Chapter 22. Analysis of Key Characteristics of Human Carcinogens
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part 3. statistical analyses of concordance and key characteristics 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) in collaboration with other participants (see the Contributors list) in the Workshop on Tumour Site Concordance and Mechanisms of Carcinogenesis, which was convened by IARC in April and November 2012 in Lyon Introduction evaluate and integrate the evidence limited evidence of carcinogenicity, provided by human epidemiological inadequate evidence of carcinogen- PART 3 Since its establishment in the ear- studies, animal cancer bioassays, icity, or evidence suggesting lack of CHAPTER 22 ly 1970s, the IARC Monographs and information on possible biolog- carcinogenicity. The information on Programme has evaluated more ical mechanisms of action, to clas- biological mechanisms of action may than 1000 agents with evidence of sify agents into one of the following be evaluated as strong, moderate, or human exposure and for which some categories: carcinogenic to humans weak, and is taken into consideration suspicion exists of an increased (Group 1), probably carcinogenic to in the overall evaluation. cancer risk to humans. The IARC humans (Group 2A), possibly carci- The role of mechanistic informa- Monographs Programme has devel- nogenic to humans (Group 2B), not tion in evaluating carcinogenicity oped detailed criteria against which classifiable as to its carcinogenicity to has increased substantially during to evaluate the available scientific humans (Group 3), and probably not the history of the IARC Monographs evidence on the carcinogenic poten- carcinogenic to humans (Group 4). Programme. In 1991, IARC convened tial of such agents. These criteria, These evaluations involve classifying a Working Group on the Use of Data which are described in the Preamble the data from both the human and on Mechanisms of Carcinogenesis to the IARC Monographs (Cogliano the animal studies as providing suf- in Risk Identification, to explore how et al., 2004; IARC, 2006), are used to ficient evidence of carcinogenicity, mechanistic data could be used to Part 3 • Chapter 22. Analysis of key characteristics of human carcinogens 257 identify agents with the potential to processes at the cellular and mo- electrophile can react with cellu- cause cancer in humans. The con- lecular level and thought to be rele- lar macromolecules such as DNA, sensus report of the Working Group vant to carcinogenesis. Information RNA, and proteins to form adducts. documented several mechanisms on these 24 end-points was derived Some chemical carcinogens are di- that were considered to be relevant from human in vivo, human in vitro, rect-acting electrophiles (e.g. form- to human carcinogenesis at that animal in vivo, and animal in vitro aldehyde; sulfur mustard, and ethyl- time, including genotoxicity, cell studies (see Al-Zoughool et al., 2019). ene oxide), whereas others require proliferation, receptor mechanisms During the November 2012 meeting, biotransformation by enzymes in a in mitogenesis, alterations in DNA the Workshop participants identified process termed metabolic activation repair, intercellular communication, 10 broader key characteristics of car- (e.g. polycyclic aromatic hydrocar- and immune defects and immuno- cinogens (see Chapter 10, by Smith, bons and benzene) (Miller, 1970). suppression (Vainio et al., 1992). and Smith et al., 2016). Information Characteristic 2: Is genotoxic Toxicokinetic and other variables on these characteristics was extract- were also identified as factors affect- ed from the IARC Monographs and Genotoxicity is the ability to induce ing multistage carcinogenesis. Since used to develop a database of key DNA damage or other chromosomal 1991, IARC (2006) and other orga- characteristics for Group 1 agents alterations, as measured by three nizations – for example, the United (see Al-Zoughool et al., 2019). This associated toxicological end-points: States National Toxicology Program chapter focuses on the key charac- (i) DNA damage: an alteration in (National Toxicology Program, 2014) teristics of the Group 1 agents iden- the chemical structure or integrity of DNA, including a break in a DNA and the United States Environmental tified in the IARC Monographs up to strand, and/or chemical modifica- Protection Agency (EPA) (EPA, and including Volume 106, and pre- tions such as covalent binding to 2005) – have stressed the increas- sents the results of an exploratory the nucleotide bases (Hoeijmakers, ing importance of mechanistic infor- analysis of this database. 2009); (ii) gene mutations: changes mation in cancer risk assessment. in the normal nucleotide sequence of Related risk assessment practic- Methods cellular DNA that may have a central es concern mode of action (Meek Key characteristics role in human carcinogenesis (Ding et al., 2014) and pathways of toxic- et al., 2008); (iii) clastogenic effects ity (Krewski et al., 2014; Bourdon- As mentioned above, Chapter 10, reflect damage to chromosomes, in- Lacombe et al., 2015; Cote et al., by Smith, and Smith et al. (2016) cluding DNA breakage, or the rear- 2016), as well as dosimetric consid- describe 10 key characteristics of rangement, gain, or loss of chromo- erations (Gurusankar et al., 2017). human carcinogens, as listed in some fragments (Snyder, 2010). This chapter examines the avail- Table 22.2. The toxicological end- Characteristic 3: Alters DNA able data on mechanisms of action points initially considered by the repair or causes genomic of the Group 1 agents identified up Workshop participants and used instability to and including Volume 106 of the as indicators of these characteris- IARC Monographs (Table 22.1). The tics are also noted in Table 22.2. Alterations in DNA repair result in de- present analysis is based on a re- A brief summary of each of these fects in processes that monitor and view of human cancer mechanisms, characteristics and the associated correct DNA replication fidelity. Such conducted by the participants in the toxicological end-points is provided defects can confer strong mutator two-part Workshop on Tumour Site below. phenotypes that result in genomic Concordance and Mechanisms of instability. Characteristic 1: Is electrophilic Carcinogenesis, which was con- or can be metabolically Characteristic 4: Induces vened by IARC in April and Novem- activated to electrophiles epigenetic alterations ber 2012 in Lyon. This approach initially involved retrieval of informa- The first characteristic refers to Induced epigenetic alterations are tion from the IARC Monographs on agents that act as electrophiles stable changes in gene expression 24 toxicological end-points identi- themselves or that can be metab- and chromatin organization that are fied as likely indicators of biological olized to form electrophiles. An independent of mutation and that 258 Table 22.1. Number of Group 1 agents in Volumes 100–118 of the IARC Monographs, by type of agenta Type of agent Volume Total 100 105 106 107 109 110 111 113 114 117 118 Pharmaceuticals 23 – – – – – – – – – – 23 Biological agents 11 – – – – – – – – – – 11 Arsenic, metals, 10 – – – – – 2b – – – – 12 fibres, and dusts Radiation 18 – – – – – – – – – 1c 19 Personal habits and 12 – – – – – – – 1d – – 13 indoor combustions Chemical agents and 33 1e 1f 2g 2h 1i – 1j – 1k 1l 43 related occupations Total 107 1 1 2 2 1 2 1 1 1 2 121 a At the time that the present analysis was conducted, mechanistic information was available only for the 109 Group 1 agents evaluated in the IARC Monographs up to and including Volume 106. b Fluoro-edenite fibrous amphibole; occupational exposures associated with the Acheson process in the manufacture of silicon carbide fibres. c Ultraviolet radiation from welding. d Processed meat. e Diesel engine exhaust. f Trichloroethylene. g Polychlorinated biphenyls (PCBs); dioxin-like PCBs. h Outdoor air pollution; particulate matter in outdoor air pollution. i 1,2-Dichloropropane. j Lindane. k Pentachlorophenol (PCP). l Welding fumes. can be inherited through cell divi- reactive oxygen and detoxification of leading to the recruitment and acti- sion. Epigenetic phenomena include the radical species within cells and vation of inflammatory cells. Strong genomic imprinting, X-chromosome tissues. Reactive oxygen species links exist between inflammation PART 3 inactivation, global reconfiguration induce a cascade of events that can and the induction of oxidative stress CHAPTER 22 of the DNA methylome, changes in include DNA mutation and oxidative and genomic instability; this makes chromatin compaction states and DNA damage. Both are key events in it difficult to separate out the rel- histone modification patterns, and carcinogenesis (Klaunig et al., 2011). ative importance of each of these altered expression of microRNAs mechanisms. These linkages might Characteristic 6: Induces (miRNAs). These phenomena occur be the basis of the relationship be- chronic inflammation during organ development and con- tween chronic inflammation and can- tribute to the lineage-specific epi- Chronic inflammation can arise from cer (Multhoff and Radons, 2012). genome that is maintained over the persistent infection (e.g. with human Characteristic 7: Is lifetime of an organism. papillomavirus or with Helicobacter immunosuppressive pylori) as well as from exogenous ir- Characteristic 5: Induces ritants (e.g.