, the reaction develops in shorter time. The basis for this statement appears in the data of the inhalation A) experiment with long fiber asbestos. For that experiment the average concentration of the atmospheric dust was about 40 million particles per cubic foot of air, and size-frequency determinations disclosed that 6.7 per cent of the air-suspended materia! consisted of fibers longer than 10 microns (table 11). Thus, by calculation, it is estimated that the con centration of the longer fibers was 2.7 million (6.7 per cent X 40 mil lion). The lungs of animals exposed to the long fiber asbestos dust revealed that the pulmonary reaction developed in approximately onehalf the exposure time required ior its development in animals inhaling the ball-milled product, for which the concentration of the longer fibers was only 0.8 miiiion (0.6 per cent X 138 million). F. Established experimental aslrcstosis ceases to progress on discon tinuance of dust exposure. The experimental im estigation shows, in fact, that on discontinuance of exposure there was an appreciable clearing of the mature pulmonary VORU'ALD ET AL.--STUDIES Of ASBFST0S1S 43 tzK.,is, due lo contraction of the fibrous tissue. In contrast, an imrr.a-*turc tissue response, evidenced primarily by cells with little or no1 fibrosis, continued to progress. It is assumed that, following attainment of fibrotic maturity, the same process of contraction would ensue as was noted for the mature lesion. G. The formation of asbestosis bodies represents a coating-of the fibers by blood and tissue elements, winch results in loss of ability of the fiber to produce fibrosis. Intratracheal injection of asbestosis bodies failed to produce the typical asbestotic tissue reaction in experimental animals. The cessation of progressive reaction observed soon after exposure terminates may be due to the formation of asbestosis bodies. H. Aluminum hydroxide failed to neutralize the fibrosing action of the long fiber asbestos. Aluminum hydroxide added to the suspension of chrvsotile asbestos prior to intratracheal injection did not retard or prevent the development of asbestosis in rats. I. Inhalation of asbestos dust did not alter significant!}' the final outcome of experimental tuberculosis in two series of guinea pigs exposed to the dust. The apparently mild influence of asbestos dust is in distinct contrast to the stimulating effect exerted by inhaled quartz on a tuberculous process in the lung. The interpretation must remain tentative, however, since it is based on an investigation limited to two series of guinea pigs exposed to only one kind of asbestos, namclv. King's floats: Table 4 shows that when the infection was coincidental with the onset of dust exposure, there was temporary progression of the infectious process, with subsequent healing; when infection was initiated after 26 months of dust exposure, the course of the tuberculosis was not appreciably altered. The latter finding is quite different from our usual experience with quartz 1 dust cr with mixed dusts containing quartz, wherein the adverse influence of quartz on a tuberculous infection is manifested most strikingly when infection is initiated after a period of dust exposure, viz., superimposed on a background of established silicosis. As indicated above, this more sensit.ve test, when applied to asbestos dust, failed to demonstrate that the latter had an adverse influence on a tuberculous infection. The inability of asbestos dust in that experiment to afreet unfavorably the tuberculous process furnishes strong support for the interpretation that inhaled asbestos dust has no more than a mildly unfavorable effect on pulmonary tuberculosis. This invesiijption was made possible by the generous financial support of a group of companies of the asbestos industry.