کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5561105 | 1562113 | 2017 | 7 صفحه PDF | دانلود رایگان |
- Combined TK and toxicity data suggested 3X gender difference in rats.
- Three fold different high doses were used for males and females in the 2-year rat study.
- MTDs were achieved at 4800Â ppm in males and 1600Â ppm in females.
For agrochemicals tested in a carcinogenicity rodent study, it is often not possible to use the same high dose to achieve maximum tolerated dose (MTDs) without overdosing or insufficiently challenging one gender if significant gender differences are known. Toxicokinetic (TK) data for pesticide FR from a 28-day rat study showed that males required a 3-fold higher external dose compared to females to produce similar internal exposure levels of the parent compound. In the 90-day study, 8%/17% (M/F) decrease in bodyweight gain (BWG) and 15%/15% (M/F) increase in relative liver weights were observed in the 6000Â ppm males and 2000Â ppm females, respectively. Based on the above TK and toxicity data, different high dose levels were selected for females (1600Â ppm) and males (4800Â ppm) for a 2-year combined chronic/carcinogenicity study in rats. In the 2-year study, 14%, 13%, 13% and 21% reduction in BWG of males and 10%, 12%, 19% and 20% reduction in BWG of females were observed at weeks 13, 26, 52 and 104, respectively in the highest dose tested. Similar reductions in bodyweight gain in males and females at the different high dose levels clearly demonstrated that appropriate MTDs were reached. Therefore, it is scientifically sound and practical to use TK and toxicity data to use different high dose levels to achieve MTDs for a pesticide with large gender differences.
Journal: Regulatory Toxicology and Pharmacology - Volume 90, November 2017, Pages 153-159