Epidemiological Methodology

28 May

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.

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 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.

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