Abstract

This Scientific Publication reviews the information on cancer sites and mechanistic events for the more than 100 agents classified in Group 1 (carcinogenic to humans) by the IARC Monographs Programme. This category of agents is diverse and includes chemicals and chemical mixtures; occupations; metals, dusts, and fibres; radiation; viruses and other biological agents; personal habits; and pharmaceuticals.

For the Group 1 agents, there were cross-cutting questions about the relevance to humans of certain cancer sites or mechanistic pathways in animals. This publication is based on a systematic identification and comparison of the cancer sites observed in humans and those observed in experimental animals, and a compilation of mechanistic events for agents known to cause cancer in humans.

Relevant information was analysed on all the agents classified in Group 1 in Monographs up to and including Volume 109, most of which are reviewed in Volume 100A–F. A database of tumour sites seen in humans and animals was used to examine the degree of concordance by use of an anatomically based tumour classification scheme. The analysis of mechanistic aspects of the IARC Group 1 agents focused on 10 key characteristics of human carcinogens developed during the course of this work. Genotoxicity was the most prevalent mechanistic characteristic, consistent with the process of carcinogenesis necessarily involving genomic changes.

The IARC concordance database represents a useful source of information for comparing animal and human data with respect to the tumours caused in different species. The results of the mechanistic analysis can provide a basis for future efforts to categorize mechanistic data for carcinogens through a systematic review process.

These reviews and analyses were discussed during a two-part Workshop on Tumour Site Concordance and Mechanisms of Carcinogenesis convened by IARC. This Scientific Publication is the report of that Workshop and of subsequent work by the participants, both individually and collectively. This publication also presents a statement of consensus among the Workshop participants, which summarizes the main findings and their implications for human cancer risk assessment.

Contents

• Library Cataloguing Information
• IARC Library Cataloguing in Publication Data
• Contributors
• Acknowledgements
• Introduction
  Vincent J. Cogliano.
• Consensus statement
• Abbreviations
• Part 1. Concordance between cancer in humans and in experimental animals
  • Chapter 1. Electrophilic agents
    James A. Bond and Ronald L. Melnick.
    • Introduction
    • Chemical disposition
    • Absorption
    • Metabolic activation or detoxification and elimination
    • Direct-acting compounds
    • Molecular interactions (DNA adducts, genetic alterations, etc.)
    • Polymorphisms and susceptibility
    • References
  • Chapter 2. Aromatic amines and aristolochic acids
    Frederick A. Beland and M. Matilde Marques.
    • Carcinogenicity in humans
    • Metabolism and DNA adduct formation
    • Alterations in the TP53 tumour suppressor gene in humans
    • Tumour sites and the mechanism of tumour induction in experimental animals
    • Oncogene alterations in experimental animals
    • Summary
    • Disclaimer
    • References
  • Chapter 3. Arsenic and metals
    Michael P. Waalkes.
    • Arsenic and arsenic compounds
    • Beryllium and beryllium compounds
    • Cadmium and cadmium compounds
    • Chromium(VI) compounds
    • Nickel and nickel compounds
    • Comparative mechanisms of the inorganic human carcinogens
    • References
  • Chapter 4. Smokeless tobacco and its constituents
    Stephen S. Hecht.
    • Introduction
    • Coherence: carcinogenicity of smokeless tobacco in humans versus experimental animals
    • Coherence: carcinogenicity of smokeless tobacco in humans versus carcinogenicity of smokeless tobacco constituents in experimental animals
    • Coherence: mechanistic studies of carcinogenicity of smokeless tobacco
    • Conclusions
    • Acknowledgement
    • References
  • Chapter 5. Tobacco smoke and its constituents
    Stephen S. Hecht and David M. DeMarini.
    • Coherence: carcinogenicity of tobacco smoke in humans versus experimental animals
    • Concordance: carcinogenicity of tobacco smoke in humans versus carcinogenicity of tobacco smoke constituents in experimental animals
    • Concordance: overall mechanism of cancer induction in humans versus laboratory studies
    • Disclaimer
    • References
  • Chapter 6. Anticancer agents: qualitative and quantitative aspects
    Kari Hemminki and Harri Vainio.
    • Introduction
    • Therapeutic applications and trends in use
    • Tumour sites
    • Carcinogenic potency
    • Mechanisms of action
    • Conclusions
    • References
  • Chapter 7. Polycyclic aromatic hydrocarbons and associated occupational exposures
    Charles William Jameson.
    • Properties of PAHs
    • Occupational exposure to PAHs
    • Classification of PAHs
    • Studies of cancer in humans
    • Tumour site concordance
    • References
  • Chapter 8. Benzene and haematological cancers
    Bernard D. Goldstein and Martyn T. Smith.
    • Introduction
    • Studies in experimental animals
    • Epidemiological studies
    • Changing diagnostic criteria for haematological disorders
    • Evidence for an overlap between myeloid and lymphoid cancers in humans
    • Mechanism of benzene-induced haematotoxicity
    • Conclusions
    • References
  • Chapter 9. Human tumour viruses
    Paul F. Lambert and Lawrence Banks.
    • Epstein–Barr virus (EBV)
    • Hepatitis B virus (HBV)
    • Hepatitis C virus (HCV)
    • Kaposi sarcoma-associated herpesvirus (KSHV)
    • Human papillomaviruses
    • Human immunodeficiency virus type 1 (HIV-1)
    • Human T-cell lymphotropic virus type 1 (HTLV-1)
    • References
• Part 2. Mechanisms of Carcinogenesis
  • Chapter 10. Key characteristics of carcinogens
    Martyn T. Smith.
    • Introduction
    • Characteristic 1: Is electrophilic or can be metabolically activated to electrophiles
    • Characteristic 2: Is genotoxic
    • Characteristic 3: Alters DNA repair or causes genomic instability
    • Characteristic 4: Induces epigenetic alterations
    • Characteristic 5: Induces oxidative stress
    • Characteristic 6: Induces chronic inflammation
    • Characteristic 7: Is immunosuppressive
    • Characteristic 8: Modulates receptor-mediated effects
    • Characteristic 9: Causes immortalization
    • Characteristic 10: Alters cell proliferation, cell death, or nutrient supply
    • Multiple mechanisms of action of human carcinogens
    • Factors modulating human carcinogenesis
    • References
  • Chapter 11. Mechanisms of carcinogenesis: from initiation and promotion to the hallmarks
    Bernard W. Stewart.
    • Introduction
    • Multistage carcinogenesis
    • A decade on: “the next generation”
    • Identifying mechanisms of carcinogenesis
    • Public health decision-making: the definitive consideration
    • Systematic appraisal of mechanisms of carcinogenesis
    • Tobacco smoke, cancer of the lung, and the hallmarks
    • Summary
    • Possible inferences from hallmark-based studies
    • References
  • Chapter 12. The role of genotoxicity in carcinogenesis
    David M. DeMarini.
    • The process of mutagenesis
    • A brief history of the nexus between mutagens and carcinogens
    • Mutations in tumours
    • Models of agent-induced carcinogenesis
    • Summary
    • Disclaimer
    • References
  • Chapter 13. Alterations in cell proliferation, cell death, or nutrient supply
    Jane C. Caldwell.
    • Introduction
    • Genetic drivers of cell proliferation and apoptosis: complex relationships and pleiotropic roles of cell signalling molecules
    • Genetic variability in cell signalling between species, strains, and target organs
    • Variability in mutation targets and cell signalling across tissues and in tumours
    • Alterations in nutrient supply
    • Cell proliferation as a component or cause of cancer
    • Conclusions
    • Disclaimer
    • References
  • Chapter 14. Receptor-mediated mechanisms
    Maarten C. Bosland.
    • Introduction
    • General comments
    • Non-genomic receptor-mediated mechanisms and carcinogenesis
    • Nuclear receptor-mediated mechanisms and carcinogenesis
    • Summary
    • References
  • Chapter 15. Oxidative stress and radical-induced signalling
    John R. Bucher.
    • Sources of oxygen radicals
    • Oxidative damage
    • Defence mechanisms
    • Oxygen radicals in cancer
    • Vulnerable tissue sites and selected carcinogenic exposures
    • Summary
    • References
  • Chapter 16. Immunosuppression
    Jerry M. Rice.
    • Introduction
    • Immunosuppression and genotoxicity
    • Immunosuppressive carcinogens
    • Malaria, a probable human carcinogen
    • References
  • Chapter 17. Inflammation
    Agnes B. Kane.
    • Introduction
    • Intrinsic and extrinsic pathways linking inflammation and cancer
    • How do exogenous infectious agents and environmental exposures trigger tumour-associated inflammation?
    • Inflammation and genomic instability
    • Inflammation, fibrosis, and cancer
    • Summary and conclusions
    • Acknowledgement
    • References
  • Chapter 18. Ionizing radiation
    Mark A. Hill and Robert L. Ullrich.
    • Introduction
    • The nature of ionizing radiation
    • Genotoxicity and the importance of radiation track structure
    • Other potential mechanisms for modifying cancer risk from radiation exposure
    • The importance of dose distribution with respect to tumour sites
    • Human exposures to ionizing radiation typically occur at low dose and low dose rate
    • Generality of response after exposure to different types of ionizing radiation
    • References
  • Chapter 19. Host susceptibility
    Jane C. Caldwell, Ronald L. Melnick, and Lauren Zeise.
    • Introduction
    • Analogous transgenic, strain-specific, or species-specific animal models
    • Influence of study design on determination of site concordance
    • Lifestyle, disease status, and co-exposures
    • Conclusions
    • Disclaimer
    • References
  • Chapter 20. Age and susceptibility
    Jerry M. Rice and Zdenko Herceg.
    • Introduction
    • Studies in experimental animals
    • Epidemiological findings in humans
    • Summary
    • References
• Part 3. statistical analyses of concordance and key characteristics
  • Chapter 21. Analysis of tumour site concordance
    Daniel Krewski, Jerry M. Rice, Michael Bird, Brittany Milton, Brian Collins, Pascale Lajoie, Mélissa Billard, Yann Grosse, Vincent J. Cogliano, Jane C. Caldwell, Ivan I. Rusyn, Christopher J. Portier, Ronald L. Melnick, Julian Little, and Jan M. Zielinski, deceased.
    • Introduction
    • Methods
    • Results
    • Discussion
    • Conclusions
    • Summary
    • References
  • Chapter 22. Analysis of key characteristics of human carcinogens
    Daniel Krewski, Mustafa Al-Zoughool, Michael Bird, Nicholas Birkett, Mélissa Billard, Brittany Milton, Jerry M. Rice, Vincent J. Cogliano, Mark A. Hill, Julian Little, and Jan M. Zielinski, deceased.
    • Introduction
    • Methods
    • Results
    • Discussion
    • Further analyses
    • Conclusions
    • Summary
    • References
• Annex 1. Development of a data set on tumours and tumour sites in humans and in experimental animals for Group 1 agents identified up to and including Volume 109 of the IARC Monographs
  Yann Grosse, Pascale Lajoie, Mélissa Billard, Daniel Krewski, Jerry M. Rice, Vincent J. Cogliano, Michael Bird, and Jan M. Zielinski, deceased.
• Disclosures of interests