Ten key characteristics of carcinogens
1. Is electrophilic or can be metabolically activated to an electrophile
2. Is genotoxic
3. Alters DNA repair or causes genomic instability
4. Induces epigenetic alterations
5. Induces oxidative stress
6. Induces chronic inflammation
7. Is immunosuppressive
8. Modulates receptor-mediated effects
9. Causes immortalization
10. Alters cell proliferation, cell death, or nutrient supply
Studies in exposed humans and in human primary cells or tissues that incorporate end-points relevant to key characteristics of carcinogens are emphasized when available. For each key characteristic with adequate evidence for evaluation, studies are grouped according to whether they involve (a) humans or human primary cells or tissues or (b) experimental systems; further organization (as appropriate) is by end-point (e.g. DNA damage), duration, species, sex, strain, and target organ as well as strength of study design. Studies investigating susceptibility related to key characteristics of carcinogens (e.g. of genetic polymorphisms, or in genetically engineered animals) can be highlighted and may provide additional support for conclusions on the strength of evidence. Findings relevant to a specific tumour type may be noted.
Other informative evidence may be described when it is judged by the Working Group to be relevant to an evaluation of carcinogenicity and to be of sufficient importance to affect the overall evaluation. Quantitative structure-activity information, such as on specific chemical and/or biological features or activities (e.g. electrophilicity, molecular docking with receptors), may be informative. In addition, evidence that falls outside of the recognized key characteristics of carcinogens, reflecting emerging knowledge or important novel scientific developments on carcinogen mechanisms, may also be included. Available evidence relevant to criteria provided in authoritative publications (e.g. Capen et al., 1999; IARC, 2003) on thyroid, kidney, urinary bladder, or other tumours in experimental animals induced by mechanisms that do not operate in humans is also described.
Based on formal considerations of the quality of the studies (e.g. design, methodology, and reporting of results), the Working Group may give greater weight to some included studies.
For observational and other studies in humans, the quality of study design, exposure assessment, and assay accuracy and precision are considered, in collaboration with the Working Group members reviewing exposure characterization and studies of cancer in humans, as are other important factors, including those described above for evaluation of epidemiological evidence (Garcia-Closas et al., 2006, 2011; Vermeulen et al., 2018) (Part B, Sections 1 and 2).
In general, in experimental systems, studies of repeated doses and of chronic exposures are accorded greater importance than are studies of a single dose or time point. Consideration is also given to factors such as the suitability of the dosing range, the extent of concurrent toxicity observed, and the completeness of reporting of the study (e.g. the source and purity of the agent, the analytical methods, and the results). Route of exposure is generally considered to be a less important factor in the evaluation of experimental studies, recognizing that the exposures and target tissues may vary across experimental models and in exposed human populations. Non-mammalian studies can be synthetically summarized when they are considered to be supportive of evidence in humans or higher organisms.
In vitro test systems can provide mechanistic insights, but important considerations include the limitations of the test system (e.g. in metabolic capabilities) as well as the suitability of a particular test article (i.e. because of physical and chemical characteristics) (Hopkins et al., 2004). For studies on some end-points, such as for traditional studies of mutations in bacteria and in mammalian cells, formal guidelines, including those from the Organisation for Economic Co-operation and Development, may be informative in conducting the quality review (OECD, 1997, 2016a, b). However, existing guidelines will not generally cover all relevant assays, even for genotoxicity. Possible considerations when evaluating the quality of in vitro studies encompass the methodology and design (e.g. the end-point and test method, the number of replicate samples, the suitability of the concentration range, the inclusion of positive and negative controls, and the assessment of cytotoxicity) as well as reporting (e.g. of the source and purity of the agent, and of the analytical methods and results). High-content and high-throughput in vitro data can serve as an additional or supportive source of mechanistic evidence (Chiu et al., 2018; Guyton et al., 2018), although large-scale screening programmes measuring a variety of end-points were designed to evaluate large chemical libraries in order to prioritize chemicals for additional toxicity testing rather than to identify the hazard of a specific chemical or chemical group.
The synthesis is focused on the evidence that is most informative for the overall evaluation. In this regard, it is of note that some human carcinogens exhibit a single or primary key characteristic, evidence of which has been influential in their cancer hazard classifications. For instance, ethylene oxide is genotoxic (IARC, 1994), 2,3,7,8-tetrachlorodibenzo-para-dioxin modulates receptor-mediated effects (IARC, 1997), and etoposide alters DNA repair (IARC, 2012a). Similarly, oncogenic viruses cause immortalization, and certain drugs are, by design, immunosuppressive (IARC, 2012a, b). Because non-carcinogens can also induce oxidative stress, this key characteristic should be interpreted with caution unless it is found in combination with other key characteristics (Guyton et al., 2018). Evidence for a group of key characteristics can strengthen mechanistic conclusions (e.g. induces oxidative stress together with is electrophilic or can be metabolically activated to an electrophile, induces chronic inflammation, and is immunosuppressive); see, for example, 1-bromopropane (IARC, 2018).
Exposure data are summarized to identify the agent and describe its production, use, and occurrence. Information on exposure prevalence and intensity in different settings, including geographical patterns and time trends, may be included. Exposure assessment methods used in key epidemiological studies reviewed by the Working Group are described and evaluated.
(b) Cancer in humans
Results of epidemiological studies pertinent to an evaluation of carcinogenicity in humans are summarized. The overall strengths and limitations of the epidemiological evidence base are highlighted to indicate how the evaluation was reached. The target organ(s) or tissue(s) in which a positive association between the agent and cancer was observed are identified. Exposure-response and other quantitative data may be summarized when available. When the available epidemiological studies pertain to a mixed exposure, process, occupation, or industry, the Working Group seeks to identify the specific agent considered to be most likely to be responsible for any excess risk. The evaluation is focused as narrowly as the available data permit.
(c) Cancer in experimental animals
Results pertinent to an evaluation of carcinogenicity in experimental animals are summarized to indicate how the evaluation was reached. For each animal species, study design, and route of administration, there is a statement about whether an increased incidence, reduced latency, or increased severity or multiplicity of neoplasms or pre-neoplastic lesions was observed, and the tumour sites are indicated. Special conditions resulting in tumours, such as prenatal exposure or single-dose experiments, are mentioned. Negative findings, inverse relationships, dose-response patterns, and other quantitative data are also summarized.
(d) Mechanistic evidence
Results pertinent to an evaluation of the mechanistic evidence on carcinogenicity are summarized to indicate how the evaluation was reached. The summary encompasses the informative studies on absorption, distribution, metabolism, and excretion; on the key characteristics with adequate evidence for evaluation; and on any other aspects of sufficient importance to affect the overall evaluation, including on whether the agent belongs to a class of agents for which one or more members have been classified as carcinogenic or probably carcinogenic to humans, and on criteria with respect to tumours in experimental animals induced by mechanisms that do not operate in humans. For each topic addressed, the main supporting findings are highlighted from exposed humans, human cells or tissues, experimental animals, or in vitro systems. When mechanistic studies are available in exposed humans, the tumour type or target tissue studied may be specified. Gaps in the evidence are indicated (i.e. if no studies were available in exposed humans, in in vivo systems, etc.). Consistency or differences of effects across different experimental systems are emphasized.
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