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Purpose: Nine bladder cancer (BCa) cases were reported among aromatic amine-exposed male workers at a factory manufacturing organic dye/pigment intermediates in Japan. We aimed to evaluate the characteristics of aromatic amine-exposed workers by cross-sectional observation, and the risk of BCa by assessing the standardized incidence ratio (SIR). Methods: In the cross-sectional study, our subjects were: 9 BCa patients, 36 aromatic amine-exposed non-patients, and 79 non-exposed workers from 3 factories. We evaluated the subjects' medical history, urinalysis, qualitative determination of nuclear matrix protein 22, and urinary cytology. For SIR assessment, 98 aromatic amine-exposed workers from 1 factory were included, and the Japanese general male population was used as a referent population. Since no direct aromatic amine-exposure data were available, we calculated surrogate exposure levels using information on job sites, exposure potency, and duration. Results: Coexistent aromatic amines were ortho-toluidine (OT), aniline, para-toluidine, ortho-anisidine, 2,4-xylidine, and ortho-chloroaniline. The prevalence rates of cystitis and bladder lesion-related symptoms in both BCa patients and aromatic amine-exposed non-patient workers were significantly higher than those of non-exposed workers. Overall, the SIR for BCa in OT-exposed workers was 56.8 (95% CI 27.7–104.3) and apparent dose–response relationships were revealed between the SIR and the surrogate exposure level in the 0–10-year lagged analyses. Overall, SIRs in other aromatic amine-exposed workers were also significantly high but no or unclear dose–response relationships were observed. Conclusions: We conclude that OT may be responsible for the increased risk of BCa. Regular monitoring of bladder lesion-related symptoms is essential for the early identification of BCa. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to cross-sectionally investigate how work and sleep conditions could be associated with excessive fatigue symptoms as an early sign of Karoshi (overwork-related cerebrovascular and cardiovascular diseases; CCVDs). Methods: We distributed a questionnaire regarding work, sleep, and excessive fatigue symptoms to 5410 truck drivers, as the riskiest occupation for overwork-related CCVDs, and collected 1992 total samples (response rate: 36.8%). The research team collected 1564 investigation reports required for compensation for Karoshi. Of them, 190 reports listed the prodromes of Karoshi, which were used to develop the new excessive fatigue symptoms inventory. Results: One-way analyses of variance showed that the excessive fatigue symptoms differed significantly by monthly overtime hours (p < 0.001), daily working time (p < 0.001), work schedule (p = 0.025), waiting time on-site (p = 0.049), number of night shifts (p = 0.011), and sleep duration on workdays (p < 0.001). Multivariate mixed-model regression analyses revealed shorter sleep duration as the most effective parameter for predicting excessive fatigue symptoms. Multiple logistic regression analysis confirmed that the occurrences of CCVDs were significantly higher in the middle [adjusted ORs = 3.56 (1.28–9.94)] and high-score groups [3.55 (1.24–10.21)] than in the low-score group. Conclusion: The findings suggested that shorter sleep duration was associated more closely with a marked increase in fatigue, as compared with the other work and sleep factors. Hence, ensuring sleep opportunities could be targeted for reducing the potential risks of Karoshi among truck drivers. [ABSTRACT FROM AUTHOR]

Recent epidemiological studies have indicated that occupational exposure to the aromatic amine acetoaceto-o-toluidide (AAOT) was associated with a marked increase in urinary bladder cancers in Japan. However, little is known about the carcinogenicity of AAOT. To evaluate the urinary bladder carcinogenicity of AAOT, male and female F344 rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks followed by dietary administration of 0, 0.167, 0.5, or 1.5% AAOT for 31 weeks. The incidences and multiplicities of bladder tumors were significantly increased in the 0.5 and 1.5% groups of male and female rats in a dose-response manner. AAOT and seven downstream metabolites were detected in the urine of the male and female rats administered AAOT with levels increasing in a dose-dependent manner. The most abundant urinary metabolite of AAOT was the human bladder carcinogen o-toluidine (OTD), which was at least one order of magnitude higher than AAOT and the other AAOT metabolites. In a second experiment, male F344 rats were administered 0, 0.167, or 1.5% AAOT for 4 weeks. Gene expression analyses revealed that the expression of JUN and its downstream target genes was increased in the urothelium of male rats treated with 1.5% AAOT. These results demonstrate that AAOT promotes BBN-induced urinary bladder carcinogenesis in rats and suggest that overexpressed of JUN and its downstream target genes may be involved the bladder carcinogenicity of AAOT. In conclusion, AAOT, like other carcinogenic aromatic amines, is likely to be a carcinogen to the urinary bladder, and OTD metabolized from AAOT is the ultimate carcinogen. [ABSTRACT FROM AUTHOR]

The Japanese Ministry of Health, Labour, and Welfare recently reported an outbreak of bladder cancer among workers who handled aromatic amines in Japan. 2,4-dimethylaniline (2,4-DMA) is one of the chemicals that workers are considered to have the most opportunities to be exposed. Genotoxic events are known to be crucial steps in the initiation of cancer. However, studies on the genotoxicity of 2,4-DMA are limited, particularly studies investigating the mechanism behind the genotoxicity by 2,4-DMA are completely lacking. We examined genotoxic properties of 2,4-DMA using phosphorylated histone H2AX (γ-H2AX), a sensitive and reliable marker of DNA damage, in cultured human urothelial and hepatic cells. Our results clearly showed that 2,4-DMA at a concentration range of 1-10 mM generates γ-H2AX in both cell lines, indicating that 2,4-DMA is genotoxic. During mechanistic investigation, we found that 2,4-DMA boosts intracellular reactive oxygen species, an effect clearly attenuated by disulfiram, a strong inhibitor of cytochrome P450 2E1 (CYP2E1). In addition, CYP2E1 inhibitors and the antioxidant, N-acetylcysteine, also attenuated γ-H2AX generation following exposure to 2,4-DMA. Collectively, these results suggest that γ-H2AX is formed following exposure to 2,4-DMA via reactive oxygen species produced by CYP2E1-mediated metabolism. Continuous exposure to genotoxic aromatic amines such as 2,4-DMA over a long period of time may have contributed to the development of bladder cancer. Our results provide important insights into the carcinogenicity risk of 2,4-DMA in occupational bladder cancer outbreaks at chemical plants in Japan. [ABSTRACT FROM AUTHOR]

The article presents a study which aims to trace the amounts of polychlorinated biphenyls (PCBs) in the blood serum of females born between 1940 and 1953 in Japan. It says that previous studies claim that PCB exposure has gradually decreased between 1950 and 1970. It states that higher serum PCBs found in women of older generations are parallel with the noted increase of hepta PCB. Meanwhile, the findings of the study are somewhat contradictory with studies in the previous years.