K1 K. Straif
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K1 K. Straif K1 K. Straif Presentation Transcript

  • The IARC Monographs Program: The increasing use of mechanistic data in cancer hazard identification Kurt Straif, MD PhD MPH 9th ISBM, Manchester, 2013
  • “The encyclopaedia of carcinogens” The IARC Monographs evaluate Chemicals Complex mixtures Occupational exposures Physical and biological agents Lifestyle factors More than 950 agents have been evaluated 110 are carcinogenic to humans (Group 1) 65 are probably carcinogenic to humans (Group 2A) 274 are possibly carcinogenic to humans (Group 2B) National and international health agencies use the Monographs As a source of scientific information on known or suspected carcinogens As scientific support for their actions to prevent exposure to known or suspected carcinogens Lorenzo Tomatis 1929-2007
  • Overall carcinogenicity evaluation View slide
  • 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) View slide
  • Known and suspected causes of cancer
  • Dissemination of information LIVER
  • IARC Monographs, Vols 105–107
  • 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 (V69, 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(V100F, 2009) • dioxin-like polychlorinated biphenyls (Vol 107, 2013)
  • Vol 100: Lessons learned New research continues to find additional human carcinogens & Use of mechanistic data to identify carcinogens is accelerating Types of mechanistic upgrades Ethylene oxide: Dose-related increase in the frequency of SCE, CA, and MN in lymphocytes of exposed workers. DNA adducts and A:T→T:A transversions in TP53 identified aristolochic acid as the carcinogen in herbal remedies -> environmental exposures: cereal fields in the Balkans where Aristolochia plants grow as weeds Benzidine-based dyes: Metabolism results in the release of free benzidine in humans and in all experimental animal species studied.
  • PAH: 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)
  • Evaluated in category of higher concern on the basis of mechanistic data Sufficient evidence in experimental animals and mechanistic upgrade Benzo[a]pyrene Group 1 Cyclopenta[cd]pyrene Group 2A Dibenz[a,h]anthracene Group 2A Dibenzo[a,l]pyrene Group 2A Limited evidence in experimental animals and mechanistic upgrade Benz[j]aceanthrylene Group 2B Benzo[c]phenanthrene Group 2B
  • Vol. 100 Workshops 16–18 April and 28–30 November 2012 • 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 JNCI paper?
  • “Tumour concordance & mechanisms of carcinogenesis” Lessons learned from Vols 100A–F of the IARC Monographs (Workshops 16–18 April and 28–30 November 2012) Aim: to develop IARC Scientific Publication(s) that build on the Review of human carcinogens (Monograph Vols 100A–F), focusing on tumour concordance in humans and animals, and mechanisms of carcinogenesis. Approach: data on target organs for human and animal cancer have been extracted from Vols 100A–F to create a database amenable to biostatistical analysis of concordance/discordance; another data set will be developed based on key characteristics identifying the most important mechanistic pathways. Expected outcome: we hope that this review will provide coherence, in which concordance is confirmed, and discordance explained. This may lead to new insights that could inform hazard identification in the future.
  • Volume 100 Workshop, 28-30 Nov, 2012
  • Medium- and long-term planning of Monographs Joint IARC NIOSH-NORA, ACS, US NIEHS & NCI Workshop Research Recommendations for Selected IARC-Classified Agents Pre-Monograph meeting analyses of (pooled) datasets (e.g SYNERGY, AGRICOH), NOCCA, and meta-analyses IARC Workshops to resolve carcinogenicity of selected agents Am J Respir Crit Care Med Vol 183. pp 941–948, 2011
  • Joint IARC, NIOSH-NORA, ACS,n US NIEHS and NCI Workshop Acetaldehyde Atrazine Carbon black Chloroform Cobalt metal with tungsten carbide Dichloromethane Diesel engine exhaust Di-2-ethylhexyl phthalate Formaldehyde Indium phosphide Lead and lead compounds Polychlorinated biphenyls (PCB) Propylene oxide Refractory ceramic fibers Shiftwork that involves nightwork Styrene Tetrachloroethylene Titanium dioxide Trichloroethylene Welding fumes
  • Future evolution of IARC Monographs • Research gap: Many chemicals vs. relatively few epidemiological studies and decreasing number of cancer bioassays Molecular epidemiological studies using validated biomarkers Alternative animal models (eg validated short-term tests) • Further Evolution of criteria for weight of evidence evaluation Integration of results from Vol 100 Workshops and from future high-throughput data -> Facilitate identification of carcinogens based on mechanistic data in absence of cancer studies in animals or humans • AG on Quantitative Risk characterization, Nov 2013 Recommendations if & how IARC should develop quantitative RC • Advisory Group on Future priorities, April 2014: Call for nominations of agents for future priorities Recommendations from Vol 100 workshops, AG on QRC
  • Advisory Group, June 2008 Volumes 101 and beyond Acetaldehyde Acrylamide and furan Air pollution Bitumen (Vol 103) Carbon-based nanomaterials Crystalline fibres other than asbestos Growth hormone Iron and iron oxides Malaria (Vol 104) Motor vehicle engine exhausts (V 105) Nucleoside-analogue antiviral drugs PFOA, other perfluorinated compounds Polyomaviruses (SV40, BK, JC, Merkel cell virus) (Vol 104) Radiofrequency electromagnetic fields and radar (includes mobile telephones) (Vol 102) Sedentary work Statins Stress Testosterone, other androgenic steroids Ultrafine particles Welding Agents recently tested in experimental animals (Vol 101) ► Never before reviewed ► Bold: Meeting still to be planned
  • Forthcoming meetings snip from w3
  • The IARC Monographs are supported by grants from U.S. National Cancer Institute (since 1982) European Commission, DG Employment, Social Affairs and Inclusion (since 1986) U.S. National Institute of Environmental Health Sciences (since 1992) Acknowledgements