disorder (Inskip and others 1990a) is higher and closer to that for LSS women. The most striking discrepancies are for stomach cancer in ankylosing spondylitis patients (Weiss and others 1994) and lung cancer in tuberculosis fluoroscopy patients (Howe 1995). In both cases, there is little evidence of risk in the medically exposed cohorts and estimates appear incompatible with those based on the LSS cohort. The stomach cancer discrepancy is especially striking if one considers that the baseline risk is much higher in the LSS cohort. Howe found no evidence of bias from several potential sources that were investigated in the fluoroscopy study and attributed this finding to the fractionated nature of the exposure. Nevertheless, modification of radiation-induced risk by the presence of lung disease (tuberculosis) in this cohort seems a reasonable and perhaps likely possibility.

Little (2001) has also made relevant comparisons. He compared estimates of the ERR/Gy from 65 studies of persons treated with radiation therapy for benign and malignant disease with estimates from LSS incidence (Thompson and others 1994) and mortality data (Pierce and others 1996). Little (2001) expanded on an earlier study by Little and colleagues (1999b). To address differences in ages at exposure and length of follow-up, Little derived estimates using only the portion of the LSS cohort corresponding to the age and follow-up period for each of the individual studies evaluated. A total of 116 cancer site-specific estimates were derived, including estimates for cancers of the salivary glands, esophagus, stomach, colon, rectum, liver, pancreas, larynx, lung, bone, nonmelanoma skin cancer, female breast, uterus, and ovary.

Little found that estimates of the ERR/Gy based on the medical studies were generally lower than those based on the LSS, although in most cases the differences were not statistically significant. He also found that the ratio of the medical and LSS results decreased with increasing dose and concluded that cell sterilization largely accounts for the discrepancy between estimates based on the LSS and the medical studies. Dose fractionation and differences in baseline risks were noted as additional contributing factors. The data used by Little included cancer cases through 1987 and cancer deaths through 1990, in contrast to 1995 for incidence data and 1998 for mortality data used by the BEIR VII committee. Also, using only subsets of the LSS data may result in less stable estimates than modeling age at exposure and time since exposure or attained age.

In addition to the overall level of risk, medical studies can potentially inform us regarding patterns of risk by sex, age at exposure, and time since exposure. However, many of the relevant studies (such as those included in Table 12-11) were primarily single-sex studies involving exposure in adulthood, thus providing little information on the modifying effects of these factors. Several studies have confirmed the persistence of excess risk 30 or more years after exposure. The study of ankylosing spondylitis patients (Weiss and others 1994) is noteworthy in that there is no evidence of excess lung cancer risk 25 years or more after exposure. Other cancers in this cohort also exhibited a decline in risk with time since exposure, although there was still evidence of risk at a reduced level after 25 years. Little and colleagues (1998) used data on cancer incidence in the LSS cohort and in five studies of patients exposed for medical reasons in childhood to investigate the pattern of risk with time since exposure. They found no evidence of heterogeneity in the magnitude of the decrease in relative risk with time since exposure.

Leukemia

Little (2001) found particularly striking differences between LSS-based estimates of the ERR/Gy for leukemia and those based on medically exposed persons. In all 17 studies evaluated, the estimated ERR/Gy was lower than that based on a comparable subset of the LSS, and for many of the studies, the differences were statistically significant. He also found that the ratio of the LSS and medical study estimates showed a strong decrease with increasing dose. Little conducted additional analyses that took account of curvature in the dose-response, cell sterilization, and fractionation of dose. When these variables were accounted for, the differences in the LSS and medical study estimates largely disappeared. Little concluded that cell sterilization is the primary reason for differences in estimates of the ERR/Gy that do not account for this factor.

In an earlier paper, Little and colleagues (1999c) evaluated patterns in the ERR/Gy for leukemia with age at exposure, time since exposure, and attained age in the LSS cohort, women treated for cervical cancer, and patients treated for ankylosing spondylitis. They found that patterns varied by leukemia subtype. Preston (1995) also found evidence of heterogeneity among subtypes based on LSS leukemia incidence data alone, although these analyses were based on the EAR rather than the ERR. Within each type of leukemia, Little and colleagues found no indication that patterns varied among the three cohorts. However, analyses treating all non-CLL leukemia as a single category showed patterns that were cohort dependent. A limitation of these analyses was that interactions of age at exposure with time since exposure or attained age were not investigated, whereas analyses by Preston (1995; Preston and others 2003) and by the BEIR VII committee of the LSS data indicate a need to include such interactions. There also was no evaluation of the comparability of the EAR among studies and subtypes of leukemia.

The committee’s leukemia models are based on combined analyses of all types of leukemia within the LSS cohort. This was done both to yield more stable risk estimates and because updated leukemia incidence data (which would allow distinctions by subtype) were not available. It is acknowledged that subtype-specific models might have advantages, particularly if the relative frequencies of leukemia subtypes differed for the LSS cohort and the general U.S. population.



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