regarded by the sponsor as proprietary information, i.e., trade secrets, that may never be published in a scientific journal. The database for evaluation of new chemicals as possible carcinogens may therefore be much more limited, and previous scientific peer review much less vigorous, than for environmental agents that have been studied more widely.
Agencies that have responsibilities for carcinogenic hazard identifica-tion exist in several internaidentifica-tional organizaidentifica-tions, including the Commission of the European Union and the World Health Organization (WHO). Such agencies also exist in many individual countries, at the national level and sometimes also within the governments of constituent geopolitical units, such as individual states of the United states of America (e.g., California).
Generally, all such agencies work from the same basic kinds of data, but they differ fundamentally in whether they evaluate:
Agents and exposures that already exist in the human environment or
Novel substances proposed for introduction into that environment.
Within the WHO, an internationally recognized carcinogen identification program is conducted by the International Agency for Research on Cancer (IARC). The IARC Monographs on the Evaluation of Carcinogenic Risks to Humans is an international, interdisciplinary approach to carcinogenic hazard identification. Monographs evaluations are assessments of the strength of the published scientific evidence for the existence of an environ-mental carcinogenic hazard to humans, but they are qualitative rather than quantitative in nature and do not address issues of relative carcinogenic potency. Also, the Monographs are confined to published scientific data, and therefore do not evaluate novel agents about which only proprietary data exist. The Monographs are published as a basis for cancer prevention initiatives, which are not limited to regulation. The IARC is not a regulatory agency, and the Monographs explicitly avoid any recommendation regarding regulation or legislation. The Monographs are widely consulted by regula-tory agencies worldwide, however, and the series can serve as a model for how regulatory agencies determine what is a carcinogen, and how different kinds of data are used to make carcinogenic hazard identifications. The criteria applied, and some examples of overall evaluations based on those criteria, are summarized in the following pages.
2. IARC MONOGRAPHS IDENTIFICATIONS
new data have become available in the scientific literature. Because the nature and the strength of published evidence for carcinogenicity vary greatly from one agent or exposure circumstance to another, in most cases it is not possible to conclude definitively whether a given agent or exposure is either definitely a human carcinogen or is probably not one. Of these 888 agents and exposure circumstances, only 89 are currently classified as defi-nitely carcinogenic to humans. In 1987 a classification system was intro-duced (2) which stratifies agents according to the strength of the total evidence for carcinogenicity to humans. This evidence may include epide-miological studies of cancer risk in humans; bioassays for carcinogenicity in experimental animals; and other relevant data of various kinds that may modify the conclusions that would be drawn on the basis of epidemiol-ogy and=or bioassays alone.
2.1. Epidemiological Studies
Epidemiological Studies to assess the possibly increased risks of cancer in exposed humans are critically reviewed, and the strength of that evi-dence is evaluated according to the criteria listed in Table 1. The IARC Monographs criteria require specific, critical consideration of the possibility that the results of each published study may be affected by chance, bias or confounding.
The strength of an association between an exposure and a disease out-come, and the possible role of chance are estimated by standard statistical methods. These methods commonly report the strength of an association as an odds ratio, relative risk, standardized mortality ratio, or other mea-surement that presents the observed incidence of disease in a study popula-tion relative to that in an unexposed control populapopula-tion. For example,
Table 1 IARC Criteria for Strength of Evidence for Increased Cancer Risk in Exposed Humans
Sufficient—a positive relationship has been established between exposure to the agent and increased risk of cancer in humans, in which chance, bias, and confounding can be ruled out with reasonable confidence.
Limited—a positive relationship has been observed between exposure to the agent and human cancer for which a causal association is credible, but chance, bias, and confounding cannot be ruled out with reasonable confidence.
Inadequate—available studies are of insufficient quality, consistency, or statistical power to permit a conclusion regarding presence or absence of a causal association (or no data are available).
Evidence suggesting lack of carcinogenicity—several adequate studies covering the full range of exposures encountered by humans are mutually consistent in showing no positive association between exposure to the agent and human cancer, at any observed level of exposure.
a ratio of 5.0 indicates that there were five times as many cases of the disease in question among members of the study population as among controls.
Whether this ratio is consistent with simple chance association or not is indi-cated by the calculated confidence interval surrounding the point estimate;
in this hypothetical case, a 95% confidence interval of 2.8–7.7 would strongly support a significant association. On the other hand, a confidence interval of 0.3–15 for the same ratio would indicate that the ratio is not statistically significant and is likely due to chance. Any confidence interval that includes unity indicates lack of statistical significance at the level specified.
In epidemiology, bias refers to ‘‘systematic errors in the way subjects are selected or followed up, or in the way information was obtained from them. Confounding occurs when an estimate of the association between an exposure [e.g., occupational exposure to mineral dusts containing crystalline silica] and an outcome [e.g., lung cancer] is mixed up with the real effect of another exposure [e.g., cigarette smoking] on the same outcome, the two exposures being correlated’’ (3).
In general, the criteria for causality in epidemiological studies are those articulated by Hill (4) (Table 2). A comment is in order, however, on the criterion of biological plausibility. What is considered biologically plausible at any given point in time depends on the state of knowledge at that time.
Observations of increased cancer rates in certain populations have often been made before the cause was understood. A striking example is that of lung
Table 2 Hill Criteria for Causality
Temporal relationship: for an exposure to be the cause of a disease, it has to precede its biological onset.
Biological plausibility: the association is more likely to be causal if it is consistent with other biological knowledge.
Consistency: the association is more likely to be causal if similar results have been found in different populations (however, a lack of consistency does not exclude a causal association).
Strength: the stronger the association—the greater the relative measure of effect—the more likely it is to reflect a true causal association.
Exposure–response relationship: further evidence is provided if increasing levels of exposure are associated with increasing incidence of disease.
Specificity: if a particular exposure increases the risk of a certain disease, but not the risk of other diseases, this provides evidence favoring a cause–effect relationship.
Reversibility: when the removal of a possible cause results in a reduced incidence of the disease, the likelihood that the association is causal is strengthened.
Coherence: the putative cause–effect relationship should not seriously conflict with the natural history and biology of the disease.
Source: From Hill (4), modified by Silva (3).
cancer among hard-rock underground miners in Europe (5), which was a mystery when first described but is now generally attributed to high levels of radon in the atmosphere in poorly ventilated mines. This observation preceded the discovery of radioactivity, and of radon, by more than a decade.
Credible evaluation of chance, bias, and confounding and application of the Hill criteria to establish causality require considerable experience. For further details, a textbook (3) or a treatise (6) on cancer epidemiology should be consulted.
2.2. Bioassay Data for Carcinogenicity in Experimental Animals
Bioassay data for carcinogenicity in experimental animals (generally rats and mice) are similarly evaluated according to the criteria listed in Table 3. For sufficiency of evidence, these criteria emphasize reproducibility of outcomes among studies and malignant tumors, evaluated and confirmed histologically, as experimental findings. As all kinds of tumors do occur naturally in untreated animals, at frequencies that can range from 1% or less (e.g., tumors of the brain or intestine in rats) to 50% or more, careful quan-tification of tumors in treated animals and untreated controls and proper statistical evaluation of the results is essential.
In the absence of adequate data in humans, in general IARC considers that ‘‘it is biologically plausible and prudent to regard agents for which there is sufficient evidence of carcinogenicity in experimental animals as if they
Table 3 IARC Criteria for Strength of Evidence for Carcinogenicity in Experimental Animals
Sufficient—a causal relationship has been established between exposure to the agent and increased incidence of malignant neoplasms, or an appropriate combination of benign and malignant neoplasms, in two or more species or in two or more independent studies in one species, conducted at different times or in different laboratories or under different protocols; exceptionally, a single study in one species may suffice when malignant neoplasms occur to an unusual degree with regard to incidence, site, tumor type, or age at onset.
Limited—data suggest a carcinogenic effect, but consist of a single experiment; or questions regarding adequacy of design, conduct, or interpretation of the studies are unresolved; or the effect is limited to benign tumors or lesions of uncertain neoplastic potential only, or to certain neoplasms that may occur spontaneously in high incidences in certain strains.
Inadequate—the studies cannot be interpreted as showing either presence or absence of a carcinogenic effect because of major qualitative or quantitative limitations; or no data are available.
Evidence suggesting lack of carcinogenicity—adequate studies in at least two species are negative, within the limits of the tests used.
presented a carcinogenic risk to humans.’’ However, not all tumors in experimental animals are considered equally predictive of cancer hazard to humans. Some kinds of tumors occur in such high and variable incidence in the inbred strains of mice and rats that are conventionally used in bioas-says (e.g., Leydig cell tumors of the testis in male Fischer 344 rats, hepatocel-lular tumors in male mice of many inbred strains and their F1hybrids) that when an apparent increase in tumor frequency in treated animals is limited to these kinds of tumors, the evidence for carcinogenicity may be considered suggestive (‘‘limited’’ in the IARC vocabulary) rather than conclusive.
It is now clearly established that tumors can be induced in certain tissues through several distinct mechanisms of carcinogenic action, and that not all these mechanisms operate in all species. Animal carcinogenicity data may not predict carcinogenic risk to humans when tumors are induced in animals by a mechanism of carcinogenicity that does not operate in humans.
This subject is discussed further below, and in the Appendix, and represents another exception to the basic principle that carcinogenicity in experimental animals predicts human cancer risk.
2.3. Other Relevant Data
These are data other than tumor incidence in humans and in experimental animals, and include how a substance is metabolized in experimental animals and in humans, whether the substance and=or its metabolites are genotoxic, manifestations of toxicity other than carcinogenicity, and the mode of action by which the substance acts as a carcinogen.
2.4. Overall Evaluations of Carcinogenicity
Evidence from epidemiological and experimental studies is finally combined with other relevant data to produce an overall qualitative evaluation and classification in one of the five groups defined in Table 4. This table reflects criteria that were introduced in 1992 for use of ‘‘other relevant data’’ in overall evaluations of carcinogenicity (7). Carcinogenic hazard identifica-tions formulated on the basis of bioassay data in rodents can be either strengthened or weakened by additional information on the mode of action of the carcinogen in animals.
As new data are published, agents are re-evaluated. When the strength of the total evidence for carcinogenicity of an agent changes as a result of new data, the classification of the agent may also change. All evaluations, and narrative summaries of the supporting data, are available in the Internet at http:==monographs.iarc.fr.
Some representative examples of IARC Monographs evaluations and classifications at various levels of evidence are presented in the sections that follow. These are intended to illustrate how the IARC criteria have been applied to a variety of substances and exposures, but are necessarily
abbreviated. The serious student of the process of carcinogenic hazard iden-tification will find numerous additional examples in the Monographs data-base at the above website.