资源描述
Click to edit Master title style,Click to edit Master text styles,Second Level,Third Level,Fourth Level,Fifth Level,PMD Foster,*,Selection of Dose Levels for Mammalian,in Vivo,Tier 1 Assays:Discussion Points,Paul MD Foster,PhD,23,rd,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 the rat.Many other variables:,Gender,age,route of administration,duration of exposure,castration status.,Dose levels may be selected based on previous relevant toxicological information.,Some agents with little,or no data will require a pilot study,Pilot studies-2,Recommendations,Take a stepwise approach.,Use the route of exposure needed for assay.,Maximally for duration of study.,Minimize use of animals(max 4-5).,Use up/down methodology.,For short duration assays sensible to take target organs(e.g.uterus).,Increases in weights of pharmacologically important organs much easier to interpret than decreases accompanied by bodyweight reductions.,Validation efforts,Dose setting guidance and validation of protocols can occur in parallel.,Protocol validation with given dose levels:,Can labs produce comparable results?,Is the protocol robust and transferable?,Is the lab competent to undertake the assay?,Could run a test“unknown to include dose setting prior to Tier 1 assay.,Test of guidance information and the investigators.,Dose levels should be qualitatively similar between labs.,Ability to discern response should be fulfilled.,
展开阅读全文