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2-(2'-Hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB), the Benzotriazole UV-stabilizer (BUVSs) known as UV-320, is widely used in plastic materials for protection against UV-irradiation. Previously, we reported that oral ingestion of HDBB induce hepatotoxicity including hepatocyte hypertrophy and necrosis in rats and, males was more susceptible compared with females in young rats while no sex-related difference was observed in preweaning rats. Phenotypes observed in our previous study imply involvement of peroxisome proliferator-activated receptor (PPAR) α in HDBB hepatotoxicity, however, direct evidence that HDBB can activate PPARα has not been provided and the mechanism which underlying the gender difference of HDBB hepatotoxicity was not clearly elucidated. Here, we conduct transcriptome analysis using microarray expression profiles in the livers of rats administered HDBB. PPARα agonist activity of HDBB was elucidated by comparison with gene expression data of typical PPARα agonist, i.e. clofibrate, WY-14643, gemfibrozil, and fenofibrate, from TG GATEs database. Moreover, we analyzed for PPARα mRNA expression in the liver of developing male and female rats. PPARα mRNA expression level was higher in males than in females on postnatal days (PNDs) 28 and 35, whereas no sex-related difference was found on PNDs 7 and 22. These results suggest that HDBB exerts its hepatotoxicity through the PPARα signal pathway and the sex-related difference in PPARα expression may contribute to the sex-related difference in susceptibility to hepatotoxicity.

The revision of the Japanese drinking water quality guidelines was established in May 2003. The WHO drinking water quality guidelines for the 3(rd) edition were also revised and the draft has been open to the public since last year. Most guideline values of each chemical in both Japan and WHO were quite similar; however, there are different overt values for three chemicals. In this short communication, we describe them and discuss the reason for taking the different toxicity endpoints and derivation method for these three chemicals, di(2-ethylhexyl) phthalate, toluene and vinyl chloride.

To determine susceptibility of infants to 3-methylphenol, a repeated dose toxicity study was conducted with oral administration to newborn and young rats. In an 18-day newborn study from postnatal days 4 to 21 at doses of 30, 100 and 300 mg/kg/day, various clinical signs including deep respiration, hypersensitivity on handling and tremors under contact stimulus, and depressed body weight gain were observed at 300 mg/kg. At 100 mg/kg, hypersensitivity and tremors were also noted in a small number of males only on single days during the dosing period. No adverse effects were observed in the 30 mg/kg group. There were no abnormalities of physical development, sexual maturation and reflex ontogeny. The no observed adverse effect level (NOAEL) for newborn rats was considered to be 30 mg/kg/day and the unequivocally toxic level 300 mg/kg/day. In a 28-day study starting at 5 weeks of age, clinical signs and depression of body weight gain, as observed in the newborn rats, appeared in both sexes at 1000 mg/kg but not 300 mg/kg. The NOAEL and the unequivocally toxic level were 300 mg/kg/day and 1,000 mg/kg/day, respectively. From these results, newborn rats were concluded to be 3 to 10 times more susceptible to 3-methylphenol than young rats. However, the realistic no adverse effect dose for the newborn must be slightly lower than 100 mg/kg/day, at which the toxicity incidence was very low, rather than 30 mg/kg/day. Based on this speculation and the equal toxicity at unequivocally toxic levels, the differences in the susceptibility to 3-methylphenol could be concluded to be 3 to 4 times. This is consistent with the results of our previous comparative studies on 4-nitrophenol, 2,4-dinitrophenol and 3-aminophenol, which showed 2 to 4 times differences in the susceptibility between newborn and young rats.