Significance minimum effective dose

Liver enzymes and serum bilirubin should be measured before treatment is commenced to indicate the degree of cholestasis. These parameters should then be closely monitored, with treatment being stopped if a significant increase is seen. The optimum duration of treatment has yet to be defined, but it is recommended that the minimum effective dose should be used for the shortest period. 

Gong et al. [78] demonstrated phytogenotoxicity of 2,4-DNT and 2,6-DNT using the Tradescantia micronucleus bioassay (Trad-MCN) [79] in a hydroponic culture. Exposure to 2,4-DNT concentrations ranging from 0 to 30 mg L 1 caused a linear concentration-dependent change in MCN frequency, whereas exposure to 2,6-DNT significantly increased MCN frequency at 135 mg 1. 1 compared to response in control. Based on these results, the authors [78] established the minimum effective dose (MED) for 2,4-DNT and 2,6-DNT of 30 and 135 mg/1, respectively. 

While effective doses of 1 to 2 mg seem small, the total body pool of /3C can be estimated at 15 to 20 mg, with a total plasma pool of ateut 0.5 to 1 mg. In comparison with these pool sizes, a 2-mg effective dose is relatively large. In addition, the average daily effective dose of jSC from food sources is likely to be less than 1 mg, since matrix effects probably impair bioavailability of /3C to a larger extent than with supplements such as that used by van Vliet et al (1995). The minimum effective dose required to yield a significant TGR fraction response, taking into account the error associated with measurement, has not been determined, but is not likely to be much less than 1 mg. Consequently, use of unlabeled jSC, even coupled with use of the TGR fraction, is probably not well suited to study /3C uptake and metabolism at effective doses typically derived from dietary sources. 

Note also that the requirement of finding a minimal dose that is proved to be efficacious is rather different from what is often required of the maximum tolerated dose. Here a dose is likely to be abandoned, if some tolerability problems emerge, even if the dose cannot be proved to be worse by the standard of statistical significance than a dose that is retained. For example, the CRM methods discussed in Sections 20.2.7 to 20.2.9 do not use the notion of statistical significance. Of course, one reason for this is that the primary object of interest is selecting a correct dose for the next patient rather than for all future patients. Nevertheless, the difference in attitude to minimum effective and maximum tolerated (or maximum acceptable) doses is striking. 

In vivo Effects of TRH. Porcine TRH is active in vivo at doses as low as 1 nanog in mice treated with codeine and 1 ug th3rroKine (3). Porcine and bovine TRH show linear log dose relationship in this system (3, 11). TRH is also active in a linear dose response relationship in mice treated with 0.1 ug Triiodothyronine (3) and will increase plasma TSH in th]rroidectIntravenous administration of a highly purified preparation of bovine or porcine TRH will also cause a significant depletion of pituitary TSH content in mice (12). The minimum active dose of TRH required for significant pituitary TSH depletion is 4 nanograms. 

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