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 ad-hoc 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

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 given. 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 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. 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 countries as indications of potential exposures, but they may not reflect the most recent situation, since such limits are continuously reviewed and modified. 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.

8. Studies of Cancer in Humans

9. Studies of Cancer in Experimental Animals

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.

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 http://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.

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.

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