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31 January 2006 WORLD HEALTH ORGANIZATION WHO Workshop on Mechanisms of Fibre Carcinogenesis and Assessment of Chrysotile Asbestos Substitutes 8-12 November 2005, Lyon, France SUMMARY CONSENSUS REPORT1 Introduction 1. The WHO Workshop on Mechanisms of Fibre Carcinogenesis and Assessment of Chrysotile Asbestos Substitutes was convened at IARC in Lyon, in response to a request from the Intergovernmental Negotiating Committee (INC) for the Rotterdam Convention on the Prior Informed Consent Procedure for Certain Hazardous Chemicals and Pesticides in International Trade (Annex 1). The substitutes considered by the WHO workshop included the 12 chrysotile substitutes identified by the INC for priority assessment by WHO, 2 substances from a second list provided by the INC to be assessed if resources allow, and one further substance for which data was submitted in response to WHO's public "call for data" for the workshop. 2. The workshop opened on 8 November with a one-day session devoted to taking statements from observers mainly representing various commercial interests, along with some government observers and the Rotterdam Convention Secretariat. In addition a statement submitted by a labour organization was read by the workshop Secretariat. Observers were invited to submit any comments on the pre-workshop working drafts in writing. Invited specialists and observers did not participate the evaluations of the substitutes (Part 2 of the following report), or the final agreement of Part 1. A list of participants appears at Annex 2. Part 1: Methodological Aspects 3. The workshop considered the mode(s) of action of fibre carcinogenesis and the developments in the field after the IARC 1996 report, but did not produce a formal assessment of the state of the art. The workshop established a framework for hazard assessment based on: epidemiologic data (whether data are sufficient to determine carcinogenicity); in vivo animal data (whether there is a indication of carcinogenicity or lung fibrosis); mechanistic information (whether critical indictors of carcinogenicity exist, e.g. positive results for genotoxicity in in vitro tests); and physico-chemical and biopersistence data as determinants of dose at the target site and possible indicators of carcinogenic potential . The workshop conclusions on each of these factors appear in the following paragraphs.1 1 This report contains the collective views of an international group of experts, and does not necessarily represent the decisions or the stated policy of the World Health Organization. Page 1 of 4 31 January 2006 4. In light of the workshop scope to assess fibrous forms of the substitutes, the workshop confined its considerations to effects related to cancer, focusing on lung cancer, mesothelioma and lung fibrosis. Further, noting that substitutes may be used in a variety of applications with different exposure potential, either alone or in combination with other substances, the workshop did not embark on risk assessment, but rather, limited its work to assessing the hazard. 5. Epidemiologic studies on fibres have a clear advantage over toxicological studies in that they involve studies of humans. They also have the advantage that they study the effects of exposure in the real world where the effects of these exposures may be mitigated or enhanced by other factors. Despite these obvious advantages, the presence or absence of evidence of risk from epidemiologic studies does not always override contrary findings from toxicological studies. The interpretation of either positive or non-positive epidemiologic findings needs to be carefully considered in light of the strengths and weaknesses of the study design. 6. In in vivo animal studies, carcinogenic response (lung cancer, mesothelioma) and fibrosis were considered to be the key effects; epithelial cell proliferation; and inflammation were not regarded to be equally important indicators of human health hazard. From studies with asbestos, it is apparent that the sensitivity of the rat inhalation studies to fibre induced lung tumours is clearly lower than that of humans. This holds true when the effect is related to exposure concentrations and lung burdens. The workshop discussed the hypothesis that differences in sensitivity could be due to greater lung mass and/or longer life span in humans, however the question remains open as to whether this sensitivity difference remains if individual or rat or human lung cells are taken as a basis for comparison. In comparison, testing of fibres by intraperitoneal injection represents a useful and sensitive assay, which also avoids confounding effects of granular dusts. 7. Genotoxic potential in experimental systems can be assessed via cell-free in vitro assays, in vitro tests with cultured cells, and via in vivo studies, usually in mice or rats. Fibres may act in principle on all steps in tumour development. However, of these interactions the in vitro genotoxicity tests are mainly indicative of genotoxic effects involved in the first steps of tumour initiation. Effects related to bio persistence of fibres (such as continuous "frustrated phagocytosis") and secondary genotoxicity arising from reactive oxygen species and reactive nitrogen species and mitogen release by macrophages and inflammatory cells are not detected in routinely used genotoxicity tests. Therefore, negative results indicate a lack of primary genotoxicity, but do not exclude effects on later steps of carcinogenesis. A completely inert fibre that could be used as a negative control in the above-mentioned assays has not been identified. 8. The chemical composition of the substitutes is a key factor influencing structure and physico-chemical properties, such as surface area, surface reactivity, solubility, etc. Attention should be paid not only to the chemical composition of the fibres, their major and trace elements, but also to contaminants or accompanying elements, including their speciation. Fibre-derived free radical generation favours DNA damage and mutations. Surface properties are a determining factor in the inflammatory response. In relation to fibre dimension and deposition, one can assume that there exists a continuous variation on the carcinogenic potency of respirable fibre, Page 2 of 4 31 January 2006 which increases with length. Biopersistence of a fibre increases tissue burden, and therefore, may increase any toxicity the fibre might possess. For synthetic vitreous fibres, there is evidence in animals that the potential for carcinogenicity increases with biopersistence. This has not been demonstrated however for other fibres. 9. For all fibres, the fibres must be respirable to pose an appreciable hazard. Respirability is mainly determined by diameter and density, thus with a given fibre diameter a higher specific density is associated with lower respirability (note the specific density of most organic fibres is lower that the specific density of inorganic fibres. Part 2: Hazard Assessment 10. The workshop decided to group substitutes roughly into hazard groupings of high, medium and low. However for some substitutes there was insufficient information to draw any conclusion on hazard and in this case the workshop categorized the hazard as indeterminate (a category which is not comparable to the other groupings). The hazard groups high, medium and low should be considered in relation to each other, and did not have reference to formal criteria or definitions, as such. For details of each substance, the reader is referred to the full workshop report (to be published subsequently). It is important to note that for each substitute, the fibre dimensions of commercially available products may vary and the workshop did not assess this variation. The substitutes are listed below in alphabetical order. 11. para-Aramid releases respirable fibres with dimensions similar to known carcinogenic fibres. p-Aramid fibres have induced pulmonary effects in animal inhalation studies. Biopersistence was noted. The workshop considered the human health hazard to be medium. 12. Most natural deposits contain attapulgite fibres which are < 5 pm in length and at workplaces the mean fibre length was less than 0.4 pm. The hazard from exposure to respirable attapulgite is likely to be high for long fibres, low for short fibres. This assessment is mainly based on findings in long-term inhalation experiments in animals, in which tumours were seen with long fibres; no tumours were seen in studies with short fibres. 13. The nominal diameter of carbon fibres ranges from 5 to 15 pm. Workplace exposure in production and processing is mostly to non-respirable fibres. The workshop considered that the hazard from inhalation exposure to these fibres to be low. 14. Most cellulose fibres are not respirable; for these the hazard is low. For respirable fibres, the available data do not allow the evaluation of the hazard; the hazard is thus indeterminate. 15. The dimensions of graphite whiskers indicate high respirability and they have a long half time in the lungs. However in the absence of any further useful information, the hazard from inhalation exposure was considered to be indeterminate. Page 3 of 4 31 January 2006 16. Magnesium sulphate whiskers did not induce tumours in limited inhalation and intratracheal administration studies, were negative in limited short term tests, and are very quickly eliminated from the lung. It was discussed whether the hazard grouping should be low or indeterminate, and on the basis of the data available, in the time available, consensus was not reached. 17. For respirable polyethylene, polyvinyl chloride, and polyvinyl alcohol fibres, the data was insufficient for hazard classification, and the working group thus considered the hazard indeterminate. 18. In facilities producing polypropylene fibres, exposure to respirable fibres occurs. After intratracheal administration, respirable polypropylene fibres were highly biopersistent, however no fibrosis was reported in a sub-chronic animal study. However the data are sparse and the human health hazard potential was considered to be indeterminate. 19. The workshop considered that respirable potassium octatitanate fibres are likely to pose a high hazard to humans after inhalation exposure. At workplaces there is exposure to respirable fibres. There was a high and partly dose-dependent incidence of mesothelioma after intraperitoneal injection in two species (high incidence indicating high potency). There is evidence of genotoxicity. Biopersistence was noted. 20. Wool-like synthetic vitreous fibres (including glass wool/fibrous glass, mineral wool, special purpose vitreous silicates, and refractory ceramic fibres) contain respirable fibres. For these fibres, the major determinants of hazard are biopersistence, fibre dimensions and chemical/physical properties. It was noted that the available epidemiologic data are not informative, due to mixed (vitreous fibre) exposures or other design limitations. Based on inhalation exposure studies, intraperitoneal injection studies and biopersistence studies, it was concluded that the carcinogenic hazard could vary from high to low, with high for the biopersistent fibres and low for non-biopersistent fibres.. 21. Natural wollastonite contains respirable fibres. In occupational settings exposure is mainly to short fibres. In chronic studies wollastonite did not induce tumours after intraperitoneal injection in animals; however, samples of wollastonite were active in different studies for genotoxicity. After considering this apparent discrepancy it was concluded that the hazard was likely to be low. 22. In a limited study with intraperitoneal implantation xonotlite did not induce tumours. After intratracheal injection in a chronic study no inflammatory or fibrotic reaction of the lung was observed. The chemical composition of xonotlite is similar to wollastonite, but it is more rapidly eliminated from the lung. The workshop considered the human health hazard to be low. Further Information The full report of this workshop will be published after scientific and language editing. Page 4 of 4 Secretariatfor the Rotterdam Convention on the Prior Informed Consent Procedurefor Certain Hazardous Chemicals and Pesticides in International Trade UNEP Plant Protection Service Plant Production and Protection Division Food and Agriculture Organization of the United Nations (FAO) Viale delle Terme di Caracalla 00100 Rome, Italy Tel: (+39 06) 5705 3441 Fax: (+39 06) 5705 6347 E-mail: pic@fao.org Subject: Chrysotile asbestos - assessment of alternatives, Chemicals United Nations Environment Programme (UNEP) 11-13, Chemin des Anemones CH- 1219 Chatelaine, Geneva, Switzerland Tel: (+41 22)917 8183 Fax: (+41 22) 797 3460 E-mail: pic@unep.ch Geneva, 25 March 2004 Dear Dr Meredith I refer to the request of the Intergovernmental Negotiation Committee at its tenth session to the World Health Organisation to conduct an assessment of alternatives to chrysotile asbestos. At this meeting, the WHO agreed that such an assessment would be able to be conducted, however requested that the fifth session of the Interim Chemical Review Committee for the Rotterdam Convention would consider the alternatives proposed by governments and develop a priority risk.. The Interim Chemicals Review Committee considered the alternatives proposed by governments, and developed a priority list for consideration by the WHO. They also developed a list of additional alternatives which were prioritised. These alternatives are identified in the attached document, which is an extract from the report of the Interim Chemical Review Committee. I therefore invite the WHO to proceed with the agreed assessment of the proposed alternatives to chrysotile asbestos. If possible, it would be appreciated if an update on the progress of the assessment could be provided to the Intergovernmental Negotiating Committee at its eleventh session. letter. Please do not hesitate to contact us should you have any questions in regard to this Yours sincerely, Address Dr T. Meredith Coordinator IPCS / World Health Organization CH-1211 Geneva 27 - Switzerland cc Ms Carolyn Vickers Annex I Report of the contact group on chrysotile 1. The contact group considered the list of substitutes for chrysotile asbestos proposed by Governments for assessment by the World Health Organization (WHO). WHO indicated that it welcomed the guidance provided by the group on important alternatives used by Governments. 2. The list was prioritized initially on the basis of the number of Governments which had nominated the substances. Information on which substances had previously been assessed in environmental health criteria reports by IPCS was also considered. Where possible, the group's knowledge of important uses was also considered. 3. The first group of substances are listed on a priority basis, in the order in which the contact group would like them to be considered by WHO. The second group of substances, which were proposed by only one country, had undergone no previous assessment by WHO and could be considered if resources allowed. Group 1: Substances identified and prioritized for assessment by WHO Aramid and para-aramid fibres Fibrous glass (glass fibres, glass wool) Carbon/graphite Ceramic fibres Wollastonite Cellulose fibres Mineral wool (rock wool, slag wool) Polyvinyl alcohol (PVA) fibres Polypropylene fibres Polyvinyl chloride (PVC) fibres Attapulgite Polyethylene fibres Group 2: Substances identified as alternatives to chrysotile, to be assessed if resources allow Aluminium silicates, basic magnesium sulphate whisker, erionite, ductile iron, mica, phosphate, polyacryl nitryl, polytetrafluoroethylene, potassium titanate whisker, semi-metallics, silicon carbide whisker, steel fibres 2 World Health Organization Workshop on Mechanisms of Fibre Carcinogenesis and Assessment of Chrysotile Asbestos Substitutes Lyon, 8-12 November 2005 LIST OF PARTICIPANTS Members1 Elke Dopp University Hospital Essen Institute of Hygiene and Occupational Medicine Hufelandstrasse 55 D-45122 Essen Germany Bice Fubini University of Torino Interdepartmental Center `G. Scansetti' for Studies on Asbestos and other Toxic Particulates Via P. Giuria 7 I-10125 Torino Italy Andrea Hartwig Technische Universitat Berlin Fak. III - Institut fur Lebensmitteltechnologie und Lebensmittelchemie Sekr.: TIB 4/3-1 Gustav-Meyer-Allee 25 D-13355 Berlin Germany F. Javier Huertas CSIC, Estacion Experimental del Zaidin Department of Earth Sciences and Environmental Chemistry Prof. Albareda 1 E-18008 Granada Spain Marie-Claude Jaurand Institut National de la Sante et de la Recherche Medicale (INSERM) Genomique fonctionelle des tumeurs solides U674 - IFR 105 - CEPH - IUH 27, rue Juliette Dodu F-75010 Paris France Aparna M. Koppikar United States Environmental Protection Agency National Center for Environmental Assessment 1200 Pennsylvania Ave, N.W. Washington, D.C. 20460 USA Dr Yasuo Morimoto Department of Occupational Pneumology University of Occupational & Environmental Health 1-1 Iseigaoka, Yahatanishiku Kitakyushu City 807-8555 Japan Paul A. Schulte National Institute for Occupational Safety and Health (NIOSH)/CDC Robert A. Taft Laboratories 4676 Columbia Parkway Cincinnati OH 45226-1998 USA Leslie Stayner University of Illinois at Chicago School of Public Health (M/C 923) 1603 West Taylor Street, Room 971 Chicago, IL 60612 USA Peter Wardenbach 1 Working Group Members and Invited Specialists serve in their individual capacities as scientists and not as representatives of their government or any organization with which they are affiliated. Affiliations are provided for identification purposes only. Federal Institute for Occupational Safety and Health (BAuA) Friedrich-Henkel-Weg 1-25 D-44149 Dortmund Germany Invited specialists2 Suresh Moolgavkar3 Fred Hutchinson Cancer Research Center Division of Public Health Sciences Fairview Avenue North, M2-B500 PO Box 19024 Seattle, Washington DC 98109-1024 USA Hartwig Muhle4 Fraunhofer Institute of Toxicology and Experimental Medicine Nikolai-Fuchs-Strasse 1 D-30625 Hannover Germany Jay Turim5 Sciences International Inc. King Street Station 1800 Diagonal Road, Suite 500 Alexandria, VA 22314 USA Observers Observer for the American Forest & Paper Association, Inc. (AFPA) 2NOTE: Minor pertinent interests are not listed. Examples of minor interests include stock valued at no more than US$10 000 overall, research grants that provide no more than 5% of the unit's research budget, and consulting and speaking engagements, on matters not related to courts or government agencies, that do not exceed 2% of time or compensation. All consulting or speaking on matters before a court or government agency is listed as a significant pertinent interest. 3Is advising a law firm that is representing a corporation with asbestos interests. 4 The Fraunhofer Institute is doing contract research for many companies that produce glass wool, rock wool, or ceramic fibres. 5 Is advising a law firm that is representing a corporation with asbestos interests. Received research support from the Refractory Ceramic Fibers Coalition, an association of producers of refractory ceramic fibres. David Bernstein6 40, chemin de la Petite-Boissiere CH-1208 Geneva Switzerland Observer for the European Ceramic Fibres Industry Association (ECFIA) R.C. Brown7 6, Stocken Hall Mews GB-Stretton LE15 7RL United Kingdom Observer for Health Canada, Government of Canada Michel Camus University of Montreal 3875, Rue Saint-Urbain Montreal, Quebec H2W 1V1 Canada Observer for the Institute ofDefense ofNational Property, Brazil Carlos Crespo Avenida 18 No 149 Rio Claro, Sao Paolo Brazil Observer for NYCO Minerals Inc. Christophe de Bellefroid8 NYCO Minerals Inc. 45, av, de Citeaux B-1348 Louvain-la-Neuve Belgium Observer for the Belgian Ministry ofHealth Frederic Denauw Direction generale environnement - Maitrise des risques Place Victor Horta 40 Boite 10 B B-1060 Brussels Belgium Observer for the US EPA IRIS Program 6 Consultant to the American forest and paper industry. Received research support from the chrysotile industry. 7 Consultant to ECFIA. Partner owns shares in the Morgan Crucible Company, a producer of ceramic fibres. 8 Employed by NYCO Minerals, a producer of wollastonite. 2 Danielle DeVoney United States Environmental Protection Agency National Center for Environmental Assessment 1200 Pennsylvania Avenue, NW 8601D Washington DC 20460 USA Observer for Sama Mineragao de Amianto Ltda Milton do Nascimento9 Sama Mineragao de Amianto Ltda Rua Dr Fernandes Coelho 85 2o andar Sao Paolo 05404-014 Brazil Observer for the Chrysotile Institute Jacques Dunnigan10 11 380 Chemin de North-Hatley PO Box 123 Ste-Catherine-de-Hatley, QC, J0B 1W0 Canada Observer for l'Agence Frangaise de Secutite sanitaire de l'environnement et du travail (AFSSET) Anne-Marie Fillet AFSSET 27-31 Avenue du General Leclerc F-94704 Maisons Alfort France Observer for International Ban Asbestos (IBAS) Morris Greenberg11 14, North End Road GB-London NW11 7SY United Kingdom Observer for the North American Insulation Manufacturers Association (NAIMA) John Hadley12 Owens Corning Science and Technology Center Granville, Ohio USA 9 Employed by Sama Mineragao de Amianto, a producer of asbestos. 0 Consultant to the chrysotile industry. 11 Has advised plaintiffs seeking compensation for disease related to asbestos or mineral fibres. May receive travel support for this meeting from IBAS. 12 Employed by Owens Corning, a producer of glass fibres. Observer for the Swiss Agency for the Environment, Forests and Landscape Bettina Hitzfeld Designated National Authority Rotterdam Convention Swiss Agency for the Environment, Forests and Landscape SAEFL Substances, Soil, Biotechnology Division CH-3003 Berne Switzerland Observer for Future Pipe Industries Llc. Mustafa Kabbara13 Future Pipe Industries Llc PO Box 1371 Dubai United Arab Emirates Observer for the Research Institute of Occupational Health ofthe Russian Academy of Medical Science Evgeny Kovalevskiy State Run Organization Research Institute of Occupational Health Russian Academy of Medical Science The WHO Collaborating Center in Occupational Health 31, Prospect Budennogo 105275 Moscow Russian Federation Observer for the Russian Register ofPotentially Hazardous Chemicals Boris Kurlyandskiy 18/20, Vadkovskiy per 127994 Moscow Russian Federation Observer for the French Ministry ofHealth Claude Lambre Ministere de la Sante DGS/CAS 14, avenue Duquesne F-75350 Paris SP07 France Observer for the Secretariat ofthe Rotterdam Convention 13 Employed by the Future Pipe Company, a producer of chrysotile cement pipe. 3 Sheila Logan Secretariat of the Rotterdam Convention United Nations Environmental Program 11-13 Chemin des Anemones Chatelaine 1219 Geneva Switzerland Observer for Refractory Ceramic Fibers Coalition (RCFC) Daniel Maxim14 15 N. Main Street Cranbury, NJ 08512 USA Observer for the European Tissue Symposium (ETS) and the Confederation ofthe European Paper Industry (CEPI) Anthony S. Panepinto Procter and Gamble 5299 Spring Grove Avenue Cincinnati, OH 45217 USA Observer for the Austrian Federal Ministry for Economic Affairs and Labour, Labourinspection Reinhild Purgy Federal Ministry for Economic Affairs and Labour Favoritenstrasse 7 A-1040 Wien Austria Observer for the Finnish Ministry ofSocial Affairs and Health Antti Tossavainen Finnish Institute of Occupational Health Topeliuksenkatu 41 SF-00250 Helsinki Finland Observer for the International Federation of Building and Wood Workers Lars Vedsmand BAT-Kartellet Kampmannsgade 4 DK-1790 Copenhagen V Denmark Observer for l'Agence Frangaise de Secutite sanitaire de l'environnement et du travail (AFSSET) Antoine Villa AFSSET 27-31 Avenue du General Leclerc F-94704 Maisons Alfort France WHO Secretariat Antero Aitio Robert Baan Vincent Cogliano Fatiha El Ghissassi Yann Grosse Beatrice Secretan Kurt Straif Carolyn Vickers Administrative Assistance Sandrine Egraz Helene Lorenzen-Augros 14 Employed by Everest Consultants, Inc. Consultant to RCFC, ECFIA, NAIMA, and NYCO Minerals. 4