The reduction in statistical significance with adjustment for HBV and HCV infection status might be due to loss of power when further parameters for the risks of HCC for hepatitis virus infection are estimated or the number of subjects is reduced by exclusion. As with the results reported previously,1 there is evidence that alcohol consumption

of ≥40 g/day ethanol and BMI >25.0 kg/m2 10 years before diagnosis are associated with non-B, non-C HCC risk (Table 4). However, the evidence is not Lumacaftor cell line as strong given the small amount of data after excluding persons infected with HBV and HCV. The current study demonstrates that smoking is significantly associated with non-B, non-C HCC risk, although lack of continuous data precluded estimation of the relationship to amount smoked. This finding is consistent with recent assessments by the International Agency for Research

on Cancer (IARC) where HCC has been positioned as a smoking-related malignant disease.39 Some studies have shown effects of smoking on risk of HCC, but few studies have incorporated, in a strict and in-depth manner, HBV and HCV infections.11, 40 Cohort studies of atomic bomb survivors13-16 and Mayak nuclear facility workers22-24 have indicated beyond a doubt that radiation increases liver cancer risk, even though hepatitis virus infection was not taken into account. It is also well known that persistent long-term internal exposure to α particles PS-341 mouse from Thorotrast, a radioactive contrast agent, can induce hemangiosarcoma, cholangiocarcinoma, and HCC in humans.41-43 Because a significant radiation effect is observed in a high

proportion of HCC cases having a p53 mutation, it has been suggested that p53 is one of the intracellular targets of atomic bomb radiation and thus a cause of the increased HCC incidence among atomic bomb survivors.44 A lifespan study in mice exposed Terminal deoxynucleotidyl transferase to continuous low-dose-rate γ rays demonstrated that the incidence of HCC was significantly increased, especially in male mice.25 Liver weights of irradiated mice were significantly greater than those of nonirradiated controls, and the lipid content was significantly increased in irradiated mouse livers.45 It is considered that hepatic steatosis itself is a state conferring risk for high carcinogenicity, and that in steatohepatitis, oxidative stress due to fatty acid oxidation in hepatocytes may cause DNA injury and eventually lead to carcinogenesis.46 There is a significant association of radiation dose with prevalence of fatty liver among Nagasaki AHS participants, although a significant association has not been found between obesity (BMI ≥26.0 kg/m2) and radiation dose.47 These findings may explain part of the mechanism of increased risks of HCC with radiation exposure.