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International Agency for Research on Cancer Lyon, France The Carcinogenicity of Asbestos World Health Organisation.

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Presentation on theme: "International Agency for Research on Cancer Lyon, France The Carcinogenicity of Asbestos World Health Organisation."— Presentation transcript:

1 International Agency for Research on Cancer Lyon, France The Carcinogenicity of Asbestos World Health Organisation

2 The IARC Monographs Consensus evaluations of the weight of the evidence that an agent can increase the risk of cancer in humans Approximately 900 agents evaluated since carcinogenic to humans 110 2A - probably carcinogenic to humans 64 2B - possibly carcinogenic to humans 243 National and international health agencies use the Monographs As a source of information to identify potential carcinogens As scientific support for their actions to prevent cancer

3 Overview of IARC classification criteria

4 IARC Monographs on Asbestos Serpentines Chrysotile (White asbestos) Amphibole s Actinolit Amosite Anthophyllite Crocidolite Tremolite (Brown asbestos) (Blue asbestos) Asbestos

5 IARC Monographs on Asbestos: 2, 1973 Carcinogenicity to animals Inhalation experiments can produce fibrotic lesions in the lung and pleura similar to those found in man Injection of asbestos into the pleural cavity: all major commercial forms can produce mesotheliomas. By inhalation, mesotheliomas and lung carcinomas in rats exposed to the 4 commercial types of asbestos. Probably not due to contaminants such as oils More likely the size and shape of the particles

6 IARC Monographs on Asbestos: 2, 1973 Carcinogenicity to humans Risk of lung carcinoma and mesothelioma in workers in chrysotile mines and mills Mesotheliomas have been observed in Communities in the neighbourhood of these mines In manufacturing and application industries mesotheliomas have been caused by exposure to crocidolite, and less frequently to amosite and chrysotile.

7 IARC Monographs on Asbestos: 14, 1977 Carcinogenicity to animals All commercial forms of asbestos tested are carcinogenic in mice, rats, hamsters and rabbits Oral administration of asbestos filter material to rats also resulted in an increased incidence of tumours The size and shape of the fibres influence the incidence of tumours

8 IARC Monographs on Asbestos: 14, 1977 Carcinogenicity to humans Small amounts of chrysotile has also caused an increased incidence of lung cancer Many pleural and peritoneal mesotheliomas observed after occupational exposure to chrysotile Excess risk of laryngeal & gastro-intestinal cancers in groups exposed occupationally to chrysotile Not possible to assess whether there is a safe level of exposure in humans

9 IARC Monographs on Asbestos Actinolite, amosite, anthophyllite, chrysotile, crocidolite, tremolite Vol 2, 1973:sufficient evidence in humans, sufficient evidence in animals (1) Vol 14, 1977: sufficient evidence in humans, sufficient evidence in animals (1) Suppl 7,1987: sufficient evidence in humans, sufficient evidence in animals, 1

10 IARC Scientific Publications, 140, 1996 Mechanisms of fibre carcinogenesis Conclusions Insufficient understanding of how the physical and chemical properties of fibres contribute to mechanisms of fibre-induced carcinogenesis Overall, the available evidence in favour of or against any of these mechanisms leading to the development of lung cancer and mesothelioma in either animals or humans is evaluated as weak

11 Environmental Health Criteria Inter-organization programme for the sound management of chemicals IOMC: UNEP, ILO, FAO, WHO, UNIDO, UNITAR, OECD Chrysotile Asbestos, EHC 203, 1998 In numerous long-term inhalation studies in laboratory rats various samples of chrysotile fibres have caused interstitial fibrosis and cancer of the lung and pleura Fibrogenic and carcinogenic effects found in long- term animal studies (mainly in rats) using other modes of administration (e.g., intratracheal instillation and intrapleural or intraperitoneal injection)

12 Chrysotile Asbestos, EHC 203 Quantitative estimates and mechanistic evidence Data from inhalation studies are inadequate for providing quantitative estimates of the risk to humans, and there are uncertainties concerning the sensitivities of the animal studies for predicting human risk. The mechanisms by which chrysotile and other fibres cause fibrogenic and carcinogenic effects are not completely understood.

13 Chrysotile Asbestos, EHC 203 Conclusions and Recommendations Exposure to chrysotile asbestos poses increased risks for asbestosis, lung cancer and mesothelioma in a dose-dependent manner. No threshold has been identified for carcinogenic risks. Where safer substitute materials for chrysotile are available, they should be considered for use. Asbestos exposure and cigarette smoking have been shown to interact to increase greatly the risk of lung cancer.

14 IARC Monographs, Volume 100 A Review of Human Carcinogens Scope of volume 100 Update the critical review for each carcinogen in Group 1 Identify tumour sites and plausible mechanisms Compile information for subsequent scientific publications The volume was developed over the course of 6 meetings A. Pharmaceuticals (23 agents, Oct 2008) B. Biological agents (11 agents, Feb 2009) C. Metals, particles and fibres (14 agents, Mar 2009) D. Radiation (14 agents, June 2009) E. Lifestyle factors (11 agents, Sept 2009) F. Chemicals and related occupations (34 agents, Oct 2009)

15 Straif et al, Lancet Oncol, 2009

16 Asbestos: Mesothelioma and lung cancer, V100C The epidemiologic evidence has only strengthened over time and there is currently overwhelming evidence that all commercial forms of asbestos fibers are causally associated with an increased risk of mesothelioma and lung cancer. There are still current controversies about the extent to which there are potency differences for the particular forms of asbestos (i.e. chrysotile versus amphiboles) and sizes (i.e. long and thin fibers). However, these issues do not alter the fundamental conclusion that the epidemiologic evidence indicates that all forms and sizes of commercial asbestos fibers are carcinogenic to humans.

17 Chrysotile and cancer – recent epidemiological evidence Cohort of 3072 workers of 1 textile plant in SC, USA, followed- up Lung cancer was most strongly associated with exposure to thin ( 10 μm) fibers (TEM) (Stayner et al, 2008) Cohort of 5782 workers of 4 textile plants in NC, USA, followed-up Lung cancer SMR 2.0 (95%CI ), mesothelioma SMR 11.1 (95%CI ); RR increased with time since first employment and duration of employment (Loomis et al, 2007) Cluster of 14 mesothelioma cases among workers who were active in the Balangero mine, Italy, and 13 among other people exposed to Balangero chrysotile adds further evidence to the carcinogenicity of tremolite-free chrysotile (Mirabelli et al, 2008).

18 Asbestos: Laryngeal cancer, V100C Fairly consistent findings of both the occupational cohort studies as well as the case-control studies, plus the evidence for positive exposure-response relationships between cumulative asbestos exposure and laryngeal cancer that is reported in several the well conducted cohort studies. Meta-analyses of 29 cohort studies encompassing 35 populations and of 15 case-control studies of asbestos exposure and laryngeal cancer undertaken by the Institute of Medicine (2006). There is sufficient evidence to infer a causal relationship between asbestos exposure and laryngeal cancer.

19 Asbestos and Ovarian Cancer Camargo et al (subm.)

20 Asbestos: mechanistic data, V100C The mechanistic basis for asbestos carcinogenicity is a complex interaction between these crystalline mineral fibres and target cells in vivo. The most important physicochemical properties of asbestos fibres related to pathogenicity are surface chemistry and reactivity, surface area, fibre dimensions, and biopersistence. Multiple direct and indirect mechanisms have been proposed based on numerous in-vitro cellular assays and acute and subchronic animal bioassays. These complex mechanisms most likely interact at multiple stages during the development of lung cancer and diffuse malignant mesothelioma.

21 Asbestos: mechanistic data, V100C Species differences There are significant species differences in the responses of the respiratory tract to inhalation of asbestos fibres. The biological mechanisms responsible for these species differences are unknown. Based on comparative animal experimental studies, there may be differences in deposition and clearance of fibres in the lungs, in severity of fibrosis, in kinetics of translocation of fibres to the pleura, and in levels or types of antioxidant defence mechanisms.

22 Asbestos: Overall evaluations, V100C There is sufficient evidence in humans for the carcinogenicity of all forms of asbestos (chrysotile, crocidolite, amosite, tremolite, actinolite and anthophyllite). All forms of asbestos cause mesothelioma and cancers of the lung, larynx and ovary. The Working Group classified the evidence for colorectal cancer as limited although the Members were evenly divided as to whether the evidence was strong enough to warrant classification as sufficient. There is limited evidence in humans for cancers of the pharynx and of the stomach.

23 Burden of asbestos-related cancer Recently, several new global and national estimates of attributable fractions (AF) for occupational cancer have been published - Nurminen & Karjalainen, Finland (2001); - Steenland et al, USA (2003); - Driscoll et al, WHO GBD (2005); - Rushton et al, UK (2008) Used different methods to estimates asbestos- related lung cancer (based on mesothelioma mortality and mesothelioma/lung cancer ratio estimate; Levin’s or Miettinen’s equation)

24 Burden of asbestos-related cancer 85-90% of male mesothelioma cases due to occupational asbestos exposure Among men, 17-29% of all lung cancer due to occupational exposure Lung cancer accounted for 54-75% of occupational cancer Asbestos accounted for ca. 50% of occupational lung cancer. Straif, Occ Env Med, 2008

25 Carcinogenicity of MMVF, V81 Overall evaluation Special-purpose glass fibres (e.g. E-glass and ‘475’ glass fibres) are possibly carcinogenic to humans (Group 2B). Refractory ceramic fibres are possibly carcinogenic to humans (Group 2B). Insulation glass wool, continuous glass filament, rock (stone) wool and slag wool are not classifiable as to their carcinogenicity to humans (Group 3).

26 Chrysotile substitutes WHO Workshop on Chrysotile Asbestos Substitutes, 2005 (upon request from the Intergovernmental Negotiating Committee (INC) for the Rotterdam Convention) Substitutes considered 12 substances identified by the INC for 1st priority 2 substances from a 2nd list provided by the INC 1 substance (data submitted in response to WHO’s public “call for data”) Summary consensus report published on the Rotterdam Convention COP3 webpage, Full report published on the COP4 webpage

27 Chrysotile substitutes para-Aramid releases respirable fibres with dimensions similar to those of 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. 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 that of wollastonite, but it is more rapidly eliminated from the lung. The workshop considered the human health hazard to be low.

28 Other International & National Evaluations ICSC: chrysotile is carcinogenic to humans NTP, USA, 2005, asbestos and all commercial forms: known to be human carcinogen Australia: category 1, established human carcinogen German MAK, 2004, asbestos all forms: K1 ACGIH, 2004, asbestos, all forms: A1 US-EPA, , asbestos: a human carcinogen EU, January 2005, chrysotile asbestos ban

29 Asbestos: colorectal cancer, V100C RR RR of colorectal cancer among people in highest exposure category compared to non-exposed

30 Asbestos: open questions Lung cancer potency varies by fiber type? pro review by Hodgson & Darton 2000 (10x), con review by Stayner et al Lung cancer potency varies by fiber size? indirect epidemiologic evidence (textile industry) supports belief that fibers > 10  m have higher carcinogenic potency for lung cancer Mesothelioma potency varies by fiber type? chrysotile < amphiboles, amosite may be < crocidolite, but: mesothelioma among Chinese workers exposed to “pure” chrysotile (Yano 2001) Mesothelioma potency varies by fiber size? pro: mesothelioma at South Carolina > Quebec miners con: South Carolina textile < New Orleans cement plant

31 Carcinogenicity of Asbestos Carel et al, Occup. Environ. Med. 2007, ;64;

32 Carcinogenicity of Asbestos Peters et al, Occ Env Med (published online 24/09/10) Lung cancer risk within INCO by exposure assessment method

33 IOM Report (2006) Asbestos: Selected Cancers The committee concluded that the evidence is sufficient to infer a causal relationship between asbestos exposure and laryngeal cancer. suggestive but not sufficient to infer a causal relationship between asbestos exposure and cancer of the pharynx, stomach and colorectum.

34 Exposure to asbestos and mesothelioma mortality in UK Adapted from Hodgson et al, 2005

35 IARC Scientific Publications, 140, 1996 Mechanisms of fibre carcinogenesis 5 mechanistic hypotheses for fibre carcinogenicity Fibres generate free radicals that damage DNA Fibres interfere physically with mitosis Fibres stimulate proliferation of target cells Fibres provoke a chronic inflammatory reaction leading to prolonged release of ROS, cytokines & growth factors Fibres act as co-carcinogens or carriers of chemical carcinogens to the target tissue

36 IARC Scientific Publications, 140, 1996 Mechanistic Hypotheses for Fibre Carcinogenicity Experimental designOxidanti nduced damage Aneu ploidy Cell prolif- eration Inflam- mation Co- carcino- genicity In vitro Rodent cell lines++ +/-+++/- Human cell lines++/-0++0 In vivo Rodents – short term Rodents –long term00++ +/- Humans000+++/- ++, strong effect; +, weak effect; –, no effect; 0, no data; +/–, contradictory data

37 Asbestos: mechanistic data, V100C Direct interaction between asbestos fibres and target cells in vitro. a) Asbestos and erionite fibres have been shown to generate free radicals that directly induce genotoxicity as assessed by DNA breaks and oxidized bases in DNA. b) Asbestos fibres have also been shown to interfere with the mitotic apparatus by direct physical interaction resulting in aneuploidy and polyploidy.

38 Asbestos: mechanistic data, V100C Indirect mechanisms In laboratory animals, asbestos fibres have been shown to induce macrophage activation and persistent inflammation that generate reactive oxygen and nitrogen species contributing to tissue injury, genotoxicity and epigenetic alterations. Persistent inflammation and chronic oxidative stress have been associated with activation of intracellular signalling pathways, resistance to apoptosis, and stimulation of cell proliferation.

39 Physico-chemical properties involved in the biological activity of asbestos fibers Adapted from Fubini & Fenoglio, (2007) Inhaled fibers Clearance (3) Frustrated phagocytosis impaired clearance Fiber derived free radicals Iron release in solution Depletion of antioxidants Deposition of endogenous iron on fiber surface Macrophage activation: Release of oxidants, cytokines, growth factors; recruitment of AM and PMN Target cell injury epithelium fibroblasts mesothelium (1) Fiber in the lung fluid (4) Macrophage death (2) Phagocytosis by alveolar macrophages Fiber release Lung lining fluid Protein/lipid adsorption; oxidation of ascorbic acid and GSH

40 Proposed mechanism for carcinogenicity of asbestos fibers Adapted from Shukla et al 2003; Kane 2006; Nymark et al 2008 Asbestos fibers + macrophages Frustrated phagocytosis Impaired clearanceInflammasome activation TRANSLOCATION IL-1  Bronchial epithelium MesotheliumFibroblasts in interstitium Inflammatory cell recruitment and activation Tobacco smoke Oxidants Release of ROS, RNS, cytokines, chemokines, growth factors DNA damage, apoptosis, persistent inflammation Activation of intracellular signaling pathways Resistance to apoptosis Cell proliferation Insufficient DNA repair Activation of oncogenes: inactivation of tumor suppressorgenes Mesothelioma Lung cancer Fibrosis

41 Physico-chemical properties involved in the biological activity of asbestos fibers Adapted from Fubini & Fenoglio, (2007)

42 Proposed mechanism for carcinogenicity of asbestos fibers Adapted from Shukla et al 2003; Kane 2006; Nymark et al 2008

43 UK Burden of Occupational Cancer All IARC Group 1 and 2A carcinogens with ‘‘strong’’ or ‘‘suggestive’’ evidence for specific site in humans (Siemiatycki et al, 2004) Rushton et al, Occ Env Med; 2008.

44 Estimates of the ratio of excess lung cancer deaths to mesothelioma deaths by asbestos fibre type Chrysotile Crocidolite Ratio McCormack et al (in prep)


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