Methodologies metabolite concentration measurements

The USEPA reviewed a number of registrant-submitted studies to assess exposure to handlers applying chlorpyrifos in agricultural and residential settings (USEPA, 2001). The biomonitoring studies measured urinary concentrations of the primary chlorpyrifos metabolite and back-calculated these to the absorbed dose of the parent. The passive dosimetry study results were corrected for 3 % dermal absorption from a human dosing study (Nolan et al 1984). The results of the studies are reported in Table 1.4 and demonstrate fairly close concordance between the two methodologies. 

Close co-operation for a year or more before the first administration to humans is likely to lead to a smooth transfer of the compound and the rapid movement of a compound out of preclinical into man. This lead time can be used to devise the ED plan, design the first studies and, when appropriate, to select and develop methodologies which will contribute to the drug s evaluation in man. This may include validation of pharmacodynamic measures to be used in the clinical pharmacology unit, assessment of various imaging techniques, development of bioanalytical methods for biomarkers, the drug and metabolites. Not infrequently, the assays that were perfectly adequate to support preclinical work are insufficiently sensitive, specific or accurate to quantify the comparatively low concentrations in humans. At the very least, assays require validation in human plasma and urine. 

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