Document 62e3eV5KL4ang0Zm56n19ve4

I COPT THIS SARANAC LABORATORY FOR THE STUDY OF TUBERCULOSIS OF THE EDUARD L. TRUDEAU FOUNDATION Post Qffloe Box 651 7 Churoh Street SARANAC LAKE, N. Y. April 19, 1938 Nr, Vandiver Brown Johns-ilanvillo Corporation 22 East 40th Street Now Yoric City Dear Mr. Brownt I am enoloaing herewith a aumaary of our experiments on asbestosis. As the results differ materially from those obtained in the previous experiment I am appending sono comparative photographs. In aeso you wish to onho several copies of the report for the various contributors, I am sending along duplicate prints for this purpose. Trusting that you ma7 not be too dis appointed by the negative charaotor of the results, I am, with very best regards Sincerely yours, LUGlCC Enclosures (s) Leroy U. Gardner, U.D. Director 'IV Cll 0Q89 Second Progress Report on Experimental Aabestosls by the Saranac Laboratory, April 18. 193B The inhalation experiment with asbestos dust has now progressed sufficiently to permit a more detailed discussion. The conditions defining this experiment are briefly summarized by the following data: The Duet - is predominantly fibrous asbestos (ehryaotile) with some serpentine, dolomite, chromite end magnetite. As rsaelved from the plant much of it was too coarse to bo inhaled. It was therefore reground in a case-hardened steel ball mill until the max imum partiolo size was 3 mlorons and a greet majority of the fibres were 1 micron or loss in diameter. This roground satorlal was too ex pensive to ubo in the ordinary 5x6x8 foot dusting ohambers and it ves so fine that it paoked in tho dusting hoppers. Therefore a limited amount of unground material was added to it to set up a duat oloud. Dust Counts are made with a Greenburg-Smith ispinger appaxatua from time to time, Tho average concentrations maintained inside the animal aages dally, 6 days a week* ore indicated by the follow- Aa the animals spent their entire lives in tho dusting room the7 were subjected to a considerable but unmeasured concentration of dust during the remaining 24 hours of each day. Enough dust adhered to their bedding so that at night they were oxpoaed to conoentrationa of the order of 2 million or lees partioles per cubic foot. 2 lag figures Partiolea more than 10 mlcrono 643,000 per cubic foot of air(light fie! Particles leas than 10 microns 86,100,000 per " ""* 471,300,000 " " * n (darJc fdald The last figure, obtained bp counting the partiolea under dark field Illumination, indicates that thpro wars an exoess of fines. In moat dusts tho ratio of dark to light field counts 1b 2 or 3 to 1; here it la over 3 to 1. 3lzo Prequenor Counts Partiolea less than 3 microns 79.4$ Particles 2 to 6 microns 13.0 Partiolea 3 to 10 miorons 3.4 Partiolea more than 10 microns 2.0 AgMn the great preponderance of small partiolea is indicated. The first roport mads on Hay 3, 1937 pointed out that the Inhalation of high concentrations of very finely ground, asbestos dust had*not produced any significant changes in the lungs of guinea pigs, rabbits, white rats or cats during a period of 3 months. On Uarch 22, 1938 tho du3t exposures of these animals hod been continued for a period of one year. Representatives of eaoh species were killed and their lung tissues were examined microscopically for evidences of aobestosis. The lung tissues of the guinea plg3 were also subjected to chemical analysis. The results have beon somewhat surprising. -3- 8 Guinea Pigs - foiled to show enough evidence of roaotion to the dust to be detected on gross examination of their lungs. Even in thin mioroaoopia sections the changes wore too slight to bo visualized without magnification (seo figure 1). When so * observed it was found that only the very earliest stages of asbestosis had developed (figure 2), No fibrosis had appeared; the reaction was very largely one of the dust cello which had surrounded and walled off myriads inhaled fibres and partloles of dust. Asbestosis bodies, which customarily form about asbestos fibres in the lungs of guinea pigs and human beings had developed but most of them wero extremely snail, as would be expected in dealing with suoh fine dust. A moderate number, presumably from the unground dust wore much longer and often extracellular. The lungs of three of these guinea pigs wero analysed ohemioally for their total mineral and silica oontent. The results obtained are indicated as follows: Dry Tissue Ho. Ash $ Si02 Ash 54 Si0: 0 11 12 Normal Controls 5.02 4.53 6.16 5.61 0,51 0,46 0.34 0.10 10.23 10.0Q 10.54 1.83 3^2 Controls 12.02 5.2S 43.88 These figures indicate that the total weight of inorganic material in the lungs is not inorensed even though the seotlons reveal groat numbers of fine particles within tho dust cells. This oould be explained on the basis of the very small size of ths particles whose ooabined weight is negligible .' That there are appreciable quantities of cilioa-containing foreign bodies is > t shown in tho other oolumhs} the dried lung tissue oontaina 4 or ' 9 tines the normal amount of silica and in the ash the silica oontent is nearly 10 times the normal amount* When compared with the average figures for a group of animals exposed to pure quartz for one year it will be noted that the total amount of aah and the percentage of silica in the asbestos series is relatively low* The results of theoo chemical analyses seem to indioato that asbestos dust, even when very finely divided in not as readily inhaled as a particulate dust like quartz. ' 3 Rabbits - Autopaied after one year of exposure shew slightly more cellular reaotlon in the lungs than tho guinea pigs* The ohongea wero visible on gross examination of thin mioroscopla sections but not on inspeoticn of the lungs as they wars removed from the body. Uioroacoplc examination of the 3sctlon3 disclosed con siderable accumulations of phagocytic oells about the inhaled dust. The fibres were unchanged und no esbestosis bodies had developed. There was no evidence of fibrosis. A similar result was obtained in a previous experiment on rabbits. 3 white Hats revealod ohangas comparable to those in the rabbits without the formation of aabootosio Ifcodios, in two other animals killed on the Qth month tharchanges were similar in character but lsaa intense. Tive other rats have died of inter-- ourreat chronic pulmonary infections. They were discarded as their lungs showed little or no inhaled dust. Tho findings in this species confirm those obtained in a former experimentf 8 Cate died of infeotlona within the first 3 or 4 months. Their lungs revealed little or no dust or reaction to it. One oat was killed after one year's exposura. Grossly there was no evldenae of dust reaction. Microscopic sections showed numerous v aoattered phagocytes containing minute particles of esbestos. Nfot , long fibres or asboetosla bodies could bo found. The lnjaotion experiments with 1 to 3 aioron particles of the various fibrous silicates and serpentine mentioned in the previous report have uniformly failed to produoe soar tissue either in rabbits or in guinea pigs. Anthophyllito, orooldollte, soda tremolite and serpentine have now been observed for one year. Amoslta and esphlbola for 6 months, Tha difficulties attoadant upon Intravenous injection of chrysotilo -have not been overaome but the attempt has not been abandoned. All of these minerals are without offoot upon the extrapulmonary tissues and none have produced asbeatosis bodies. Comments - At first sight the negative character of these inhalation results might seem discouraging for tha original objectives are apparently not being attained. Instead of producing pulmonary asbeatosis at a rapid rate the reaction is relatively insignificant. A whole year's exposure to a comparatively high concentration of exceedingly fine dust has not produced enough change to be visible without high magnification of niorosoopio sectIona. The reoults ars not only surprising but they challenge explanation* '.'/hen they are compared with the findings of a previous inhalation experiment on guinea pigs they suggest that the original hypotheses aooeptod in planning the present experiment wars erroneous. The vory fine duat employed for this test has oauaed muoh less reaotlon than the ooarser material used in the first one. This result was obtained in splto of the facts that the amount of fibrous material in tho new duat was 3 or more times as great as that in the old, and that the atmosphorlo concentrations maintained were perhaps 10 or 15 times as great. The factor of particle oize is apparently the one responsible for the difference in results. Host of the asbestos fibres in the lungs of the new experiment animals are small enough to be entirely contained within the body of a dust cell. Some, originating from the unground material placed in the dust hopper to facilitate generation of duBt are_longor. The short intra cellular fibres ere treated by tho lung more or less like parti culate dust. Instead of being concentrated about the terminal bronohlolea as in the case with longer fibres, they are scattered widely throughout the air spaces. Few establish oontaot with the pulmonary framswork os they ore protected by tho bodies of the duat cells which surround them. If their action be ohsmical, not enough are oonoentrated in any particular focus to expect apprec iable reaotlon. 3hat little effect there has been might readily be due to the limited number of long fibres. It is unfortunate that any unground fibre was added for otherwise It might have boen possible to state with certainty that the short fragments caused no fibrosis. If these early results are substantiated on subsequent observation of the animals exposed for longer periods, it is believed tha the chemical hypothesis of the action of aabostos will have to he abandoned* In Its place It will be proposed that asbestos fibres aot an mechanical Irritants* Already there is considerable evidenoo to support ouch a hypothesis, The particulate serpentine which has the same chemical ooaposition as the fibrous ohryaotile has been proved to be incapable of producing a fibrosis in organs other than the lungs, When ohryaotile is ground so finely that it approximates sorpentino in physiaal state it loses its oapaoity to cause flbrosia. If its action were ohemical in nature it should beaome more active as the partlole size decreases for under suoh olraumstances relatively more surface should he presented to the cells and fluids of the body. Quartz, whose action has been proved to he physico-chemical, behaves quite differently. The smaller the particles of free Si02 the more rigorous and rapid the reaction they promote. Their offact3 are not restricted to the lungs of certain species but oan be elioited in any organ of any animal, bird or fish. In the case of asbestos, on the other hand, irritating properties are only manifested in the lungs, and than only in the lungs of certain species of animals. The smallest fibres, which should theoretically be most active are apparently inert while only the longer ones seem to causa fibrosis. It is Inferred thoreforo that their action is meohanlcal and that the long stiff fibres are irritating only in the lung because this organ is in active motion during respiration. In sluggishly moving organs like the liver, spleen and subcutaneous tissue the factor of motility is minimised. The most serious objection to discarding the chomioal hypothesis at the present time Is the imperfootly known relationship between the osbestoois body and tha development of fibrosis. The # > -8 osbestoais body must form as tbs result of oberaloal reaotion. The question which recoins unonsTrored is whether ouch chemical rsaotlon is also responsible for the development of scar tissue* Some observers ere of the opinion that the formation of the bodies la a protective mechanism by which the tlaruea attempt to coat the irritating asbestos fibre with a smooth non-irritating membrane* Oar own experiments and those of others have demonstrated that asheatoaia bodies recovered from human lungs by chemical digestion, will not produae fibrosis In the subcutaneous tissues of guinea pigs* Their action must also be tested in the longs before a final answer to this question con be given* The evidence now available suggest that the reaction responsible for the formation of tho bodies is not the one producing fibrosis* But on the other hand, it^is-known that asbootoala body formation occurs only in tissues which do develop fibrosis In response to local accumulations of asbestos fibres* Thus far only the lungs of guinea pigs, dogs end human beings have responded to the inhalation of asb eetos dust by the formation of scar tissue and asbeatosls bodies. Injection of asbestos into other organa *a of guinea pigs produces only ocoaslonel bodies end little or no fibrosis* The asbestos corns of tho skin in human beings do not contain tta bodies* Tho lungs of apeoies like the rabbit, white rat and oat have shown neither asboetosis bodies nor fibrosis. In their case it will have to be determined whether the lack of ro- aotioa is due to more effective upper respiratory protection which precludes the Inhalation of effective quantities of asbestos fibres or whether it is due to ohomieal faotors peculiar to these speoies which prevent reaction with asbestos. * 9- . The possibilities oro under investigation and if decioive results ooa to obtained the validity of one or the. other h7pothasia should boestablished. Slrmlflennca - while the inhalation experiments havo failed to produce pulmonary fibrosis at tho rapid rate antioipatod they oreneverthelosa instructive* Verification of the proposed mechanical hypothosio and tho establishment of a relationship between the length of fibre and the irritating properties of asbestos would explain the hitherto mysterious distribution of aebostooia in various departments of this industry* In the Thotford mills there seems to be little or no disease in spite of heavy atmoepherio con centrations of dust* Here the fibrous oloaente of the dust are largely vory short and hence perhaps not irritating. In the English plants it has been stated that the- process of "mattress beating'* is productive of the greatest amount of asbastoais* Gaia proaess oould readily break many fibres longitudinally* liberating a dust rich in fragments short enough to be Inhaled but long enough to be irritating* In the American factorios tho amount of disease has Vt not always paralleled the atmospheric concentration of dust* iitore cases havo developed after exposures to the "opening" maohinos than elsewhere. Since opening io a crushing operation it night produce tho most effective lenght of fibre. If.theeo theoretical considerations can bo substantiated, thoy should be of value in planning a program of prevention. Special precautions would than be instituted in departments where fibrous types of dust are generated. In prooosoing mills dealing largely with the extromely fine asbestos powders employed for insulation only sufficient exhaust to conform to aooopted standards of good housekeeping would be adequate. Until the hygienic algal- fioanoo of fibro length has been established ell asbestoo dust uuidt still be oonsidered hazardous* Summary - An inhalation experiment upon guiaoa pigs, rabbits V7hite rata and cats using high concentrations of asbestos fibre ground so finely that most of tho partioleo are under 1 aioron in maximum diameter has foiled to produce evidence of aabestoais in one year'a time* The amount and severity of the reaction is not noarly as great as that produced in a previous axperiment by tho inhalation of 1/10 to 1/lS this oonaontration of asbestos dust* The only other appreciable difference in the too experiments is the particle size of tho dust* Those observations together with those from collateral injection experiments suggest that the injury from asbestos nay be meohanical in nature and produced only by fibres which exoeed an unknown minimum length. If this ultimately proves to be the case it may explain the /Uxzling absence of asbestoais in certain very dusty parts of the industry* It may also direct attention to the points whero dust enaction- is most important In preventing the development of '.Gestosis* , *.v To anawor tho questions that have now boon raised it is 'mned to continue the Inhalation of the fine dust for another years and to parform aertain other Injection experiments. "> reproduce the pathological picture of gansraliuod asbostosis *k.hor inhalation experiment with a dust ooapoojd of longer fibre 'll be started within the near future.