Chhabra R S, Bucher J R, Haseman J K, Elwell M R, Kurtz P J, Carlton B D
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Fundam Appl Toxicol. 1993 Aug;21(2):174-86. doi: 10.1006/faat.1993.1087.
Chronic toxicity and carcinogenicity studies of 5,5-diphenylhydantoin (DPH), were conducted in F344/N rats and B6C3F1 mice of each sex. The major objective of the study was to determine if incorporating exposure to DPH during the perinatal period, in addition to conventional exposure of animals for 2 years, enhances the sensitivity of the bioassay to identify the carcinogenic potential of chemical. The studies were designed to determine the toxic and carcinogenic effects of dietary DPH in rats and mice receiving; (1) the perinatal administration including exposure of maternal animals prior to breeding, through gestation, lactation, weaning, and continued dietary exposure of offspring to the age of 8 weeks followed by control diet for 2 years, (2) exposure for 2 years beginning at the age of 8 weeks, and (3) of combined perinatal/adult exposure to DPH (perinatal exposure to 8 weeks of age followed by the adult exposure for 2 years). During the perinatal period, rats were exposed to DPH at dose levels ranging from 63 to 630 ppm and adult exposure concentrations ranged from 240 to 2400 ppm in diet. In the mice, the perinatal exposure ranged from 21 to 210 ppm in both males and females. In the adult exposure portion of the mouse studies, the dietary levels ranged from 30 to 300 ppm in males and 60 to 600 ppm in females. A total of eight dose groups (including controls) were used with 60 animals in each group. The only effect of perinatal exposure alone on tumor rate was a marginal increase in the incidence of hepatocellular neoplasms in female mice. The adult exposure to DPH significantly increased the incidence of hepatocellular neoplasms in female mice. There were also marginal increases in the incidence of liver tumors in male rats exposed to high DPH dietary concentrations during the adult-only regimen. Combined perinatal and adult dietary exposure to 5,5-diphenylhydantoin confirmed the findings for the increased incidences of hepatocellular neoplasms in male rats and female mice, although combined exposure did not enhance these effects. However, in male mice, perinatal and adult exposure resulted in an increase in the incidence of hepatocellular neoplasms that was not seen when dietary exposure was limited to the adult period only.
对5,5 - 二苯基乙内酰脲（DPH）进行了慢性毒性和致癌性研究，实验对象为F344/N大鼠和B6C3F1小鼠的各性别群体。该研究的主要目的是确定，除了对动物进行常规的2年暴露实验外，在围产期加入DPH暴露，是否会提高生物测定对识别化学物质致癌潜力的敏感性。这些研究旨在确定饮食中DPH对接受以下处理的大鼠和小鼠的毒性和致癌作用：（1）围产期给药，包括在繁殖前对母鼠进行暴露，贯穿妊娠、哺乳、断奶阶段，并持续让后代饮食暴露至8周龄，随后给予对照饮食2年；（2）从8周龄开始暴露2年；（3）围产期/成年期联合暴露于DPH（围产期暴露至8周龄，随后成年期暴露2年）。在围产期，大鼠饮食中DPH的暴露剂量范围为63至630 ppm，成年期暴露浓度范围为240至2400 ppm。在小鼠中，围产期雄性和雌性的暴露范围均为21至210 ppm。在小鼠研究的成年期暴露部分，雄性饮食水平范围为30至300 ppm，雌性为60至600 ppm。总共使用了八个剂量组（包括对照组），每组60只动物。仅围产期暴露对肿瘤发生率的唯一影响是雌性小鼠肝细胞肿瘤发生率略有增加。成年期暴露于DPH显著增加了雌性小鼠肝细胞肿瘤的发生率。在仅成年期给药方案中，暴露于高浓度DPH饮食的雄性大鼠肝脏肿瘤发生率也略有增加。围产期和成年期联合饮食暴露于5,5 - 二苯基乙内酰脲证实了雄性大鼠和雌性小鼠肝细胞肿瘤发生率增加的结果，尽管联合暴露并未增强这些影响。然而，在雄性小鼠中，围产期和成年期暴露导致肝细胞肿瘤发生率增加，而仅在成年期进行饮食暴露时未观察到这种情况。
