INTRODUCTIONAs part of a collaborative study on toxicity related to female fertility, we performed experiments using di-(2-ethylhexyl) phthalate (DEHP), widely used as a plasticizer of polyvinyl chloride (PVC) and a known peroxisome proliferator (Lake et al., 1987), liver carcinogen (Reddy and Lalwai, 1983) and ovarian toxicant in rodents (Davis et al., 1994). Short-term exposure to DEHP resulted in hypoestrogenic anovulatory cycles and polycystic ovaries in adult rats (Davis et al., 1994). Longterm exposure to DEHP resulted in continuous diestrous stage with reduced serum estradiol, follicle stimulating hormone (FSH), pituitary FSH and luteinizing hormone (LH) (Hirosawa et al., 2006). The active metabolite of DEHP mono-(2-ethylhexyl) phthalate (MEHP) decreased aromatase in rat granulosa cells in vitro (Davis et al., 1994). Because the toxic effects of DEHP on ovaries are thought to be endocrine disorders and an aromatase inhibitor is expected to impact both ovarian morphology and female fertility, we selected DEHP as the test compound for the evaluation of ovarian toxicity.The present study was designed to determine whether 2-or 4-week administration periods for detecting histopathological changes in a repeated-dose toxicity study to compare the potential ovarian toxicity with the female reproductive function in a fertility study. MATERIALS AND METHODS Test articleDEHP was obtained from Kanto Chemical (Tokyo, Japan). Corn oil was purchased from Sigma-Aldrich Japan (Tokyo, Japan) and used as a vehicle. DEHP was ABSTRACT -The main purpose of this collaborative work is to determine the optimal administration period required to detect toxic effects in evaluation of ovarian morphological changes in repeated-dose toxicity studies. To assess the morphological and functional changes induced in the ovaries by di-(2-ethylhexyl) phthalate (DEHP), two repeated-dose toxicity studies (repeated dose for 2 or 4 weeks) of DEHP administrated to female rats at dose levels of 0, 300, 1,000 and 3,000 mg/kg were conducted in collaboration with a female fertility study at the same dosages from 2 weeks prior to mating to Day 7 of pregnancy. Histopathology of the ovaries in both repeated-dose toxicity studies showed vacuolation of stromal cells in the groups receiving 300 mg/kg or more and an increase of large atretic follicles in groups at 1,000 mg/ kg or more. In the 4-week study, a decrease in new corpora lutea was observed in the 3,000 mg/kg group. In the female fertility study, the 3,000 mg/kg group showed prolongation of the mean estrous cycle and irregular estrous cycles. Cesarean section revealed a decrease of pregnancy rate in the 3,000 mg/kg group. No effects on fertility or early embryonic development were found in groups at 1,000 mg/kg or less. -ation of drugs which induce ovarian damage. In conclusion, for a repeated-dose toxicity study, a 2-week

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-Interstitial lung disease has been reported in cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib and gefitinib. Preclinical safety studies with erlotinib did not show any evidence for an induction of injury on intact lungs in rats and dogs. In the present study, we investigated the effects of erlotinib on lung injury induced by intratracheal administration of bleomycin (BLM) in rats. In Experiment 1, we examined the effects of short-term (7-and 21-day) administration of erlotinib (10 mg/kg/day, p.o.; subtoxic dose) on the BLM (0.1 or 0.6 mg/rat)-induced lung injury of slight and moderate severity. In Experiment 2, we examined the effects of long term (up to 63-day) administration of higher-dose (up to 20 mg/kg/day; toxic dose; accompanied with decreased body weight gain and severe skin lesions) erlotinib on the BLM-induced lung injury. In rats receiving erlotinib alone, no lung lesions were noted. In rats receiving BLM alone, diffuse alveolar damage (DAD) and, subsequently, pulmonary fibrosis of slight or moderate severity was observed. The administration of erlotinib to BLM-treated rats showed no exacerbation of lung injuries in indices such as macroscopic findings, lung weights, histopathological scores (lung lesion density and lung fibrosis score), and pulmonary hydroxyproline (HyP) level. These results suggest that erlotinib does not have any exacerbating effects on lung injuries induced by BLM in rats.