stomach appears to be a strong risk factor for stomach cancer, and its effect is likely to be mainly through tumor promotion (although there is increasing evidence that it may also cause tumor initiation; Parsonnet and others 1994; Aromaa and others 1996; Goldstone and others 1996). Environmental risk factors include low consumption of fruit and vegetables; consumption of salted, smoked, or poorly preserved foods; and cigarette smoking (Fuchs and Mayer 1995). The majority of these agents are likely to influence the promotion of tumors.
The above considerations would therefore suggest that for stomach cancer, relative risk transport may be better supported than absolute risk transport. This is also supported by a study of predominantly male peptic ulcer patients, where the estimated ERR/Gy based on patients with doses to the stomach of less than 10 Gy (mean 8.2 Gy) was 0.20 (95% CI 0, 0.73), very similar to that based on male A-bomb survivors (Carr and others 2002; see Table 12-2).
The incidence of liver cancer (mainly hepatocellular carcinoma) is also much higher in Japan than in the United States (IARC 2002). The main risk factors for this disease are chronic infection with hepatitis B or C virus, dietary exposure to aflatoxins, and chronic alcohol consumption (IARC 2003). Tobacco smoking also plays a role in the etiology of liver cancer (IARC 2004).
Aflatoxins induce mutations in several genes involved in hepatocellular carcinoma and are thus likely to be involved in the early or initiating stages of carcinogenesis. Hepatitis B and C infections and alcohol consumption, on the other hand, are likely to be involved in the promotion of tumors. They are thought to increase the risk of liver cancer through inflammation that may result in liver cirrhosis. The latter is the major clinical determinant of hepatocellular carcinoma, with 70–90% of these tumors developing in patients with macronodular cirrhosis (IARC 2003).
Baseline risks for liver cancer are much higher in Japan than in the United States, and rates of infection with hepatitis B and C undoubtedly contribute to this difference. The mechanistic arguments above and the limited epidemiologic data tend to support the use of the multiplicative transportation model.
Lung cancer is the most common cancer worldwide and the major cause of death from cancer, particularly among men (IARC 2003). In the United States, based on SEER (Surveillance, Epidmiology, and End Results) registry data, the annual incidence rates, age-standardized to the world population, were 55.7 and 33.5 per 100,000, respectively, in men and women in 1993–1997. Comparable rates in Hiroshima and Nagasaki during the same period were lower (40–44 per 100,000 in men and 11.8–12.9 per 100,000 in women), particularly among women (IARC 2002).
The major risk factors for lung cancer are tobacco consumption, occupational exposure to a number of carcinogens, and air pollution (Pope and others 2002; IARC 2003). Geographic and temporal differences in lung cancer incidence are determined overwhelmingly by tobacco consumption (IARC 2003).
Tobacco smoke contains approximately 4000 specific chemicals, including nicotine, polycyclic aromatic hydrocarbons, N-nitroso compounds, aromatic amines, benzene, and heavy metals. Lung cancer is not thought to be attributable to any one chemical component, but rather to the effect of a complex mixture of chemicals in tobacco smoke, which may act at different stages of the carcinogenic process. Based on the mechanistic arguments above, this suggests that neither a pure absolute nor a pure relative risk transport model is appropriate.
The estimated ERRs/Gy for lung cancer in several studies involving medical exposures in predominately Caucasian patients are lower than those based on A-bomb survivors (Table 6-3), and this might be interpreted as indicating that absolute risks are more comparable than relative risks. However, the lower ERR estimates may also have resulted from other differences in the study populations, particularly the much higher doses in several of the medical studies.
Pierce and colleagues (2003) evaluated the joint effect of smoking and radiation exposure on lung cancer risks in A-bomb survivors and found that they were significantly submultiplicative and consistent with an additive model. They also demonstrate that inferences about the modifying effects of gender and age at exposure on the ERR/Gy can be distorted if analyses do not account for smoking; this is because smoking habits in the LSS cohort depend strongly on both factors.
By contrast, studies of lung cancer risks in underground miners exposed to radon (NRC 1999) or of Hodgkin’s disease (HD) patients treated with high doses of radiation (Gilbert and others 2003) rejected additive interactions and found that multiplicative interactions were compatible with the data. However, these studies may be less relevant for estimating the risks of low doses of low-LET radiation than those of A-bomb survivors. Underground miners were exposed to α-emitting (high-LET) radon progeny. In addition, the evidence for a multiplicative relation of radiation and smoking comes primarily from analyses of data on miners in Colorado and China, where doses to the lung (in sieverts) were much higher than in the LSS cohort (NRC 1999). Although data on miners were compatible with a multiplicative effect and not with an additive one, the estimated interaction was submultiplicative. HD patients were also exposed to very high doses (mean dose to the lung 25 Gy) and, in addition, were subject to the immunodeficiency