Epidemiology has been defined as the study of the distribution and determinants of health and disease (Stewart and Sarfaty, 1978). Epidemiological methods seek to infer from observation rather than experimentation. Epidemiological observations may take a number of forms (cf. Rogan and Brown, l979). Already in Chapter 1 one of the principal techniques of epidemiology was discussed—that of surveys resulting in statistical findings of the incidence, morbidity, and mortality of disease. In addition to such studies, the following are some of the general means of obtaining epidemiological data:
1. Episodic observations. The observation of isolated cases of cancer in relation to a spe- cific environmental factor has yielded clues in the past to cause-and-effect relation- ships. However, deductions must be carefully evaluated in properly designed studies.
2. Retrospective studies. Investigations of the histories, habits, and other characteristics of groups of individuals who have developed a disease have been frequent sources of epidemiological data. This type of study is usually the first step in attempting to iden- tify causative factors. An important factor in such investigations is the use of case controls, and in many instances the suitable designation of such controls is the critical component in the study. Controls in case-control studies should be as similar as possi- ble in every way to the case population, differing only in the presence of the disease or condition in the cases. A study design of such a retrospective study is noted in Table 11.1. In case-control studies, a number of patients with the disease under study (cases) are investigated in relation to another variable such as exposure to a chemical or dietary component. As noted in the table, one may readily determine the propor- tions of cases in controls that are exposed to the material. The calculation of the odds ratio, which is basically a cross-product ratio, may be related, sometimes very closely, to another parameter termed the relative risk, the risk in the exposed group/risk in the unexposed group (Rogan and Brown, 1979). An odds ratio that is close to one implies
aDesign of a retrospective (case-control) epidemiological study. The cases and controls, selected as shown, differ only in the presence or absence of the disease in question. This study attempts to relate expo- sure to a specific agent to the presence or absence of the disease. From these data as shown, one may calculate an odds ratio, which is impor- tant in determining both causation and risk.
Adapted from Goldberg, 1983, with permission of the author and publisher.
that there is no association between the chemical or component of interest and the disease being studied. An odds ratio less than one suggests a negative association be- tween the two parameters, while an odds ratio greater than one implies a positive as- sociation. Increasing odds ratios connote an increase in exposure-related risk of having the disease (Goldberg, 1983). However, retrospective studies have a number of problems, such as the ability of the subject to recall previous environmental expo- sures, selection bias, and survivor bias (Lilienfeld, 1983).
3. Prospective studies. Prospective investigations involve analyses of the development of cancers in individuals with specific social habits, occupational exposures, etc. Such investigations require large populations, long follow-up periods (usually several years), and high follow-up rates for both controls and test groups. Many such investi- gations are presently under way in the United States and throughout the world.
Any one or all of these types of studies may be concerned with a single or with multiple factors involved in the causation of specific human cancers. Factors that lead to cancer or affect its development in humans are probably multifactorial in the vast majority of instances. Such factors include chemicals, radiations, genetic background, and biological agents and may be ad- ditive, synergistic, or antagonistic. Several agents may act at the same stage (that is, initiation or promotion) or at different stages.
Epidemiological studies can only identify factors that are different between two popula- tions and that are sufficiently important in the etiology of the condition under study to play a determining role under the conditions of exposure. Furthermore, on the basis of epidemiological studies alone, it is usually very difficult to determine whether a specific chemical is or is not carcinogenic to the human. The reasons for this difficulty are the extended periods between first exposure and clinical occurrence of the neoplasm, the high background incidence for many can- cers in the general population, the relatively imprecise knowledge of the nature of the exposure in most instances, exposures to multiple agents, and other confounding variables. Thus, many negative epidemiological studies must be considered as inconclusive for indicating the risk fac-tor of relatively weak carcinogens or of low doses of carcinogens for inducing neoplastic disease in the human population.
In view of the fact that epidemiological studies in themselves are often insufficient to es- tablish the carcinogenicity of an agent for humans, laboratory studies have been employed to complement or in some cases to supplant epidemiological observations where they exist. Many recent epidemiological investigations employ studies of biological markers such as DNA ad- ducts, mutations in tumor suppressor genes and cellular oncogenes, genotypes for specific genes, and a variety of metabolites, proteins, and histopathological indications of preneoplasia as intermediate end points in a variety of studies (Perera, 1996). These and other methodologies are considered in Chapter 13, but at this point the discussion is restricted to a consideration of epidemiological data in determining the carcinogenicity of agents for humans. One of the pio- neer agencies in the assessment of the carcinogenic risk of chemicals for humans has been the International Agency for Research on Cancer (IARC). In the recent preambles to monographs on the evaluation of carcinogenic risks to humans, IARC has defined the overall evaluation of the carcinogenicity to humans of an agent, mixture, or circumstance of exposure in the following manner (IARC Monographs, 1996):
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 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.
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 carcino- genicity in experimental animals. Agents, mixtures, and exposure circumstances are assigned to either group 2A (probably carcinogenic to humans) or group 2B (possibly carcinogenic to hu- mans) on the basis of epidemiological and experimental evidence of carcinogenicity and other relevant data.
Group 2A—The agent (mixture) is probably carcinogenic to 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 carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals as well as strong evidence that the carcinogenesis is mediated by a mechanism that 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.
Group 2B—The agent (mixture) is possibly carcinogenic to humans. 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 experimental animals. 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, to- gether 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 carcinoge- nicity 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 ex- perimental 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.
This category is used for agents or mixtures for which there is evidence suggesting lack of carci- nogenicity 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 strongly supported by a broad range of other relevant data, may be classified in this group.
Despite the limitations of epidemiological studies in determining etiological factors for human cancer, under most circumstances an agent cannot be classified as carcinogenic for hu- mans unless significant epidemiological evidence for its carcinogenic action in humans is avail- able. From such evidence, a number of agents—chemical, physical, and biological—have been shown to be carcinogenic in humans. A recent detailed listing of such chemical carcinogens in the human has been presented by the National Toxicology Program of the U.S. government (Re- port on Carcinogens, 1998). The remainder of this chapter considers the majority of such agents classified as carcinogenic for the human at the present time.