Document NGgDG86Bg9Jw96zxXpNBN3EEw

Jr.:. J. iiuiustr, \fcd.y 1965, 22, 165. *\ jL AND RECOMMENDATIONS C7 THE WORKING GROUP ON ASBESTOS AND CANCER Cor.vc.-cd under the auspices of the Geographical Pathology Committee of the International Union against Cancer (U.I.C.C.) Preface TV.o Geographical Pathology Committee of the International Union Against Cancer (U.I.C.C.) convened a Working Group on 22 to 23 October, 1964 in New York to discuss evidence of an association between exposure to asbestos dust and cancer. Forty delegates from eight countries attended, and separate panels on epidemiology, pathology and experimental pathology, and physics and chemistry met and, at the final session, under the Chairmanship of Dr. Harold Stewart (U.S-A.) prepared the Report and Recommendations published below. Terms of Reference I. G;;idc.-.iiuh>gy A. To investigate the incidence of mcsolhelial tu.'.'.cw.i of the pleura and peritoneum in groups a.Wor regions where exposure to only one type of asbestos ilbre has occurred. II. To investigate the risk of bronchial carcinoma in populations exposed to asbestos dusts where the incidence of asbestosis is known, or believed, to be low. C. To investigate the incidence of other tumours. If. Pathology and Expcri--ental Pathology A. To establish criteria for tile diagnosis of meso- theli;.; tamew.*s, to assemble material to assist in the stanuarUtetu.on of diagnosis, and to form consulta tive panels. -- Q. To develop a standard of grading of fibrosis of the lung due to asbestosis. C. To develop a standard method of assessing semi-cun.uiuiivcly the amount of asbestos fibres and/or bodies in sputum, fresh lungs, and fixed tissue. D. To collate work done in various countries. III. Physics and Chemistry A To investigate the usefulness of providing in one centre a set of standards of the main types of asbestos fibres and their extracted organic matter for distribution to centres investigating the biological, physical, and chemical properties of this material; if it is regarded as useful and practice1. to suggest a centre. B. To suggest a minimum list of characteristics by which differences between these samples should be identified. C. To suggest standard methods for the identifica tion of types of asbestos in the lung in (a) large samples, and (b) tissue sections. Association of Exposure to Asbestos Dust and Cancer The main types of asbestos of commercial interest arc amositc, anthophyllitc, chrysolite, crocidolitc, and trcmolitc. There is evidence of an association between exposure to asbestos and malignant neoplasia. This has been established mainly on information from Germany, Italy, South Africa, the United Kingdom, and the United States of America. The types of tumours which have been shown to be associated with exposure to asbestos dust arc (I) carcinoma of the lung, and (2) dilTusc mesothelioma of the pleura and peritoneum. There is some suggestion of an association also with gastrointestinal carcinoma, and possibly ovarian tumours. The latent period between first exposure to the dust'and detection of the related tumours is many years, usually 20 or more. Instances up to 60 years have been reported. For this reason, further eases of these associated tumours arc expected to occur for many years to come, even if dust exposures arc now greatly reduced. Present evidence indicates that the associated carcinoma of the lung is not limited to exposure a \ t i t 1018 ! iv f i DUP 0900413 ! 66 BRITISH JOURNAL OF INDUSTRIAL MEDICINE so any one type of asbestos fibre. However, further investigation* are urgently needec to establish whether the degree of risk is importantly .-e'.-.ed to the type of fibre inhaled. In the case of mcsotheliomata, evidence from several countries suggests that exposure to crocidoSite may be of particular importance, but it cannot be concluded that only this Type of fibre is concerned with ti.-v. tumours, and further investigation of this problem is needed. Certain types of asbestos fibres in the virgin state have been found to contain oils, waxes, and other organic matter. In addition, asbestos fibres absorb hydrocarbons subsequent to mining. Small or trace amounts of various elements such as nickel and c.'.romium are also found associated with some types of fibre. The possible role of such associated materials in the development of tumours after exposure to asbestos dust is not yet clear. These findings, when considered in relation to the great increase in the use of asbestos for many purposes in all countries! suggest that a more serious and widespread hazard front exposure to asbestos dust may exist than is widely appreciated. Recommendations on Problems Requiring Epidemiological Study 1. That the Importance of Fibre Type on the Risk of Developing Asbcstosis, Carcinoma of the Lung, and Mcsotholiul and Other Tumours' be Investigated.-- International and intranutional comparative studies of mining and other populations exposed to only one type of fibre are recommended. Among the countries in which and between which studies should, if possible, be made are Australia (crocidolitc), Canada (chrysotile), Cyprus (chrysotilc), Finland (anthophyllite), Italy (chrysotile). South Africa (nniositc, chrysotilc, and crocidolitc), the United States of America (chrysotile and treinolitc), and the Union of Soviet Socialist Republics (chrysotilc). The studies of the elfect of exposure to different types of fibre within a country arc likely to be of special value, but studies of groups exposed to apparently similar fibres in dififerent pans of the same country arc also likely to be informative. 2. That the Relationship of Dust Dosage (including Concentration and Duration of Exposure), and the Composition and Physical State of the Dust to the Incidence of Asbcstosis, Carcinoma of the Lung, Mcsotbciioreata, and Other Cancers be Studied.-- Comparative studies in factory populations in the asbestos textile and other manufacturing processes using asbestos are likely to be useful, especially when there are records of past dust measurements. In any prospective studies of new entrants, the measurement of dust by a standardized method should be regarded as an essential par; of the investigation. 3. That the Effects of Removal from Further Exposure to Asbestos Dust be Investigated.--It is imporiant to establish the subsequent morbidity ana mortality from asbcstosis, and the mortality from cancers associated with exposure to asbestos, in population groups no longer exposed to the dust. 4. That Further Investigations be made of Past and All Future Cases of Diffuse Mcsoihelial Tumours of the Pleura and Peritoneum to establish Any Associa tion with Asbestos and Other Factors.--These tumours should be diagnosed on the criteria suggest ed by the Panel on Pathology (sec below) and reviewed by a Panel of Pathologists with experience of these rare tumours. The tumour and lungs should be investigated for the presence of asbestos by physical and chemical methods (sec below). 5. That Studies of Morbidity and Mortality be Extended to Asbestos-exposed Populations that have not so fur been widely Investigated. I. It is recommended that special attention be directed to surveys in (a) the insulating industry, including that in ships; (b) the asbestos cement industry; (c) asbestos products industry; and (</) other plants in which asbestos is regularly used, such as certain paper, paint, and plastic lactones. 3. It is also recommended that, since incidental exposure to asbestos dust may cccur in certain trades and occupations, attention be directed to (a) handling and transporting asbestos; (b) the building industry; (e) pipe fitting; and (el) ship building and breaking. 3. It is recommended that surveys be made to study environmental and community exposures, including populations near mines and factories and elsewhere. 4. It is recommended that general population surveys be made nationally and internationally to establish by standardized methods, in areas of presumed high and low exposure to asbestos dust, the prevalence of asbestos bodies and fibres, 5. It is recommended that surveys of asbcstosis in domestic and wild animals be extended to areas of high and low exposure. 6. Epidemiological Methods 1. General (a) In addition to the usual information about the individual collected in such surveys, special attention should be directed to adetailed, social (including smoking habits), occupational, environmental, and i I I j > , [ I I DUP 0900414 .IMPORT OF THE '.FORKING GROUP ON ASDEETOS AND CANCER 167 .......-.ory fro.-.". e../.y ch.iuhobd ;o eluciu.uc ,iov>..c exposure :o or association with any type o;' oc .u.s or other dusts. A study of the family unit or nouxe..o.d may be of interest In view of the oee..s.on... reports of significant neighbourhood and ho,,xc,.oiu exposures. l hi i.. view of the association between exposures to asbestos dust and pulmonary fibrosis and its complicai.or.s, it is important to obtain as much information as possible about morbidity and mortality from all causes with particular attention to asbestosis, chronic bronchitis and emphysema, bronchiectasis, diffuse interstitial fibrosis, pneu- mon.a. tuberculosis, cor pulmonale, carcinoma of the lung, diffuse mesotheiiai tumours ofthc pleura and peritoneum, gastro-intcstinal tumours, and ovarian tumours. ~ (c) Tiie principal epidemiological surveys likely to be used are retrospective, cross-sectional, and prospective, or a combination of these. In most of the surveys one or preferably more control groups will be needed. It is strongly urged that early and full consultation with statisticians be made at all stages front planning to an analysis of the findings. 2. Clinical Criteria.--The need to establish the minimal clinical information to be obtained in surveys of workers exposed to asbestos was agreed. A small panel met informally after the main working party and their recommendations arenas follows: (a) Symptoms: It was agreed that in all surveys the presence or absence of cough, sputum, dyspnoea, and chest pain should be recorded as a minimum. This should be recorded using a standardized questionnaire. The British Medical Research Council Question naire on Respiratory Symptoms (1960), with the acditional questions relating to chest pains in the V/.H.O. Questionnaire on Cardiovascular Disease (Rose, 1967), is suitable for this purpose; these questionnaires have been widely used internationally for interview surveys. The Cancer Society Question naire in the Cancer Prevention Study has been widely applied in the U.SA It contains questions about a wide range of symptoms and diseases and was designed for seif-completion. (h) Signs: It was agreed that when physical examination was possible, the minimal observations should include the presence or absence of clubbing of the fingers, cyanosis, and basal rales in the chest. It was agreed that the measurement of sputum volume (first hour on rising) and degree of purulcnce recorded in a standard way (Miller, 1963) were useful in association with the questionnaires for assessing the prevalence of bronchitis, and this may be relevant to tne disability caused by asbestosis. The epidemiological usefulness of examinations of spu.-m for t.snestos bodies and fibres is at present uncertain but needs investigation. 3. Classification of Chest Radiographs of Asbestosexposed Individuals.--There is no international or national standardized classification of the radio logical appearances of asbestosis. It is recommended that a scheme based if possible on an extension of the I.L.O. Classification (1939) be developed. Possible means of doing this were presented at the New York Academy of Sciences Symposium on the Biological Effects of Asbestos (1965) by Finnish, German, South African, and British contributors. The aim should be to specify separately and record semi-quaiUitativcly the principal radiological fea tures seen in asbestos-exposed groups, but exposure to mixed types of dust is not uncommon, and the appearances may therefore include those caused in part by other pneumoconioses. The classification should be purely descriptive of the radiological features and should not imply pathological change or the extent of disability. It is probable that the type and severity of alterations in radiological features, such as pleural piaques, etc., vary with the type of dust exposure and other factors so that a classification based on the principles in the I.L.O. Classification for Pneumoconiosis, in which there is a semi-quantitative assessment of several qualitatively dilTcrcnt types of abnormality, may be expected to be useful. It is recommended that a working group be set up to develop and test a new international classification. 4. Lung Function Assessment.--Tnc preferred lists of lung functions to be used will vary according to the type of survey and the facilities available. A list of minimal and additional tests likely to be of use is as follows:-- Minimal Forced vital capacity (F.V.C.) Forced expiratory volume over 1 see. (F.E.V.j.j) Additional Transfer factor (diffusing capacity) of lung for carbon monoxide--single breath method Lung compliance Standard exercise test Peak expiratory flow Airways resistance. Recommendations on Pathology and Experimental Pathology I. Diagnosis of Asbestosis (a) Macroscopic Examination: (1) At necropsy the parietal pleura should be t II DUP 0900415 :6S BRITISH JOURNAL OF INDUSTRIAL MEDICINE stripped if possible with the thoracic contents. It is desirable that at least one lung be inflated wit a fixa tive and whole lung sections be prepared. (2) It is recommended that special note be made of the following.--- Tile pleurae should be examined for thickening and plaques (defined as localized areas of stiff horn like material (Gloync, 1933)). The site and size of all pleural lesions should be recorded. The lungs should be examined for the presence of interstitial fibrosis, bronchiectasis, cystic change, tuberculosis, pneumonic consolidation, and tumours. The site of any tumour should be recorded as precisely as possible. Mediastinal tissues should be examined for evidence of neoplastic infiltration and for tuberculo sis. Parietal and visceral fibrosis in the peritoneum, such as parietal plaques and `sugar-icing' of the spleen, should be recorded. (It) Microscopic Examination.--It is recommended that at least six sections be examined from the lungs before the degree of asbestosis is decided, and these blocks should be taken from specific sites and identified in the followingstandard manner: (1) Apex of right upper lobe, pleural surface; (2) right middle lobe, lateral pleural surface; (3) right lower lobe, middle of, basal surface; (4) left upper lobe, central section; (3) lingula, central section; and (6) left lower lobe, central basal section. In addition, sections should be taken from the bronchi and peri tracheal and peri-bronchial lymph glands. It is presumed that all examining pathologists will take further sections of any suspicious or abnormal tissue, (c) Assessment of the Severity of Asbestosis.--The need to assess this in some standard way was agreed. It was recommended that the assessment should be based on the severity of interstitial fibrosis and the amount of tissue involved. The proposed scheme is as follows: Extent of Lung Involvement Degree of Asbestosis Degree of Interstitial Fibrosis Moderate Moderate *----------- Moderate Marked Marked -c*------------- Marked A category of minimal asbestosis is also proposed to describe slight focal fibrosis in the region of the respiratory bronchioles associated with the presence of asbestos bodies; such changes are commonly confined to scc:ions taken from the bases of the lower lobes. This scheme puts more emphasis on the extent of the lesions than the degree of fibrosis (which should be averaged for the six sections). Thus, a lung with moderately extensive disease but only slight severity of fibrosis is graded as "moderate asbestosis'. The use of an average assessment of the six sections makes it impossible to have a grading of slight in volvement and moderate or marked degree of fibrosis. (tl) Detection anti Significance of Asbestos Bodies and Fibres (1) Sputum: The presence of asbestos bodies and fibres is an indication of exposure to asbestos dust and not evidence of asbestosis. It is therefore suggested that the bodies should be referred to as `asbestos bodies' and not by the previously used term `asbestosis bodies'. Because of their sporadic appearance and, in the case of fibres, their relation to recent dust exposure, the Group were of the opinion that the quantitative assessment of bodies and fibres in sputum was not, in the light of present knowledge, a very useful procedure but might become more use ful when further investigated. In sputum, detection by direct examination under a coverglass and the use of phase contrast, oblique illumination or narrowed condenser diaphragms is proposed. If sputum concentration is used, antiformin or `Eusoi' treatment is recommended. If this technique is used for large-scale comparative epi demiological surveys, the exact method should be standardized. (2) Lungs: From fresh lungs, the highest positive results arc obtained from smears from the base of a lower lobe (of the thickness of a thick blood smear as for malaria! parasites), air-dried and mounted in balsam. A rough quantitative examination by lowpower magnification is easy and practicable.' For lixed lungs, the smear technique is of limited value, and unstained sections 30 microns thick arc recom mended. (3) For investigation of asbestos fibres in lung sections, micro-incineration, acid treatment, and examination by phase-contrast are suggested. Morphologically, the fibres appear as straight rods of varying lengths and thickness, but with longitudinal shredding, and in the thicker fibres smaller fibrils may be recognized. Although there arc other structures described as pseudo-asbestos bodies, or curious bodies, it was the view of the Group that in practice little difilculty is found in distinguishing the genuine from the others. These other types usually have a carbon-black centre, a shape which is other DUP 0900416 REPORT or THE P/ORKIHC CROUP OH ASDEETOS AHD CAHCER 169 ,...c..\ but ihc b.iuy can r.ii.nic ;;n axbcxios j,>.t> completely is ;hc small one fount! in talcosis, whlcr, may be iremo..;c, a form of asbestos. ( ) Chemical Analysis of Lam; Tissue.--Where nossihie, blocks of tissue from these six arcus chosen for histology shou.u be taken, anti the amount of collagen relative to total proteins should be estimated by the standard itydroxyprolinc methods. The results of collagen estimations should be expressed in absolute amounts and as percentages of defatted drieo lung tissue (Harington and Kilroc-Smith, 196-t). 2. u>iaa--isLs of Diffuse Mcsothclial Tumours ,a) A lacroscopic ___ i I) The salient characteristic of the dilTusc meso thelioma is its predilection to spread along the serosal membrane in which it occurs. In the pleural cavity, the entire surface may become replaced by a continuous layer of tumour due to symphysis of the picurai surfaces. Titis is uncommon in the periton eum where the surfaces often remain separate but covered by isolated plaques and nodules or dilTusc infiltration. Only those mcsothclial tumours in which serosal spread is unequivocal should be termed 'diffuse'. A few benign diffuse mcsothclio- mata have been described. Almost all diffuse mcsothciiai tumours show evidence of malignancy by direct infiltration of adjacent tissues and organs and mctastascs to regional lymph nodes. (2) Tlte diifercntiation from metastatic tumour is the main problem in diagnosis and can only be made with complete certainty by the exclusion of all other sources of tumour at necropsy. Because of the tendency of the tumour to surround and infiltrate subserosai organs, these organs most commonly come under suspicion as points of origin. Tlte possibility that the primary growth may have been surgically removed must be borne in mind. w. uc.i form complex meslnvorks and laminated a...alias. Omar examples of these tumours may have a.i entirely non-specific structure presenting the appearar.ee of a spindle-cell sarcoma or of an an. .p..ixiic tumour. " .localise oi me difficulty in distinguishing clearly on histological grounds alone some of these growths irom metastatic tumours, eases diagnosed from biopsy material should be called `probable meso theliomas'. In epidemiological studies precise details of me pathological evidcr.ce on which the diagnosis was based should be stated. (c) Histochemistry (1) Most of the mucoid material within mesothe liomatap almough otten intimately associated win; the surfaces ot the tumour ceils, is extracellular. Intracellular or intratubular mucin of an adeno carcinoma will usually take mucioarminc or PAS stains. The absence of these reactions in a tumour which contains mucoid material can, when taken with the other features, be useful additional evidence for a mcsothclial tumour. (2) Hyaluronic acid is often present in mcsothclial tumours. The demonstration of its removal from the tissue sections by specific hyaluronidasc preparations is a useful histochcmical test, but since tlte acid is soluble in water, the test requires that the tissues be fixed in a special precipitating fixative, such as fomiol alcohol acetic acid (Wagner, Munday, and Harington, 1962). It also appears likely that the quantitative measurement of hyaluronic acid in etTusions, where this polysaccharide has been isolated and chemically characterized, may well become a reliable method for assisting in the diagnosis of meso thelioma, but it is emphasized that positive resuits for both the histochcmical and chemical tests for hyalur onic acid arc found in only a proportion of cases of mesothelioma, and they should not be used as sole diagnostic criteria. (A) Microscopic.--Diagnosis is possible because the growth commonly shows histological patterns which are infrequent in other tumours and especially those which might metastasize to serosal membranes. Particularly helpful is the presence in some diffuse mcsothcliomata of a mixed structure of malignant elements of both epithelial and mesenchymal character, or other diverse combinations. Growths in which only one type of cytoarchitccture is present may also have a highly distinctive pattern; for example, (1) a tubular or tubulo-papillaiy pattern in which the tumour ceib show marked uniformity and arc cubical or flattened; (2) masses of collagen in which there are either (a) clef-like spaces lined or occupied by tumour cells, or (A) fine hyaline strands (cl) Exfoliative Cytology.--The contribution to .he diagnosis of diffuse malignant mesothelioma by ex foliative cytology ofserous fluids requires that (1) the exfoliated neoplastic mcsothclial cells sufltcicnily resemble exfoliated non-neoplastic mcsothclial cells for them to be recognized as having a mcsothclial origin, and (2) that they also possess the generally accepted features of malignancy. The latter are not often present so a definite diagnosis of mesothelioma is then difficult. Usually mesothelioma cells, while atypical, do not appear malignant but still show evidence of mcso thclial origin. From cytology of the serous fluid it is possible to be strongly suspicious, and, in a few cases, confident of the diagnosis of mesothelioma, but DUP 0900417 173 BRITISH JOURNAL OF INDUSTRIAL MEDICINE usually its presence can only be reported as possible. The diagnosis of malignant mesothelioma by exfoliative cytology requires a familiarity with the non-ncoplastic mesothelial cell. Mesoihelia! hyper plasia and hypertrophy can easily be mistaken for malignant mesothelioma and vice vena. It may be imprudent to do more than suggest malignant mesothelioma if there is not good supporting clinical, radiological, or biochemical evidence. The exfoliated malignant mesothelioma cell must also be distinguished from the adenocarcinoma cell, by far the commonest malignant cell recovered from serous fluids. This cell is well described in standard texts of exfoliative cytology. (e) Use of Tissue-culture in the Diagnosis.--The various manifestations of mcsothcliomata in some uses cause difficulty in distinguishing such tumours from bronchogenic carcinoma, metastatic ovarian carcinoma, fibrosarcoma, etc. It is therefore recom mended that where possible biopsy specimens of pleural and peritoneal neoplasms should be studied after short-term passage (a) in vivo, and (A) in vitro, to determine whether the rate of growth and/or morphology after transplantation can provide useful criteria for a differential diagnosis of mcsothcliomata. To achieve this it is recommended that clinical pathologists who see these tumours should co operate with workers in experimental carcinoucncsis who arc using tissue-culture methods. 3. Contribution of Experimental Pathology.--It was agreed that various types of asbestos induce in many species of animals lesions similar to those seen in human eases of asbestosis, mesothelioma, and possible carcinoma of the lung, but the need for more precisely planned experiments was emphasized. The desirability of using healthy animals of known response to asbestos under quantitative conditions of exposure by inhalation, feeding, and parenteral injection at several sites was agreed. Experiments in great variety are being undertaken in many parts of the world, particularly in Canada, Great Dritain, South Africa, and the U.S.A. The prospect of providing standardized samples of chrysolite, amositc, crocidolitc, tremolite, and anthophyllite asbestos for experimental work was welcomed. it was agreed that there was a need for improving methods of identifying the type of asbestos in submicroscopic fibres in tissues. Further studies of the rate of formation and resistance to destruction of asbestos bodies in different species ofanimals may be useful. It is recommended that there be closer collabora tion between clinical and experimental pathologists and other scientists in the field of experimental pathology, biochemistry, and biophysics, as applied ' to the problems of the oiological action of asbestos. 4. Propo-et! for Pathology Reference Panels.--It is recommended that centra! consultation and reference panels be set up on regional, national, and inter national levels. These panels will (!) assist in estab lishing standards for the pathological classification of asbestosis; (2) serve as consultation centres for the diagnosis of mcsothcliomata and other tumours associated with exposure to asbestos; (3) serve as a general exchange of pathological material related to asbestosis and its associated tumours; (4) it is sug gested that a comprehensive atlas on the pathology of mcsothcliomata should be prepared. Recommendations Relating to Physics and Chemistry 1. Reference Samples of Asbestos for Experimental Work.--it is anticipated that there will be an expansion of demand for asbestos of various types for biological and other studies. It is at present impossible to predict the biological effects of differences in mineral composition, size distribution, associated organic matter, and trace metals in differ ent samples ofasbestos. Also fibres from a particular mine may vary in composition and in the amount of' absorbed material. It is therefore recommended that: () Standard reference samples, of respirable size, of amositc, chrysolite, crocidolitc, tremolite, and anthophyllite be prepared from as pure parent material as possible and held at the Pneumoconiosis Research Unit (P.R.U.) in Johannesburg for dis tribution to centres that require them. (These standards should also serve as references for comparison with larger amounts of material, such as may be required for inhalation or chemical extrac tion.) It is proposed that samples of chrysotilc from different countries, for example, Arizona, Havelock (Swaziland), Quebec, and Shabani (S. Rhodesia) be included in the reference collection. (A) The standard samples be analysed and charac terized quantitatively by (!) chemical and spectrographicanalysis; (2) optical and electron microscopy, for the determination of shape, size distribution, and optical properties, such as refractive indices, extinction angle, etc.; (3) x-ray diffraction analysis by the powder technique; (4) specific surface measurement by low temperature gas adsorption; and (5) determination of the amount and type of the organic matter present. (c) Oils and waxes isolated from asbestos be prepared and also distributed through the P.R.U., Johannesburg. 1 tI DUP 0900418