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EXHIBIT 4 JVABA r/tmvx, 1977. 32, 377 3S6 Relationship between occupations and asbestosfibre content of the lungs in patients with pleural mesothelioma, lung cancer, and other diseases ['. WHITWEU.. JEAN SCOTT. AND MYRA GRIMSHAW From the Department of Pathology, Broatlercen Hospital. Liverpool IJ Whilst ell. F.. Scott, Jean, and Grimsltaw. Myra (1977). Thorax, 32, 377-386. Relationship between occupations and asbestos-fibre content of the lungs in patients with pleura! mesothelioma. lung cancer, and other diseases. The light-visible asbestos-fibre content of 300 lung specimens has been measured using a potash-digestion and phase-contrast microscopy technique, and the results have been correlated with the occupations of the patients. Among 100 pleural mesothelioma specimens were 88 where the patients had been exposed to asbestos, and in 73 of these (83i) the lung tissue contained over 100 000 asbestos fibres per gram of dried lung, and only one specimen showed less than 20 000 fibres per gram. When ashestosis was present, the lungs nearly always showed over 3 million fibres per gram. In 100 control lungs (those without industrial disease or lung cancer) there were less than 20 000 fibres per gram of dried lung in 71 "i of specimens. Lungs from 100 patients with lung cancer but no industrial disease contained less than 20 000 fibres per gram of dried lung in 80; of cases. Patients with parietal pleural plaques nearly all had over 20 000 fibres per gram in their lungs. The number of asbestos fibres found in the lungs vvas closely related to the occupations of the patients but not to iheir home environment. Patients who had lived near likely sources of atmospheric ashestos pollution did not have higher asbestos fibre counts than the rest of the patients. It is concluded that there is a definite dose relationship between asbestos exposure and mesothelioma formation but that' 'sub-ashestosis' levels of asbestos exposure do not contribute to the formation of lung cancer in those not subjected to industrial asbestos exposure. In I960 a link between pleural mesothelioma and previous asbestos exposure was described by Wagner ct a!., the degree of exposure usually hav ing been insufficient to cause ashestosis. and ucuuired more orten in the home than in the industrial environment. Shortly afterwards Thomson et /. (1963) reported that ashestos bodies were present in ahout 30" of adult lungs examined at necropsy from patients w>ho had haJ no known industrial exposure. Both these findings have been confirmed many times from ditferent countries, with only slight modification. I he asbestos exposure of patients with asbestos-induced mesotheliomas has usually come from industrial exposure, though a few eases have been reported where the only known asbestos hazard had been the home environment, con taminated by nearby industrial plants, work clothes, or even household articles containing asbestos (Ncwhousc and Thompson. 1965: Green berg and Davies. 1974), The percentage of urban lungs containing asbestos bodies has been found to be much higher than in the original scries examined, sometimes over 90'.(L'tidjian et ai.. I96S). largely due to more elaborate methods of extracting ashestos bodies from lungs. Another possible effect of 'suh-ashestusis' levels of asbestos exposure is an enhancement of the carcinogenic elTcet of cigarette smoking in induc ing lung cancer, as suggested hv Sclikolf et al- ASARCO ALV 0005397 37K /'. W'hitwell, Jean Sent!, anil Myra (irimshaw (197.1) from surveys of large numbers of insulation ing some histories, but unless the information is workers in the United States. Their view has been obtained from the patients it becomes lost as the supported by Warnock and Churg (1975). who relevant asbestos exposure often happened before found that in a community free from industrial surviving relatives were born. asbestos exposure lung cancer patients had signifi For other patients in this series similar informa cantly more asbestos bodies in their lungs than tion was sought from patients or their relatives by were found in control patients without lung the staff of the hospitals where the patients were cancer from the same community. treated, or by the medical staff of the Manchester The shortcomings of many studies have been Pneumoconiosis Medical Panel. the inadequacy of occupational histories of patients, the crude methods of assessing from the lungs the degree of previous asbestos exposure, and orten the absence of postmortem confirma tion of the nature of tumours. The early work on the link between ashestos . exposure and meso thelioma naturally relied upon retrospective studies in which case records contained little in formation about occupation and often little or no lung tissue had been preserved. A similar dearth of histological evidence confuses the pos sible link between `sub-asbestosis' asbestos exposure and lung cancer. Normal control scries The usual inadequacies of occupational histories in hospital case-records made this the most difficult scries to collect, and it proved difficult to arrange interviews with relatives after patients had died. Although there are over 600 postmortem examina tions per year in the hospital it took about six months to collect the first 50 cases with adequate occupational histories. The problem was solved with the help of the Merseyside coroner, who permitted his staff to complete a questionnaire about jobs and residences for each patient when The present study is an analysis of the asbestos- ' interviewing relatives for other purposes. The fibre content of the lungs from 100 pleural meso second half of this scries therefore consists of thelioma patients. 100 control patients (who had those brought dead into the hospital. died from conditions other than industrial lung disease or lung cancer), and 100 lung cancer patients who did not have industrial lung disease. In nearly all patients occupational histories have been taken in some detail, and in many cases residential histories have also been obtained. The work began as an attempt to find out which pleural mesotheliomas were induced hy asbestos and which were spontaneous tumours, and was later extended to study a normal control series and patients with lung cancer. Lung cancer series These patients provided the fullest histories as they were all patients in the Cardiothoracic Surgical Centre at Broadgreen Hospital being treated hy pneumonectomy or lobectomy for lung cancer. One week after operation they were inter viewed by one of us (MG) when notes were made of all occupations, residences, hobbies, occupa tions of close relatives, and smoking histories. In order not to alarm the patients the interviews were carried out with all surgical patients, not just those Methods of the investigation with lung cancer. The only patients not inter viewed after pneumonectomy or lobectomy were HISTORY TAKING Mesothelioma scries Over half the patients died in Merseyside hospitals, many in Broadgrccn Hospital. Often those who those who died early in the postoperative period, and a few who were quickly transferred to another hospital because their' lesions proved to be tuberculous. died in other Merseyside hospitals had previously been investigated in Broadgrccn Hospital. In MATKRIAI. <>! ritH STUDY these cases detailed occupational, residential, and 'Mcsothilioma series family histories were taken covering possible The scries comprised MX) consecutive pleural ashestos exposure during the whole of the mesothelioma lung specimens, ohtained at patients' lives. Though these were usually easily necropsy, which had been submitted to the Man obtained, cases occurred where the exposure had chester Pneumoconiosis Medical Panel by coroners been for only a few months over half a century in north-west England between 1975 and I9~`I ago. likely to be overlooked by the patients unless The specimens had been fixed in formalin, in most questioned closely, and often quite unknown to eases hy its inicction into the bronchial tree to relatives. Considerable patience and a knowledge inflate the lungs. Eighteen patients had died in of the past uses of asbestos were needed in obtain- Broadgrccn Hospital. 57 patients were front other I i ASARCO ALV 0005398 [ llcltintinshifi hr'swett ncrttfier'iniH and oshcstos-lihrc nmtcii' id the lnn.es 579 Merseyside hospitals. and 45 patients were from other parts or north-west Uneland. Normal control series The normal control scries consisted of Broadgrecn Hospital patients in 1975 and 1976 svho were over 20 years of <age at necropsy, had neither industrial lung disease nor lung cancer, and had a lower lobe of lung free of pneumonia or in farction. This lobe was then inflated with formol saline through the bronchial tree. Where an ade quate occupational history had been obtained the lobe was used for asbestos-librc analysis. From August 1976 only lungs from coroner's necropsies were used. Apart from being selected hy the availability of an occupational history, and later cases heing those referred from the coroner, the specimens formed a consecutive scries until 50 had been c.samincd. From that time only lohes from male patients between 50 years and 70 years of age were used, in order to avoid excessive im balance of the sex and age distribution in the three scries (Table It. Imiic cancer series This consisted of 100 lungs or lobes removed sureically at Broadereen Hospital in 1975 and 1976 because they had contained lung cancers. They were consecutive specimens, except for the omission of some specimens with insufficient normal lung tissue due to the size of the tumour or because of secondary lung changes. Also, cases were omitted when the patient died before an adequate history had been ohtained. The speci mens were fixed either in the operating theatre by formalin injection through the bronchial tree, or later in the pathology department. ItSSIH. Stimt-S O! HTHCrs Ctl AMIKKKI.S EXfOSCRK In the mesothelioma and normal control series the parietal pleura was examined at necropsy for collagenous plaques. The necropsy reports of pathologists submitting mesothelioma specimens to the Pneumoconiosis Medical Panel orten com mented on the presence or absence of pleural plaques. In the lung cancer series the surgeons usually did not see or comment on pleural plaques, though these were often found at necropsy in patients who had died after operation. In all cases the lungs were examined macroscopically for asbestosis and microscopically for ashestosis and asbestos bodies. In addition to routine sections, thick unstained sections were examined in many specimens. In the mesothelioma series lung iuice smears were prepared using a method already described (Whitwell and Rawclill'c. 1971). and the numbers of asbestos bodies on slides were counted. When unfixed lung tissue was used in making .these preparations the results provided a roughly quan titative assessment of previous asbestos exposure. When the preparations had to be made from fixed lung tissues far fewer asbestos bodies were seen and it was not possible to correlate the findings with previous asbestos exposure. As most of the specimens examined were al ready fixed, a more reliable indicator or asbestos exposure was sought. Asbcs'ns'lihre counts on tune tissue Because of the limitations of the previous tech nique. it was decided to count the asbestos fibres, coated and uncoatcd. which could be extracted from lung tissue. Ideally, one would wish to count all fibres, including those too fine to be seen by light microscopy, but this was beyond our re sources. However, it has been stated that the ratio of light-visihlc fibres to total fibres is fairly constant (Timbrell. 1975; Ashcroft and Heprleston. 1975) so it was thought worth while to count the light-visihle fibres. In I96X Cold evolved a method of counting asbestos fibres in lung tissue hy macerating a known weight of dried lung tissue in potash, wash ing the diccsiion mixture three times in distilled water, and counting the fibres in an aliquot of the suspension in a Ftiehs-Rosenthal chamber. We used this method in 1972 hut found few fibres, and the results were difficult to reproduce with con sistency. Ashcroft and Hepplcston (1975) improved the method, largely hy reducing the washings of the deposit to one. using wet lung tissue with I ahlc I ,\(*v anti nee distribution nl the three series I inp cancer \/ / x'ft |j i *2 * *# 12 in m \ J ut Ju < - * ** <*/ 2? IQ m 40 2* << "/ *v U 10 5 wi # o n ASARCO ALV 0005399 .wo F. Whitwcll. lean Scntt, and Myra Grim.thaw calculation of the equivalent dry weight, and using phase-contrast microscopy. These workers could see finer fibres and also more fibres than were seen by Gold's method, counting fibres of about 3 /t in length or 0-4 /i diameter, whereas byGold's method it was difficult tp see fibres of less than about 12 /i in length. Since the end of 1972. and for the whole of the present investigations, we have followed the method of Ashcroft and Heppleslon. except that wc count only fibres over 6 p in length, as smaller fihres can be confused with bacteria. Coated and uncoated fibres are counted together. Although the method sounds crude, the results are repro ducible with a coefficient of variance of about V;, (Table 2). More variation can arise through the selection of lung tissue than in the actual count ing. and with all specimens we have used the base of the more normal lower lobe, iust above the diaphragmatic pleural membrane, except with upper lobe carcinoma specimens where we have used the lower part of the upper lobe. The fihres counted arc nearly always amphibole asbestos, as it is very difficult to see the finer crysotile fibres. Before using this test routinely familiarisation with the appearances of different ashestos fihres in digestion mixtures in counting chambers was gained hy studying digested normal lung tissues which had been fixed with formol saline contain ing l IC'C* asbestos samples. In the following text, where numbers of fihres arc mentioned, the figure refers to fibres per gram dried lung, usually from the base of a lower lobe. Table 2 Ten asbestos-fibre counts on one digestion mixture CfHitt 1 2 3 4 j h 7 X 9 to S'ttmhrr roamed Fibres per front dried lortf 175 32SOOO IMS 315 000 I5`> 298 000 145 272 000 1*2 5(W 000 300 OoO 1)9 26t 000 144 274 000 157 . 295 000 I4t 302 000 Mean 21S 000. so :o son. C'ocll of varuncc 4 95 Results Mt-.SOntKI.tOMA SERIES The range of ashestos fihres per gram of dried lung Tound in the hasc of the lower lobe in the speci mens ranged from nil to 70 million, as shown in Fig. I, which also indicates the relevant occupa tion of each patient, except for five patients whose history was unknown. When patients had followed more than one occupation that carried an asbestos 25 phipyord 43 j Asbestos foctory lb 1 Insulators 7 20 JHession sock repair factory b iAsbestos hazords feme) b ggggra jGosmask foctory 5 15 j Docker 3 Navy 2 :!il!lllil!:lli I Unknown 5 IQ J No osbestos exposure 7 5323 S' f ig. I ^ O o O O-- <NI U-l O -- Asbestos fibres per qram dried lunq OO tn ZZ OO .-I i/iei/m- h/irc content and occupations oj ItIO picurai mestuhclioma patients. ZZZ OOo ASARCO ALV 0005400 Relationship between occupations mid asbestos-fibre content of the lungs 281 exposure risk the more hazardous one was used in the classification: for example, several shipyard workers had previously been in the Navy. There were 88 cases with a history of asbestos exposure, and in all hut one of these the tunes showed over 20 000 fibres. The one patient with probable asbestos exposure and fewer fibres was a man aged 79 years who. between the ages of 15 and 21 years, had been a plumber in a shipyard, afterwards becoming an office clerk. No pleural plaques were found at necropsy. Seventy-three patients (82'/) with a history of asbestos exposure had over 100 000 fibres, and in 22 of these patients (26-'.) there was some histological ashestosis. Most of the lungs showing ashestosis contained over 2 million asbestos fibres, and the numbers of asbestos fibres present corresponded roughly with the degree of ashestosis (Table 2). Ashestosis was present in over half the patients who had worked in asbestos factories or gas-mask factories but in less than one-fifth of patients who had worked in shipyards or sack-repair factories. Table 2 Ashestos iihrr (inun\ in millions per gram dried fling in 22 of the it>t> mesotheliomas which \hn\eed unite ashestosis 4thr\titux Arithmetic mean (ic.imctric r.ie.m t <1 14 ,K1 1-3 f. 0 X 11 2.1 X 47 Slsitlttntf :o 4 f, y.y H0 10 17 :4 44 14 j-r. Snrrr ft 5 IX 23 4* 57 70 ?7 :k The patients who had worked in gas-mask and stick-repair factories form an interesting group, being among the few who had worked for only a brief period in a hazardous environment, usually during the first or second world war. and had otherwise Iveen housewives. 'The residual aslicstos fibre count found in some of these patients' lungs is given in Table 4, show-ing that 60 years after an asbestos exposure of less than one year's dura tion which had heen insufficient to cause asbestosis, the lung retained over half a million asbestos fibres. The gas-mask case listed in F:ig. I with between 50 (XX) and 100 OtX) fihres is the only home environment asbestos-induced mesothelioma in the scries, being the son of a worker from a gas mask factory where the workers took crocidolite home to pack into canisters. The seven patients with no credible history of ashestos exposure were three housewives, a farmer, a fireman, a clerk, and a crankshaft fitter. Pleural plaques were not noted in any of their necropsy reports, all had under 40 000 asbestos fibres, six being less than 20 000 fibres, and no fihres were seen in two cases. These cases must he spontaneous pleural mesotheliomas. NOKMAI CONTROL MERITS 'The commonest causes of death in this series were ischaemic heart disease in 48'.. malignancy in lO''., and pulmonary embolus in The high frequency of heart disease was due to the inclusion of many coroner's cases. No ashestosis or excess ashestos bodies were found in the routine histological studios. Bilateral pleural plaques were seen in 21 cases, all male. The asbestos-fibre counts of this series arc shown in Pig. 2. 57"' having less than 10 000 fibres and 71!' having less than 20 000 fihres. Thirty-five per cent of male patients, but only 14", of female patients, had over 20 000 fihres. Nearly all the patients had lived the greater part or their lives in Liverpool hut it was not possible to assess any influence of home environment on the ashestos-fibre levels. However, the iobs of the 10 patients with the highest and low;est counts in the series (Tahle 5) suggest that the patients' work is largely responsible for the amount of asbestos in the lungs. The 10 patients with the lowest Tahle 4 Limited ashestos exposure in housewives feuding to mesothelioma .Icritr tlnitfitir) 74 *<r <) 47 << <1 * it* Il'nrJt Sa^Lw.tre fjcnw (atm.ivk Ijcltirv Durofum of *to'k t vr) 1 1 % < 4 5 05 Inte*utl hrtwrr* titxt r.xpoxiirf nndtirrutt { vr\ <0 W 30 30 Ml l 50 jy /:t>rr m(mi OtX) 550 XVI JOO flOCI 3 too Ono ?7 (XXt nort 23 Ooo (XV) 17 000 `VVi 1 P.O'UUKl ASARCO ALV 0005401 JISO Fig. 2 ,-t sbestos fibre content ol normal control series (If highest not shown in figure). /'. Whitwvll. Jeuit Sent!, anti Myra (irimshaw smoking habits of patients with tumours of the commoner cell-types. The overall frequency of cigarette smoking in the series was 83%. 67%, of patients smoking over 15 cigarettes per day. None of the patients had a history of industrial lung disease and routine histological sections showed no asbestosis in any cases; only occasional asbestos bodies were present. The asbestos-fibre content of the scries is shown in Fig. J. and it is very similar to that of the control series. Fifty-seven per cent of patients had less than 10 000 fibres and 80% had less than 20 (XX) fibres. The occupations and homes of the 10 patients with the lowest asbestos-fibre counts are shown in Table 7. All the occupations are traditional jobs which do not involve the use of asbestos. Six of these patients had lived their lives in industrial cities, although 22% of patients in the lung cancer Table 5 Occupations anil homes of 10 patients in control series with the lowest and highest asbestos fibre counts / ** < OUfll\ \itmhrr Jttb \ tinupfr Jiti) 0 0 0 n 0 0 MOO 2100 2400 2AW Tai1orcs% Housewife HlMIvCWifc CifIKCf l.orrv driver Dance-lintl manager, RTS driver Tea m<pcctor. medical ordcrlv Office clerk Food packer in factors* Bookbinder 521 ooo 109 00(1 145000 2*5 000 109 000 245 000 101 000 109 OO0 70 <00 000 f)ocker Joiner. IreneK poluher Merchant navy Ship repairer Pjmtcr. huitdmp site icalTnlder Hncfcla>er Roof repairer Coat merchant Oo.ker. merchant n.iw Tliter's labourer at chemical work* counts had little or no contact with asbestos at work, whereas the 10 patients with the highest counts were in occupations associated with asbestos exposure. Pleural plaques were present in 550'. of the patients with over 20 000 fihres per gram, hut in only 5-5'of those with fewer fibres. t.CS'ti CANCER SERIES The histological cell-types of the tumours in this scries arc shown in 'fable 6. together with the rahle 6 Cell type frequency and smoking habits ol lung cancer patients Fttrcurm y Vipr (M si...tm*tt\ <2 (1 ll-VClt It. \iU*utH.*.triin*Ht. uud nulipiMiit .nlcuouuuvi\ I- C'.irunomj iimplrv <> AdcnoMpurnouv A Cjijoi-ceJl - *ICieiir*rrr * n.rrU) \ltUtl |Tt lewru/iil* KK 7* S7 t.Z If, 59 Fig. 3 Asbestos fibre content of lung cancer scries (<' highest not shown in figure). series had lived in rural Wales. Cheshire. I ancashirc or the Isle of Man. The occupations of the It) patients with the highest counts are shown in Table 8. and the jobs are similar to those of subjects with high counts ASARCO ALV 0005402 licUttioitsliip between oceti/'Otiints null asbestos-fibre content of the limes .W Table 7 Oeenpations anil homes of the 10 patients with the lowest asbestos fibre counts in Itme euneer series x. Ot. uptiiitut //urm* 0 Butcher St, Helen* 0 Oroccr Liverpool n Agricultural under Me of Man 0 Butcher Liverpool n farmer Lancashire jeno Parmer North Wale* 1000 1400 Tailor t tve.'pool 1 IouxcvmI'c. school canteen worker St. Helens 2ono Oicui( factory worker Liverpool 2HOO liotocwiic. laundry worker Quecnslerry Table 8 highest Occupation* the ft) patient* with the fibre < ottnt* ht /mic (oncer series 115 000 107 000 I.Vs ooo 151 000 Uf.noo 61 000 XX 000 r.i non 5< 000 42 000 ()t riiptihtin Ship's carpenter Docker RojiKuccpcr Docker Propcrtv repairer, plasterer Ship repairvatd labourer Sewer excavator and budd'nc site labourer Merchant service, atomic works construction Decorator, painter Dovker in tlie control series, and to those or patients in the mesothelioma scries who had had considerable exposure to asbestos, six of them in docks or shipyards. Discussion DOSE REI .U IOSSU1I' nr.lWP.EV ASHESTOS EXPOSURE \M> MESOtllt'l IOXIA Statements have often been made in news media and in the medical press suggesting that there is no dose relationship between asbestos exposure and mesothelioma, and this is probably a maior source of alatm to the public, who have been told that nearly all adult lungs contain ashestos. As recently as 1976 a leading article in the Lancet stated that death from mesothelioma can follow quite casual and short-term exposure to crocidolitc. In a search for the asbestos sources of 246 confirmed mesotheliomas which had been re corded in the British Mesothelioma Register in 1967 and 1968. Greenberg and Davies (1974) in cluded 14 cases which they called non-occupational asbestos-induced mesotheliomas, where the actual ashestos exposure must in most cases have been slight and often very brief. Wagner (1972) stated that mesothelioma may follow brief, but not ncccssarils light, ashestos exposure, and said that there did not appear to be any clear pattern of dose response between ashestos exposure and mesothelioma. However. New house (I97.M. from studies of asbestos factory workers, found that the mesothelioma rate increased with the .severity and duration of asbestos exposure, and concluded that the formation of asbestos-induced mesothe lioma is dose related. The present study suggests a definite dose re lationship between the numbers of asbestos fibres seen in the patients' lungs and the presence of asbestos-induced mesotheliomas. Ninety-fisc per cent of the patients with asbestos-induced meso theliomas had over 50 000 asbestos fibres per gram of dried lung in the base of a lower lobe, whereasonly 15.' of the control scries had as much asbestos (big. 4). It is true that in mans cases the asbestos exposure of mesothelioma patients had been of short duration, sometimes only three months, but from the amount of ashestos fibres found in these patients' lungs the exposure must have been quite intense.. The risk of asbestos-induced mesothelioma to the general public, such as those in the control scries, is probably confined to the top 15 re ferred to above, which include no women and onh men working in jobs with a definite occu pational hazard from inhaled ashestos. MHKCH ol' \MIUSIOS IN* SHUT PROAS" t I'M IS In the control scries, and in the lung cancer scries. 57 of the patients had up to 1(1000 asbestos fibres per gram of dried lung in the bases of their lower lobes. I his amount of asbestos is probably harmless and may represent a background urban level created by the widespread use of asbestos in I'ic. 4 Compansttn of asbestos Ithre loiuent oi lanes front mesothelioma amt normal eontrnl series. n ASARCO ALV 0005403 y.'A F. Wltitwvll, Jean Scott, anti Myra (irimsltuw the lust half century. Higher levels of asbestos in lungs appears to be derived mainly from the occupations of the patients. If urban asbestos pollution, severe enough to have caused mesothelioma, can be derived from living in the vicinity of asbestos factories, docks, and shipyards, as suggested by Ncwhousc and Thompson (1965) and Greenberg and Davies (1974), it would be expected that patients living near such areas would have high asbestos-fibre counts. Although Merseyside has contained no asbestos factories, which may be the heaviest source of atmospheric pollution, it contains many shipyards and docks, and sack-repair factories. In the lung cancer and control scries there were 75 patients who bad lived the greater part of their lives in one district of Merseyside. Figure 5 is a map of the conurbation on which is indicated by stippling the sites of shipyards, docks, and sackrepair factories. The sites of patients' homes arc indicated, those with less than 10 000 fibres per gram of lung being scored differently from those with higher counts; where a high count is fully explained by the patients' jobs this is also shown. o Potientj with under lOOOOfibres/q over > . "fi .. ., over ,, ond occupational asbestos exposure Fig. 5 Map of Merseyside showing sites of expected asbestos concentrations and the homes of patients with high and low a\hestos-fthrc counts. There is no concentration of high aslscstos count cases in the vicinity of docks and shipyards, or to the north-cast of them, allowing for the prevailing wind. Most high count cases near the suspect areas are fully explained by the jobs of the patients. In fact the map shows that shipyard workers and dockers tend to live near their jobs. The four high count patients inland of the city were dockers who. in later life, had moved to new housing estates. itOME-t'.NVIRON'MCNT ASttESrOS-tNOLCEtl MESOTHELIOMAS Evidence supporting the existence ` of these tumours is provided by Newhouse and Thompson (1965) and Greenberg and Davies (1974). the for mer being a retrospective study of cases diagnosed in the London Hospital between 1917 and 1964, and the latter being an analysis of mesothelioma cases recorded by the Mesothelioma Panel in 1967 and 1968. Bohlig and Hain (1973) have laid down criteria for acceptance of such tumours, including tumour histology, asbestos exposure history, and quantita tive evidence of asbestos exposure from examined lung tissues. Few published cases meet these cri teria, yet Bohlig and Hain do not emphasise the importance of obtaining `detailed occupational histories from living patients. This point is illustrated by many patients who were sack-repairers on Merseyside. .The first two such cases were recorded by Owen in 1964. a further four cases were described by Whitwell and Rawcliffe in 197.1, since when we have seen a fur ther six patients, nearly all women. Since the beginning of the century, until the practice was changed quite recently, asbestos was imported into Liverpool in hessian sacks for further trans port to Rochdale. Damaged sacks were repaired in sack-repair factories on Merseyside, where there were a dozen such factories. Although this hazard has been noted only on Merseyside, it is highly probable that asbestos was also shipped into London docks in similar containers for transfer to ashestos factories, and that damaged sacks were repaired locally in sack-repair factories, which were numerous in London. The patients, or moreoften their relatives, who were questioned by New house and Thompson, were asked about employ ment in asbestos factories, not sack-repair factories, so many of the cases described as homeenvironment mesothelioma may. in fact, have been sack repairers. Dependence upon relatives to provide industrial histories of deceased patients is often unreliable. ASARCO ALV 00054-04 Relationship between occupation* and asbestos-fibre content of the lion:s 3S5 One or s (l-W) has several times attended in quests on eases of mesothelioma where close rela tives knew nothing about the relevant occupation of the deceased, who sometimes had lived near the docks. If the patients had not been interviewed about jobs while in hospital usually months before death, so that a true occupational history was known, the mesotheliomas might have been attri buted to home-environment asbestos contamina tion from the docks. Apart from the consideration of undisclosed occupational hazards, the possibility of a meso thelioma being a spontaneous tumour must he considered before it is accepted as being due to home-environment asbestos contamination, and this involves assessment of the asbestos fihre con tent in the lungs, and the age of the patient. Many spontaneous mesotheliomas occur in young patients, even children, as can he seen from a study of the older literature. The actual age of the patient may often be less than the usual induction period of an_ asbestos-induced mesothelioma. In the present series only 7" of pleural meso theliomas were thought to be spontaneous tu mours. hut this is much lower than their true incidence in the community, as spontaneous meso theliomas arc not always reported to the coroner. Probably only around 15',of mesotheliomas arc spontaneous neoplasms at the present time on Merseyside where there are many sources of oc cupational aslvcstos exposure. of regular cigarette smoking have eight times the risk of lung cancer compared with smokers not exposed to asbestos. In the various series studied there have usually been about three times the number of deaths ascribed to lung cancer com pared with ashestosis. In spile of the large numbers of ratients in these scries there have hecn very few necropsy confirmations of the diagnosis, which has been made largely from radiographs and death certificates. The only study of the pathology of these cases is that of Kannerstein and Churg (1972) based upon 33 necropsy and II surgical specimens, many showing fibrosis and asbestos bodies as well as lung cancers, but the authors saw no correlation between the nunihcrs of asbestos bodies and lung fibrosis in the areas examined. If `sub-asbestosis* asbestos exposure really in creases the incidence of cigarette-induced lung cancer, as has been suggested, the lung tissues of an urban scries of lung cancer patients might be expected to show higher concentrations of asbestos fibres than arc present in a control scries of lungs from a population of similar age and sex distribu tion. It was to answer this question that the present scries of lungs from lung cancer patients was examined. The results show a very similar asbestos fibre content in the lungs of lung cancer patients and of controls. In both series 57'/. of patients had less than 10 000 fibres and there were fewer patients in the cancer series than in the control series with high counts. `Sfll-SSItESIOSIS* ASUCSIOS EXPOSURE ANO t UNO CANCER Lung cancer occurring with ashestosis has hecn known since 1935 (Lynch and Smith. 1935) hut the incidence of this complication has increased greatly, so that nowadays over half the patients with ashestosis die from lung cancer (Buchanan. 1965). The tumour is usually found in parts of the lung most severely affected hv ashestosis. and it is not clear whether the carcinoma is a reaction to the asbestos itself or to the fibrosis caused by it. It is generally held that ashestos exposure leads to lung cancer only when considerable ashestosis is present. This finding is the opposite of that reached by Warnock and Churg (1975), who compared the numbers of asbestos bodies in 30 cancer lungs and 100 control lungs, both series from an area of low asbestos pollution, and found significantly more asbestos bodies in the lung cancer series. They concluded that even extremely low levels of ashes tos exposure may have a carcinogenic cfiect. How ever. their two series were ill-balanced. 77V. of the cancer series hut only 49% of the control scries being men. The significant differences they reported arc fully explained by the known higher incidence and levels of asbestos bodies in male lungs. However, studies in America on large numbers of insulation workers, summarised by Selikoff cr al. (1973) and Hammond and Selikoff (1973). sug gest that the incidence of lung cancer in ashestos workers who do not have ashestosis is far higher than the incidence in an unexposed population, and that this high rate of lung cancer is dependent upon the workers being cigarette smokers. It is said that ashestos insulation workers with a historv Our investigations into asbestos levels in the lungs of lung cancer patients in the general popu lation provides some assurance that urban ashestos pollution does not contribute to the present high incidence of eigarctte-induecd lung cancer How ever. it docs not provide an answer to the import ant question whether asbestos workers can de velop lung cancer from asbestos without first having ashestosis. Such an answer can be found ASARCO ALV 0005405 386 F. Wltitwell. Jean Seim. am! MyruCrimshmc only after extensive necropsy studies incorporating ashestos-tihre analysis. We thank Drs W. B. Lister anti A. N'. Dempsey, senior nietlical officers to the Manchester Pneumo coniosis Medical Panel, for their help in providing industrial histories of mesothelioma patients, and MrS. R. Barter. HM Merseyside coroner, and his staff for obtaining histories of patients in the control scries. We acknowledge with gratitude the receipt of a grant from the North West Cancer Research l-'und to support this work. References Ashcroft. T.. ami Hepplesum. A. G. (1973), The optical and electron microscopic determination of pulmonary asbestos libre concentration, and its relation to the human pathological reaction. Journal oI Clinical Pathology. 16. 124-1.74. Bohtig. H.. anti Hain. E. (19751. Cancer in relation to environmental exposure. In Biological Effects of .-I shesros. edited by P. Itogovski cl al., pp. 217-221. International A genes for Research on Cancer. Lyons. Buchanan, W. D. (1965). Asbestosis and primary inlrathoracie neoplasms. Annals of the S'esv York Academy n[ Science. 132, 507-518. Gold. C. (I96X). The quantitation of asbestos in tissue (abstract). Journal of Clinical Pathology. 21. 537. Greenberg. M.. and Davies. T. A. L. (1974). Meso thelioma Register I967-6X. flrilir/i Journal of Industrial Medicine. 31. 9|-|(I4. Hammond. E. C.. ami Sclikoff. I. J. (1975). Relation of cigarette smoking to risk of death of asbestosassociated disease among insulation workers in the United .States. In liiolnyical Effects of A shestos. edited by P. Bngovxki et at., pp. 512-317. Inter national Agency for Research on Cancer. Lions. Kamier-tem. M.. and Churg. J. 11972). Pathology of carcinoma of the lung associated with asbestos exposure. Cancer. 30, 14-21. Lancet (1976). Asbestos in the air. Leading article. Lancet. I, 914-945. Lynch. K. M.. and Smith. \V. A. (19557. Pulmonary asbestnsis III. Carcinoma of the lung in ashestosilicosis. American Journal of Cancer. 24. 56-64. Ncvvhouse. M. L. (19731. Asbestos in the work place anil the community. Annals of Occupational Hy giene. 16, 97-107. N'ewbouse, M. L.. and Thompson. H. (1965). Meso thelioma of pleura and peritoneum following expo sure to asbestos in the London area, British Journal of Industrial Medicine. 22, 261-269. Owen. W. G. (1964). Diffuse mesothelioma and expo sure to asbestos dust in the Merseyside area. British Medical Journal. 2, 214-218. SclikolT. I. i.. Hammond.. E. C.. and Scidman. H(197.7). Cancer risk of insulation workers in the United States. In Biological Effects of A she'tos. edited by P. Bogovski et at., pp. 20-2ln. The Inter national Agency for Research on Cancer. Lyons. Thomson. J. (J.. Kasehula. R. O. C.. and MacDonald. R. R. (1963). Asbestos as a modern urban hazard. South African Medical Journal. 37, 77-SI. Timbrcll. V. (1975). Discussion Summary. In Binlocisal Effects of Asbestos, edited by P. Bogovski et a!.. p. 131. The International Agency for Research on Cancer. Lyons. Ulidjian. M.' !>.. Gross. !>.. and deTre-.ille. R. T-- nM*>. Ferruginous bodies in human lungs. ( valence at random autopsies. Arel'ircs of Environ mental Health. 17, 327-337. Wagner. J. C.'(1972). Current opinions on the ashestos cancer problem. Annals of Occupational Hygiene. 15. 61-64. Wagner. J. C.. Sieggs. C. A., and Marehand. P. (I960). Dillttse pleural mesnthclinma anti asbestos exposure in the North Western Cape Province. British Journal of Industrial Medicine. 17, 260-271. Warnock. M. L.. and Churc. A. M. (1975). Associa tion of asbestos and bronchogenic carcinoma in a pnpulation with low asbestos exposure. Cancer (Philadelphia). 35. 1236-1242. Wltitvvell. r-'.. and Rawclilfc. R. M. (1971'. Diffuse malignant pleural mesothelioma and ashe.tos ex posure. Thorax. 26, 6-22. Requests for reprints tn: Dr F. Whim ell. Department of Pathology'. Broadgreen Hospital. Thomas Drive. Liverpool LI4 31.11. 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