With the help of my colleagues, I have been conducting epidemiological studies on biliary tract cancer (BTC), including gallbladder cancer (GBC) and extrahepatic bile duct cancer (BDC), in Japan and Chile for about 19 years. Clustered areas with high mortality rates, especially for female GBC were found to correspond with places or prefectures in Japan that were famous for rice production. The roles of known risk factors, such as gallstones and cholecystitis, were examined, but no single factor was implicated in the high mortality rates for GBC in these areas. A working hypothesis, called the “rice production hypothesis” was formulated; this initial hypothesis was replaced by a new multifactorial causation hypothesis: GBC is more likely to occur in individuals with a genetic susceptibility and a past history of gallstones or cholecystitis who are exposed to geographically specific environmental factors, such as agricultural chemicals. On the basis of various analytical studies, it is concluded that a certain agricultural chemical was responsible for the occurrence of GBC. At the time of writing, no evidence has been obtained to disprove our hypothesis. We have also conducted international collaborative studies in Chile, which has the highest mortality rate for GBC in the world. Bile from Chileans was found to have a higher mutagenic activity than that from Japanese subjects; Chileans with a history of constipation or a habit of consuming red chilli pepper had a high risk of developing GBC, if they also had gallstone(s). The presence of a regional difference in p53 mutagenesis was also observed.

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Most chemical carcinogens are metabolized and activated in vivo by phase I enzymes including the microsomal cytochromes P450 and epoxide hydroxylases. The carcinogens and their metabolites are detoxified by phase II enzymes that include various transferases such as glutathion-S-transferases (GST). Increasing numbers of studies have demonstrated the association of the polymorphisms in GSTM1 (a member of GST) and CYP1A1 genes with the susceptibility to lung cancer. Subsequently, the polymorphisms appear to be important biomarkers that provide information for assessment of exposure and total burden of environmental carcinogens. Therefore, the investigation of the polymorphisms in these genes will provide information not only for the prediction of individual cancer risk but also for the prevention of cancer. In this review, we will summarize the polymorphisms in the GSTM1 and CYP1A1 genes and their relation to lung cancer susceptibility.

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Hepatocellular carcinoma, (HCC) is a serious health problem. It is prevalent in certain parts of the world where food contamination with aflatoxin is common. Aflatoxin, especially AFB₁, has been shown to induce HCC in many species of laboratory and wild animals, including subhuman primates. Carcinogenesis studies have demonstrated that AFB₁ is a potent genotoxic carcinogen. After bioactivation it may covalently bind with protein and with DNA. The former reaction is positively correlated with AFB₁ exposure, and the latter signifies initiation of the carcinogenesis process.
With these biomarkers, epidemiological studies have amply demonstrated the etiological role of aflatoxin in HCC. However, hepatitis B virus also contributes to the development of HCC. Risks and VSD (virtual safe dose) have been estimated from animal and epidemiological studies. These estimates further confirm that AFB₁ is a potent carcinogen. Furthermore, the effects of AFB₁ exposure and hepatitis B are synergistic. Some preventive measures, such as lowering the contamination level of AFB₁ in food and appropriate vaccination programs, have been implemented in many parts of the world. Chemopreventive agents, which may abolish or reduce the effects of AFB₁ are being tested for their effectiveness.

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Erythropoietin is the prime regulator of red blood cell production. However, recent evidence suggests that the hormone has multiple effects outside the hematopoietic system. Functional receptors have been identified on a wide variety of normal and malignant cell types, and numerous biologic effects of the hormone on these cells have been observed both in vitro and in vivo. These findings are causing a reassessment of the understanding of erythropoietin physiology. Moreover, there are important implications for the use of recombinant erythropoietin in the clinical setting.

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The adverse health effects of elevated exposures to PM₁₀ (particulate matter collected through a size selective inlet with an efficiency of 50% for particles with an aerodynamic diameter of 10 μm) in relation to morbidity and mortality, especially in susceptible individuals, are now well recognised. PM₁₀ consists of a variable cocktail of components differing in chemical composition and size. Epidemiological and toxicological data suggest that transition metals and ultrafine particles are both able to drive the cellular and molecular changes that underlie PM₁₀-induced inflammation and so worsen disease status. Toxicological evidence also suggest roles for the biological components of PM₁₀ including volatile organic compounds (VOC’s), allergens and bacterial-derived endotoxin. Many of these components, in particular transition metals, ultrafine particles, endotoxin and VOC’s induce a cellular oxidative stress which initiates an intracellular signaling cascade involving the activation of phosphatase and kinase enzymes as well as transcription factors such as nuclear factor kappa B. Activation of these signaling mechanisms results in an increase in the expression of pro-inflammatory mediators, and hence enhanced inflammation. Given that many of the components of PM₁₀ stimulate similar or even identical intracellular signaling pathways, it is conceivable that this will result in synergistic or additive interactions so that the biological response induced by PM₁₀ exposure is a response to the composition rather than the mass alone. A small number of studies suggest that synergistic interactions occur between ultrafine particles and transition metals, between particles and allergens, and between particles and VOC’s. Elucidation of the consequences of interaction between the components of PM₁₀ in relation to their biological activity implies huge consequences for the methods used to monitor and to legislate pollution exposure in the future, and may drive a move from mass based measurements to composition.

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The porphyrias are uncommon, complex, and fascinating metabolic conditions, caused by deficiencies in the activities of the enzymes of the heme biosynthetic pathway. Two cardinal symptoms of the porphyrias are cutaneous photosensitivity and neurologic disturbances. Molecular analysis of gene defects has shown that there are multiple and heterogeneous mutations in each porphyria. Patients with symptomatic porphyria can suffer greatly, and, in rare cases, may die. While congenital porphyrias are inherited, other forms of porphyria occur as acquired diseases. In addition, not all gene carriers of inherited porphyrias develop clinical disease and there is a significant interplay between the gene defect and acquired or environmental factors. The variable response of porphyrias to acquired factors may likely reflect genetic polymorphisms in drug metabolism. The lessons from acute hepatic porphyria, such as acute intermittent porphyria, are very useful in clarifying the complex nature of the clinical expression of metabolic disorders.

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Multiple chemical sensitivity/idiopathic environmental intolerance (MCS/IEI) is a commonly used diagnostic term for a group of symptoms. These symptoms have been described and commented on for more than 15 years in the USA. Recently, it has also been observed in Japan. The main features of this syndrome are multiple symptoms involving in multiple organ systems that are precipitated by a variety of chemical substances with relapses and exacerbation under certain conditions when exposed to very low levels which do not affect the population at large. There are no laboratory markers or specific investigative findings. Although traditional medical organizations have not agreed on a definition for this syndrome due to the lack of obvious evidence to demonstrate the existence of these symptoms, it is being increasingly recognized. It constitutes an increasing percentage of the caseload at occupational/environmental medical clinics.
Part one of this review article discusses pathophysiological theories, substances which cause symptoms, prevalence in the general and specific populations, past history and family history, and clinical symptoms of MCS/IEI patients.

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Multiple chemical sensitivity/idiopathic environmental intolerance (MCS/IEI) is a commonly used diagnostic term for a group of symptoms without apparent organic basis. The symptoms are characteristic of dysfunction in multiple organ systems. They wax and wane fluctuate according to exposure to low levels of chemical agents in the patient’s environment, and sometimes begin after a distinct environmental change or injury such an industrial accident or chemical introduced after remodeling. Although traditional medical organizations have not agreed on a definition for this syndrome, it is being increasingly recognized and makes up an increasing percentage of the caseload at occupational/environmental medical clinics.
Part two of this review article discusses diagnosis, clinical examination, long-term follow up of MCS/IEI, and the role of physicians, research on odor and treatment, diseases with similar symptoms, and further research regarding MCS/IEI patients.

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Biomedical research has uncovered the mechanisms whereby tea promotes good health and lowers the risk of major chronic diseases, such as heart disease and many types of cancer. The active components in tea are polyphenols, epigallocatechin gallate in green tea, theaflavins and thearubigins in black tea. Green and black tea and the polyphenols have similar beneficial effects. The mechanisms are categorized into 5 groups. 1) Tea polyphenols are powerful antioxidants. They decrease the oxidation of LDL cholesterol and lower the risk of heart disease, and also inhibit action of reactive oxygen species mediating the oxidation of DNA associated with carcinogenesis 2) Tea polyphenols induce detoxifying enzymes, glucuronosyl transferases, eliminating active forms of carcinogens and other toxicants, accounting for the lower cancer risk. 3) Tea polyphenols lower duplication rates of cancer cells and inhibit the growth of cancer, increase apoptosis and lower angiogenesis. 4) Tea polyphenols alter the intestinal bacterial flora, suppressing undesirable bacteria and favoring growth of beneficial bacteria. 5) Aging phenomena, and diseases associated with the formation of reactive oxygen species (ROS) are inhibited.

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Objectives: The purpose of this study was to investigate the effect of tomato juice drinking on the anti-mutagenicity of saliva.
Methods: Subjects were 22 healthy male university students. They were divided into tomato group and control group. The tomato group drank tomato juice for 10 days. The anti-mutagenicity of saliva was measured using the umu test.
Results: In the tomato group, there was a significant increase in the inhibiting capacity of saliva on the mutagenicity of AF-2 after tomato juice drinking for 10 days. This increase was, however, temporary. In the control group, there was no such change in the inhibiting capacity of saliva.
Conclusions: These findings suggest the significant effect of tomato juice drinking on the anti-mutagenicity of saliva. In addition, lycopene may have played an important role in its mechanism.

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Objective: The fibrogenicity of fur dust was studied in rat lung tissues.
Methods: Intratracheal instillation of fur dust, morphologic examination of lungs and analysis of collagen content were performed in Wistar rats.
Results: Morphologic examination revealed that the earliest changes consisted of alveolar edema, increased numbers of intraalveolar macrophages, and marked thickening of interalveolar septa with mixed cellular infiltrate. After sixth months, there was moderate thickening of the alveolar walls and the peribronchioli. After 12 months, interstitial positive fibrosis of the alveolar wall and the peribronchioli were weakly seen. In the carding dust group (silica content 17.6%), interstitial nodules were observed composed of fibroblasts, reticular fibers, and collagen fibers. Electron microscopic examination also showed that alveolar walls became thickened and collagen fiber bundles were seen around bronchioles and small vessels in the carding groups after 12 months. At all stages of analysis, the collagen content in lungs of the fur dust groups was significantly higher than that of the control group.
Conclusions: Our study suggested that fur dust might induce weak interstitial fibrosis in the lung.

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