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| EPI6-2: Sources Of Exposure Data (Continued) |
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| EPI6-2: Sources Of Exposure Data (Continued) |
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Strictly speaking, the term exposure refers to the presence of a substance (for example, fine particulate matter) in the external environment, whereas the term dose refers to the amount of substance that reaches susceptible targets within the body, such as the airways. In some situations (for example, in a coal mine) measurements of external exposures may be strongly correlated with internal dose, whereas in other situations (for example, environmental lead exposure) the dose may depend on individual lifestyle and activities and may therefore be only weakly correlated with the environmental exposure levels.
Exposure levels can be assessed with regard to the intensity of the substance in the environment (for example, dust concentration in the air) and the duration of time for which exposure occurs. The risk of developing disease may be much greater if the duration of exposure is long and/or the exposure is intense, and the total cumulative exposure may therefore be important. For protracted etiologic processes, the time-pattern of exposure may be important and it is possible to assess this by examining the separate effects of exposures in various time windows prior to the occurrence and recognition of clinical disease (Pearce, 1992). For example, in cancer studies recent exposures may not be relevant since the cancer may have first become established some years previously (Pearce, 1988). Similarly, recent work suggests that occupational asthma is most likely to occur after about 1-3 years of exposure to a sensitising agent (Antó et al, 1996).
Methods of exposure measurement include personal interviews or self-administered questionnaires (completed either by the study participant or by a proxy respondent), diaries, observation, routine records, physical or chemical measurements on the environment, or physical or chemical measurements on the person (Armstrong et al, 1992). For example, table 5.1 summarizes the types of exposures data most commonly used in occupational epidemiology studies (Checkoway et al, 1989). Measurements on the person can relate either to exogenous exposure (for example, airborne dust) or internal dose (for example, plasma cotinine); the other measurement options (for example, questionnaires) all relate to exogenous exposures.
In most instances, information on demographic factors such as age, gender and ethnicity can be obtained in a straightforward manner from routine health care records or with questionnaires. In studies focusing on ethnicity, the etiologically relevant definition will depend on the extent to which an ethnic difference is considered to be due to genetic and/or cultural and environmental factors, but the available information will vary from country to country depending on historical and cultural considerations. For example, in New Zealand, Maori ethnicity is defined as: "a person who has Maori ethnicity and chooses to identify as Maori" (Pomare et al, 1991), whereas some other countries use solely biologically-based definitions (Polednak, 1989).
Socio-economic status poses more significant measurement problems. It can be measured in a variety of ways, including occupation, income, and education (Liberatos et al, 1988; Berkman and MacIntyre, 1997). These measures may pose problems in some demographic groups; for example, occupation and income may be poor measures of socio-economic status in women, for whom the total family situation may reflect their socio-economic status better than their individual situation, and measures of socio-economic status in children must be based on the situation of the parents or the total family situation. Nevertheless, the various measures of socio-economic status are strongly correlated with each other, and asthma epidemiology studies are usually based on whichever measures are available, unless socio-economic status is the main focus of the research and it is necessary to obtain more detailed information.
Raum et al. (2001) studied the impact of maternal socio-economic status on intrauterine growth in the former West and East Germany. Information on socio-demographic or lifestyle factors and pregnancy outcome was available for 3374 live-born singletons from West Germany (1987/88) and 3070 from East Germany (1990/91). Women were recruited during pregnancy and given a self-administered 30-page questionnaire covering socio-demographic, psychosocial, nutritional, environmental and occupational factors. The two school systems were not identical, but in each system maternal educational level was grouped into five categories. Women with the lowest education had a significantly elevated risk of small-for-gestational-age (SGA) newborns compared to women with the highest education in both the West (OR = 2.58, 95% CI 1.17-5.67) and the East (OR = 2.77, 95% CI 1.54-5.00). The authors concluded that social inequalities existed and caused health inequalities in both the West, and in the former socialist country of East Germany.
Traditionally, exposure to most non-biological risk factors (for example, tobacco smoking) has been measured with questionnaires, and this approach has a long history of successful use in epidemiology (Armstrong et al, 1992). Questionnaires may be self-administered (for example, postal questionnaires) or interviewer-administered (for example, in telephone or face-to-face interviews) and may be completed by the study subject or by a proxy (for example, parental completion of questionnaires in a study of children, or completion by the spouse of deceased cases). The validity of questionnaire data also depends on the structure, format, content and wording of questionnaires, as well as methods of administration and selection and training of interviewers (Armstrong et al, 1992).
Vartia studied the consequences of workplace bullying in the municipal sector in Helsinki, Finland. Every 35th member of the Municipal Officials Union was selected and 1037 (65.5%) responded to a postal questionnaire. A definition of bullying was provided and study participants were asked if they felt themselves subjected to such behaviour, or if they had observed someone else at their workplace being bullied. They were also asked about the frequency and duration of such acts. Both the targets of bullying and the observers reported more general stress and mental stress reactions than did respondents from workplaces with no bullying. The targets of bullying used sleep-inducing drugs and sedatives more often than did the respondents who were not bullied.
In many studies, for example, community-based case-control studies, questionnaires are the only source of exposure information. However, in some instances, particularly in occupational studies, questionnaires may be combined with environmental exposure measurements (for example, industrial hygiene surveys) to obtain a quantitative estimate of individual exposures.
Saracci et al (1984) conducted a historical cohort study of mortality and cancer incidence of workers exposed to made-made vitreous fibres at 13 European plants. At 12 of the plants an environmental survey was conducted to measure present concentrations of fibres in air samples. This was used to create a job-exposure matrix. Within each plant, job/plant areas were grouped into six main occupational categories: not specified, office, preproduction, production, secondary processes and maintenance. For each worker a cumulative exposure index was created by multiplying the time spent in each job category by the mean concentration of respirable fibres in the job category. The relative risk of lung cancer was elevated, particularly in the group with 30 years or more since first employment (RR=1.92, 95% CI 1.17-3.07). There was a tendency for the risk to increase with cumulative exposure, but the pattern was not consistent
In some instances, quantified personal exposure measurements may be available, for example, in radiation workers wearing radiation dosimeters (Checkoway et al, 1989). This information is invaluable when it is available, but it is rarely available for historical exposures with the exception of some industries such as the nuclear power industry. Such information can of course be collected prospectively. This is rarely practical for cohort studies of rare diseases with long latency periods (for example, cancer), but is more appropriate for cohort studies of relatively common conditions. For example, infant cohort studies of respiratory disease frequently prospectively collect information on individual levels of allergen exposure (for example, Lau et al, 2001).
Quantified person exposure measurements can also be used in case-control studies to estimate historical exposures. However, a potential problem in this situation is that exposure may have changed over time, or study participants may change their behaviour as a result of having been diagnosed with disease. This has been a particular issue in case-control studies of electromagnetic field exposure and childhood leukemia where it has been argued that current personal exposure measurements may be inferior to "wire code" information (i.e. whether the wiring to the house is underground, or by overhead wires, etc) in estimating historical exposures (Neutra and del Pizzo, 1996).
Wing et al (1991) conducted a historical cohort mortality study among workers at Oak Ridge National Laboratory, Tennessee. Individual exposures to external penetrating radiation, primarily gamma rays, were measured using pocket ionising chambers from 1943 until June 1944, film badges from then until 1975, and thermoluminescent dosimeters since 1975. This information used to estimate individual exposures over time. After accounting for age, birth cohort, socio-economic status, and active worker status, external radiation with a 20-year exposure lag (that is, exposures were only considered up until 20 years previously) was associated with an increased risk of death (2.68% increase per 10 mSv cumulative exposure), particularly from cancer (4.94% increase per 10 mSv).
More recently, there has been increasing emphasis on the use of molecular markers of internal dose (Schulte, 1993). In fact, there are a number of major limitations of currently available biomarkers of exposure (Armstrong et al, 1992), particularly with regard to historical exposures (Pearce et al, 1995). For example, serum levels of micronutrients reflect recent rather than historical dietary intake (Willett, 1990). Some biomarkers are better than others in this respect (particularly markers of exposure to biological agents), but even the best markers of chemical exposures usually reflect only the last few weeks or months of exposure. On the other hand, with some biomarkers it may be possible to estimate historical levels provided that certain assumptions are met. For example, it may be possible to estimate historical levels of exposure to pesticides (or contaminants) from current serum levels provided that the exposure period is known, and the half-life is known. Similarly, information on recent exposures can be used if it is reasonable to assume that exposure levels (or at least relative exposure levels) have remained stable over time (this may be particularly relevant in occupational studies), and have not been affected by lifestyle changes, or by the occurrence of the disease. However, if the aim is to measure historical exposures, then historical information on exposure surrogates may be more valid than direct measurements of current exposure or dose levels. This situation has long been recognised in occupational epidemiology, where the use of work history records in combination with a job-exposure matrix (based on historical exposure measurements of work areas rather than individuals) is usually considered to be more valid than current exposure measurements (whether based on environmental measurements or biomarkers) if the aim is to estimate historical exposure levels (Checkoway et al, 1989). On the other hand, some biomarkers have potential value in validation of questionnaires which can then be used to estimate historical exposures. Furthermore, biomarkers of internal dose may have relatively good validity in studies involving an acute effect of exposure.
A more fundamental problem of measuring internal dose with a biomarker is that it is not always clear whether one is measuring the exposure, the biological effect, or some stage of the disease process itself (Saracci, 1984). Thus the findings may be uninterpretable in terms of the causal association between exposure and disease. When it is known that the "biologically effective dose" is the most appropriate measure, then the use of appropriate biomarkers clearly has some scientific advantages. However, choosing the appropriate biomarker is a major dilemma, and biomarkers are frequently chosen on the basis of an incomplete or erroneous understanding of the etiologic process (or simply because a particular marker can be measured). An environmental exposure (for example, tobacco smoke) may involve hundreds of different chemicals, each of which may produce hundreds of measurable biological responses (there are exceptions to this, of course, such as environmental lead exposure, but most environmental exposure involves complex mixtures). A biomarker typically measures one of the biological responses to one of the chemicals. If the chosen biomarker measures the key etiological factor, then it may yield relatively good exposure data; however, if a biomarker is chosen which has little relationship to the etiological component of the complex exposure mixture then the biomarker will yield relatively poor exposure data.
A further major problem with the use of biomarkers is that the resulting expense and complexity may drastically reduce the study size, even in a case-control study, and therefore greatly reduce the statistical power for detecting an association between exposure and disease.
Ross et al (1992) studied urinary aflatoxin biomarkers and risk of hepatocellular carcinoma as part of an ongoing prospective study of 18,244 middle-aged men in Shanghai. After 35,299 person-years of follow-up, a nested case-control study was conducted based on the 22 identified cases of liver cancer, and 140 density-matched controls (matched for age and neighbourhood or residence). The cases of liver cancer were more likely than controls to have detectable concentrations of aflatoxin metabolites (OR = 2.4, 95% CI 1.0-5.9).
Thus, questionnaires and environmental measurements will continue to play a major role in exposure assessment in epidemiology, but biomarkers may be expected to become increasingly useful over time, as new techniques are developed. The emphasis should be on using "appropriate technology" to obtain the most practical and valid estimate of the etiologically relevant exposure. The appropriate approach (questionnaires, environmental measurements or biological measurements) will vary from study to study, and from exposure to exposure within the same study, or within the same complex chemical mixture (for example, in tobacco smoke).
