Oncogenicity studies dose selection

Farber, T.M. (1987). Pesticide assessment guidelines, subdivision F, position document Selection of a maximum tolerated dose (MTD) in oncogenicity studies. Toxicology Branch, Hazard Evaluation Division, Office of Pesticides Programs, USEPA. NTIS PB88-116736. 

Summary Methamidophos given in the diet for periods of one or two years, resulted in body weight loss in the rat and mouse, but not the dog. There was an increase in relative brain weight at the highest dose tested (HDT) in these rodents, in both sexes, but not in the dog. There were few clinical signs and no evidence of oncogenicity. In all three species, inhibition of AChE in plasma (which also includes butyryl cholinesterase), red blood cell (RBC) and brain was reported. The LOEL for inhibition of brain AChE was 2 ppm, equivalent to 0.1, 0.3 or 0.06 mg/kg/day in the rat, mouse and dog, respectively. An estimated NOEL of 0.02 mg/kg/day, after 11-18% inhibition of brain AChE at 0.06 mg/kg/d in a 1-yr. dog study, was the critical one selected for chronic risk characterization. The use of an uncertainty factor of 3 (rather than 10) in calculating an estimated NOEL from a LOEL was supported by Benchmark Dose (BMD) calculations. 

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