IARCs klassificering av dieselavgaser 2012

IARCs klassificering av dieselavgaser 2012 Per Gustavsson Professor, överläkare Institutet för Mijömedicin Per Gustavsson, Karolinska Institutet, 2012 1

Vad är IARC Hur går IARCs evaluering till? Hur såg evidensen ut ang dieselavgaser Per Gustavsson, Karolinska Institutet, 2012 2

WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER IARC Monographs on the Evaluation of Carcinogenic Risks to Humans IARC Monograph Evaluations LYON, FRANCE Per Gustavsson, Karolinska Institutet, 2012 3

Per Gustavsson, Karolinska Institutet, 2012 4

IARCs klassificering 1 Cancerframkallande för människa 2A Sannolikt cancerframkallande för människa 2B Möjligen cancerframkallande för människa 3 Ej klassificerbart 4 Sannolikt ej cancerframkallande System för värdering av både experimentella och icke-experimentella data System för riskidentifiering, inte riskvärdering Per Gustavsson, Karolinska Institutet, 2012 5

Värdering av Exponeringsdata Humandata (epidemiologi) Djurexperimentella data Övriga data (mekanistiska studier, genotox etc) Per Gustavsson, Karolinska Institutet, 2012 6

Per Gustavsson, Karolinska Institutet, 2012 7

Evaluation of the weight of the Cancer in humans evidence Cancer in experimental animals Mechanistic and other relevant data Sufficient evidence Limited evidence Inadequate evidence Evidence suggesting lack of carcinogenicity Sufficient evidence Limited evidence Inadequate evidence Evidence suggesting lack of carcinogenicity 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 Per Gustavsson, Karolinska Institutet, 2012 8

Evaluating human data Cancer in humans Preamble, Part B, Section 6(a) Cancer in experimental animals Mechanistic and other relevant data Sufficient evidence Limited evidence Inadequate evidence Causal relationship has been established Chance, bias, and confounding could be ruled out with reasonable confidence Causal interpretation is credible Chance, bias, or confounding could not be ruled out Studies permit no conclusion about a causal association Several adequate studies covering the full range of exposure levels are Evidence suggesting mutually consistent in not showing a positive association at any lack of carcinogenicity observed level of exposure Conclusion is limited to the cancer sites and conditions studied Per Gustavsson, Karolinska Institutet, 2012 9

Evaluating mechanistic and other data 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? Is the mechanism likely to be operative in humans? Search for alternative explanations: Could multiple mechanisms be involved? Could different mechanisms operate in different dose ranges, in humans and experimental animals, or in a susceptible group? Note: An uneven level of support for different mechanisms may reflect that disproportionate resources were focused on one mechanistic hypothesis Per Gustavsson, Karolinska Institutet, 2012 10

A tour of IARC s classifications Preamble, Part B, Section 6(d) EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC Sufficient EVIDENC E IN HUMANS Limited Inadequate ESLC Per Gustavsson, Karolinska Institutet, 2012 11

Group 1 (carcinogenic to humans) whenever there is sufficient evidence in humans EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC Sufficient Group 1 EVIDENC E IN HUMANS Limited Inadequate ESLC Per Gustavsson, Karolinska Institutet, 2012 12

Group 2A (probably carcinogenic) with limited evidence in humans and sufficient evidence in animals EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC Sufficient Group 1 Limited Group 2A EVIDENC E IN HUMANS Inadequate ESLC Per Gustavsson, Karolinska Institutet, 2012 13

Group 2B (possibly carcinogenic) with either limited evidence in humans... EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC Sufficient Group 1 Limited Group 2A Group 2B (exceptionally, Group 2A) EVIDENC E IN HUMANS Inadequate ESLC Per Gustavsson, Karolinska Institutet, 2012 14

... or sufficient evidence in animals EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC Sufficient Group 1 Limited Group 2A Group 2B (exceptionally, Group 2A) EVIDENC E IN HUMANS Inadequat e Group 2B... it is biologically plausible that [these agents] also present a carcinogenic hazard to humans. ESLC Per Gustavsson, Karolinska Institutet, 2012 15

Group 3 (not classifiable) with less than sufficient evidence in animals EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC Sufficient Group 1 EVIDENC E IN HUMANS Limited Inadequat e Group 2A Group 2B (exceptionally, Group 2A) Group 2B... it is biologically plausible that [these agents] also Group 3 present a carcinogenic hazard to humans. ESLC Per Gustavsson, Karolinska Institutet, 2012 16

Group 4 with evidence suggesting lack of carcinogenicity in both humans and animals EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC Sufficient Group 1 Limited Group 2A Group 2B (exceptionally, Group 2A) EVIDENC E IN HUMANS Inadequate Group 2B Group 3 ESLC Group 4 Per Gustavsson, Karolinska Institutet, 2012 17

Mechanistic data can be pivotal when the human data are not conclusive... EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC Sufficient Group 1 Limited Group 2A Group 2B (exceptionally, Group 2A) EVIDENC E IN HUMANS Inadequat e 2A strong evidence mechanism also operates in humans Group 2B Group 3 ESLC Group 4 Per Gustavsson, Karolinska Institutet, 2012 18

Mechanistic data can be pivotal when the human data are not conclusive... EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC EVIDENC E IN HUMANS Sufficient Limited Inadequat e ESLC Group 1 1 strong evidence in exposed humans agent acts through a relevant 1 mechanism strong evidence Group in exposed 2A humans agent acts through a relevant mechanism 2A strong evidence mechanism also operates in humans Group 2B Group 2B (exceptionally, Group 2A) Group 3 Group 4 Per Gustavsson, Karolinska Institutet, 2012 19

Mechanistic data can be pivotal when the human data are not conclusive... EVIDENC E IN HUMANS Sufficient Limited EVIDENCE IN EXPERIMENTAL ANIMALS Group 1 1 strong evidence in exposed humans agent acts through a relevant 1 mechanism strong evidence in exposed Group 2A humans 2A strong evidence mechanism also operates in Group 3 humans Group 2B 3 strong evidence mechanism does not operate ESLC in humans Inadequat e Sufficient Limited Inadequate ESLC Group 2B (exceptionally, Group 2A) Group 4 Per Gustavsson, Karolinska Institutet, 2012 20

Mechanistic data can be pivotal when the human data are not conclusive... EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited ESLC Sufficient Group 1 1 strong evidence Inadequate EVIDENC E IN HUMANS Limited Inadequat e ESLC in exposed humans agent acts through a relevant 1 mechanism strong evidence in exposed Group 2A humans 2A strong evidence mechanism also operates in humans Group 2B 3 strong evidence mechanism does not operate in humans Group 3 Group 2B (exceptionally, Group 2A) 2B with supporting evidence from mechanistic and other relevant data Group 3 2B with strong evidence from mechanistic and other relevant data Group 3 Group 3 Group 4 Per Gustavsson, Karolinska Institutet, 2012 21

Mechanistic data can be pivotal when the human data are not conclusive... EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC EVIDENC E IN HUMANS Sufficient Limited Inadequate ESLC Group 1 1 strong evidence in exposed humans agent acts through a relevant 1 mechanism strong evidence in exposed Group 2A humans 2A strong evidence mechanism also operates in humans Group 2B 3 strong evidence mechanism does not operate in humans Group 3 2A belongs to a mechanistic class where other members are classified in Groups 1 or 2A Group 2B (exceptionally, Group 2A) 2A belongs to a mechanistic class 2B with supporting evidence from mechanistic and other relevant data Group 3 2A belongs to a mechanistic class 2B with strong evidence from mechanistic and other relevant data Group 3 Group 3 Group 4 Per Gustavsson, Karolinska Institutet, 2012 22

Mechanistic data can be pivotal when the human data are not conclusive EVIDENCE IN EXPERIMENTAL ANIMALS Sufficient Limited Inadequate ESLC EVIDENC E IN HUMANS Sufficient Limited Inadequate ESLC Group 1 1 strong evidence in exposed humans agent acts through a relevant 1 mechanism strong evidence in exposed Group 2A humans 2A strong evidence mechanism also operates in humans Group 2B 3 strong evidence mechanism does not operate in humans Group 3 2A belongs to a mechanistic class where other members are classified in Groups 1 or 2A Group 2B (exceptionally, Group 2A) 2A belongs to a mechanistic class 2B with supporting evidence from mechanistic and other relevant data Group 3 2A belongs to a mechanistic class 2B with strong evidence from mechanistic and other relevant data Group 3 Group 3 4 consistently and strongly supported by a broad range of mechanistic and other relevant data Group 4 Per Gustavsson, Karolinska Institutet, 2012 23

Evidens för cancerogenicitet av dieselavgaser Humanepidemiologi Kohortstudier Fall-kontrollstuder Djurexperimentella data Mekanistiska data Per Gustavsson, Karolinska Institutet, 2012 24

Kohortstudier Tree large studies with well characterized exposure Railroad workers pos association, dose-response, smoking data in accompanying CC study showed similar risks Trucking industry workers pos association, dose-response trend, indirect smoking adj Critical issue adjustment for employment duration Non-metal miners pos association, dose-response, smoking adj Three smaller cohort studies also specifically relating the findings to assessments of diesel exhaust Swedish bus garage workers supportive, no smoking data German potash miners smoking adj, indicative dose-response Critical issue adjustment for duration of employment Swedish dock workers pos association, indicative of trend, smoking adj Asbestos? A number of additional cohort studies with less precise definition of exposure (e.g. professional drivers, heavy equipment operators, or using self-reported exposure) generally were supportive but were considered less informative for the evaluation. Per Gustavsson, Karolinska Institutet, 2012 25

Fall-kontrollstudier Twelve independent CC studies and a pooled analysis with partial overlap Two industry-based; of US railroad workers and US trucking industry workers smoking adjusted estimates positive association, dose-response 10 population-based studies; Seven of these showed a positive and statistically significant association. All these studies were adjusted for tobacco smoking habits. A statistically insignificantly increased risk of lung cancer was reported in a British study that did not adjust for smoking Two population-based studies showed no association with diesel exhausts exposure: Turin, later showed a positive association when expanded and reanalyzed with a job exposure matrix used in the pooled European-Canadian study. The other negative study, from six US cities, was initially designed to study effects of tobacco smoking and had limited data on occupations. The pooled European-Canadian study with partial overlap applied a revised exposure assessment based on a job exposure matrix. This smoking-adjusted analysis showed a positive association, and a positive dose-response relationship in terms of duration of exposure. Per Gustavsson, Karolinska Institutet, 2012 26

Djurexperimentella studier Sufficient evidence for the carcinogenicity of Whole diesel engine exhaust (DEE) (ofiltrerade avgaser) DEE particles Extracts from DEE No evidence in animals for carcinogenicity of gas phase DEE (filtrerade avgaser) Per Gustavsson, Karolinska Institutet, 2012 27

Mekanistiska data Whole DEE är genotoxiskt (strong evidence) Orsakar DNA-skada Pos biomarkörer för exponering och effekt Per Gustavsson, Karolinska Institutet, 2012 28

Värdering DEE Sufficient evidence in humans Sufficient evidence in experimental animals (Stong mechanistic data) Diesel exhaust is carcinogenic to humans group 1 Per Gustavsson, Karolinska Institutet, 2012 29

Bensinavgaser, Sufficient evidence in experimental animals Strong evidence for genotoxicity Epidemiologin svårtolkad går inte särskilja effekten av bensinavgaser pga blandexponering med diesel inadequate evidence Grupp 2B - possibly carciongenic Per Gustavsson, Karolinska Institutet, 2012 30

Dokumentation Kommer att publiceras som Vol 105 i IARCs monografiserie (mongraphs.iarc.fr) Benbrahim-Tallaa et al. Carcinogenicity of diesel engine and gasoline engine exhaust and some nitroarenes. Lancet Oncology 2012, Vol 13, 663-664 Per Gustavsson, Karolinska Institutet, 2012 31

Kvarstående frågor Gränsvärdet för dieselavgaser i arbetsmiljön Nivå? Indikator NO2 eller EC? I allmänna miljön mycket fokus på partiklar från vägslitage glöm inte bort de avgasgenerade partiklarna mindre och lättare Hur mycket förändras risken vid användning av moderna bränslen, moderna motorer och med partikelfällor? Är andra bränslen bättre ur hälsosynpunkt? Per Gustavsson, Karolinska Institutet, 2012 32