Silica and silicates may disturb immune functions such as autoimmunity and tumor immunity, because people who are exposed to the materials sometimes develop autoimmune and malignant diseases, respectively. Although silica-induced disorders of autoimmunity have been explained as adjuvant-type effects of silica, more precise analyses are needed and should reflect the recent progress in immunomolecular findings. A brief summary of our investigations related to the immunological effects of silica/asbestos is presented. Recent advances in immunomolecular studies led to detailed analyses of the immunological effects of asbestos and silica. Both affect immuno-competent cells and these effects may be associated with the pathophysiological development of complications in silicosis and asbestos-exposed patients such as the occurrence of autoimmune disorders and malignant tumors, respectively. In addition, immunological analyses may lead to the development of new clinical tools for the modification of the pathophysiological aspects of diseases such as the regulation of autoimmunity or tumor immunity using cell-mediated therapies, various cytokines, and molecule-targeting therapies. In particular, as the incidence of asbestos-related malignancies is increasing and such malignancies have been a medical and social problem since the summer in 2005 in Japan, efforts should be focused on developing a cure for these diseases to eliminate the nation wide anxiety about these malignancies.

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Beryllium induces non-caseating granulomatous inflammation in humans exposed to the metal dust or fumes in both occupational and non-occupational settings. The resulting condition, chronic beryllium disease (CBD), affects principally the lungs, lymphatics, and skin and continues to plague modern industry. Beryllium exerts several important immunotoxic effects, including induction of a beryllium-antigen specific adaptive immune response and the triggering of inflammatory and innate immune responses. Genetic susceptibility plays a role in CBD adaptive immune responses, mainly mediated through single nucleotide polymorphisms in HLA-DP and, to a lesser extent, HLA-DR. The adaptive response is characterized by influx and proliferation of CD4+ central and effector memory T cells expressing Th1 cytokines. Insights into the immunopathogenesis of CBD have implications for the understanding of other immune-mediated granulomatous disorders and for metal antigen behavior.

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Asthma is a heterogeneous lung disorder characterized by airway obstruction, inflammation and eosinophil infiltration into the lung. Both genetics and environmental factors influence the expression of asthma, and not all asthma is the result of a specific immune response to allergen. Numerous asthma phenotypes have been described, including occupational asthma, and therapeutic strategies for asthma control are similar regardless of phenotype. We hypothesized that mechanistic pathways leading to asthma symptoms in the effector phase of the disorder differ with the inciting allergen. Since route of allergen exposure can influence mechanistic pathways, mice were sensitized by identical routes with a high molecular weight occupational allergen ovalbumin and a low molecular weight occupational allergen trimellitic anhydride (TMA). Different statistical methods with varying selection criteria resulted in identification of similar candidate genes. Array data are intended to provide candidate genes for hypothesis generation and further experimentation. Continued studies focused on genes showing minimal changes in the TMA-induced model but with clear up-regulation in the ovalbumin model. Two of these genes, arginase 1 and eotaxin 1 are the focus of continuing investigations in mouse models of asthma regarding differences in mechanistic pathways depending on the allergen. Microarray data from the ovalbumin and TMA model of asthma were also compared to previous data using Aspergillus as allergen to identify putative asthma ‘signature genes’, i.e. genes up-regulated with all 3 allergens. Array studies provide candidate genes to identify common mechanistic pathways in the effector phase, as well as mechanistic pathways unique to individual allergens.

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Objectives: Mercury allergy is a serious health problem. We investigated the relationship between positive patch test for mercury and sources of mercury exposure, indicated by concentrations in biological samples from healthy medical students.
Methods: Patch tests for mercury (Hg-PT) were performed on 580 students. For a group of 55 students with a positive Hg-PT result (Hg-PT(+)) and a reference group of 79 students with a negative Hg-PT result (Hg-PT(−)), mercury concentrations in urine (Hg-u) and hair (Hg-h) were measured. In our search for environmental indicators of mercury exposure, the level of fish intake and mercurochrome usage were determined using a self-administered questionnaire. The oral cavity was investigated and the numbers of decayed teeth filled with amalgam (NA) were counted by dentists.
Results: For the male Hg-PT(+) group, Hg-u and Hg-h were higher than those of a male reference Hg-PT(−) group; Hg-u values obtained in the early morning and after supper were significantly different. Multiple regression analysis with Hg-u as the objective variable among all students showed that increases in the level of fish intake, mercurochrome usage, and the NA independently increased Hg-u measured in the early morning for both gender groups. NA significantly affected Hg-u.
Conclusions: We showed that a higher NA was related to a higher Hg-u measured in the early morning. Therefore, exposure to amalgam may increase Hg-u. It was suggested that Hg-PT(+) might be related to a high Hg-u, and possibly to a high NA.

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Objectives: We conducted an epidemiological study of the relationship between lung cancer incidence and smoking, with special reference to the benefits of smoking cessation for reducing lung cancer incidence, to promote a local smoking control program.
Methods: The study was a retrospective cohort study. The population studied was 16,383 male examinees of lung cancer health examinations in 1995 in Tottori Prefecture, Japan. Smoking status from the questionnaire during the health examination was used as the exposure variable. Endpoint (lung cancer incidence) was obtained from the Tottori population-based cancer registry. A multivariable analysis using the Cox proportional hazard model was adapted for statistical analysis. The average follow-up period was 4.3 years.
Results: The hazard ratio of current smokers for the incidence of lung cancer was 4.9, whereas that of ex-smokers was 2.2. The dose-response relationship between lung cancer incidence and lifetime cigarette consumption (pack year) was determined. The ratio increased among younger subjects (under 65 years old). The hazard ratio of ex-smokers decreased with years just after quitting smoking, and reached the level of never smokers after 10–19 years from smoking cessation.
Conclusions: We reconfirmed that the magnitude of risk estimates of smoking for lung cancer incidence was similar to those of previous studies, and smoking cessation was effective for reducing lung cancer risk.

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