Kurt Straif

The Current Burden of Occupational Cancers and how we can identify possible carcinogens before the

damage is done

UICC World Cancer Congress Montreal August 2012

IARC Monographs “The encyclopaedia of carcinogens”

•  For national and international health agencies –  Source of scientific information on known and suspected carcinogens –  Scientific support for actions to prevent exposure

•  Over 900 agents evaluated: –  Chemicals, Complex mixtures –  Occupational exposures –  Physical and biological agents –  Lifestyle factors

•  Group Classification of agent to humans No. agents –  1 carcinogenic 108 –  2A probably carcinogenic 64 –  2B possibly carcinogenic 27

Lorenzo Tomatis 1929-2007

Classification of Carcinogens: First Combine evidence in Humans and in Animals

Evidence in ANIMALS

Sufficient Limited Inadequate ESLC

Evidence in HUMANS

Sufficient Group 1 Group 1 Group 1 Group 1

Limited Group 2A Group 2B Group 2B Group 2B

Inadequate Group 2B Group 3 Group 3 Group 3

ESLC Group 3 Group 3 Group 3 Group 4

1=Carcinogenic; 2A = Probably carcinogenic; 2B = Possibly carcinogenic

Evidence in ANIMALS

Sufficient Limited Inadequate ESLC

Evidence in HUMANS

Sufficient Group 1 Group 1 Group 1 Group 1

Limited ↑ 1

↑ 2A

↑ 2A

↑ 2A

Inadequate 2B

3

3

3

ESLC Group 3 Group 3 Group 3 Group 4

2A

↓3 ↓4

2B 2B 2B ↑1 ↑2A ↑2B ↑2A ↑2B ↑2A

Mechanistic data can be pivotal when the human data are not conclusive

Types of Mechanistic Data Upgrades •  Strong mechanistic data in exposed humans (2A/2B to 1) •  Belongs to a mechanistic class (2B to 2A) •  Supporting evidence from mechanistic and other relevant data (3 to 2B)

Downgrades •  Strong evidence mechanism does not operate in humans (2B to 3) •  Consistently and strongly supported by a range of mechanistic and other relevant data (3 to 4)

Mechanistic Data •  Toxicokinetics •  Mechanisms of carcinogenesis – biomarkers •  Effects in susceptible populations, at different life stages •  Other adverse effects

Group-1 agents with less than sufficient evidence in humans

•  Ethylene oxide (vol 60, 1994, Vol 97, 2007) •  2,3,7,8-Tetrachlorodibenzo-para-dioxin (vol 69, 1997)

•  Neutrons (vol 75, 2000)

•  Gallium Arsenide (Vol 86, 2003) •  Benzo[a]pyrene (vol 92, 2005)

•  Dyes metabolized to benzidine (Vol 99, 2007) •  MOCA (Vol 99, 2007)

•  2,3,4,7,8-pentachloro-dibenzofuran and 3,3�,4,4�,5-pentachloro-biphenyl (Vol 100F, 2009)

Polycyclic aromatic hydrocarbons( PAHs): cancer in humans and exp. animals (V 92)

PAH: Mechanistic data in exp. animals (V 92)

PAH: Mechanistic data in human cells (V 92)

PAH: Overall evaluation (V 92)

Ethylene oxide (Vol 97) C2H40 Limited evidence in humans

•  Sterilant, detergent production

•  14 occupational cohort studies

•  NIOSH, K Steenland: 18 000 employees, 14 industrial facilities in the USA where ethylene oxide was used as a sterilant –  No overall excess of deaths from NHL or multiple myeloma –  Internal analysis, mortality from lymphoid tumours (NHL,

multiple myeloma and CLL) associated with cumulative exposure among men but not women

•  Breast cancer: –  Three studies examined breast cancer incidence: –  Norman et al. (1995) found a borderline excess risk of about

60% –  Internal analysis of the NIOSH study found a significant

exposure–response relationship and doubled relative risk in the higher categories of cumulative exposure

Ethylene oxide (Vol 97) – Mechanistic Data

•  Alkylating agent that reacts with DNA •  Dose-related increase in the frequency of haemoglobin adducts

in humans and rodents •  DNA adducts in rodents •  Consistently acts as a mutagen and clastogen at all

phylogenetic levels •  Heritable translocations in the germ cells of rodents

•  Dose-related increase in the frequency of: –  Sister chromatic exchange, chromosomal aberrations, micronuclei

in lymphocytes of exposed workers (prospective studies showed that CA and MN are associated with increased risks for human cancer)

Ethylene oxide (Vol 97)

Overall Evaluation: Group 1 (carcinogenic to humans) •  limited evidence in humans •  sufficient evidence in experimental animals •  Consideration of supporting mechanistic evidence

Use of mechanistic data to identify carcinogens is accelerating

Mechanistic upgrades

Volume 100 compiled information for subsequent scientific publications

•  Tumour Site Concordance between Humans and Animals –  Increase understanding of the correspondence across species –  Identify human cancer sites without good animal models

•  Mechanisms Involved in Human Carcinogenesis

–  Organized by mechanism to facilitate joint consideration of agents that act through similar mechanisms

–  Identify biomarkers that could be influential in future studies –  Identify susceptible populations and developmental stages –  Promote research that will lead to more confident evaluations

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)

Acknowledgements