Identification et évaluation des cancérogènes : Les Monographies du CIRC Centre international de Recherche sur le Cancer Lyon, France Béatrice Lauby-Secretan, PhD Section des Monographies du CIRC (IMO)
Outline Procédés d évaluation des Monographies Exemples Formaldéhyde Certains hydrocarbures aromatiques polycycliques Les polychlorobiphényles et autres composés aromatiques chlorés
WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 40+ ans d existence (1971-2015) 1200 experts invités de 50+ pays 1000+ agents évalués 100 volumes publiés 100+ cancérogènes avérés 350 000 articles en archives LYON, FRANCE 2004
The encyclopaedia of carcinogens The IARC Monographs evaluate Chemicals Complex mixtures Occupational exposures Physical agents Biological agents Lifestyle factors National and international health agencies use the Monographs As a source of scientific information on potential carcinogens As scientific support for their actions to prevent exposure
The IARC Monographs process M-12 M-10 M-8 M M+2 M+6 M+8 M+12
Contents of a volume of Monographs Preamble General Remarks One or more Monographs Section Section Section Section 1. 2. 3. 4. Exposure data Critical review Studies of cancer in humans Studies of cancer in experimental animals Mechanistic and other relevant data Section 5. Summary Section 6. Evaluation and rationale Evaluation
Evaluation du niveau de preuve Cancer in humans Sufficient evidence Limited evidence Inadequate evidence Evidence suggesting lack of carcinogenicity Cancer in experimental animals Sufficient evidence Limited evidence Inadequate evidence Evidence suggesting lack of carcinogenicity Mechanistic and other relevant data Mechanistic data weak, moderate, or strong? Mechanism likely to be operative in humans? Overall evaluation Group 1 Group 2A Group 2B Group 3 Group 4 Carcinogenic to humans Probably carcinogenic to humans Possibly carcinogenic to humans Not classifiable as to its carcinogenicity to humans Probably not carcinogenic to humans
Données humaines Cancer in experimental animals Cancer in humans Mechanistic and other relevant data Preamble, Part B, Section 6(a) Sufficient evidence Causal relationship has been established Chance, bias, and confounding could be ruled out with reasonable confidence Limited evidence Causal interpretation is credible Chance, bias, or confounding could not be ruled out Inadequate evidence Studies permit no conclusion about a causal association Several adequate studies covering the full range of exposure levels are mutually consistent in not showing a positive association at any Evidence suggesting lack of carcinogenicity observed level of exposure Conclusion is limited to the cancer sites and conditions studied
Données animales (cancéro) Cancer in humans Cancer in experimental animals Mechanistic and other relevant data Preamble, Part B, Section 6(b) Sufficient evidence Causal relationship has been established through either: - Multiple positive results (2+ species, studies, or sexes of GLP study) - Single unusual result (incidence, site/type, age at onset, or multi-site) Limited evidence Data suggest a carcinogenic effect but: (e.g.) from a single study, unresolved questions, benign tumours only, promoting activity only Inadequate evidence Studies permit no conclusion about a carcinogenic effect Adequate studies in at least two species show that the agent is not carcinogenic Evidence suggesting lack of carcinogenicity Conclusion is limited to the species, tumour sites, age at exposure, and conditions and levels of exposure studied
Données mécanistiques Cancer in humans Cancer in experimental animals Mechanistic and other relevant data Preamble, Part B, Section 6(c) Are the mechanistic data weak, moderate, or strong? Can the steps of each mechanism be described? Has each mechanism been established? Are there consistent results in different experimental systems? Is the overall database coherent? Has each mechanism been challenged experimentally? Are there studies demonstrating that the suppression of key mechanistic processes leads to the suppression of tumour development? Search for alternative explanations: Could multiple mechanisms be involved? Could different mechanisms operate in different dose ranges, in Is the mechanism humans and experimental animals, or in a susceptible group? likely to be operative Note: An uneven level of support for different mechanisms may reflect that in humans? disproportionate resources were focused on one mechanistic hypothesis
A tour of IARC s classifications EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient EVIDENCE IN HUMANS Sufficient Limited Inadequate ESLC Limited Inadequate ESLC
Sufficient evidence in humans : Group 1 EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient EVIDENCE IN HUMANS Sufficient Limited Inadequate ESLC Limited Inadequate Group 1 ESLC
Group 2A with limited evidence in humans and sufficient evidence in animals EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient EVIDENCE IN HUMANS Sufficient Limited Group 2A Inadequate ESLC Limited Inadequate Group 1 ESLC
Group 2B with either limited evidence in humans... EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC Group 1 Limited Group 2A Group 2B (exceptionally, Group 2A) EVIDENCE IN HUMANS Sufficient Inadequate ESLC
... or sufficient evidence in animals EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient EVIDENCE IN HUMANS Limited Group 2A Group 2B ESLC Inadequate ESLC Group 1 Sufficient Inadequate Limited... it is biologically plausible that [these agents] also present a carcinogenic hazard to humans. Group 2B (exceptionally, Group 2A)
Group 3 with less than sufficient evidence in animals EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient EVIDENCE IN HUMANS Sufficient Limited Group 2A Limited Inadequate ESLC Group 1 Group 2B (exceptionally, Group 2A) Group 2B Inade quate ESLC... it is biologically plausible that [these agents] also present a carcinogenic hazard to humans. Group 3
Evidence suggesting lack of carcinogenicity in humans and animals : Group 4 EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient EVIDENCE IN HUMANS Sufficient Limited Inadequate ESLC Group 1 Limited Group 2A Group 2B (exceptionally, Group 2A) Inadequ Group 2B ate Group 3 ESLC Group 4
Mechanistic data can be pivotal when the human data are not conclusive EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited EVIDENCE IN HUMANS Sufficient strong evidence in exposed humans agent acts through a relevant mechanism Group 2A are classified in Groups 1 or 2A Group 2B (exceptionally, Group 2A) 2A 2A 2B with 2B with strong 4 consistently and strongly supporting evidence from supported by a mechanistic and evidence from broad range of other relevant data strong evidence mechanism also operates in humans Group 2B 3 strong evidence mechanism does not operate in humans ESLC 2A belongs to a mechanistic class where other members 1 strong evidence in exposed humans Inadequate ESLC Group 1 1 Limited Inadequate belongs to a 2A belongs to a mechanistic class mechanistic class mechanistic and other relevant data Group 3 Group 3 other relevant data Group 3 Group 3 mechanistic and other relevant data Group 4
1er exemple: Le formaldéhyde Utilisations: résines dans l industrie du bois et du textile désinfectant dans les hôpitaux agent de conservation par les embaumeurs, histopathologistes
Formaldéhyde (CH2O) 1982: Indication inadéquate chez l Homme Indication suffisante chez l animal Groupe 2B 1987: Indication limitée chez l Homme Indication suffisante chez l animal Groupe 2A 2004: Indication suffisante chez l Homme Indication suffisante chez l animal Groupe 1 2009: Indication suffisante chez l Homme Indication suffisante chez l animal Groupe 1 avec identification des organescible
Evolution de l évaluation EVIDENCE IN EXPERIMENTAL ANIMALS Group 1
Formaldéhyde Études chez l homme Carcinome du nasopharynx (NPC) Niveau de preuve suffisant Leucémie myéloïde aiguë (LAM) Niveau de preuve limité Cancer sinonasal Niveau de preuve limité
Formaldéhyde Études chez l animal Inhalation (rats) cancer du nasopharynx Ingestion dans l eau de boisson Papillomes stomacaux sarcomes gastro-intestinaux leucémies et lymphomes tous cancers confondus Niveau de preuve suffisant chez l animal
Formaldéhyde Autres données pertinentes Génotoxicité (in vitro, humain, animal) Cytotoxicité (Adduits ADN-protéines accrus) Preuve mécanistique très élevée pour le NPC (effet local) très basse pour les leucémies (effet systémique)
Formaldéhyde Evaluation Formaldehyde est cancérogène pour l homme Groupe 1 Organes-cible chez l homme: Nasopharynx (sufficient) Leucémie (limited) Sinonasal (limited)
2ème exemple: hydrocarbures aromatiques polycycliques (HAPs) 2005: évaluation de 60 HAPs et 10 industries avec exposition aux HAPs
HAPs et cancer Données disponibles o niveau de preuve inadéquate chez l Homme (pas d exposition aux composés isolés) Niveau de preuve chez les animaux Utilisation des données mécanistiques Niveau de Nombre preuve de chez l animal composés Evaluation par défaut Evaluation finale (mécanisme) Nombre de composés 1 3 9 2 14 Suffisant 13 2B 1 2A 2B Limité 16 3 2B 3
EVIDENCE IN EXPERIMENTAL ANIMALS Group 1
Benzo[a]pyrène, benz[a]anthracène et dibenz[a,h]anthracène Evaluations du CIRC 1973 : produces tumours dans toutes les espèces étudiées 1979 : indication suffisante de cancérogénicité chez l animal 1982 : B[a]P classé Groupe 2A 1983 : Indication suffisante dans des tests de génotoxicité 1987 : Tous les 3 classés Groupe 2A 2005 : Ré-évaluation avec le nouveau préambule Benzo[a]pyrène Dibenz[a,h]anthracène Benz[a]anthracène 1 2A 2B
1. Cancer in humans and animals Epidemiological data Cancer bioassays Preliminary evaluation Benzo[a]pyrene Dibenzo[a,h] anthracene Benzo[a] anthracene inadequate inadequate inadequate sufficient sufficient sufficient 2B
2. Mechanistic data in experimental animals Epidemiological data Cancer bioassays Benzo[a]pyrene Dibenzo[a,h] anthracene Benzo[a] anthracene inadequate inadequate inadequate sufficient sufficient sufficient Strong Moderate Moderate (lung + skin) (lung + skin) (lung + skin) Strong (skin) _ 2B Diol-epoxide Radical cation Potential additional mechanisms 3,4-quinone/ROS, AhR, immunology 3,4-quinone /ROS
3. Mechanistic data in human cells Epidemiological data Cancer bioassays Benzo[a]pyrene Dibenzo[a,h] anthracene Benzo[a] anthracene inadequate sufficient inadequate sufficient inadequate sufficient 2B Diol-epoxide Radical cation Potential additional mechanisms Data in human cells in vitro Strong Moderate Moderate (lung + skin) (lung + skin) (lung + skin) Strong (skin) _ 3,4-quinone/ROS, AhR, immunology BPDE-DNA adducts in lung explants and mammary epithelial cells 2A DNA adduct profiles in skin cells similar to those in mouse in vivo 3,4-quinone /ROS _ 2B
4. Overall evaluation Epidemiological data Cancer bioassays Benzo[a]pyrene Dibenzo[a,h] anthracene Benzo[a] anthracene inadequate sufficient inadequate sufficient inadequate sufficient 2B Diol-epoxide Radical cation Potential additional mechanisms Data in human cells in vitro Strong Moderate Moderate (lung + skin) (lung + skin) (lung + skin) Strong (skin) _ 3,4-quinone/ROS, AhR, immunology BPDE-DNA adducts in lung explants and mammary epithelial cells DNA adduct profile in skin cells similar to those in mouse in vivo 2A Data from exposed humans Classification 3,4-quinone /ROS _ 2B BPDE adducts (coke-oven workers, chimney sweeps) Mutations in Ki-ras Group 1 Group 2A Group 2B
3ème exemple: polychloro- et polybromo-biphényles PCB mix in air PCB mix in soil PCB mix in water
PCBs: Historique des evaluations Agent PCBs Year of Evidence Evidence in Mechanistic publication in Humans experimental and other (Volume) animals relevant data 1978 (18) Suggestive Experimental N.A. evidence 1979 (S1) I S L S I S S S Not genotoxic N.A. Mechanistic upgrade I S Mechanistic upgrade 1978 (18) No data Little data 1986 (41) I S No evidence 1987 (S7) 2015 (107) I I S S Not genotoxic Mechanistic upgrade 1987 (S7) 2015 (107) PCB126 2012 (100F) Dioxin- 2015 (107) like PCBs PBBs N.A. N.A. Evaluation N.A. 2B 2A 1 1 1 N.A. 2B 2A Comments No formal evaluation; Should be considered as if they were carcinogenic to humans. Possible target organs identified as skin (melanoma) and all sites. Mechanistic upgrade based on strong similarities with receptor-mediated mechanism of TCDD carcinogenicity Mechanistic upgrade based on strong similarities with receptor-mediated mechanism of TCDD carcinogenicity No evaluation could be made on the basis of the available data No formal evaluation Strong similarity with PCBs in their toxicity and carcinogenic potential, via same pathways
PCBs: Cancer in experimental animals (1) PCBs assessed: individual PCB congeners, binary mixtures, commercial PCB products: PCB 118, 126, 138, 153 Aroclor 1016, 1242, 1254 and 1260 Kanechlor 300, 400, 500 Clophen A30, A60 OH-PCB 30, OH-PCB 61 Route/protocol: gavage, diet; 2-year bioassay, perinatal exposure, initiationpromotion, co-carcinogenicity
PCBs: Cancer in exp l animals (2) There is sufficient evidence in experimental animals for the carcinogenicity of polychlorinated biphenyls. There is sufficient evidence for the carcinogenicity of PCB 126, PCB 118, Aroclor 1260, Aroclor 1254, and Kanechlor 500. There is limited evidence for the carcinogenicity of PCB 153, OH-PCB 30, OH-PCB 61, Aroclor 1242, Aroclor 1016, Clophen A30, and Clophen A60. There is inadequate evidence for the carcinogenicity of PCB 138, Kanechlor 300, and Kanechlor 400.
PCBs: Cancer in humans Études épidemiologiques (environ 70 études) Mélanome cutané malin Niveau de preuve suffisant Lymphome non-hodgkinien Niveau de preuve limité Cancer du sein Niveau de preuve limité
PCBs: Relevant biological effects Metabolic activation Genetic and related effects Epigenetic effects Organ toxicity (liver, skin) Immunotoxicity PCB mix Endocrine effects Cytotoxicity / Cell proliferation Inflammatory response Aryl hydrocarbon receptor-mediated effects Structure-activity relationship
PCBs: Carcinogenic mechanisms Low chlorinated High chlorinated Carcinogenic pathway Target receptor Induction of xenobiotic metabolizing enzymes Metabolic activationmediated effects Genetic and related effects Organ toxicity Immunotoxicity Endocrine effects Initiation/promotion potential AhR-mediated effects
The carcinogenicity of PCBs cannot be solely attributed to the carcinogenicity of the dioxin-like PCBs.
Dioxin-like PCBs 12 PCBs with a Toxicity Equivalency Factor (TEF) according to WHO : PCBs 77, 81, 105, 114, 118, 123, 126, 156, 157, 167, 169, 189 Inadequate evidence of carcinogenicity in humans : no data Sufficient evidence of carcinogenicity in experimental animals PCB-118, PCB-126, PCB-118 + PCB-126 Activity identical to 2,3,7,8-TCDD for every step of the mechanism described for TCDD-associated carcinogenesis in humans
Carcinogenicity of PBBs Inadequate evidence in humans Sufficient evidence in animals Chemical and physical characteristics Teratogenicit y Increased metabolism of sex hormones Reduced immunocompetence Effective absorption and distribution in the body Long half-life in fatty tissues PCB PBB mix Inhibition of cell to cell communication Chronic toxicity (liver, thyroid glands) Acute toxicity (liver, thymus) Induction of xenobioticmetabolic enzymes Ligands for cellular and nuclear receptors Weak initiation and strong promotion activity
The build-up of evaluations Cancer in humans Cancer in experimental animals 2,3,7,8-TCDD Limited evidence PCB126 Inadequate evidence PCBs Sufficient evidence Dioxin-like PCBs 2,3,7,8-TCDD Mechanistic and other relevant data Inadequate evidence PBBs Inadequate evidence Sufficient evidence PCB126 Sufficient evidence PCBs Sufficient evidence Dioxin-like PCBs Sufficient evidence Overall evaluation Overall evaluation Overall evaluation Overall Overallevaluation evaluation 2,3,7,8-TCDD Group 2,3,7,8-TCDD Group11 2,3,7,8-TCDD Group 1 2,3,7,8-TCDD Group 1 Group 1 2,3,7,8-TCDD PCB126 Group 1 PCB126 Group 11 PCB126 Group PCB126 GGroup roup 11 Group 1 PCBs PCBs PCBs Group 1 Dioxin-like PCBs Group 1 Dioxin-like PCBs Group 1 PBBs Group 2A PBBs Sufficient evidence
The IARC Monographs staff The IARC Monographs are supported by grants from: U.S. National Cancer Institute (since 1982) European Commission, Employment and Social Affairs (since 1986) U.S. National Institute of Environmental Health Sciences (since 1992)