English J C, Perry L G, Vlaovic M, Moyer C, O'Donoghue J L
Corporate Health and Environment Laboratories, Eastman Kodak Company, Rochester, New York 14652-6272.
Fundam Appl Toxicol. 1994 Oct;23(3):397-406. doi: 10.1006/faat.1994.1121.
Oral administration of hydroquinone (HQ) over 2 years to male Fischer 344 (F344) rats results in a dose-related nephropathy and an increase in the incidence of renal tubule adenomas. Female F344 rats, B6C3F1 mice, and Sprague-Dawley (SD) rats are resistant to the chronic renal toxicity of HQ, and nephrotoxicity was not seen in dogs or humans following subchronic exposure. To better characterize the early development of renal toxicity in rats, cell proliferation was quantitated within the proximal (P1, P2, and P3) and distal tubule segments of the kidney in rats given 0, 2.5, 25, or 50 mg/kg HQ by gavage. Male and female F344 rats were treated for 1, 3, or 6 weeks, and male SD rats were treated for 6 weeks. Cell proliferation was quantitated by incorporation of bromodeoxyuridine, detected immunohistochemically, into newly synthesized DNA. At 6 weeks, renal cell proliferation was increased over vehicle-controls in male F344 rats dosed at 50 mg/kg. Significant elevations (p < 0.001) occurred in the P1 segments (87%) and in the P2 segments (50%) but the elevation in the P3 segment (34%) was not statistically significant. Urinalyses revealed increases in the rate of excretion of enzymes indicative of proximal tubular damage. Histopathologic evaluation of the kidneys was consistent with a dose-related tubular degeneration in the male F344 rat. No chemical-related effects were observed in the kidneys of female F344 and male SD rats. These data parallel the findings of sex- and strain-specific kidney adenomas in the 2-year bioassays, and suggest that chemically induced cell proliferation secondary to toxicity may be important in the pathogenesis of benign renal tumors in male F344 rats treated with HQ.
对雄性Fischer 344（F344）大鼠口服对苯二酚（HQ）2年可导致剂量相关的肾病，并增加肾小管腺瘤的发生率。雌性F344大鼠、B6C3F1小鼠和Sprague-Dawley（SD）大鼠对HQ的慢性肾毒性具有抗性，亚慢性暴露后在犬或人类中未观察到肾毒性。为了更好地表征大鼠肾毒性的早期发展情况，对经口给予0、2.5、25或50 mg/kg HQ的大鼠肾脏近端（P1、P2和P3）和远端肾小管节段内的细胞增殖进行了定量分析。对雄性和雌性F344大鼠进行1、3或6周的处理，对雄性SD大鼠进行6周的处理。通过将溴脱氧尿苷掺入新合成的DNA中，并采用免疫组织化学方法进行检测，对细胞增殖进行定量分析。在6周时，给予50 mg/kg剂量的雄性F344大鼠的肾细胞增殖比赋形剂对照组有所增加。P1节段（87%）和P2节段（50%）出现显著升高（p < 0.001），但P3节段的升高（34%）无统计学意义。尿液分析显示，提示近端肾小管损伤的酶排泄率增加。对肾脏的组织病理学评估与雄性F344大鼠中剂量相关的肾小管变性一致。在雌性F344大鼠和雄性SD大鼠的肾脏中未观察到与化学物质相关的影响。这些数据与2年生物测定中性别和品系特异性肾腺瘤的研究结果一致，并表明毒性继发的化学诱导细胞增殖可能在接受HQ治疗的雄性F344大鼠良性肾肿瘤的发病机制中起重要作用。
