Selection of Dose Levels for Mammalian in Vivo Tier 1 Assays 在体内的1级检测哺乳动物的剂量选择.pptVIP

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Selection of Dose Levels for Mammalian in Vivo Tier 1 Assays 在体内的1级检测哺乳动物的剂量选择.ppt

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Selection of Dose Levels for Mammalian in Vivo Tier 1 Assays 在体内的1级检测哺乳动物的剂量选择

Selection of Dose Levels for Mammalian in Vivo Tier 1 Assays: Discussion Points Paul MD Foster, PhD 23rd July 2002 Email: foster2@niehs.nih.gov Background Tier 1 in vivo assays will provide information on the potential of agents to interfere with the endocrine system. These screens should employ high dose levels since detailed dose response assessment is not a requirement and some false positives are acceptable. A NOAEL is not required. Selection of highest dose level to be tested EDSTAC recommended the concept of a MTD, and if necessary other dose levels at a fraction of the MTD. Concept of a limit dose endorsed (1g/kg/d po). Dose selection based on all information available for test agent: Previous toxicology data. Predicted SAR. Member of chemical class, etc. Selection of highest dose level to be tested -2 Default Approach Up to 10% mortality. Mortality deemed by most investigators too severe for an endocrine screen. Dose level should be high enough such that agents testing negative ? hold box. Negative data considered adequate. Dose level should produce some overt systemic toxicity to confirm a “stressed system”. If limit dose not used, second level should be biased towards upper end of dose response. Half the highest level is suggested. Proposed high dose level assignment -1 Number of toxicological indices available including body weight, food consumption and clinical signs. As guidance, recommend a 10% decrease in terminal bodyweight compared to control. Less than default High enough to account for potential estrogen effects on appetite Proposed high dose level assignment -2 Dose level selected is not a “bright line”. Would not reject a study for only achieving a 9% decrease. Would not dismiss effects noted at 11% as “exceeding MTD”. Dose level selection based on individual chemical and in some instance body weight would not be appropriate. No substitute for good judgment by investigator. Pilot studies All in vivo mammalian Tier 1 assays conducted in