Document Oz2D6NGdkRmEy9xDbmyj5q3ew

SNST1T \ > SUITE n-lii rs P2-A.CE VILEE MARIE MONTREAL 113, CANADA TELEPHONE fO!4) 1170-MrWta January 12, 1973 To Member-Companies of the Quebec Asbestos Mining Association Gentlemen: Following the Conference on the Biological Effects of Asbestos in Lyon, October 1972, an Advisory Committee kept working in three panels and eventually presented to the International Agency for Research on Cancer (IARC) its Report and Recommendations for further Research. Some time ago we sent you two yellow books (Volume I. and Volume II.) of preprints of the Conference on the Biological Effects of Asbestos, in which the first drafts of the recommendations of the three panels, as were then avai-lable, were enclosed. Today we present to you, as Volume III. of the Conference, the final Report and revised final Recommendations of the Advisory Committee and its three panels. It is a very interesting and important material. The comments made under "General Review" on pages 4-6 show a valuable change in the international scientific opinion toward seeing the asbestos cancer problem in correct perspective. No doubt the studies supported by our Institute contributed to this change. Sincerely, PVP/st Premysl VV . Pelnar, MM,.D. Scientific Secretary --****.%* '*** v* AiiM >.i\ j 14wi xCji\i*A(ihAO* i oN CANChR The mooting was hold at the International Agency for Research on Cancer, Lyon, Franco on 5th and 6th October, 1972. Tho Committee consisted of three panels - Epidemiology, Pathology, Physics and Chemistry. , Epidemiology Panel Dr. M. Bccklake McCill University, Department of Epidemiology & dealt)' 3775 University Street, Montreal 13.0, Quebec, Canada. Dr. 11. Eohlig Chefarzt der Strahlenabtcilung des Stadtischcn, Krenkenhauses Ludenschoid, 566 Ludenscheid, Germany Dr. N. Day Unit of Epidemiology and Biostatistics, International Agency for Research on Cancer, 150 Cours Albert Thome: 69008, Lyon, France. Prof. P. C. Elmes Department of Therapeutics and Pharmacology, Queen's University of BelfastJ Institute of Clinical Science, Grosvenor Road, Belfast, BT12 6UJ, N. Ireland, UK. Dr. J. C. Gilson Medical Research Council, Pneumoconiosis Unit, Llandoi Hospital, Penarth, Glamorgan, Wales, UK. (Chairman) Dr. J. Lepoutre Medical Department, N.V. Eternit, Kapelle-op-dcn-Uos, Belgium'. Prof. J. C. McDonald McGill University, Department of Epidemiology Ik dealt 3775 University Street, Montreal 110, Quebec, Canada. Mr. C. E. Rossiter Medical Research Council, Pneumoconiosis Unit, I..1 an do Hospital, Penarth, Glamorgan, Wales, UK. Dr. H. Snkabe Department of Industrial Physiology, Ministry of Labo National Institute of Industrial Health, 2051 Kissukisumioyoshi-Cho, Kawasaki, Japan. * Dr. I. J. Selikoff Department of Medicine, Mount Sinai School of Medici: Fifth Avenue and 100th Street, New York, N.Y. 300291 Dr. G.K. Sluis-Cromcr South African Medical Research Council, National Rose Institute for Occupational Diseases, P.0. Box ^7^8, Johannesburg, S. Africa. - Dr. W. Smithor Cape Asbestos Co. Ltd., ll(i Park Street, London WIY ^ England, UK. Dr. G. Wright Division of Medicine, St. Luke's Hospital, 11331 Shal Boulevard, Cleveland, Ohio VrlOl, USA. * Unable to attend. Dr. A. C. Allison Clinical Research Centro, Watford Hoad, Harrow, Middlesex, 1LA1 3UJ, UK. Hr. G. Kerry Medical Rosoaixh Council, Pnoumoconiosis Unit, Llandou Hospital, Pcnarth, Glamorgan, Vales, UK. Dr. P. Dogovski Unit of Environmental Carcinogens, International Agono; for Research on Cancer, 150 Cours Albert Thomas, 69008 Lyon, Prance. Dr. M. Kmmerstcin , Pathology Department, Barncrt Memorial Hospital Centre 680 Broadway, Paterson, N.J. 07514, USA Prof. V.T.E.McCaughcy School of Pathology, Trinity College, University of Dublin, Dublin 2, Eire. Prof. D. Magner ' Prof. 11. Otto Canadian Tumour Reference Centre, Department of Pathology, University of Ottawa, Ottawa, Ontario, KIN 6N5, Canada. Direcktor dcs Pathologischen Instituts dor Stadt Krankcnanstaltcn Beurhausstrasc 40, 46 Dortmund, V, Germany. Dr. H. T. Planteydt Stichting Strccklnboratorium"Zeeland", Noordpoortploin Middclburg, Netherlands. Dr. M. Stanton Department of Health, Education and Welfare, National Institute of Health, Bothesda, MD 20014, USA. Dr. J. C. Vagner Medical Research Council, Pneumoconiosis Unit, Llandow Hospital, Ponarth, Glamorgan, Vales, UK. (Chairman) Prof. S. Vatnnabe Department of Pathology, National Cancer Centre, Resea: Institute, Tsukiji, 5-I-1, Chuoku, Tokyo, Japan. Prof. I. Webster Medical Research Council South Africa, National Rescan Institute for Occupational Diseases, P.0. Box 4788, Johannesburg, South Africa. Physics and Chemistry Panel Dr. L. Le Bouffant \ Laboratoiro du Centre. D1 Etudes et Rocherches des Chai'bormago.s de France, Verneuill-cn-Hallatte, BP No.2' 60 - Crcil, France. Mi-. G. V. Gibbs McGill University, Department of Epidemiology & Health 3775 University Street, Montreal 110, Quebec, Canada. Dr. S. Holmes Asbestos!s Research Council, c/o Turner Bros. Asbestos Co. Ltd. P.0. Box 40, Rochdale, England, UK. N Mr. A. Morgan Atomic Energy Research Establishment, Health Physics a Medical Division, Building 364 , Harwell, Berks., . England, UK. */* i' ijm iOQ-LVj Dr. S. Spoil Dr. V. Timbrel1 Dr. R. du Toit Mr. W. H. Walton w.. VA4*x\iituCio`it o<A *vy Coxit... of S. Vales and Monmouthshire, Newport Hoad, Cardiff, Walesv UK. Johns Nonviile Research and Engineering Centre, P.O. 2.59s Manville, New Jersey, USA. Medical Research Council, Pneumoconiosis Unit, Llando Hospital, Penarth, Glamorgan, Vales, UK. Government Mining Engineer's Division, Department of Mines, P.0. Box 1132, Johannesburg, South Africa. Institute of Occupational Medicine, Roxburgh Place, Edinburgh EH 8 9SU, Scotland, UK. (Chairman) The panels mot in a separate session and at the final session (Chairman Dr. Gilson) prepared this report to the Director of tho International Agency for Rosea on Cancer. * ' TERMS OF REFERENCE . 1. The Committee was to report on the present evidence relating exposure to asbestos dust to cancers, especially that obtained since tho meeting of the Ul'CC Working Group on Asbestos Cancers in 1964. 2. The Committee was to make recommendations for further research and indicate priorities for work of immediate and long-term value. CO-ORDINATION OF INTERNATIONAL CO-OPERATION Following tho meeting of the UICC Working Group on Asbestos and Cancers in 1964, a Sub-Committee of the UICC Commission on Geographical Pathology and Environmental Carcinogens (Chairman^ Dr. J. Higginson) was formed to co-ordinate work required to achieve tho recommendations. tho In April 1970 agreements between the UICC and/lARC led to the winding up of tho UICC Sub-Committee and the IARC taking on responsibility for tho Sub committee's work and extending it by supporting certain projects on asbestos cancers in several countries. The Agency has done this as part of their wider programmo of investigating environmental carcinogens. Common memberships between UMv'u OUjJ '..T.auutx u Cfcifci caUCa Cii-* k-Uuuux u L-titi caU, v x s Xil1^2 3 Cliti Xi Ai\U ^ .OIl^Ux ^ Ce> U t ll^llx C of policy. In October 1972 the IARC held an internationul Confoi'once with 137 participants from 20 countries to review all the evidence relating asbestos with cancers. Subsequently the Advisory Committee prepared its report. This is divided into two sections. First, a general review in the form of answers to a number of important general questions about the relation of asbestos to cancers of different sites and, secondly, recommendations for further research. GENERAL REVIEW . 1. Are all major commercial typos of asbestos able to cause lung carcinoma? Yes. Since 1964 the evidence of a causal relationship has been increased by epidemiological studies showing exposure-response relations for the incidence of lung carcinomas. The production of lung carcinomas in certain animals by all types of asbestos supports this conclusion. The epidemiological evidence in man, however, shows that there are clear differences in risk with type of fibre and nature of exposure. . ' 2. Is there evidence of an increased risk of lung carcinoma at low levels of exposure to asbostos, such as have been encountered by tho general population in urban areas? . The evidence of an exposure-response relationship based in part on past dust measurements and in part on the type of job within tho industry suggests that an excess lung carcinoma risk is not detectable when the occupational exposure has been low. These low occupational exposures have almost certainly been much greater than that to the public from general air pollution. 3. Since 1964 has tho ovidcncc relating past exposure to asbestos and mesotheliomas changed? " The evidence,-has been greatly strengthened by further prospective and retrospective mortality studies in many countries of populations exposed to ashes There is evidence that all commercial types of asbestos except nnthophyj15to may reaponsiuie. i^Vxueace i.or ,*. -A- xi a. jlSK ^.aJi Gj. '. GJTGaa - v occujiations and with the `typo of asbestos has increased. The risk is gioatcav with crocidolito, loss with amositc and apparently less with chrysotilo. With, amositc and chrysotilo tl-.crc appears to be a higher risk in manufacturing than in mining and milling. There is also evidence from population studies that a proportion of cases of mesothelioma have no known association with exposure to asbestos. h. Is there evidence of an increased risk1of mesothelial cancers at low levels of exposure to asbestos, such as have been encountered by the general population in urban areas? . There is evidence of an association of mesothelial tumours with air pollution in the neighbourhood of crocidolito mines and of factories using mixtures of asbestos fibre types. The evidence relates to conditions many years ago. There is evidence of no excess risk of mesotheliomas from asbestos air pollution which has existed in the neighbourhood of chrysotilo and amositc mines. There are reported differences on incidence of mesothelioma between urban and rural areas, the causes of which have not been established. There is no evidence of a risk to the general public at present. 5. Since 1964 has the evidence changed on the importance of other factors such as cigarette smoking, waxes, oils and trace elements as cot,' -- y factor to the cancer risks? The evidence has accumulated indicating: (1) Cigarette smoking is an important factor enhancing the lung carcinoma risk in asbestos-exposed workers, in both men and women. Asbestos workers have specially strong grounds for giving up smoking to protect thoir health. No association has been demonstrated between cigarette smoking and mesotheliomas. (2) Animal experiments designed thus far to test the importance of waxes and oils as contributory factors in the production of -6- mesothelioma have shown these contaminants arc unlikely to bo relevant. ' (3) From animal experiments there are no good clues suggesting that trace elements .are likely to be a major factor in the production of asbestos cancers. G. What other types of cancer arc related to exposure to asbestos? Prospective surveys of occupational groups exposed to asbestos have in general shown a small excess risk of some other typos of cancers (in addition to bronchial and mesotholial), especially those of the gastro-intestinnl tract. The excess of these tumours is relatively small compared with that for bronchial cancer. Evidence for an association with ovarian tumours has not been supported by the first large mortality survey of women previously exposed to asbestos. 7. Is there evidence of an increased risk of cancer resulting from asbestos fibres present in water, beverages, food or in the fluids used for the administration of drugs? Such evidence as there is does not indicate any risk. 8. Is there evidence of a risk of lung fibrosis from low levels of exposure to asbestos such as have been encountered by the general population in urban areas? There is at present no evidence of lung damage by asbestos to the general public. The amount of asbestos in the lungs of members of the general public is very small, compared to those occupationally exposed. It is greatest where asbestos is mined or* worked and lowest in rural areas. 9. Has the relationship between <vsbostos exposure and the development of pleural plaques been established? Pleural plaques hove been associated with past exposure to all commercial typos of asbestos. But additional factors, other than asbestos itself, are involved. The plaques may remain fibrous or become calcified. Not all pleural plaques r r> > unr, > rJ r%A with a 'ost'' " ufjCOMWcndatioms fop further research Projects which the Panels rated high in priority are marked *; those which will require close co-operation between the Panels are marked / EPIDEMIOLOGY , The Panel agreed that asbestos x'datod cancers occur in several sites in the body. The incidence of the different cancers varies with a number of definable factors and for other reasons, such as competing causes of death. Epidemiological studies will usually provide information on more than one typo of cancer. Research directed at only a single typo may, on occasions, be useful but in general the inevitable uncertainties, in some cases in the differential diagnosis of, for example, peripheral lung carcinomas and pleural mesotheliomas, and between peritoneal mesotheliomas and other intra-abdominal cancers will require that more than one type is st.udicd at the same time. The Panel recognised that some of the cpi'deiniological projects could only be pursued if there was close co-operation between epidemiologists, pathologists, physicists and chemists, and others, because their success will depend upon the development of improved techniques, some of which arc referred to in the recommendations of the other two Panels. PROJECTS (l) Further development of objective methods for early detection and surveillance of effects caused by asbestos. Topics for particular study include : (a) Immunological techniques for screening for fibrosis '. \ and neoplasia. (b) Functional tests of changes in the peripheral airways. (c) Detection of pleural thickening. * (d) Assessment of the specificity of small irregular opacities in the chest radiograph as defined in the ILO !)/C * ' n '*\ -G- (c) Tests of the usefulness of different techniques of chest radiography, including the use of 100 mm films. (f) Development of statistical procedures for analysis and presentation of serial observations. / (2) Evaluation of the usefulness of early detection in the prevention of progressive fibrosis and asbestos cancers, also in the identification of hazardous conditions. Routine health surveillance of industrial populations ' should should be designed to assist epidemiological studies and/includc measurement and recording of environmental dust levels. Surveillance of new entrants could be particularly valuable. Arrangements should be made to register workers so that their Morbidity and mortality experience can be studied oven after cessation of exposure to asbestos. ' - (3) Assessment of excess cancer risks following exposure to only one type of fibre. ' (a) Chrysotilc: The much higher cancer risk reported for chrysotile textile workers compared with mine and mill workers requires explanation. How much is explicable by differences in size of past airborne fibres and/dustincss? There is need to make more use of past dust records for relating to indices of disease. (b) Amositc: The excess lung carcinoma and mesothelioma risk is apparently much greater in the manufacturing and application ' sections of the industry than in the mining and milling of this type of fibre. What^are the important factors in this reported difference? (c) Croc 3 del 5 te: Further studies are requix-od in occupational groups exposed only to crocidolitc or amositc or chrysotile in the manufacturing and application parts of the industry to establish more clearly differences in risks due to different fibres J" * / (U) Studies of the amount and typo of asbestos in tho Jungs of cases of tO mesotheliomas (if possible by coll type) in (a) national survey of mesotheliomas, (b) representative samples of cases arising in groups with a definable past exposure. * (5) Studies of secular changes in incidence of pleural and peritoneal mesotheliomas nationally and internationally. * (6) Epidemiological studies to investigate the association between past exposure to asbestos and cancer of sites other than lung, pleura, and peritoneum. (7) Studies of secular trends in the asbestos content of the lungs in the general population. * / (0) Studies to relate amount and type of asbestos in the lung and estimates of past dust exposure aiid interval since last exposure. (9) Experimental and epidemiological studies-to investigate possible differences of effect of continuous low and intermittent high exposure to asbestos. (10) Opportunities afforded by intcrcurrent deaths should be used to interrelate radiographic appearances, lung pathology, respiratory function, dust content, and typo in asbestos workers. Standardised techniques and classification recommended by the Panels should be used. . (11) Investigate the prognostic significance and aetiological factors in the development of calcified and uncalcified pleural plaques in different environments. (12) Investigate talc-exposed groups in mining and manufacturing to establish any differences in morbidity or mortality which might be related to the amount and shape of the pTine respirable particles. ' (13) Development of cost/bcnefit analyses to study the health, safety, social and economic intcrrclatjons of the use of asbestos. -10PATHOLOC.V ANT) EXPERIMENTAL PAT1107,00Y The Panel reviewed the progress made on the lyd'i UICC recommendations. It was agreed that considerable progress had been made on the majority of the recommendations. Some require further study, or modification of previous methods of investigation; these arc included in the list of recommendations that follows. The recommendations are divided into three categories, morbid anatomy and histology, clinical research, and experimental studios. PROJECTS Morbid Anatomy .and Histology 1. Asbestosis . * (l) Further consideration should be given to methods for determining the amounts, types and. structural features of asbestos in tissue.. A Sub committee should bo established with members of the Physics and Chemistry Panel, and others to accelerate work on this problem. (2) The methods for assessing the sevei'ity of asbestosis (see paper 9) should be tested for consistency by different observers. 2. Carcinoma * / (l) An investigation of whether reduction of asbestos exposure to levels below those producing asbestosis also abolishes excess risk of carcinoma was considered important. (2) A comparison of lung carcinomas in persons occupationally exposed to asbestos and those not so exposed, including both cigarette smokers and non-smokers, in respect of sites of origin and cytology of tumours and presence or absence of asbestosis, would bo of value. 3- hoi iotnas * . (l) The International Panel of Pathologists and National Panels established following the meeting have served n useful purpose. It is * recommended that panels be established in other countries and membership of the International Panel bo extended. The main purposes of these Panels is to ensure uniformity of diagnostic criteria and recording of histological types of diffuse mcsothcliorrias. Collaborative study of histology slides in National Panels is recommended. The diagnosis of mesothelioma can be made by exfoliative cytology of the pleural fluid. If the cytological diagnosis is made by a competent cytologist, biopsy may be unnecessary. (2) To improve consistency of diagnosis there is an urgent need for a Comprehensive Atlas on mesotheliomas, or alternatively, for inclusion of an enlarged section on mesotheliomas in the new edition of the WHO Monograph on Tumours of the Lung. Criteria for diagnosis by exfoliative cytology and a description of the fine structure of mesotheliomas should bo included. Clinical Research ' * / (l) Monitoring by immunological methods of populations exposed to asbestos should be investigated to ascertain whether it is possible to recognize those who are developing, or will develop, tumours. (2) The use of chromatographic methods for the study of inucopolysnccbnr and other tumour-associated substances in pleural fluids should be explored. Sensitive methods might be developed and applied to identify secretory products of mesotheliomas in blood and urine. The International Pane], consists of: Dr. M. Kanncrstcin (USA), Prof. D. Magner (Canada), Dr. L. Moorman (Finland), Prof. '.v'.T.E. McCnughoy (Eire), Prof. II. Otto (FUG), Dr. 51. T. Plantcydt (Netherlands), Dr. E. Roitzwch, (GDR) , Prof. L. S'anti (Italy), Prof. I. Webster (South Africa), and Dr-. J.C.Wagner (UK) as Secretary. 2 Great Dritain, Soutli Africa, United States, Canada, Netherlands Further Experimental Studios . * (l) Information is required about the role of fine particles, especially influence of fibre size, in the induction of tumours. Those studies should be extended to include fibres other than .asbestos. A Sub-Committee should bo established to review the need for, and arrange the distribution of standard samples of asbestos and other fibres in addition to the UICC Reference Samples. / (2) The fate of inhaled particles of various sizes, shapes and chemical compositions, should bo studied to determine, more precisely the quantities and sites of initial deposition, change within the body and later retention. The feasibility of increasing fibre elimination by various methods should be explored. Studies should be made of means of reducing the fibrogcnici.ty and carcinogenicity of fibres already retained in the lungs. t (3) The use of `cell and organ culture, including mesothelial tissue from man and other species, should be further .investigated with a view to developing methods of screening dusts for fibrogenic and carcinogenic properties. (4b) Further studies should be carried out to determine the nature of the combined effect on tumour induction when animals are exposed to asbestos dust and cigarette smoke, metals or other chemical carcinogens, including those which act systemieally such as nitrosaminos. (5) Inhalation experiments should be extended to test various types of fibre; of special interest are forms of chrysotile and crocidolite including the finer grade materials. (6) It was felt that studies of the pathological effects of asbestos on species other than rodents would bo of value. (7) The effect of long-term ingestion of fibres of various sizes, shapes and chemical compositions should be studied. . (8) The effects of fibres and associated metals on the metabolism of target organs should bo investigated. PHYSTCS AND CHEMISTRY The Panel reviewed the progress made on the lOG^i UICC Recommendations. Tlie proposals for tlie preparation and characterization of the UICC reference samples of asbestos had been satisfactorily implemented, and the Panel recommended that a list of references to papers featuring the samples should be distributed to investigators in this field. Considerable progress had been made on methods of identifying the typo of fibre- in tissues but a quantitative method when several types of fibres were present had yet to be developed. The Panel discussed the further .contribution that physical and chemical studies can make to research on the biological, effects of asbestos and other fibrous materials. Of especial interest arc the effects of fibre size and shape on the retention of material in the lungs, the site of deposition, the migration of fibres within the body, and their carcinogenic or other biological activity. The following recommendations wore made: */ */ PROJECTS 1. Materials for experimental work a) Supplies of asbestos from relevant sources should be obtained whore there is evidence of variation in geological form, trace element content or significant biological findings. b) Small samples of various fibrous materials should be prepared for studios on the influence of fibre size and shape on carcinogenicity. For this purpose the samples should be milled to different degrees of fineness. c) For investigations on the influence of particle shape and size, on the inhalation and subsequent fate of asbestos fibres a chrysotilc and an amphibolc of fibre length greater than the UICC samples should be prepared. 2. Methods , a) There is an urgent need for the quantitative assessment, size analysis and characterization of particles and fibres in the lungs and other organs. Details of available methods should be circulated, international, comparison:; -J'i- b) No methods arc at present available for the preparation of fibres in narrow ranges of diameter and length in sufficient quantities for inoculation experiments. Techniques for these purposes arc urgently required, especially in view of the advantages such graded samples could provide for investigating the influence of these physical- factors on the carcinogenicity of fibres of different materials. c) Since the degree of dispersion of fibres (especially chrysotile) used in inoculation studios may have' a marked influence on their carcinogenicity, methods are required for quantifying dispersion. d) Inhalation studies require precise control of the characteristics of the dust clouds. Improved methods of dispensing fibrous dusts in such investigations need to be developed. e) Methods are available for collecting the important size fractions of dust clouds in inhalation studies when the particles are of compact shape. Similar methods must be developed for fibrous particles. f) The present membrane filter methods of measuring the levels of airborne asbestos dust require standardization. This should bo done by inter-laboratory trials on a continuing basis. Particle counting by electron microscopy should also be developed. Gravimetric assessment methods and the automation of particle counting should be explored. 3- Inhalation studies 1 Considerable information is now.available on the deposition, retention and migration of particles of compact shape. Recently developed methods, especially . \. . radio-active tracer techniques, should be used to obtain similar knowledge for fibrous particles. This- information is needed to identify the biologically important size fraction and to help interpretation of epidemiological and * pathological studios. 35 h. Occupnt i on.'i) and environmental studios ' The use of both fibre counts nnd gravimetric methods Tor assessing asbestos dust concentrations should be encouraged. Data collected over an extended period will be particularly valuable in identifying the parameters of the dust which can bo correlated with epidemiological evidence on the health hazard. 5* Physics and Chemistry Panel It is recommended that an international Panel be established to assist in implernenting these recommendations. The Panel would periodically review requirements for materials for experimental work; provide guidance on physical and chemical problems; nnd arrange national and international standardization trials.