IARC Monographs on the evaluation of the carcinogenic risks to the humans : ionizing radiation :part 1

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1. BACKGROUND

 * In 1969, the International Agency for Research on Cancer (IARC) initiated a programme to evaluate the carcinogenic risk of chemicals to humans and to produce monographs on individual chemicals.
 * The Monographs programme has since been expanded to include consideration of exposures to complex mixtures of chemicals (which occur, for example, in some occupations and as a result of human habits) and of exposures to other agents, such as radiation and viruses. With Supplement 6 (IARC, 1987a), the title of the series was modified from IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans to IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, in order to reflect the widened scope of the programme.
 * The criteria established in 1971 to evaluate carcinogenic risk to humans were adopted by the working groups whose deliberations resulted in the first 16 volumes of the IARC Monographs series. Those criteria were subsequently updated by further adhoc working groups (IARC, 1977, 1978, 1979, 1982, 1983, 1987b, 1988, 1991a; Vainio et al., 1992).

2. OBJECTIVE AND SCOPE

 * The objective of the programme is to prepare, with the help of international working groups of experts, and to publish in the form of monographs, critical reviews and evaluations of evidence on the carcinogenicity of a wide range of human exposures.
 * The Monographs may also indicate where additional research efforts are needed.
 * The Monographs represent the first step in carcinogenic risk assessment, which involves examination of all relevant information in order to assess the strength of the available evidence that certain exposures could alter the incidence of cancer in humans.
 * The second step is quantitative risk estimation. Detailed, quantitative evaluations of epidemiological data may be made in the Monographs, but without extrapolation beyond the range of the data available.
 * Quantitative extrapolation from experimental data to the human situation is not undertaken.
 * The term ‘carcinogen’ is used in these monographs to denote an exposure that is capable of increasing the incidence of malignant neoplasms; the induction of benign neoplasms may in some circumstances (see p. 19) contribute to the judgement that the exposure is carcinogenic.
 * The terms ‘neoplasm’ and ‘tumour’ are used interchangeably.
 * Some epidemiological and experimental studies indicate that different agents may act at different stages in the carcinogenic process, and several mechanisms may be involved.
 * The aim of the Monographs has been, from their inception, to evaluate evidence of carcinogenicity at any stage in the carcinogenesis process, independently of the underlying mechanisms. Information on mechanisms may, however, be used in making the overall evaluation (IARC, 1991a; Vainio et al., 1992; see also pp. 25–27).
 * The Monographs may assist national and international authorities in making risk assessments and in formulating decisions concerning any necessary preventive measures.
 * The evaluations of IARC working groups are scientific, qualitative judgements about the evidence for or against carcinogenicity provided by the available data. These evaluations represent only one part of the body of information on which regulatory measures may be based.
 * Other components of regulatory decisions vary from one situation to another and from country to country, responding to different socioeconomic and national priorities.
 * Therefore, no recommendation is given with regard to regulation or legislation, which are the responsibility of individual governments and/or other international organizations.
 * The IARC Monographs are recognized as an authoritative source of information on the carcinogenicity of a wide range of human exposures.
 * A survey of users in 1988 indicated that the Monographs are consulted by various agencies in 57 countries. About 3000 copies of each volume are printed, for distribution to governments, regulatory bodies and interested scientists.
 * The Monographs are also available from IARCPress in Lyon and via the Distribution and Sales Service of the World Health Organization in Geneva.

3. SELECTION OF TOPICS FOR MONOGRAPHS

 * Topics are selected on the basis of two main criteria: (a) there is evidence of human exposure, and (b) there is some evidence or suspicion of carcinogenicity.
 * The term ‘agent’ is used to include individual chemical compounds, groups of related chemical compounds, physical agents (such as radiation) and biological factors (such as viruses).
 * Exposures to mixtures of agents may occur in occupational exposures and as a result of personal and cultural habits (like smoking and dietary practices). Chemical analogues and compounds with biological or physical characteristics similar to those of suspected carcinogens may also be considered, even in the absence of data on a possible carcinogenic effect in humans or experimental animals.
 * The scientific literature is surveyed for published data relevant to an assessment of carcinogenicity.
 * The IARC information bulletins on agents being tested for carcinogenicity (IARC, 1973–1996) and directories of on-going research in cancer epidemiology (IARC, 1976–1996) often indicate exposures that may be scheduled for future meetings.
 * Ad-hoc working groups convened by IARC in 1984, 1989, 1991, 1993 and 1998 gave recommendations as to which agents should be evaluated in the IARC Monographs series (IARC, 1984, 1989, 1991b, 1993, 1998a,b).


 * As significant new data on subjects on which monographs have already been prepared become available, re-evaluations are made at subsequent meetings, and revised monographs are published.

4. DATA FOR MONOGRAPHS

 * The Monographs do not necessarily cite all the literature concerning the subject of an evaluation.
 * Only those data considered by the Working Group to be relevant to making the evaluation are included.
 * With regard to biological and epidemiological data, only reports that have been published or accepted for publication in the openly available scientific literature are reviewed by the working groups.
 * In certain instances, government agency reports that have undergone peer review and are widely available are considered. *Exceptions may be made on an ad-hoc basis to include unpublished reports that are in their final form and publicly available, if their inclusion is considered pertinent to making a final evaluation (see pp. 25–27).
 * In the sections on chemical and physical properties, on analysis, on production and use and on occurrence, unpublished sources of information may be used.

5. THE WORKING GROUP

 * Reviews and evaluations are formulated by a working group of experts. The tasks of the group are:
 * (i) to ascertain that all appropriate data have been collected;
 * (ii) to select the data relevant for the evaluation on the basis of scientific merit;
 * (iii) to prepare accurate summaries of the data to enable the reader to follow the reasoning of the Working Group;
 * (iv) to evaluate the results of epidemiological and experimental studies on cancer;
 * (v) to evaluate data relevant to the understanding of mechanism of action; and
 * (vi) to make an overall evaluation of the carcinogenicity of the exposure to humans.
 * Working Group participants who contributed to the considerations and evaluations within a particular volume are listed, with their addresses, at the beginning of each publication.
 * Each participant who is a member of a working group serves as an individual scientist and not as a representative of any organization, government or industry.
 * In addition, nominees of national and international agencies and industrial associations may be invited as observers.

6. WORKING PROCEDURES
Approximately one year in advance of a meeting of a working group, the topics of the monographs are announced and participants are selected by IARC staff in consultation with other experts.
 * Subsequently, relevant biological and epidemiological data are collected by the Carcinogen Identification and Evaluation Unit of IARC from recognized sources of information on carcinogenesis, including data storage and retrieval systems such as MEDLINE and TOXLINE.
 * For chemicals and some complex mixtures, the major collection of data and the preparation of first drafts of the sections on chemical and physical properties, on analysis on production and use and on occurrence are carried out under a separate contract funded by the United States National Cancer Institute.
 * Representatives from industrial associations may assist in the preparation of sections on production and use.
 * Information on production and trade is obtained from governmental and trade publications and, in some cases, by direct contact with industries.
 * Separate production data on some agents may not be available because their publication could disclose confidential information. *Information on uses may be obtained from published sources but is often complemented by direct contact with manufacturers. *Efforts are made to supplement this information with data from other national and international sources.
 * Six months before the meeting, the material obtained is sent to meeting participants, or is used by IARC staff, to prepare sections for the first drafts of monographs.
 * The first drafts are compiled by IARC staff and sent before the meeting to all participants of the Working Group for review.
 * The Working Group meets in Lyon for seven to eight days to discuss and finalize the texts of the monographs and to formulate the evaluations.
 * After the meeting, the master copy of each monograph is verified by consulting the original literature, edited and prepared for publication.
 * The aim is to publish monographs within six months of the Working Group meeting.
 * The available studies are summarized by the Working Group, with particular regard to the qualitative aspects discussed below. In general, numerical findings are indicated as they appear in the original report; units are converted when necessary for easier comparison.
 * The Working Group may conduct additional analyses of the published data and use them in their assessment of the evidence; the results of such supplementary analyses are given in square brackets.
 * When an important aspect of a study, directly impinging on its interpretation, should be brought to the attention of the reader, a comment is given in square brackets.

7. EXPOSURE DATA
given. also provided. In addition, methods of synthesis used in past and present commercial production and different methods of production which may give rise to different impurities are described. Data on production, international trade and uses are obtained for representative regions, which usually include Europe, Japan and the United States of America. countries as indications of potential exposures, but they may not reflect the most recent situation, since such limits are continuously reviewed and modified.
 * Sections that indicate the extent of past and present human exposure, the sources of exposure, the people most likely to be exposed and the factors that contribute to the exposure are included at the beginning of each monograph.
 * Most monographs on individual chemicals, groups of chemicals or complex mixtures include sections on chemical and physical data, on analysis, on production and use and on occurrence.
 * In monographs on, for example, physical agents, occupational exposures and cultural habits, other sections may be included, such as: historical perspectives, description of an industry or habit, chemistry of the complex mixture or taxonomy.
 * Monographs on biological agents have sections on structure and biology, methods of detection, epidemiology of infection and clinical disease other than cancer.
 * For chemical exposures, the Chemical Abstracts Services Registry Number, the latest Chemical Abstracts Primary Name and the IUPAC Systematic Name are recorded; other synonyms are given, but the list is not necessarily comprehensive. *For biological agents, taxonomy and structure are described, and the degree of variability is given, when applicable.
 * Information on chemical and physical properties and, in particular, data relevant to identification, occurrence and biological activity are included.
 * For biological agents, mode of replication, life cycle, target cells, persistence and latency and host response are
 * A description of technical products of chemicals includes trade names, relevant specifications and available information on composition and impurities.
 * Some of the trade names given may be those of mixtures in which the agent being evaluated is only one of the ingredients.
 * The purpose of the section on analysis or detection is to give the reader an overview of current methods, with emphasis on those widely used for regulatory purposes.
 * Methods for monitoring human exposure are also given, when available.
 * No critical evaluation or recommendation of any of the methods is meant or implied.
 * The IARC published a series of volumes, Environmental Carcinogens: Methods of Analysis and Exposure Measurement (IARC, 1978–93), that describe validated methods for analysing a wide variety of chemicals and mixtures.
 * For biological agents, methods of detection and exposure assessment are described, including their sensitivity, specificity and reproducibility.
 * The dates of first synthesis and of first commercial production of a chemical or mixture are provided; for agents which do not occur naturally, this information may allow a reasonable estimate to be made of the date before which no human exposure to the agent could have occurred. The dates of first reported occurrence of an exposure are
 * It should not, however, be inferred that those areas or nations are necessarily the sole or major sources or users of the agent.
 * Some identified uses may not be current or major applications, and the coverage is not necessarily comprehensive.
 * In the case of drugs, mention of their therapeutic uses does not necessarily represent current practice, nor does it imply judgement as to their therapeutic efficacy.
 * Information on the occurrence of an agent or mixture in the environment is obtained from data derived from the monitoring and surveillance of levels in occupational environments, air, water, soil, foods and animal and human tissues.
 * When available, data on the generation, persistence and bioaccumulation of the agent are also included.
 * In the case of mixtures, industries, occupations or processes, information is given about all agents present.
 * For processes, industries and occupations, a historical description is also given, noting variations in chemical composition, physical properties and levels of occupational exposure with time and place.
 * For biological agents, the epidemiology of infection is described. Statements concerning regulations and guidelines (e.g., pesticide registrations, maximal levels permitted in foods, occupational exposure limits) are included for some
 * The absence of information on regulatory status for a country should not be taken to imply that that country does not have regulations with regard to the exposure.
 * For biological agents, legislation and control, including vaccines and therapy, are described.

9. STUDIES OF CANCER IN EXPERIMENTALANIMALS
All known human carcinogens that have been studied adequately in experimental animals have produced positive results in one or more animal species (Wilbourn et al., 1986; Tomatis et al., 1989). For several agents (aflatoxins, 4-aminobiphenyl, azathioprine, betel quid with tobacco, bischloromethyl ether and chloromethyl methyl ether (technical grade), chlorambucil, chlornaphazine, ciclosporin, coal-tar pitches, coal-tars, combined oral contraceptives, cyclophosphamide, diethylstilboestrol, melphalan, 8- methoxypsoralen plus ultraviolet A radiation, mustard gas, myleran, 2-naphthylamine, nonsteroidal oestrogens, oestrogen replacement therapy/steroidal oestrogens, solar radiation, thiotepa and vinyl chloride), carcinogenicity in experimental animals was established or highly suspected before epidemiological studies confirmed their carcinogenicity in humans (Vainio et al., 1995). Although this association cannot establish that all agents and mixtures that cause cancer in experimental animals also cause cancer in humans, nevertheless, in the absence of adequate data on humans, it is biologically plausible and prudent to regard agents and mixtures for which there is sufficient evidence (see p. 24) of carcinogenicity in experimental animals as if they presented a carcinogenic risk to humans. The possibility that a given agent may cause cancer through a species-specific mechanism which does not operate in humans (see p. 27) should also be taken into consideration. The nature and extent of impurities or contaminants present in the chemical or mixture being evaluated are given when available. Animal strain, sex, numbers per group, age at start of treatment and survival are reported. Other types of studies summarized include: experiments in which the agent or mixture was administered in conjunction with known carcinogens or factors that modify carcinogenic effects; studies in which the end-point was not cancer but a defined precancerous lesion; and experiments on the carcinogenicity of known metabolites and derivatives. For experimental studies of mixtures, consideration is given to the possibility of changes in the physicochemical properties of the test substance during collection, storage, extraction, concentration and delivery. Chemical and toxicological interactions of the components of mixtures may result in nonlinear dose–response relationships. An assessment is made as to the relevance to human exposure of samples tested in experimental animals, which may involve consideration of: (i) physical and chemical characteristics, (ii) constituent substances that indicate the presence of a class of substances, (iii) the results of tests for genetic and related effects, including studies on DNA adduct formation, proto-oncogene mutation and expression and suppressor gene inactivation. The relevance of results obtained, for example, with animal viruses analogous to the virus being evaluated in the monograph must also be considered. They may provide biological and mechanistic information relevant to the understanding of the process of carcinogenesis in humans and may strengthen the plausibility of a conclusion that the biological agent under evaluation is carcinogenic in humans. (a) Qualitative aspects An assessment of carcinogenicity involves several considerations of qualitative importance, including (i) the experimental conditions under which the test was performed, including route and schedule of exposure, species, strain, sex, age, duration of follow-up; (ii) the consistency of the results, for example, across species and target organ(s); (iii) the spectrum of neoplastic response, from preneoplastic lesions and benign tumours to malignant neoplasms; and (iv) the possible role of modifying factors. As mentioned earlier (p. 11), the Monographs are not intended to summarize all published studies. Those studies in experimental animals that are inadequate (e.g., too short a duration, too few animals, poor survival; see below) or are judged irrelevant to the evaluation are generally omitted. Guidelines for conducting adequate long-term carcinogenicity experiments have been outlined (e.g. Montesano et al., 1986). Considerations of importance to the Working Group in the interpretation and evaluation of a particular study include: (i) how clearly the agent was defined and, in the case of mixtures, how adequately the sample characterization was reported; (ii) whether the dose was adequately monitored, particularly in inhalation experiments; (iii) whether the doses and duration of treatment were appropriate and whether the survival of treated animals was similar to that of controls; (iv) whether there were adequate numbers of animals per group; (v) whether animals of each sex were used; (vi) whether animals were allocated randomly to groups; (vii) whether the duration of observation was adequate; and (viii) whether the data were adequately reported. If available, recent data on the incidence of specific tumours in historical controls, as well as in concurrent controls, should be taken into account in the evaluation of tumour response. When benign tumours occur together with and originate from the same cell type in an organ or tissue as malignant tumours in a particular study and appear to represent a stage in the progression to malignancy, it may be valid to combine them in assessing tumour incidence (Huff et al., 1989). The occurrence of lesions presumed to be preneoplastic may in certain instances aid in assessing the biological plausibility of any neoplastic response observed. If an agent or mixture induces only benign neoplasms that appear to be end-points that do not readily progress to malignancy, it should nevertheless be suspected of being a carcinogen and requires further investigation. (b) Quantitative aspects The probability that tumours will occur may depend on the species, sex, strain and age of the animal, the dose of the carcinogen and the route and length of exposure. Evidence of an increased incidence of neoplasms with increased level of exposure strengthens the inference of a causal association between the exposure and the development of neoplasms. The form of the dose–response relationship can vary widely, depending on the particular agent under study and the target organ. Both DNA damage and increased cell division are important aspects of carcinogenesis, and cell proliferation is a strong determinant of dose–response relationships for some carcinogens (Cohen & Ellwein, 1990). Since many chemicals require metabolic activation before being converted into their reactive intermediates, both metabolic and pharmacokinetic aspects are important in determining the dose–response pattern. Saturation of steps such as absorption, activation, inactivation and elimination may produce nonlinearity in the dose–response relationship, as could saturation of processes such as DNA repair (Hoel et al., 1983; Gart et al., 1986). (c) Statistical analysis of long-term experiments in animals Factors considered by the Working Group include the adequacy of the information given for each treatment group: (i) the number of animals studied and the number examined histologically, (ii) the number of animals with a given tumour type and (iii) length of survival. The statistical methods used should be clearly stated and should be the generally accepted techniques refined for this purpose (Peto et al., 1980; Gart et al., 1986). When there is no difference in survival between control and treatment groups, the Working Group usually compares the proportions of animals developing each tumour type in each of the groups. Otherwise, consideration is given as to whether or not appropriate adjustments have been made for differences in survival. These adjustments can include: comparisons of the proportions of tumour-bearing animals among the effective number of animals (alive at the time the first tumour is discovered), in the case where most differences in survival occur before tumours appear; life-table methods, when tumours are visible or when they may be considered ‘fatal’ because mortality rapidly follows tumour development; and the Mantel-Haenszel test or logistic regression when occult tumours do not affect the animals’ risk of dying but are ‘incidental’ findings at autopsy. In practice, classifying tumours as fatal or incidental may be difficult. Several survival-adjusted methods have been developed that do not require this distinction (Gart et al., 1986), although they have not been fully evaluated.

10. OTHER DATA RELEVANT TO AN EVALUATION OF CARCINOGENICITY AND ITS MECHANISMS
In coming to an overall evaluation of carcinogenicity in humans (see pp. 25–27), the Working Group also considers related data. The nature of the information selected for the summary depends on the agent being considered. For chemicals and complex mixtures of chemicals such as those in some occupational situations or involving cultural habits (e.g. tobacco smoking), the other data considered to be relevant are divided into those on absorption, distribution, metabolism and excretion; toxic effects; reproductive and developmental effects; and genetic and related effects. Concise information is given on absorption, distribution (including placental transfer) and excretion in both humans and experimental animals. Kinetic factors that may affect the dose–response relationship, such as saturation of uptake, protein binding, metabolic activation, detoxification and DNA repair processes, are mentioned. Studies that indicate the metabolic fate of the agent in humans and in experimental animals are summarized briefly, and comparisons of data on humans and on animals are made when possible. Comparative information on the relationship between exposure and the dose that reaches the target site may be of particular importance for extrapolation between species. Data are given on acute and chronic toxic effects (other than cancer), such as organ toxicity, increased cell proliferation, immunotoxicity and endocrine effects. The presence and toxicological significance of cellular receptors is described. Effects on reproduction, teratogenicity, fetotoxicity and embryotoxicity are also summarized briefly. Tests of genetic and related effects are described in view of the relevance of gene mutation and chromosomal damage to carcinogenesis (Vainio et al., 1992; McGregor et al., 1999). The adequacy of the reporting of sample characterization is considered and, where necessary, commented upon; with regard to complex mixtures, such comments are similar to those described for animal carcinogenicity tests on p. 18. The available data are interpreted critically by phylogenetic group according to the end-points detected, which may include DNA damage, gene mutation, sister chromatid exchange, micronucleus formation, chromosomal aberrations, aneuploidy and cell transformation. The concentrations employed are given, and mention is made of whether use of an exogenous metabolic system in vitro affected the test result. These data are given as listings of test systems, data and references. The Genetic and Related Effects data presented in the Monographs are also available in the form of Graphic Activity Profiles (GAP) prepared in collaboration with the United States Environmental Protection Agency (EPA) (see also Waters et al., 1987) using software for personal computers that are Microsoft Windows® compatible. The EPA/IARC GAP software and database may be downloaded free of charge from www.epa.gov/gapdb. Positive results in tests using prokaryotes, lower eukaryotes, plants, insects and cultured mammalian cells suggest that genetic and related effects could occur in mammals. Results from such tests may also give information about the types of genetic effect produced and about the involvement of metabolic activation. Some end-points described are clearly genetic in nature (e.g., gene mutations and chromosomal aberrations), while others are to a greater or lesser degree associated with genetic effects (e.g. unscheduled DNA synthesis). In-vitro tests for tumour-promoting activity and for cell transformation may be sensitive to changes that are not necessarily the result of genetic alterations but that may have specific relevance to the process of carcinogenesis. A critical appraisal of these tests has been published (Montesano et al., 1986). Genetic or other activity manifest in experimental mammals and humans is regarded as being of greater relevance than that in other organisms. The demonstration that an agent or mixture can induce gene and chromosomal mutations in whole mammals indicates that it may have carcinogenic activity, although this activity may not be detectably expressed in any or all species. Relative potency in tests for mutagenicity and related effects is not a reliable indicator of carcinogenic potency. Negative results in tests for mutagenicity in selected tissues from animals treated in vivo provide less weight, partly because they do not exclude the possibility of an effect in tissues other than those examined. Moreover, negative results in short-term tests with genetic end-points cannot be considered to provide evidence to rule out carcinogenicity of agents or mixtures that act through other mechanisms (e.g. receptor-mediated effects, cellular toxicity with regenerative proliferation, peroxisome proliferation) (Vainio et al., 1992). Factors that may lead to misleading results in short-term tests have been discussed in detail elsewhere (Montesano et al., 1986). When available, data relevant to mechanisms of carcinogenesis that do not involve structural changes at the level of the gene are also described. The adequacy of epidemiological studies of reproductive outcome and genetic and related effects in humans is evaluated by the same criteria as are applied to epidemiological studies of cancer. Structure–activity relationships that may be relevant to an evaluation of the carcinogenicity of an agent are also described. For biological agents—viruses, bacteria and parasites—other data relevant to carcinogenicity include descriptions of the pathology of infection, molecular biology (integration and expression of viruses, and any genetic alterations seen in human tumours) and other observations, which might include cellular and tissue responses to infection, immune response and the presence of tumour markers.

11. SUMMARY OF DATA REPORTED

 * In this section, the relevant epidemiological and experimental data are summarized.
 * Only reports, other than in abstract form, that meet the criteria outlined on p. 11 are considered for evaluating carcinogenicity.
 * Inadequate studies are generally not summarized:such studies are usually identified by a square-bracketed comment in the preceding text.

(a) Exposure

 * Human exposure to chemicals and complex mixtures is summarized on the basis of elements such as production, use, occurrence in the environment and determinations in human tissues and body fluids.
 * Quantitative data are given when available.
 * Exposure to biological agents is described in terms of transmission and prevalence of infection.

(b) Carcinogenicity in humans

 * Results of epidemiological studies that are considered to be pertinent to an assessment of human carcinogenicity are summarized.
 * When relevant, case reports and correlation studies are also summarized.

(c) Carcinogenicity in experimental animals

 * Data relevant to an evaluation of carcinogenicity in animals are summarized.
 * For each animal species and route of administration, it is stated whether an increased incidence of neoplasms or preneoplastic lesions was observed, and the tumour sites are indicated.
 * If the agent or mixture produced tumours after prenatal exposure or in singledose experiments, this is also indicated. Negative findings are also summarized.
 * Dose–response and other quantitative data may be given when available.

(d) Other data relevant to an evaluation of carcinogenicity and its mechanisms

 * Data on biological effects in humans that are of particular relevance are summarized.
 * These may include toxicological, kinetic and metabolic considerations and evidence of DNA binding, persistence of DNA lesions or genetic damage in exposed humans.
 * Toxicological information, such as that on cytotoxicity and regeneration, receptor binding and hormonal and immunological effects, and data on kinetics and metabolism in experimental animals are given when considered relevant to the possible mechanism of the carcinogenic action of the agent.
 * The results of tests for genetic and related effects are summarized for whole mammals, cultured mammalian cells and nonmammalian systems.
 * When available, comparisons of such data for humans and for animals, and particularly animals that have developed cancer, are described.
 * Structure–activity relationships are mentioned when relevant.
 * For the agent, mixture or exposure circumstance being evaluated, the available data on end-points or other phenomena relevant to mechanisms of carcinogenesis from studies in humans, experimental animals and tissue and cell test systems are summarized within one or more of the following descriptive dimensions:
 * (i) Evidence of genotoxicity (structural changes at the level of the gene): for example, structure–activity considerations, adduct formation, mutagenicity (effect on specific genes), chromosomal mutation/aneuploidy
 * (ii) Evidence of effects on the expression of relevant genes (functional changes at the intracellular level): for example, alterations to the structure or quantity of the product of a proto-oncogene or tumour-suppressor gene, alterations to metabolic activation/inactivation/ DNA repair
 * (iii) Evidence of relevant effects on cell behaviour (morphological or behavioural changes at the cellular or tissue level): for example, induction of mitogenesis, compensatory cell proliferation, preneoplasia and hyperplasia, survival of premalignant or malignant cells (immortalization, immunosuppression), effects on metastatic potential
 * (iv) Evidence from dose and time relationships of carcinogenic effects and interactions between agents: for example, early/late stage, as inferred from epidemiological studies; initiation/promotion/progression/malignant conversion, as defined in animal carcinogenicity experiments; toxicokinetics
 * These dimensions are not mutually exclusive, and an agent may fall within more than one of them. Thus, for example, the action of an agent on the expression of relevant genes could be summarized under both the first and second dimensions, even if it were known with reasonable certainty that those effects resulted from genotoxicity.

12. EVALUATION

 * Evaluations of the strength of the evidence for carcinogenicity arising from human and experimental animal data are made, using standard terms.
 * It is recognized that the criteria for these evaluations, described below, cannot encompass all of the factors that may be relevant to an evaluation of carcinogenicity.
 * In considering all of the relevant scientific data, the Working Group may assign the agent, mixture or exposure circumstance to a higher or lower category than a strict interpretation of these criteria would indicate.

(a) Degrees of evidence for carcinogenicity in humans and in experimental animals and supporting evidence

 * These categories refer only to the strength of the evidence that an exposure is carcinogenic and not to the extent of its carcinogenic activity (potency) nor to the mechanismsinvolved.
 * A classification may change as new information becomes available.
 * An evaluation of degree of evidence, whether for a single agent or a mixture, is limited to the materials tested, as defined physically, chemically or biologically.
 * When the agents evaluated are considered by the Working Group to be sufficiently closely related, they may be grouped together for the purpose of a single evaluation of degree of evidence.

(i) Carcinogenicity in humans
be ruled out with reasonable confidence.
 * The applicability of an evaluation of the carcinogenicity of a mixture, process, occupation or industry on the basis of evidence from epidemiological studies depends on the variability over time and place of the mixtures, processes, occupations and industries.
 * The Working Group seeks to identify the specific exposure, process or activity which is considered most likely to be responsible for any excess risk.
 * The evaluation is focused as narrowly as the available data on exposure and other aspects permit.
 * The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:
 * Sufficient evidence of carcinogenicity: The Working Group considers that a causal relationship has been established between exposure to the agent, mixture or exposure circumstance and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could
 * Limited evidence of carcinogenicity: A positive association has been observed between exposure to the agent, mixture or exposure circumstance and cancer for which a causal interpretation is considered by the Working Group to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.
 * Inadequate evidence of carcinogenicity: The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association between exposure and cancer, or no data on cancer in humans are available.
 * Evidence suggesting lack of carcinogenicity: There are several adequate studies covering the full range of levels of exposure that human beings are known to encounter, which are mutually consistent in not showing a positive association between exposure to the agent, mixture or exposure circumstance and any studied cancer at any observed level of exposure.
 * A conclusion of ‘evidence suggesting lack of carcinogenicity’ is inevitably limited to the cancer sites, conditions and levels of exposure and length of observation covered by the available studies. In addition, the possibility of a very small risk at the levels of exposure studied can never be excluded.
 * In some instances, the above categories may be used to classify the degree of evidence related to carcinogenicity in specific organs or tissues.

(ii) Carcinogenicity in experimental animals
Sufficient evidence of carcinogenicity: The Working Group considers that a causal relationship has been established between the agent or mixture and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) in two or more independent studies in one species carried out at different times or in different laboratories or under different protocols.
 * The evidence relevant to carcinogenicity in experimental animals is classified into one of the following categories:
 * Exceptionally, a single study in one species might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset.
 * Limited evidence of carcinogenicity: The data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. (a) the evidence of carcinogenicity is restricted to a single experiment; or (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the study; or (c) the agent or mixture increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential, or of certain neoplasms which may occur spontaneously in high incidences in certain strains.
 * Inadequate evidence of carcinogenicity: The studies cannot be interpreted as showing either the presence or absence of a carcinogenic effect because of major qualitative or quantitative limitations, or no data on cancer in experimental animals are available.
 * Evidence suggesting lack of carcinogenicity: Adequate studies involving at least two species are available which show that, within the limits of the tests used, the agent or mixture is not carcinogenic. A conclusion of evidence suggesting lack of carcinogenicity is inevitably limited to the species, tumour sites and levels of exposure studied.

(b) Other data relevant to the evaluation of carcinogenicity and its mechanisms
in exposed humans that are on the causal pathway to carcinogenesis.
 * Other evidence judged to be relevant to an evaluation of carcinogenicity and of sufficient importance to affect the overall evaluation is then described. This may include data on preneoplastic lesions, tumour pathology, genetic and related effects, structure–activity relationships, metabolism and pharmacokinetics, physicochemical parameters and analogous biological agents.
 * Data relevant to mechanisms of the carcinogenic action are also evaluated.
 * The strength of the evidence that any carcinogenic effect observed is due to a particular mechanism is assessed, using terms such as weak, moderate or strong.
 * Then, the Working Group assesses if that particular mechanism is likely to be operative in humans.
 * The strongest indications that a particular mechanism operates in humans come from data on humans or biological specimens obtained from exposed humans.
 * The data may be considered to be especially relevant if they show that the agent in question has caused changes
 * Such data may, however, never become available, because it is at least conceivable that certain compounds may be kept from human use solely on the basis of evidence of their toxicity and/or carcinogenicity in experimental systems.
 * For complex exposures, including occupational and industrial exposures, the chemical composition and the potential contribution of carcinogens known to be present are considered by the Working Group in its overall evaluation of human carcinogenicity.
 * The Working Group also determines the extent to which the materials tested in experimental systems are related to those to which humans are exposed.

(c) Overall evaluation
this conclusion is added to the evaluation narrative; an additional evaluation may be made for this broader group of compounds if the strength of the evidence warrants it.
 * Finally, the body of evidence is considered as a whole, in order to reach an overall evaluation of the carcinogenicity to humans of an agent, mixture or circumstance of exposure.
 * An evaluation may be made for a group of chemical compounds that have been evaluated by the Working Group. In addition, when supporting data indicate that other, related compounds for which there is no direct evidence of capacity to induce cancer in humans or in animals may also be carcinogenic, a statement describing the rationale for
 * The agent, mixture or exposure circumstance is described according to the wording of one of the following categories, and the designated group is given. The categorization of an agent, mixture or exposure circumstance is a matter of scientific judgement, reflecting the strength of the evidence derived from studies in humans and in experimental animals and from other relevant data.

Group 1 —The agent (mixture) is carcinogenic to humans.
The exposure circumstance entails exposures that are carcinogenic to humans. This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

Group 2
This category includes agents, mixtures and exposure circumstances for which, at one extreme, the degree of evidence of carcinogenicity in humans is almost sufficient, as well as those for which, at the other extreme, there are no human data but for which there is evidence of carcinogenicity in experimental animals. Agents, mixtures and exposure circumstances are assigned to either group 2A (probably carcinogenic to humans) or group 2B (possibly carcinogenic to humans) on the basis of epidemiological and experimental evidence of carcinogenicity and other relevant data.

Group 2A—The agent (mixture) is probably carcinogenic to humans.
also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.
 * The exposure circumstance entails exposures that are probably carcinogenic to humans.
 * This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of animals and strong evidence that the carcinogenesis is mediated by a mechanism that

Group 2B—The agent (mixture) is possibly carcinogenic to humans.
in experimental animals.
 * The exposure circumstance entails exposures that are possibly carcinogenic to humans.
 * This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity
 * In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.

Group 3—The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans.

 * This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals.
 * Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans.
 * Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

Group 4—The agent (mixture) is probably not carcinogenic to humans.
strongly supported by a broad range of other relevant data, may be classified in this group.
 * This category is used for agents or mixtures for which there is evidence suggesting lack of carcinogenicity in humans and in experimental animals. In some instances, agents or mixtures for which there is inadequate evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity in experimental animals, consistently and