Document XRadkK08GgQg10BzkKRgM442x

REPORT OF THE ADVISORY COMMITTEE ON ASBESTOS CANCERS TO THE DIRECTOR OF THE-INTERNATIONAL AGENCY FOR RESEARCH ON CANCER u)o/?aD___ , -1 r--.- . The meeting was held at the International Agency for Reseaz'ch on Cancer-, Lyon, France, on 5 and. 6 October 1972* The Committee consisted of three panels -Epidemiology, Pathology, Physics and Chemistry.. EPIDEMIOLOGY PANEL . Dr M. Becklake McGill University, Department of Epidemiology and-Health, 3775 University Street, Montreal 110, Quebec, Canada. Dr H. Bohlig Dr N. Day Municipal Hospital Lizdenscheid, 588 Ludenscheid, Germany. i. 1 International Agency for Research on Cancer, Unit of Epidemiology and BiostatisT;ic3, 150- Gours Albert Thomas., 69OC8 Lyon, France. Prof. P.C. Elmes Queen's. University of Belfast, Department of Therpeutics and .Pharmacology, Instixute of Clinical Science, Grosvenor Road, Belfast BT12 6BJ, N. Ireland, UIC. Dr J.C. Gib on Medical Research Council, Pneumoconiosis . Unit, Llandough Hospital, penarth, Glamorgan, Hales, UIC. (Chairman). Dr J. Lepoutre SA. Etemit, Medical Department,. 2920 Kapelie-op-den-Bos, Belgium. Pro f, J.C. Me Donald McGill University, Department of Epidemiology and Health, 3775 University Street, Montreal 110. Quebec, Canada. Mr. C.E. Ros3ter Medical Research Council, Pneumoconicsis Unit, Llandough Hospital, Penarth, Glamorgan. Wales, UK. Dr H. Sakabe Ministry of Labour, Department of Indust:rial Physiology, National Institute of Industrial Health, 2051 Kizukisumayoshicho , Kav/asalcL, Japan. , Dr I.J. Selikoff . -----------------------_ y ; f-io to att er>.d Mount Sinai School of Medicine, Environment:'..' Sciences Laboratory, 100th Street arid Fifth Avenue, Kew York, N.Y. 10020, USA. W PLAINTIFF'S EXHIBIT II UC-5213 UCASB00663842 Dr G.K..Sluis-Cremer * South African Medical .Research Council, National Research Institute of Occupational Diseases ,--P-.0 . Box 4788, Johannesburg, South Africa. Dr V. Smither British Asbestos Research.Council, 114 Park Street, London TflY 4AB,. England Dr G. Wright Head, Department of Medical- Research, St Luke's Hosp. 11311 Shaker Blvd. Cleveland, Ohio 44101, USA PATHOLOGY PANEL Dr A.C. Allison l. ` . Mr. G. Berry- Medical Research Council, Clinical Research Centre, Watford Road, Harrow , Middlesex HA1 3UJ, England, UK. Medical Research Council, Pneumoconiosis Unit, Llandough Hospital, -Penarth,Glamorgan, .Wales,UK. Dr. P. Bogovski 1 ..t International Agency for Research on Career, Unit of EnvironmentalCarcinogens , 150 Cours Albert Thomas, Lyon 69OOS, France. Dr M. Earnerstein Bamert Memorial Hospital Centre, Pathology Dept. 680 Broadway, Paterson, H.J. 07514,USA. Prof. W.T.E. KcCaughey Trinity College School of Pathology, University of Dublin, Dublin 2, Eire. Prof. D. Magner Canadian Tumour Reference Centre, Department of Pathology, University of Ottawa, Ontario, KIN 6N5. Canada. Prof. H. Otto- Direlct-or des Pathologischen Institute der Stadt Krankcnanstalten, Beurhausstrasse 40, 46 Dortmund, W. -Germany.- Dr H.T. Planteydt ` ' . 1 i*. Dr M. Stanton Stichting-Stroeklaboratorium "Zeeland" , Noorpoortplein 2, Middelburg, The Netherlands National Institute of Health, Department of Health, Education and Welfare, Bethesda, Md. 20014, USA. Dr. J.C. Wagner Medical' Research Council, Pneumoconiosis Unit, Llandough Hospital, Penarth., Glamorgan, Wales, UK. (Chairman). Prof.. S. Watanbc National Cancer Centrq, Department'of'Pathology, Research Institute, Tsukiji, 5.1.1., Chomc Chu-ku, Tokyo, Japan.' Prof. I. Webster Medical Research Council Sath Africa, National Research Institute for Occupational Dis.as>.-a. P.0. Box 4788, Johannesburg, Souch Africa- ../... UCASB00663843 PHYSICS AND CHEMISTRY PANEL Dr :L Le Bouffant i^ `` i Mr G.W. Gibbs Centre d'Etudes ot de Recherches des Charbormages de France, Vcmeuil-on.Hallatte, B. Pi n 27, 6055 Creil,-France. McGill University, Department of Epidemiolo. gy' and Health., 3775 University Street, . .. Montreal 110, Quebec, Canada. Dr S. Holmes Asbestosis Research Council, c/o Turner Bros. Asbestos Co. Ltd. P.0. Box 40, '. Rochdale, England, UK. Mr A. Morgan Atomic Energy Research Establishment, Health Physics and Medical Division, Building ,364, Harwell, Didcot, Berkshire, England UK. Dr F.D. Poo.ley University College of S. Wales and.Monmouthshire, Department of Mineral ..'Exploitation, Newport Road, Cardiff, Wales,UK. Dr S. Spoil .. Johns-Manville Research and Engineering Centre, Greenwood Plaza, Denver, Colorado, USA. Dr V. Timbrell Medical Research Council, Pneumoconiosis Unit, Llandough Hospital',' Penarth, Glamorgan, Hales, UK. i Dr R.S.J. du Toit Government Mining Engineer's Di-vision, i Department of Mines, P.0. Box 1132, Johannesburg, South Africa. tt \ i Mr W.H. Walton Institute of Occupational Medicine, Roxburgh Place, Edinburgh EHS 9su, Scotland, ' UK. (Chairman) . The panels mot in a separate session and at the final session (Chairman-Dr J.C. Gilson) prepared this report to the Director of the International Agency for Research on Cancer. TERMS OF REFERENCE* 2 s 1 . The Committee was to report on the present evidence \ relating exposure to asbestos dust to cancers, especially that obtained since the meeting of the UICC Working^ Group on Asbestos Cancers in 1964. 2. The Committee was to make recommendations for further research and indicate pr-.o cities for work cf immediate and long-- term value. ) I i UCASB00663344 CO-ORDINATION OF INTERNATIONAL CO-OPERATION Following the meeting of the UICC Working Group on Asbestos 'and Cancers in 1964,- a Sub--Committeo of the UICC Commission on Geographical Pathology and Environmental Carcinogens (Chairman Dr J. Higginson) was formed to co-ordinate work required to achieve the recommendations. In April 1970 -agreements between the UICC and the IARC led to the winding up of the UICC Sub--Committee and the IARC taking on responsibility for the Sub-Committee's work and extending it :by supporting contain projects on asbestos cancers in several countries. The Agency has doneihis as part of their wider programme of investigating environmental carcinogens. Common memberships between the UICC Sub-Committee and the Committee advising the IARC ensured continuity of policy. . In'October 1972 the IARC held an international conference with 137 participants from twenty 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 lesearch. GENERAL REVIEW1 2 (/ . 1. Aro all major commercial types of asbestos able to cause lung carcinoma ? * c^a,J Yes. Since 1964 the evidence of a causal relationship has been increased by epidemiological studios showing exposure-response relations for the incidence of lung carcinomas . The production of lung carcinomas in certain animals by all typos of asbestos supports this conclusion. The epidemiological evidence in'man, however, shows that there are clear differences in risk with typo of fibre and nature of exposure. 2. Is`there evidence of an increased risk of lung caj cinoma at low levels of exposure to asbestos, such as have been encountered by the 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. 1 )1 3 Since 1964 has the evidence relating past exposure to I asbestos and mesotheliomas changed ? i The evidence has been greatly strengthened by further i prospective and recreance five mortality studies in many countries 1 j 1 UCASB00663845 of populations exposed to asbestos. There is evidence that all. commercial types, ox asbestos except anthophyllitc mav bo resjuxuaible. Evidence for an important: difference in risk in different: occupations and with the type of asbestos has increased. The risk is greatest with crocidolite, less with amosite and apparently less with chrysotile. With amosite and chrysotile there 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 ofmesothelioma have no known association with exposure to asbestos. 4. . Xs there evidence of an increased risk of mesothclial 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 crocidolite mines and of factories using mixtures of asbestos fibre types. Tho 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 chrysotile and amosite 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 tho importance of other factors such as cigarette smoking, waxes, oils and trace elements as contributory factors to tho cancer risk' ? The evidence has accumulated indicating : i (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 their 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 mesothelioma havo shown these contaminants are unlikely to bo relevant. (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. 6. .-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 risk of some other types of cancers (in addition to bronchial and mesothclial). especially those of the gustro-infccstina1 tract- The excess of these UCASB00663846 tumours is relatively snail compared with. that1 for bronchial cancer4 `.Evidence "for an association with ovarian tumours: has .not been' supported by the first large mortality survey-of women previously expos ed to asbestos. ! 1 ' 7;.-. there evidence of-an increased risk of cancer-resulting ;:fr6m-;asbcstos` fibres present -in water, beverages, food or in the fluids used for the administration of drugs ? " . ` f '' ' -4 ' 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 whore asbestos is mined or worked and lowest in rural areas. 9. Has the relationship between asbestos exposure and the development -of pleural plaques been established ? .been Pleural plaques have/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 are associated with asbestos. ' RBCOI-IKBHDATI0NS FOP FURTHER RESEARCH ' r *. `. ' i. . Projects which the Panola rated high in priority are marked * those which will require close co-operation between the Panels ape marked /. . Epidemiology .f ,-.Thp. Panel agreed that. asbestos related 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 type 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, raosotholionas, and between peritoneal mesotheliomas and other intra-abdominal cancers will require that more than one typo is studied at the same time. .The Panel recognised thafp some- of the epidemiological projects could only be pursued if. .there was close co-operacior. between, epidemiologists ,. pathologists, physicists and chemists, and others, bjeause their success will depend upon the '* / UCASB00563847 development of improved techniques, seme of which are referred to in the recommendations of the other two Panels . Projects (1) Further development of objective methods for early defection .and surveillance of effects caused by asbestos- Topics for particular study include : a) Tmmuno.logical techniques for screening for fibrosis and neoplasia. .. b) Functional tests of changes in the peripheral airways. c) Detection of pleural .thickening. d) Assessment of tho specificity of small irregular opacities in the chest radiograph as defined in XLO U/C Classification (1971) e) Tests of tho usefulness of different techniques of chest ..radiography, including the use of 100 msi. films. f) Development of statistical procedures for analysis and presentation of serial observations. / . (2) Evaluation of tho usefulness of early detection in the prevention of progressive fibrosis and .asbestos cancers., also in tho identification of hazardous conditions. Routine health surveil lance of industrial populations should be designed to assist epidemiological studios, and should include 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 bo 'studied even after cessation of exposure to asbestos . x (3) As sessmeni of excess cancer risks following exposure to only one type of fibre. a) Chryg-otilo : The much higher cancer risk reported for textile workers compared with mine and mill workers requires explanation. How much is explicable by differences in size of airborne fibres and past dustiness' ? There 'is- need to make more use of past dust records for relating to indices of disease. b) Amosito : The excess lung carcinoma and mesothelioma risk is apparently much greater in the manufacturing and application sections of tho industry thap in the mining and milling of this type of fibre. "What are the important factors in this reported difference ? . c) Crocidoiitc: Further studies are required in occupational groups exposed only to crocidolitc- or amosite or chrysotilc in manufacturing and application parts of trie industry to establish,.more, clearly differences in risks due to different fibres. UCASB00663848 a. K / (4) Studies of the amount and typo of asbestos in tho lungs of cases of mesotheliomas' (if possible by cell typo) in (a) national survey of mesotheliomas, (b) representative samples of cases arising in groups with a definable part exposure. (^) Studies of secular changes in incidence of pleural and peritoneal mesotheliomas nationally and internationally. X (<$)' ' Epidemiological studios to- investigate the association between past exposure to asbestos and cancer of sites other than lung, pleural and peritoneum. (2) Studios of secular trends in tho asbestos content of. tho lungs in tho general population. 3; / () Studies to relate amount' and typo of asbestos in the lung and estimates of past dust exposure and interval since last exposure. ' (cj) Experimental surd epidemiological studios to investigate possible differences of effect of continuous low and intermittent high exposure to asbestos. (1C) Opportunities afforded by intercurrent deaths should be used to interrelate radiographic appearances, lung pathology, respiratory function, dust cont ent,'.-and type in asbestos workers . Standardised techniques and classification recommended by the Panels should be used. (l 1 ') 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 fine respirable particles. 03) Development of cost/benefit analyses to study the health, safety, social and -economic interreIatipns....of the use of asbestos . Pathology and experimental pathology 'The Panel reviewed the progress made on the 196b 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 are included in the list of recommendations that follows. The recommendations are divided'into three categories ; morbidity anatomy and histology, clinical research, and experimental studies. Proj ects Morbid Anatomy and Histology 1. Asbestosis . .. - 1 x (l) Further consideration should be given to methods for determining the amounts , types an '. structural features of . UCASB00663849 .`asbestos in tissue- A .3.ub--Committee should be established with. ... -,-..members of the Physics and Chemistry Panel, and others to accelerate work on this problem. (2) The methods for assessing `the severity of asbestosis (See Paper 9) should be tested for consistency by different ob3 ervers. 2. Carcinoma . * ; / (1) An 'investigation cf 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 occupationallyexposed to asbestos and those not'so exposed, including both cigarette smokers and non-smolcers, in respect of sites of origin and cytology of tumour? and presence or absence of asbestosis, would be of value. Mesotheliomas -" (1) The International Panel of Pathologists 1 and National Panels established following the 196^ meeting^ have served a useful purpose. It is recommended that panels be established in other countries and membership of the International Panel be extended. The'main purpose of these Panels'is to ensure uniformity of diagnostic'criteria and recording of histological types of diffuse mesotheliomas. 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 cytological1diagnosis is unde 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 ?/H0 Monograph on Tumours of the Lung. Criteria `.for diagnosis by exfoliative cytology and a description of the fine structure of mesotheliomas should be included. 4. Clinical Research */ (1) 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 devebp, tumours. ..J... 1 The International Panel consists of : Dr M. Kannerstein (USA), Prof. D. iiagner (Canada),. Dr L. Leuman (Finland), Prof. W.T.E. McCaughey (Eire-), Prof. H. Ottc (FRG), Dr H. Plant eydt (Netherlands), Dr E. Roitzsch (GUR), Prof L. Santi >Italy), ,. . .Prof I. Webster (South. Africa), arid Dr J.C. lagner (UK) as Secretary. ^ Great Britain, South Africa, United States, Canadr ,Netherlands- ! UCASB00663850 (2) "The us'e of chromatographic methods "for the study of mucopolysaccharides and other tumour-associated substances in pleural fluids should be- explored.Sensitive methods might be developed and applied to identify secretory products of mesothe liomas in blood and urine.- 5. Further Experimental Studies (l) Information is required about the role of fine particles, . especially influence of fibre size, in the induction of tumours. . These studies should be extended to include fibres other than asbestos. A Sub-Committee should be established to reviow the need for, and arrange .the distribution of standard samples of . asbestos and other fibres in addition to the UICC Reference Samples . . The fate of'inhaled particles of various si. 23, shapes and chemical compositions, should be 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 bo made, of means of reducing the fibrogenicity and caciriogenicity of fibres already retained in -the lungs. (3) The use of coll 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. (4) Further studies should be carried out to determine the nature of the combined effect of tumour induction when animals are-exposed to asbestos dust and cigarette smoko, metals or other chemical carcinogens, including those which act systemically such as nitrosamines. {$) Inhalation experiments should be extended to test various types of fibre ; of special interest arc 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 be of value. .. . , : I". The effect of long-term ingestion of fibres of various sizes, shapes and chemical compositions should be studied.8 (8) The effects of fibres and associated metals on the metabolism of target organs should be investigated. Physics and Chemistry -- -- The Panel reviewed tho progress made on the 1964 UICC Recommendations. The proposals for the preparation and characterisation of the UICC Reference Samples of asbestos been satisfactorily impienien t cd, and the Panel re conn ended had .. . UCASB00663851 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 type of fibr.e in tissues but'a quantitative method-when several' types; of-fibres were present had yet to be developed. - ' ' s. 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 are the effects of fibre size and shape on the" retention of material ixi the lungs', the site of deposition, the migration of- fibres within the body, and their carcinogenic or other biological activity. The following recommendations were made : , Pro.j ects .1,, -Materials for experimental work .- a) Supplies of asbestos from relevant sources should be .-obtained where there is evidenqe of variation in geological form, itrace element, content or significant biological findings. b) Small samples of various fibrous materials should bo prepared for studies on the influence of fibre size and shape on carcinogenicity. For"this"purpose the samples * should be milled .tb different degrees of fineness.. .. v a) For inves tigations on the influence of particle shape and size, on the inhalation and subsequent fate of asbestos -fibres a chrysotile and an amphibole .of fibre length greater than the UICC samples should be prepared. 2. Methods "' a). .There is an urgent need for tho quantitative assessment, size analysis and characterisation of particles and fibres in the lpngs and other organs. Details of available methods should be circulated, international comparisons undertaken, methods standardised and new techniques developed. ;- b) No methods are 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 studies may have a marked influence on their carcinogenicity, methods are requix-od for quantifying diapers ion- d) Inhahtion studios require precise control of the characteristics of the dust cJouds. Improved methods of dispensing fibrous dusts in such investig :tions need to be developed. UCASB00663852 12. ,<r v..j, , o) Methods are available for' collecting the' important ..size fractions .of dust" clouds ''in' inhalation studies wh.cn' the parti cl os ' are of compact'' shape.' Similar methods must bo d'ovolcpod for fibrous particles-' "\ ' `` - ...... . ,j. f).-The present membrane filter methods of measuring the .'l.ey.e-ls of, airbom asbestos uust require standardisation. This should : be. done by. inter-laboratory trials .on a continuing basis. Particle counting by electron microscopy should also be developed. Gravimetric assessment methods and tho .automation of particle counting- should be explored. '. ' . 3. Inhalation Studies :. 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 studies. i-k`. Occupational 'and Environmental Studies . : - ........ The use of both fibre counts and gravimetric methods for 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 be 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 implementing those recommendations. The Panel would periodically review requirements for materials for experimental work ; provide guidance on physical and chemical problems ; and arrange national and international standardisation trials. .. . UCASB00663853