Document R264D4rM3Lory912ZDQ8DZdQ8

DIRECTOR OK THE INTERNATIONAL AGENCY I'OP, RESEARCH ON CANCER G-^eG' OC' OC OOC O The mooting was held at the International Agency for Research on ' Lyon, France on 5tb and 6th October, 1972 The Committee consisted of panels - Epidemiology, Pathology, Physics and Chemistry Ep .idcm io1ogy Pa nc1 Dr. M. Bccklake McGill University, Department of Epidemiol 3779 University Street, Montreal 110, Quel Dr. He Bohlig Chefarzt der Strahlenabteilung des Stadtii iCrenkcnliaur.es Ldenscheid, 5^0 Ludenscheic Dr*_N. Day Unit of Epidemiology and Biostatistics, Ii Agency for Research on Cancer, 150 Cours J 69008. Lyon, France, Prof, P. C. Eimes Department of Therapeutics and Phanaacolof University of Belfast, Institute of Clinii Grosvcnor Road, Belfast, BT12 6)3J, N. Ire Di' J. C, Gilson Medical Research Council, Pneumoconiosis Hospital, Penarth, Glamorgan, Vales, UK. Dr. J. Lepoutre Medical Department, N.Y. Eternit, Kapelle Bel g iutn. Prof, J. C. McDonald McGill University, Department of Epidomio 3775 University Street, Montreal 110, Quo Mr. C. E e Rossiter Medical Research Council , Pneumoconiosis Hospital, Penarth, Glamorgan-, Vales, UK. Dr. II. Sakabe Department of Industrial Physiology, Mini National Institute of Industrial Health, 2051 Kizukisumioyoshi-Cho, Kavasaki, Japi * Dr. I. J. Sclikoff Department of Medicine, Mount Sinai Scho< Fifth Avenue and lOOih Street, Ncv York, Dr. G.JC. Sluis-Crcmcr South African Medical Research Council, Institute for Occupational Diseases, P.0 Johannesburg, S. Africa. Dr. V. Smither Dr. G. V/right . Cape Asbestos Co. Ltd. ,.llA. Park Street, England, UK* & Division of Medicine, St. Luke's llosn.ita Boulevard, Cleveland, Ohio h h 101, USA. Dr* Ac Cc Allison Clinical ucacnrcn u u n u u, rt 1.1 1 / O . U i VjI ! v vy V i , Middlesex, 1IA1 3UJ, UK. Mr* G c Merry Medical Research Council, Pneumoconiosis Un Hospital, Penarth, Glamorgan, Wales, UK- Dr* P* Bogovski Unit of Environmental Carcinogens, Internat for Research on Cancer, 150 Cours Albert Th Lyon, Prance. Dr* M, Kannerstein Pathology Department, Darnert Memorial Hosp 680 Broadway, Paterson, N.J. 075 USA Prof. W.T. E. McCavighey School of Pathology, Trinity College, Univc Dublin, Dublin 2, Eire. Prof* D* Magner Canadian Tumour Reference Centre, Departmer Pathology, University of Ottawa, Ottawa, Or KlK1 6R5 , Cana da. ProfL H. Otto Dirccktor des Pathologischen Instituts der Krankenanstalten Beurhausstrase /jO, liG Dori V* Germany. Dr. i. T* Plantcydt Stickling StrecklaboratoriumnZecland", N001 Middelburg, Netherlands. Dr. M. Stanton Department of Health, Education and Wolfan Institute of Health, Dethesda, MO 2001^1 , U` Dr* J. C. Vagner Medical Research Council, Pneumoconiosis Ui Hospital, Pcnarth, Glamorgan, Wales, UK. Prof. S. Vatanabe Department of Pathology, National Cancer C Institute, Tsukiji, 5-l~i Chuoku, Tokyo, Prof. I, Webster -Medical Research Council. South Africa, Nat Institute for Occupational Diseases, P.0. Johannesburg, South Africa. Physics and Chemistry Panel Dr* L. Le Bouffant 1. Laboratoirc du Centre D 'Etudes et Rcchcrch Charbonnagcs de Franco , Vcrncuill-cn-JIall a 60 - Creil, Prance. Mi-* G,, W. Gibbs McGill University, Department of Epidemiol 3775' University Street, Montreal 110, Qacl: Dr. S Holmes Asbestosis Research Council, c/o Turner Be Co. Ltd. P.0: Box hO] Rocl)dale, England, l Mr* A. Morgan Atomic Energy Research Establishment, Heal Medical Division, Building 36A , Harwell, ) Imi.,1 rnul. !ri' Dr* F, D e Dooley D r 6 S, Speil Dr. V. Timbrcll Dr. R. du To it Mr. V. Jf, Val ton Department of Mineral Exploitation, Universi of S* Vales and Monmouthshire, Newport Hoad, Vales, UK. * Johns Manvillc Research and Engineering Ceni 159 Manvillc, New Jersey, USA. Medical Research Council, Pneumoconiosis Uni Hospital, Penarth, Glamorgan, Vales, UK. Government Mining Engineer's Division, Depai Mines, P.0. Box 1132, Johannesburg, South Al Institute of Occupational Medicine, Roxburgh Place, Edinburgh Eli 0 9SU, Scollane (Chairman) The panels met in a separate session and at the final session (Chai Gilson) prepared this report to the Director of .the International Agency on Cancer. TERMS OF REFERENCE 1. The Committee was to report on the present evidence relating exposi asbestos dust to cancers, especially that obtained since the meeting of i Working Group on Asbestos Cancers in 1964. 2. . The Committee was to make recommendations for further research and priorities for work of immediate and long-term value. CO-ORDINATION OF INTERNATIONAL CO-OPERATION Following the meeting of the UICC Working Group on Asbestos and Cai 1964, a Sub-Committee of the UICC Commission on Geographical Pathology a: Environmental Carcinogens (Chairman^Dr. J. Hiyginson) was formed to co-01 work required to achieve the recommendations. the In April 1970 agreements between the UICC and/lARC led to the wind; up of the UICC Sub-Committee and Die IARC taking on responsibility for t! t Committee's work and extending it by supporting certain projects on asbe: 0 .* cancers -in several countries. The Agency lias done this as part of their programme of investigating environmental carcinogens. Co mnion m emb ersh ip of policy* _ ' In October 1972 the 1AUC held an international Conference v/ith 13 7 participants from 20 countries to review all the evidence relating nsbest cancers* Subsequently the Advisory Committee prepared its report* This divided into two sections* First, a general review in the form of ansvei a number of important general questions about the relation of asbestos t( of different sites and, secondly, recommendations for further research* GENERAL REVIEW 1* Are all major commercial types of asbestos able to cause lung carci Yes* Since ItyGU the evidence of a causal relationship lias been inc by epidemiological studies shoving exposure-response relations for .the i of lung carcinomas* The production of lung carcinomas in certain animal types of asbestos supports this conclusion. The epidemiological evidenc however, shows that there arc clear differences in -risk with typer of fil nature of exposure^ 2*' Is there evidence of an increased risk of lung carcinoma at low le1 exposure to asbestos, such as have been encountered by the general popu urban areas? The evidence of an exposure-response relationship based in part on measurements and in part on the type of job within the industry suggest excess lung carcinoma risk is not detectable when the occupational ex"pc been low* These low occupational exposures have almost certainly been greater than that to the public from general air pollution. 3* Since 196A has the evidence relating mesotheliomas changed? past exposure to asbestos r The evidence lias been greatly strengthened by further prospective retrospective mortality studies in many countries of populations expos There is evidence that all commercial types of asbestos except anthopl occupations and with the*, typo of asbestos lias increased. Tim risk is gn with croc5.do3.itc, less with nmositc and apparently 3css with chrysotilo. amositc and chrysotilo there appears to bo a higher risk in manuf actor 5n in mining and milling. There is also evidence from population studies t proportion of bases of mesothelioma have no known association with expos asbestos. 4 Is there-evidence of an increased risk*of msothlial cancers at lo of exposure to asbestos, such as have been encountered by the general po in urban areas? . There is evidence of an association of msothlial tumours with ail pollution in the neighbourhood of crocidol ite' mines and of factories usi mixtures of asbestos fibre types. The evidence relates to conditions m< years ago. There is evidence of-no excess risk of mesotheliomas from re air pollution which has existed in the neighbourhood of chrysotilo and y mines. There arc reported differences on incidence of mesothelioma bet', urban and rural areas, the causes of which have not been established, no evidence of a risk to the general public at present.*12 5>o Since 1964 has the evidence changed on the importance of other fac such as. cigarette smoking, waxes, oils and trace elements as contributo to the cancer risks? 'The evidence has accumulated indicating: (1) Cigarette smoking is an important factor enhancing the lung c.r risk in asbestos-exposed workers, in both men and women. Asbc workers have specially strong grounds for giving up smoking tc protect their health. No association has been demonstrated between cigarette smoking and mesotheliomas. (2) Animal experiments designed thus far to test the importance oJ waxes and oils as contributory factors in the production of bo relevant* , iI (3 ) From animal experiments there are>no good clues suggesting that trace elements are likely to bo a major factor in the production of asbestos cancers. 6c What other types of cancer are related to exposure to asbestos? Prospective surveys of occupational groups exposed to asbestos have in general shown a small excess ri.sk of some other types of cancers (in ad to bronchial and mcsotholi.al), especially those, of the gastro-intestinal t The execs5; of these tumours is relatively small compared w ith that for bro cancer. Pvidoncc for an association with ovarian tumours has not boon sup by the first large mortality survey of women previously exposed to asbesto 7 Is there evidence of an increased risk of cancer resulting from nsbot fibres present in vat or, beverages, food or in the fluids used for the adusi ni stration of drugs? ' * Suedi evidence as there is docs not indicate any risk. 8. Is there evidence of a risk of lung fibrosis from low levels of expo? asbestos such as have been cuccami creel by the general population in urban There is at present no evidence of lung damage by asbestos to the go; public. The amount of asbestos in Die lungs of members of the general pul i r very small, compared to those occupationally exposed. It is great osi ' .aoestos js mined or worked and lowest in rural, areas. 9- )las Die reiat ion.ship between asbestos exposure and Die development o pleural plaques been established? Pleural plaques have been associated with past exposure to all cornino typos of asbestos. Put additional factors, other than asbestos itself, * involved. The plaques may remain fibrous or become calcified. Not all j plaques are associated with asbestos. y/hich will require* close co-operation between the Panels are niarked EPIDEMIOLOGY The Panel agreed that asbestos related cancers occur in several site in the body. The incidence of the different cancers varies with a numbo definable factors and for oilier reasons, such as competing causes of dea' Epidemiological studies will usually provide information on more than on of cancer Research directed at only a single type may, on occasions, 1> useful but in general the inevitable uncertainties, in some cases in the differential diagnosis of, for example, peripheral lung carcinomas and ; mesotheliouias, and between peritoneal mesotheliomas and other intra-nbdo; cancers will require that more than one type is st.udied at the same time The Panel recognised that -some of the epidemiological projects couli only be pursued if there was close co-oporal ion between epidomiologists, pathologists, physicists and chemists, and other*;, because their success depend upon the development of improved techniques, some of which arc re: to in the recommendations of the other tiro Panels. PROJECTS a ) Further development of objective methods for early detection and siu of effects caused by asbestos. Tojij.cs for particular study include : (a) Immunological techniques for screening for fibrosis \. and neoplasia, (b) Functional tests of changes in tine peripheral airways. (c) Detection of pleural thickening. * (d) Assessment of the .specificity of small irregular opacities in the chest radiograph as' defined in the JLO U/C > Classification (l9?l). 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 progressive fibrosis and asbestos cancers, also in the identification hazardous conditions. Routine health surveillance of industrial populc -------- ----- " ' should should be designed to assist epidemiological studies and/incltidc mcasui recording of environmental dust levels. Surveillance of new entrants c particularly valuable. Arrangements should be made to register v/orkerf their Morbidity and mortality experience can be studied even after ccssr exposure to asbestos. . o > Assessment of excess cancer risks following exposure to only one 1 fibre. |j (a) Chrysotil c : The much higher cancer risk reported for chi textile workers compared with mine and mill workers requ: explanation. How much is explicable by differences in s past airborne fibres and/dustincss? There is need to make mo: of past dust records for relating to indices of disease. : (b) Amosite: The excess lung carcinoma and mesothelioma ri apparently much greater in the manufacturing and applica sections of the industry than in the mining and milling type of fibre. What-arc the important factors in this r difference? (c) Croc.l del i1e : Further studies are required in oecupatioi exposed only to croeidolite or amosi.tc or chrysotilc in manufacturing and npplication parts of the industry to c more d.ciarly differences in risks due to different fibre mesotheliomas (if possible by coll type) in (a) national survey of / mesotheliomas, (b) representative samples of cases arising in groups vi 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 general population. , (0) Studies to relate amount and type of asbestos.in the lung and esti of past dust exposure and interval since last exposure. (9) Kxperimental and epidemiological studies- to investigate possible differences of effect of continuous low and intermittent high exposure asbestos, .. (10) Opportunities afforded by intcrcurrent deaths should bo used to interrelate radiographic appearances, lung pathology, respiratory funca dust content, and type in asbestos workers. Standardised techniques ni classification recommended by the Panels should he vised. ( u ) Investigate the prognostic significance and acti.ologicnl factors the development of calcified and uncalcificd'pleural plaques in differ environments. (12) Investigate talc-exposed groups in mining and manufacturing to e any diff crcnccs .in morbidity or mortality which might be related to t): and shape-of the fine respirable particles. (13) Development of cost/benefit analyses to study the health, safety social and economic interrelations of the use of asbestos. The Panel rcvi.cved the progress made on the 196(1 U1CC rccommendat5.on It was agreed that considerable progress had been made on the majority of recommendations. Some require further study, or modification of previous methods of investigation; these are included in the list of rccommcndatio that follows. The recommendations are divided into three categories, tnor anatomy and histology, clinical research, and experimental studies, PROJECTS Morbid Anatomy and Histology12 1 , Asbestos5s * f'l) Further consideration should be given to methods for deten the amounts, types and structural features of asbestos in tissue, A Sub Committee should be established with members of the PJiys5.es and Chemistr Pane],, and others to accelerate, work on th5s problem, (2 ) The methods for assessing the severity of asbestosis (sec should be tested for consistency by different observers. 2 , Carcinoma * / (l) An investigation of whether reduction of asbestos exposure levels below those producing asbestosis also abolislies 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 be of value. A (1) The*IniCrnntional Panel cf Pathologists and National Panels established following the meeting''2 have served a useful purpose. It recommended that panels be established in other countries and membership the International Panel be extended. The main purposes of these Panels i to ensure uniformity of diagnostic criteria and recording of histological types of diffuse mesotheliomas. Collaborative study of histology slides National Panels is rocommenelpd. The diagnosis of mesothelioma cam be mac exfoliative cytology of the pleural fluid. If the cytological diagnosis made by a competent cytologist, biopsy m a y b e unnecessary. (2) To improve consistency of diagnosis there is an urgent need a Comprehensive Atlas on mesotheliomas* or alternatively* for inclusion c enlarged section on mesotheliomas in the now edition of tlie V1J0 Monograp) Tumours of Dio Lung. Criteria for diagnosis by exfoliative cytology and description of the fine structure of mesotheliomas should be included. C15.n:lca1 P osearch * / o.) Monitoring by immunological methods of populations exposed asbestos should be investigated to ascertain whether it is possible to recognize those who. arc developing, or will develop, tumours. :() The use of chromatographic methods for the study of mivcopo and other tumour-associated substances in pleural fluids should be c.xplo Sensitive methods might be developed and applied to identify secretory p of mesotheliomas in blood and urine. Tlie International Panel consists of: Dr. M. Kannorstcin (USA), Prof. D (Canada), Dr. L. Mourman (Finland), Prof. W.T.E. McCnughcy (Eire), Prof. (PNG), Nr. 11. T. Plant eycH: (Nethorl ends), IV, , Poitzsoh, (GJ)I'O , Prof, (Italy), Prof. I. Webster (South Africa), and Dr. J.C.Wagner (UK) as Sec 2 Great Dritain, South Africa, United States, Canada, Netherlands. * (l) .Information is required about the role of line particles, e influence .of fibre size, in the induction of tumours.' Those studies she extended to include fibres other than asbestos. A Sub-Committee should established to review thci need for, and arrange the distribution of stru samples of asbestos and other fibres in addition to the UICC Reference ,c / (2 ) The fate of inhaled particles of various sizes, shapes and compositions, should be studied to determine, more precisely the quantit sites of initial deposition, change within the body and later retention feasibility of increasing fibre elimination by various methods should b explored. Studies should be made of means of reducing the'fibrogenicit carcinogenicity of fibres already retained in the lungs (3 ) The use of cell and organ culture, including niosothelial i from man and other species, should be further .investigated with a view |. .** developing methods of screening dusts for- fibrogcnic and carcinogenic j ( h ) Further studies should be carried out to determine the na the combined effect on tumour induction when animals are exposed to as dust and cigarette smoke, metals or other chemical carcinogens, includ those which act systcmically such as nitrosamines. (3 ) Inhalation experiments should be extended to test various of fibre; of special interc-st are forms of chrysotilc and crocidolite the 5.)icr grade materials. (6) It was felt that studies of the pathological effects of < on species other than rodents would be of value. (7) The effect of long-term ingestion of fibres of various s shapes and chemical compositions' should be studied. . (8) The effects of fibres and associated metals on the metnb of target organs should be investigated, The Panel revicv:cd the progress made on m e j.yu'i un.v .v-.,-.. proposals for the preparation and characterization of the UICC reference of asbestos had been satisfactorily implemented, and the Panel rccommcndo a list of references to papers featuring the samples should be distribute investigators in-this field. Considerable progress had been made on met] identifying the type1of fibre in tissues but a quantitative method when : types of fibres were present had yet to be developed. The Panel discussed the further contribution that physical and chain studios can make to research on the biological effects of asbestos and o fibrous materials. Of especial interest are Die effects of fibre size a shape on the retention of material in the lungs, the site of deposition, migration of fibres within the body, and their carcinogenic or oilier bic activity. The following recommendations were made: PROJECTS 1. Materials for ex-peri mental work a) Supplies of asbestos from relevant sources should be obtained w there is evidence of variation in geological form, trace element conter significant biological findings. b) Small samples of various fibrous materials should be prepared : studies on the influence of fibre size and shape on carcinogenicity. purpose the. samples should be milled to different degrees of fineness. c) For investigations on the influence of particle shape and size inhalation and subsequent fate of asbestos fibres a chrysotile and an f of fibre length greater than Die UJCC samples should be prepared. 2. Methods ' ' . * a) There is an urgent need for the quantitative assessment, size and characterization of parti,cles and fibres in the lungs and other o '' .. *1 ii(' 1iods should be circulated, international c.omr narrow ranges of diameter and length in sufficient quantities for inocula experiments Techniques for these purposes are urgently required, espoci in' view of the advantages such graded samples could provide for investiga the influence of those physical, factors on the carcinogenicity of fibres different materials. c) Since the degree of dispersion of fibres (especially chrysotilc) in inoculation studies may have" a marked influence on their carcinogenic! methods are required for quantifying dispersion, d) Inhalation studies require precise control of the characteristics dust clouds. Improved methods of dispensing fibrous dusts in such invest need to be developed. e) Methods arc available for collecting the important size fractiondust clouds in inhalation studies when the particles are of compact shnpi Similar methods must be developed for fibrous particles. f) The present membrane filter methods of measuring the levels of a asbestos dust require standardization. This should be done by inter-lab trials on a continuing basis. Particle counting by electron microscopy also be developed. Gravimetric assessment methods and the automation of countirig 'should be explored. 3 Inhala,tien stu ciles Considerable information is no w .available on the deposition, retent migration of particles of compact shape. Recently developed methods, cs \. radio-active tracer techniques, should be used to obtain similar knovlec fibrous particles. This- information is needed to identify the biologic; important size fraction and to help interpretation of epidemiological ai pat ho 1og5ca1 studies. x t> ,U1 The use of both fibre counts and gravimetric methods for assessing a: dust concontrat5ons should bo encouraged. Data collected over an extcndC' will be particularly valuable in identifying the. parameters of the dust v be correlated with epidemiological evidence on the health hazard* h . Physics and Chemistry Panel It is recommended that an international Panel be cstabl ished to assn implementing these recommendations. The Panel would periodically review requirements for materials for experimental voids;; provide guidance on phy and chemical problems; and arrange national and international standnrdiz: trials. G*