The IARC Monographs Program: The increasing use of mechanisticdata in cancer hazard identification

Kurt Straif, MD PhD MPH 9th ISBM, Manchester, 2013

“The encyclopaedia of carcinogens”

The IARC Monographs evaluateChemicalsComplex mixturesOccupational exposuresPhysical and biological agentsLifestyle factors

More than 950 agents have been evaluated110 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 MonographsAs a source of scientific information on known or suspected carcinogensAs scientific support for their actions to prevent exposure to known or suspected carcinogens

Lorenzo Tomatis 1929-2007

Overall carcinogenicity evaluation

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 meetingsA. 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)

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 learnedNew 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 upgradeBenzo[a]pyrene Group 1 Cyclopenta[cd]pyrene Group 2ADibenz[a,h]anthracene Group 2ADibenzo[a,l]pyrene Group 2A

Limited evidence in experimental animals and mechanistic upgradeBenz[j]aceanthrylene Group 2BBenzo[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 evaluationsJNCI 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 providecoherence, 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 agentsAm J Respir Crit Care Med Vol 183. pp 941–948, 2011

Joint IARC, NIOSH-NORA, ACS, n

US NIEHS and NCI Workshop

AcetaldehydeAtrazineCarbon blackChloroform Cobalt metal with

tungsten carbideDichloromethane Diesel engine exhaustDi-2-ethylhexyl phthalate

FormaldehydeIndium phosphideLead and lead compoundsPolychlorinated biphenyls (PCB)Propylene oxideRefractory ceramic fibersShiftwork that involves nightworkStyreneTetrachloroethyleneTitanium dioxideTrichloroethyleneWelding fumes

Future evolution of IARC Monographs

• Research gap: Many chemicals vs. relatively few epidemiological studies and decreasing number of cancer bioassaysMolecular epidemiological studies using validated biomarkersAlternative 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 mechanisticdata in absence of cancer studies in animals or humans

• AG on Quantitative Risk characterization, Nov 2013Recommendations if & how IARC should develop quantitative RC

• Advisory Group on Future priorities, April 2014:Call for nominations of agents for future prioritiesRecommendations from Vol 100 workshops, AG on QRC

Advisory Group, June 2008Volumes 101 and beyond

AcetaldehydeAcrylamide and furanAir pollutionBitumen (Vol 103)Carbon-based nanomaterialsCrystalline fibres other than

asbestosGrowth hormoneIron and iron oxidesMalaria (Vol 104)Motor vehicle engine exhausts (V 105)Nucleoside-analogue antiviral drugsPFOA, other perfluorinated compounds

Polyomaviruses (SV40, BK, JC, Merkel cell virus) (Vol 104)

Radiofrequency electromagnetic fields and radar (includes mobile telephones) (Vol 102)

Sedentary workStatinsStressTestosterone, other androgenic

steroidsUltrafine particlesWeldingAgents 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 fromU.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