We previously established a RET-transgenic mouse line (304/B6), in which skin melanosis, benign melanocytic tumors and malignant melanoma spontaneously develop. We found that the activities of RET tyrosine kinase, Erk and c-Jun are definitely upregulated in malignant melanoma in the RET-transgenic mice of line 304/B6. We also established another RET-transgenic mouse line (192), in which skin melanosis and benign melanocytic tumors, but not malignant melanoma, spontaneously develop. Ultraviolet irradiation induced malignant melanoma from benign tumors in the RET-transgenic mice of line 192, and promoted RET tyrosine kinase, Erk and c-Jun activities. These results suggest that the ultraviolet irradiation-mediated enhancement of RET and the activity of its downstream molecules play important roles in malignant melanoma development.

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By examining historical documents regarding occupational bladder cancer in Japan, we interpreted and followed the progress made in developing preventive measures against the outbreak of occupational bladder cancer in Japanese dye industries after World War II, and documented how these measures became well organized. During Dr. M. H. C. Williams's, who was an industrial physician for the British ICI Company, occasional visits to Japan, he encouraged the enforcement of such measures, considering them to be as important in occupational health in Japan as in Western countries. He received permission to implement these measures in Japanese dye companies. A urine cell diagnostic system was already being employed in Japanese industries as a method of diagnosing occupational bladder cancer, and its use was promoted by engineers, urologists, and pathologists even before the Industrial Safety and Health Law was enacted in 1972. It took about 10 years for these measures to become standardized industry-wide. The use of these measures has had a considerable effect on the early diagnosis of patients and extended patients' life spans. Eventually, the life spans of such patients became approximately the same as that of the average Japanese male. Some patients unfortunately died of occupational bladder cancer. Others were examined using these measures not only while employed but also after retirement. Therefore, some patients in whom occupational bladder cancer was detected are still alive at over eighty years of age.

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Toxicology research can be applied to evaluate potential human health risks resulting from exposure to chemicals and other factors in the environment. The tremendous advances that have been made in high-throughput “omics” technologies (e.g., genomics, transcriptomics, proteomics and metabolomics) are providing good tools for toxicological research. Toxicogenomics is the study of changes in gene expression, protein and metabolite profiles, and combines the tools of traditional toxicology with those of genomics and bioinformatics. In particular, identification of changes in gene expression using DNA microarrays is an important method for understanding toxicological processes and obtaining an informative biomarker. Although these technologies have emerged as a powerful tool for clarifying hazard mechanisms, there are some concerns for the application of these technologies to toxicological research. This review summarizes the impact of “omics” technologies in toxicological study, followed by a brief discussion of future research.

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Objectives: To clarify the antioxidative effects of kakisu (persimmon vinegar), plasma antioxidant power and urinary oxidative stress level in healthy subjects were measured using enzyme immunological assays.
Methods: Eighty-one subjects (age 30-69, 58.4±0.8) were randomly divided into two groups using a crossover design. Group A drank kakisu for 56 days starting in March, whereas group B drank kakisu for 54 days starting in June. Copper reducing equivalent level in plasma was measured as antioxidant power, and urinary 8-isoprostane (8-iso-prostaglandin F_2α) level was measured as oxidative stress marker.
Results: Baseline plasma antioxidant power and urinary 8-isoprostane level showed no significant correlation among the subjects in this study. By drinking kakisu for 8 weeks, total antioxidant power significantly increased, and urinary 8-isoprostane level decreased. Total antioxidant power increased more markedly in group A than in group B. In contrast, urinary oxidative stress level decreased more markedly in group B than in group A. Smoking habits significantly correlated with urinary 8-isoprostane level. Males were more sensitive to the antioxidative effects of kakisu than females.
Conclusions: Kakisu has antioxidative effects that increase plasma antioxidant power and reduce urinary 8-isoprostane level. Further study is needed to clarify the influence of season and gender on such antioxidative effects.

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Objectives: Total cholesterol (TC) level reduction decreases coronary heart disease (CHD) risk, but it is also associated with an increase in non-CHD mortality rate. Our objectives are to estimate the effect of TC level reduction on total mortality and other mortalities in the Japanese population using published data and to analyze the cost-effectiveness of drug therapy.
Methods: We analyzed three data sets for the estimation. The first data set comprised Japanese mortality rates of cardiac diseases, cerebrovascular/other vascular diseases, malignancy, and all causes according to sex and age. The second data set comprised the distributions of serum TC levels in the Japanese population. The third data set comprised the relative risks of mortality rates for the above causes according to the TC level classified into discrete intervals of 20mg/dl from an intervention study. We estimated the mortality rates of people aged 30-69, with each TC level classification group on the basis of each cause. On the assumption that TC level decreases from 240-259mg/dl to 160-179mg/dl or 180-199mg/dl with drug therapy, we calculated the differences between the mortalities of the classification. When we found a positive effect of TC level reduction, we performed cost-effectiveness analyses of Number Needed to Treat (NNT).
Results: TC level reduction increased the mortality rates except for that of cardiac diseases, and the NNT for cardiac diseases was in the range of 4,202-17,533. The cost of simvastatin, for example, was 0.25-1.05 billion yen per year.
Conclusions: TC level reduction from 240-259mg/dl to 160-199mg/dl leads to an increase in total mortality rate in the Japanese population. The treatment should be reevaluated from both viewpoints of risk benefit and cost-effectiveness.

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Objectives: The purpose of this study is to clarify the association between the daily number of accidental injuries and school size factors in elementary schools.
Methods: The accidental injuries that occurred during the school day among elementary school children were investigated in twenty-one schools for two-month periods (from October to November) in 1999 and 2004. The relationship between the number of accidental injuries and school size factors (i.e. the numbers of school children and children per class) was analyzed by nonlinear regression analysis. The number of children injured and the frequency of accidental injuries were evaluated by school size.
Results: The ratio of the average number of injuries to all injuries was 1.79 per 100 children per day. The number of injuries in the small-sized schools was 2.36 per 100 children per day, and were respectively 1.29 and 1.57 in the middle- and large-sized schools. The number of injuries was small in middle-sized schools. As a result of the nonlinear regression analysis, a statistically significant quadratic equation was provided between the number of injuries per 100 children per day and the number of children per class. The number of injuries showed a minimum value for 26.7 children per class. The number of children injured during the investigation period was larger in the small-sized schools. In the small-sized schools, in comparison with the middle- and large-sized schools, the number of accidental injuries was smaller for boys. In the large-sized schools, there were more injuries inside the school building and during the lesson break times.
Conclusion: It seems that the number of accidental injuries increases when school size is small or large. In addition, it is suggested that the number of children injured was larger in small-sized schools.

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Objective: The objective of this study is to provide basic information on the metabolic fate of five trialkyltins, namely, trimethyltin, triethyltin, tripropyltin, tributyltin, and trioctyltin, in rats.
Methods: The levels of trialkyltin and its metabolites in the liver, kidneys, brain, and blood of rats and mice were determined 24h after single oral treatment with trimethyltin, triethyltin, tripropyltin, tributyltin, and trioctyltin by gas chromatography. The doses (as tin) of the trialkyltin compounds were 2.98mg/kg for trimethyltin and triethyltin, 18.23mg/kg for tripropyltin and tributyltin and 24.09mg/kg for trioctyltin.
Results: For the trimethyltin and triethyltin treatments, no metabolites of either trialkyltin accumulated in the organs, except for the kidney in the triethyltin treatment. The levels of trimethyltin and triethyltin in the blood of the rats were markedly higher than those of the mice. For the tripropyltin and tributyltin treatments, the predominant metabolites in the liver and kidneys were found to be dialkyltins. Furthermore, despite the higher dose, the level of total tin in the organs 24h after treatment with trioctyltin were markedly lower than those of the other trialkyltins tested.
Conclusion: There are clear differences in the metabolic fates of the tin metabolites of the five trialkyltins studied. These results should be considered when carrying out toxicological research on trialkyltins.

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Objective: The purpose of this study is to determine whether the statistics from three published reports on Parkinson's disease (PD) are mutually interrelated and to clarify the relationship between the prevalence statistics and mortality statistics of PD. These statistics included data on “number of patients with PD (PD Patients)”, “number of patients with PD receiving financial aid for treatment (PD Recipients)” as an indicator showing the prevalence of PD, and “number of deaths from PD (PD Deaths, i.e., mortality)”.
Methods: The data on PD Patients, PD Recipients and PD Deaths were cited from “Patient Survey” by Ministry of Health, Labour and Welfare, a report by the Research Committee on Epidemiology of Intractable Diseases and “Vital Statistics of Japan” by Ministry of Health, Labour and Welfare, respectively. The expected PD Patients, PD Recipients and PD Deaths were calculated as products of their respective rates for the entire country and prefecture population, adjusting for a difference in population composition. Observed/expected number ratios (O/E ratio) of PD Patients, PD Recipients and PD Patients were calculated by prefecture. The correlation between the O/E ratios was examined. In addition, the relationships of the O/E ratios with the number of hospitals or physicians per person were examined.
Results: There were no significant correlations between the O/E ratios of PD Patients, PD Recipients or PD Deaths. The O/E ratio of PD Recipients significantly correlated with the numbers of hospitals and physicians per person.
Conclusion: PD Patients and PD Recipients were included in number of people with PD and PD Deaths was derived from people with PD. However, these statistics do not necessarily reflect the prevalence of PD in each prefecture. When using these published statistics as an indicator of the prevalence of PD, it is necessary to clarify the purpose of their use and to comprehend their characteristics.

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