Document 6Bb1kQrDyz0w4xG9XNXm2on9g

i i G. 3. Meyers OFFICIAL FILE COPY A<LC AUTM T(mp CALL u.Q F`H Caption. DATE January lU, 1975 c. c. ASBESTOSIS The attached is fear your information in the event you have not already seen the article. HAS:sm Attach. / v. H. A. Sinclaire, M.D. /' V* PLAINTIFF'S EXHIBIT MBL-96 002291 183956 INTEROFFICE CORRESPONDENCE to ALL DOCTORS WESTERN MEDICAL REGION oate January 8, 1975 c.c Dr. H. A. Sinclaire ASBESTOSIS ^ 19/$ I am attaching a very interesting article that appeared in THE NEW ENGIAND MEDICAL JOURNAL this past week. The article casts some doubt on previously held opinions regarding asbestosis. One of the points that has been taken as fundamental in the pathology of asbestosis in the past has been that the size of the particles must be large enough to form a block in the smaller divisions of the pulmonary tree and by so doing, begin the patho physiology of asbestosis. Unlike particles of silica that have been in jurious because of their minute size, the opposite has been held to be true for asbestos, where particles greater than 5 microns in length were used to define an asbestos fiber and were also thought to be the size that was important in causing the clinical disease. Those fibers that were smaller than 5 microns were thought to be innocous because an efficient pulmonary toilet could cough these up and clear the lung of them. How ever, this article raises some doubts in this area and by the use of electron microscopy, it has now been shown that the lung does retain some microscopic particles of asbestos and some doubt is being raised that these are innocous. As the article points out, they may be incriminating in causing asbestosis. While the article makes some mention of sub-micro scopic particles of silica in African gold miners, this is nothing really new as far as the knowledge of silica and the size of silica particles in the etiology of silicosis is concerned. I would like you to read the article, because I do believe it is timely and it does open up a new vista of thought and one that we should be following relative to the problem of particle size versus clinical disease when it comes to asbestosis. Vol. 292 No 2 M EDICAL INTELLIGENCE - MILI.ER ET AL. 91 mbui.ir necrosis have a high prevalence of potentially fatal infectious complications. Consequentiv, stringent precau tions must be emplovctl to minimize this risk, folev catheters, central-venous-pressure lines and other in dwelling devices should be used w ith extreme caution and on tv when there is a commanding indication. Prognosis In the 1940's, the mortality rate in unselected patients with acute tubular necrosis was as high as 90 percent. The introduction of antibiotics, the recognition that salt and water restriction was essential, the availability of effective treatment of hyperkalemia anti the dcvclopmecn of effec tive dialvsis procedures resulted in a dramatic decline in mortaiitv to approximately 50 per cent bv theearlv 1900 s. Surprisingly little improvement in the crude mortaiitv rate has occurred subsequently. It is t lear that, at present, death during an episode of acute tuhular net rosis is usual ly due. not to the absenc e ol renal exc retorv flint non per sc, but rather to complications of the underlying disease f urther improvement in mortaiitv rale appears like Iv to occur onlv with improved ability to pi event, or lo i ev erse more promptly, die conditions in which acute tubular necrosis is now such a frequent and ominous complica tion. . References , 1 B.irnett E. MorltfV P? Diagnostic ultrasound in rtnal disease Br Met! Bull 28 196-199 19^: 2 Cattell VAR. McIntosh CS. Moseley IF. el al: Excreiion urography in ..cute renji failure Br Med J 2.57'-<7R. *973 } Cousins MJ. Mane Rl. Methowflurane nephrotoxicity: a study of dose response in man. JAMA 22.'. 1611-1616. 197} 4 Mai/e Rl. Cousins Mi: Cumomcd nephrotoxicity of gentamicin and melhoxy flur.mc anaestheM.i in man. a case report. Br J Anaesih 4< 198. 197} ' Hohrow . Jaffe E. Young RC. Anuria and acute tubular necrosis asMvuied with gentamicin and sephaloihin. JAMA 222.1546-1.'47. 1972 6 l.mion A L., Bailev RR. Turnbull Dl: Relative nephrotoxicity of wcpholospunn antibiotics m .in animal model. Can Med Assoc J 11)7 414-416, 1972 7 Flamcnhuum W PiuhophyMoiog) of acute renal failure. Arch Jnfern Med I M 9(1-928. 197} X l cvmsky S(i The interpretation of protemunu and the urinary sedi ment DM. March. 1967 9 Rcnncit VA M. Singer 1. Coggins CH Guide to drug usage in adult txiaents anh imfxored renal lunctu>n a supplement JAMA 22.V99I-W7, 1'FM ;0 Rcrlsnc <iM. Ba//ard FJ Hiioth KM. et ai. The dietary treatment of iv. ute r en.il laiturc <2 J Med )6 '9.(0. 1967 !l \bel KM. Hot k CH Jr. Abbott SAM. et ;il. Improved survival from iv ute renal failure after treatment with intr.ivenous essential L-amino iwidN and eliuosc results ol i prospective, double-blind study N Engl J Med 2XK 69-649. 1971 "NONSPECIFIC" INTERSTITIAL PULMONARY FIBROSIS Association with Asbestos Fibers Delected by Electron Microscopy Albert Mii.i.er, M.D., Arrui R M. Lancfr. Ph.D., Alvin S. Teirsif.in. M.D., and Irvisc. J. Selikoff. M.D. LF.CTRON microscopy has onlv recently been ap-*-- plied to "idiopathic" interstitial pulmonary reactions. In 1971, we described a patient with interstitial granu lomas and fibrosis indistinguishable from sarcoidosis.1 A historv of occupational exposure impelled electron microscopy and x-rav diffraction studies, which revealed talc crystals in his lungs. For the patient described below, we examined lung tissue that had shown severe interstitial fibrosis, with no evidence of mineral particles, on light microscopy. Although the patient had had noexposurc to known pathogenic dusts, electron microscopy demon strated ubiquitous fibrils of chrvsotilc asbestos, averaging 27.5 nm (275A) in width and less than 100 nm (lOOOA. or 0.1 fitn) in length -- well below the resolution of a light op tical system. From the Pulmonary Laboratory, Division of Thoracic Diseases. Mount Sinai HoxpilaJ. and the Environmental Sciences Laboratory, Mount Sinai School of Medicine of City University of New York (address repnnt re quests to Dr. Miller at ihe Pulmonary Laboratory. Mount Sinai Hospital, 5th Ave A 100th Si.. New York. NY 10029). Dr. Langer is the recipient of a career award (ES44812). and Drs. Langer and Selikoff recipients of a University Center grant (ES0O928) from the Na tional Institute of Environmental Health Sciences. National Institutes of Health, and Dr. Miller the recipient of a grant from the Jack Martin Fund. Case Report \ 63-vcarnld man was admitted to the Mount Sinai Hospital. New Vnrk Citv. on Muri.li St). I971. hccausc of breathlessness of six years duration. Clubbing had been present since 195H. Me was a clerk m the civil service; his hobby had been reliinshing wood furniiiiie Physical examination revealed tachypnea, eva- noMs. c Infilling, fine rales, and signs of right ventrirular failure. I he hemoglobin wav HI 2g per 100 ml. and the hematocrit :")7 |k.t lent. One of twoaolimiclear-annliody determinations was posi tive. hut lupus preparations, latex fixation. Venereal Disease Research l.alxirulorv icsi and scrum electrophoresis were within normal limns \ roentgenogram of die chest showed moderate enlargement of ihe heart, preserved long volume and diffuse honeycombing, lung v ol nines.,ur How and maximum voluntary ventilation were notm.il. severe ht|X)xemia and compensated respiratory alkalo sis were present. The wedge pressure was 10 mm Hg. pulmon ary-artery pressure 75/35 mm Hg. with a mean of 50 mm Hg, right ventricular pressure 70/H mm Hg, and mean right atrial pressure 7 mm Hg. with a prominent A wave. There was no evi dence of mtr.iLardi.ic shunt bv angiocardiography. The patient died of respiratory failure two months after admission. Lung tissue obtained at open biopsy of the right middle lobe was examined bv light microscopy. No mineral particles or asbes tos bodies were observed. The alveoli were filled with iron-con taining macrophages that lined up along the thickened septa and were seen within the septa as well. In some areas, macrophages, lymphocytes and fibroblasts obliterated the alveoli. The histolog ic diagnosis was "interstitial inflammation and fibtosis." The lung tissue was rut into 5-pm sections and prepared by carbon exiraction for electron microscopy.* At magnifications bevond 10,000 times, numerous small fibers were seen. At 20.000 to 31.000 times, these were identified by their morpholo gy as chrysotile fibers that filled all fields of view (Fig. 1). Most striking were the large number of particles, their uniformity and their minute size. Particles were measured and counted in three 6-jim1 areas. Two thirds (238 of 361) were fibers and fibrils of chrysoule asbestos, and 95 per cent (226) of these were fibrils. Only 88 (37 per cent) of the 238 fibers and fibrils were longer than 100 nm (lOOOA, or 0.1 yim). averaging H5 nm (1450A) m length and 27.5 002233 183958 2 rm* \i:w jolhok mi.uiunii an, 'A, p75 Figur* t Transm ^sron Electron Micrograph o* Carton Extracted Lung Tissue Fibrous particles are clearly fibrils marked C (arrows) stow the characteristic capmaiy ot chrysolite Histologic struUuies are outlined asetectron-dense rebel tissues nm f27'>\) in wirtih \JI wf-rr roniHrr.ihh below VH) nm<o `\^tn r,r m nrr-;frxr <ttn-.*nsin Mean length <if ihr smaller fibrils TO nm fTiiOVi. .md mean width was j^ain 27 nm <`J7' \ i Snmr fihriU wrrr an nmail a^ 23 um (23o\) long and 3 nm i Vl \) w irir y of rnmfiar iu>n. amonite .isljcstrrs fibers m tin* liunjs (A rTfioscrf workers a^cta^c IV) nm <0 fj^m. nr t>00\i in wirlih.*1 w hir h is u vrral rimes thr length of thr present fibrils. Hx* I 21 rithcr partir lei averaged 10 nm I 4<M> \) in grc.ucM dimension, f hr\ were rnainlv < hrwni< fragments, some wereclav or talc. I be adK*M<* c nntrnt of die jmocim a lung* was c alrulated to be j minimum of 0 \r> g. I bis amount, finch divided, mas have a Mirbu c area of more than 30 m*. Discission Several questions arc raised bv this patient's illness. The vti ill t apat nv wits I Oil per ceni of the prcriicicd value, and the lot ill lung caput n y 97 |>cr tent. Normal lung volumes lie unusual in pulmonary fibrosis, especially when long standing duhhmg and cor pulmonale are present. Reduc tion in vital capacity is a reliable indicator of pulmonary fibrosis in nsltestosis and precedes roentgcnographic and (linit al evident r of disease.* I hr source of dust was not identified. The minimum tonlrm of t) l!> g of t hrvsotilc in ihe patient s lungs isconststent wtlll it low-levriot nipiilion.il exposure.4 I he small sire of the fibrils mav have resulted front tltcir fragmentation liefotr iliey were Inhaled or from tlieir degradation in situ*' 1 lie fibrils were different from "mmrtalogit spri nncn". iltnr central capillaries were divunmtuniis. I licit' walls ihin. and t lit- ir ends irregular. 00325HIn biologic environments < (itssonic filters are ihcrmcaJis unstable Magnesium is lost limn the sin fate, rsjtosmg I Ilf silu a l.i\ n to i lieiiin al le.u noil. Most musiiyjalipiis ol die tel.iltoit lielwern ihe sio of i espu ,tll<- tinnet a I pailu les ami I lie lieipirnt V and site) IIt ol |iulnimiait disease hate Iwen .based on buhl nil nmi o|n . llius mi l looting llie loir ol sulnillt Ios>unu al jvii in It's llowesei. election nm nisi ops fta show it dial up lo 97 pel i cut ol die paint Irs hi (lie lungs ol South \fnt an gold mine! s w nil sesei e silu osis wn e less than 111 HI inn It) -'pin | m di.imeieiand silu a fume pailii Irs, w it h an average si/eol 'JO um (0 OJ^im), have pi niltli eil slllmtls in animals.' As panitles range down in vwr m Jilt! nm (O.J|xmi and Itelnw, alveulai irlrnlinll and tissue leai liviiv Ixillt mi iease `1" hvulctnc loi die p.idnigenu uv nf submit riiscopit ill asItestos iilterv i nines fiom experimental iiisnllation nuo animal longs." (.'moated, small fillets were obsrived m lungs long after expel imental mh.ilaliun and t anked pro gressive tissue alleriinonv. ( xamiiialinm al our lalioiatorv, and in (iicai Hi uain, have demonstrated xuiinili ioscopital pai ti< les in the lungs of wnrker(rx|x>scd lo asltes(osfibers.12 I let ause n is n-iidilv demonstrated by Ijghl mit roacnpy, die diagnosiM inqtot lain e ol die "asfK-slos Iwwly" lias Iren Ix.iggerated In human disease, lissnr bbiosinsnot n lated lo die niimlter of aslx-sun Ixwlifi. A* in exjK*| lmeii|.d aslx-siosts. n tv likely llui die smallest, minuted filters ate t die most liluogeiiK J* I Itey mav lie present wulwut asIx-stns Itodie* IX otllet ev nleme of .tsitrslJNAlltiiSlQAO- Vol. 292 No. 2 MEDICAL INTELLIGENCE -- THOMAS 93 scopv. This characteristic is especially true of chnsotile. the most common form of .islxtstos used in the L'nucd States, which tends to fragment in tissue. The submicToscopicaJ chrvsoiile fibers found in the lungs of-80Tf of the populations of New York Citv and lamdon" n are much less numerous than those in our pa- iieni. A recent investigation at this laboratory showed only occasional filters after carbon extraction, as compared with the ubiquitous fibrils in our patient. Total asbestos content in ihe 'normal" lungs was in the range of 0.1 jag to 0.5 mg -- threetofour orders of magnitude less. The case reported above documents the association of snbmici oscopicaj chnsotile fibrils with severe pulmonary fibrosis, in the absence of fibers demonstrable"T>s light nncroscopy. Together with the case of talc pneumoconio sis previously reported.1 this case raises a question concer ning the diagnosis of "idiopathic" interstitial fibrosis. Ciaensier. Carrington and Coutu have stated that cases "mav be erroneously t lassificd (as idiopathic ] if dust parti cles are overlooked."" We suggesi that lung tissue dmw- jng alterations diagnosed as "usual interstitial pneumo nia." "fibi using alveolitis or "idiopathic pulmonat v fibto- sis" be examined In electron microscopy. It is hkcls that oilier rases will prove to Ik- pneumoconioses bv yielding evidence of mineral dusts. References 1. Miller A, Teirsiem AS. Bader ME. el al. Talc pneumoconiosis Am i Med .195-40'. I97| 2. Langcr AM. Ruhm IB. Seltknff IJ. ct al. Chemical chanurien/afion of uncoaieJ usbcMos fibers from the lungs of asbestos workers elec tron microprobe .malvsis J Histochem Cyiochcm 20'73*-740. 197? 3. Timbrell V. PocHev FD. Wagner C. Charictenstics of rexpirahlc as bestos fibers. Pncumocomosjs. ProceeUtngs of ihe International Con ference. Johannesburg. 1970. F.Jited b) HA Shapiro Capetown. Ox ford Univcrsii> Press. 1*P0. p 120 4 B.ider MK. Bader R.A, Teirstein AS. et al Pulmon.ir> function and radiographic changes in 59M workers wnh sar>ing Juration of ex posure to asbestos Mt Sinai J Med 37 492 *00, 1970 < Beattie J. Knox JF Studies of mineral content and particle sue dis tribution in the lungs of asbestos textile workers. Inhaled Particles and Vjpours. Proceedings of an International Symposium. Oxford. 1961 F.dited by CN Duvtcv Oxford. Pergamon Press. 1961. p 419 b Lunger AM. Seltkoff IJ. Sastre A: Chrysonle asbestos in the lungs of persons in New York City. Arch Environ Health 22.348-361. 197| 7 Longer AM. Pooley FD: Identification of single asbestos fibers in human tissues. Proceedings a: the International Agency for Research on Cancer The biologic effeeix of dsbestos. Lyon 1972. Edited by C Wagner tin press! 8 Nagetschmidi C: Relation between lung puthology and lung Just analysis. Proceedings of the Pneumoconiosis Conference. Johan nesburg. I960. F.dited by AJOrenstein. Boston, Little. Brown and Com pany, I960, pp 143-136 9 Vorwald A] Inhaled submicroscopic panicles in the pathogenesis and pathology of silicosis. fYoceedmgs of ihe Pneumoconiosis Con ference. Johannesburg, i960. Edited by AJ Orenstetn. Boston. Little. Brown and Company. 1960, p 137 10. Deposition and Retention Models for Internal Dosimeuy of the Hu man Respiratory Tract. Task Group on Lung Dynamics. Health Phys 12:173-207. 1966 11. Suzuki Y. Churg J: Structure and development of the asbestos body. Ami Pathol 35:79-107. l%9 12. Langer AM. Ashley R. Baden V. et al: Identification of asbestos in human tissues. J Occup Med 15 287-295. 1973 13. Pooley FD. Oldham PD. Chang-Hyun UM: The detection of asbestos in (issues. Pneumoconiosis. Proceedings of the International Con ference. Johannesburg. 1970. Edited by HA Shapiro. Capetown. Ox ford University fYess. 1970. pp 108*116 14 Gaensler F.A. Addington WW: Asbestos or ferruginous bodies. N Engl J Med 2X0:488-492. 1969 IV Gaensler E.A. Carrington CB. Coutu RE: Chrome interstitial pneu monias Chn Notes Resp Dis 10.3-16. 1972 NOTES OF A BIOLOGY-WATCHER The Deacon's Masterpiece Lewis Thonias. M.D. HTHF. brightest ,md most optimistic of my presenti-* merits about the future of human health always seems to arouse a curious mixture of resentment and dismay among some very intelligent listeners. It is as though I'd said something bad about the future. Actually, all I claim, partly on faith and partly from spottv but unmistakable bus of evidence out of the past century of biomedical science, is that mankind will someday be able to think his wav around the finite list of major diseases that now close <it( life prematurely or cause prolonged incapacitation and pain. In short, we will someday be a disease-free s|K`c ies. I xccpt (or gaming a precise insight into the nature of human i oust musness (w hich mav etude us for a verv long lime, pel flaps fniever. iH'iause of a variant of the indotcrmm.it v pi mi qile. w hit !i mav < ause it to blur and tw itch awav. <>i even explode, when we succ eed ill fixusing on it i losels enough), I 1.1111101 imagine anv other limits to the pi ofnndilv of om understanding of living things. It may h.ipjK'ii w tiliin the next few i enturies, mav be longer, but when it does it will bring along, inevitably, the most de tailed sorts o( explanations lor human disease mecha nisms. It is an article of faith with me that we will then know how 10 intervene dim tlv. to turn them around or prevent them. Something like this has alreadv happened for most of the m.i)or infections. Even though we are still in a primi tive. earliest stage ill the emergence of biology, as com pared. s.iv. to pin sics, we have accomplished enough basic science to permit the development of specific antimicro bial antiserums, and an impressive list of safe, rational v iral v.u 1 mes. Within 50 vears after the recognition of bac teria as p.uliogcm we had 1 lassificd them and learned enough of their metabolic intricacies so that the field was reads for antibiotics. In the vears since the late 1940's the first great revolution in technology in all the long history of medicine has occurred, and infectious diseases that used to devastate whole families have now been almost forgotten. Events moved rapidly in the field of infection, and this mav have represented abnormally good luck. For some of the others -- heart disease, cancer, stroke, the senile psy choses. diabetes, schizophrenia, emphysema, hyper tension. arthritis, tropical parasitism and the like -- we may be in for a longer, more difficult pull, but maybe not. With the pace of research having increased so rapidly in the last two decades, and the remarkable new young brains enlisted for the work of biology, we could be in for surprises at almost anv time. Anyway, sooner or later, thev w ill all become non-mysteries, accountable and controlla ble. These prospects seem to me exciting and heartening, Address reprint requests 10 Dr. Thomas at Memorial Sloan--Keilerinf Cancer Cemer. 1275 York Ave.. New York. NY 10021. 002295 133960