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Health Risks from Exposure to Low Levels of Ionizing Radiation: Beir VII Phase 2
most survivors who were young (under age 20) at the time of the bombings are still alive, and thus their risks at older ages, when baseline risks are greatest, have not yet been studied. This is also true of other exposed cohorts. For leukemia, risks in A-bomb survivors had dropped to negligible levels by the end of the follow-up period (Preston and others 1994; Pierce and others 1996). However, estimating lifetime risks of solid cancer for those who are young at exposure requires assumptions about the time-response patterns of disease. Approaches that have been used in past risk assessments include a multiplicative projection based on the assumption that the excess cancer rate increases in direct proportion to the baseline cancer rate and an additive projection based on the assumption that the excess rate is constant and independent of the background rate. Currently available data on A-bomb survivors and other cohorts make it clear that the additive projection method is not appropriate, and this method has not been used in recent years.
From a biological standpoint, a multiplicative projection of risk implies a mechanism whereby all host and environmental factors that modify the background cancer rate have an equivalent impact on radiation-induced disease. This would be the case if radiation were to act predominantly on an early stage in multistage tumorigenesis (i.e., as a tumor initiator). By contrast, additive projection of risk would apply if radiation acted independently as one of many cancer-modifying factors during postinitiation cellular development (e.g., as a tumor promoter). Cytogenetic and molecular studies on tumorigenic mechanisms in experimental animals (Chapter 3) suggest that acute doses of low-LET radiation act predominantly to initiate tumorigenesis rather than to promote its development. Thus, the monoclonal tumorigenic mechanism of initiation proposed for low-LET radiation is also most consistent with a multiplicative projection of cancer risk. In addition, epidemiologic studies of Japanese A-bomb survivors and of persons exposed for medical reasons indicate that exposure early in life results in greater risks than exposure later in life, which also argues against strong tumor-promoting activity and favors an initiation role.
Although multiplicative risk projection is clearly better supported than additive risk projection, current epidemiologic data indicate that relative risks may decrease with increasing attained age or time since exposure, especially for those who were young at exposure (Thompson and others 1994; Little and others 1998; Preston and others 2002b). Thus, it may not be appropriate to use the multiplicative projection method without modification. Risk assessments conducted by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR 2000), the National Institutes of Health (NIH 2003), and this committee have allowed for a decline in relative risk with attained age (see Chapter 12). Because experimental animal data seldom include detailed information on age-specific baseline and radiation-associated cancer, these data do not inform us about a decline in the relative risk with time since exposure or attained age.
Finally, because follow-up is now reasonably complete for all but the youngest A-bomb survivors, there is less uncertainty in projecting risks forward in time than in past risk assessments.
THE TRANSPORT OF CANCER RISK BETWEEN DIFFERENT POPULATIONS
Another important issue in risk assessment is applying risks estimated from studying a particular exposed population to another population that may have different genetic and life-style characteristics and different baseline cancer risks. Specifically, the application of risk estimates developed from Japanese atomic bomb survivors to a U.S. population is a concern. Two approaches that have been used are multiplicative or relative risk transport, in which it is assumed that the risks resulting from radiation exposure are proportional to baseline risks, and additive or absolute risk transport, in which it is assumed that radiation risks (on an absolute scale) do not depend on baseline risk and thus are the same for the United States and Japan. Estimates based on relative and absolute risk transport can differ substantially. For example, baseline risks for stomach cancer are much higher in Japan than in the United States, and for this reason, estimates of stomach cancer risks from radiation exposure from a recent report based on absolute risk transport are nearly an order of magnitude higher than those based on relative risk transport (UNSCEAR 2000).
In general, if the factors that account for the difference in baseline risks act multiplicatively with radiation, then relative risk transport would be appropriate, whereas if they act additively, then absolute risk transport would be appropriate. If some factors act multiplicatively and others additively, the correct estimate might be intermediate to those obtained with the relative or absolute transport models. Whether a factor acts multiplicatively or additively with radiation will depend on whether radiation and the factor of interest act principally as initiators of cancer or act at later stages in multistage cancer development as discussed below.
Two approaches based on epidemiologic data can inform us regarding the most appropriate transport method. The first is to compare risk estimates based on A-bomb survivors with those obtained from studies of non-Japanese populations, particularly predominantly Caucasian populations. If estimates of the excess relative risk (ERR)1 per sievert are comparable, this suggests that relative risk transport may be appropriate, whereas if estimates of the excess
ERR is the rate of disease in an exposed population divided by the rate of disease in an unexposed population minus 1.0.