Annual Meeting of the Japanese Society of Toxicology

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Introduction: 1,2-Dichloropropane (1,2-DCP) has been used as an intermediate in production for other chemicals and as a paint remover. IARC reclassified it as carcinogenic to humans (Group 1) according to the epidemiological studies of cholangiocarcinoma among offset color proof-printing workers exposed to 1,2-DCP in Japan. The present study investigated hepatotoxicity and proliferation in the bile duct induced by exposure to 1,2-DCP and role of P450 in its toxicity by inhibiting P450 activity using 1-aminobenzotriazole (1-ABT).
Methods: 42 male C57BL/6JJcl mice were randomly divided into 7 groups of six each. Four groups of mice administrated subcutaneously with 1-ABT at 50mg/kg were exposed to 1,2-DCP at 0, 50, 250 and 1250 ppm, respectively via inhalation route, 8hs per day for 4 weeks. The other three groups administered with saline were exposed to 1,2-DCP at 0, 50 and 250 ppm, respectively. Organ samples were collected under anesthesia at the end of the experiment. BrdU was injected intraperitoneally to the mice one hour prior to dissection for observation of proliferation in bile duct epithelial cells.
Results: Serious hepatic pathological changes were found in the groups of 1250 ppm 1,2-DCP with 1-ABT injection and 250 ppm 1,2-DCP without 1-ABT injection, including massive necrosis, inflammation, and hepatocyte degeneration. BrdU labeling index tended to increase with exposure levels of 1,2-DCP in the groups without 1-ABT treatment, but this increase was suppressed by administration with 1-ABT.
Conclusions: 1-ABT could reduce liver damage induced by 1,2-DCP exposure, indicating that P450 plays an important role in the hepatotoxicity of 1,2-DCP. P450-mediated metabolism of 1,2-DCP might contribute to proliferation in bile duct epithelial cells induced by exposure to 1,2-DCP.

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Vendex 50 WP (Fenbutatin oxide) are widely used for agriculture applications. To assess hazard potential of air-born Vendex 50 WP, the long-term inhalation study in male and female rats was performed according to OPPTS test guideline. The rats were nose only exposed to 0.002 mg a.i./L air (G2), 0.008 mg a.i./L air (G3), 0.016 mg a.i./L air (G4 and G6) for 6 h/d, 5 d/week for 4 weeks in the 28-day study, respectively. A variety of biological clinical chemistry, hematology, urine analysis, organ weight and histopathology were examined. The results of satellite group animals exposed for 28-days are available. In present study, The treatment of Vendex 50 WP was associated with decreased in prothrombin time, increased in absolute and relative weights of lungs, increased in volume and pH of urine and decreased in specific gravity of urine at 0.008 mg a.i./L air (intermediate concentration) and 0.016 mg a.i./L air (high concentration). In the absence of any histopathologic findings in organs associated with these findings, which were considered as an adaptive response to test item treatment in the absence of any histopathological findings. Therefore, the No Observed Adverse Effect Concentration Level (NOAECL) is 0.016 mg a.i./L air , when administered through inhalation for up to 28 days to in Wistar rats under the procedure and conditions followed in the present study. Whereas, the No Observed Effect Concentration Level (NOECL) of Vendex 50 WP is 0.002 mg a.i./L air.

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Primates housed in laboratory settings are required to be socially housed (Animal Welfare Act. 2013). However, separation of paired animals can sometimes be unavoidable due to the scientific constraints of the study aims and test material, or due to unscheduled necropsy or upon veterinary recommendation. The purpose of this study was to investigate the possibility of behavioral changes, as representative of stress, in female cynomolgus macaques ( Macaca fascicularis ) following a separation event.
Six pairs, who had been co-housed for at least six months, were observed while co-housed and then at three time points following social separation. Behavioral observations were taken every 30 seconds with observation sessions lasting 10 minutes per pair. All behaviors observed were mutually exclusive.
Analysis of behaviors across all subjects found that abnormal behaviors sharply increased immediately after social separation. Additional, but smaller, increases in abnormal behaviors were observed the day following separation as well as one week following separation.
These results support the understanding to minimize social restrictions and maintain social contact in research animals.

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