Estimating screening-level organic chemical half-lives in humans

Relatively few measured data are available for the thousands of chemicals requiring hazard and risk assessment. The whole body, total elimination half-life (HLT) and the whole body, primary biotransformation half-life (HLB) are key parameters determining the extent of bioaccumulation, biological concentration, and risk from chemical exposure. A one-compartment pharmacokinetic (1-CoPK) mass balance model was developed to estimate organic chemical HLB from measured HLT data in mammals. Approximately 1900 HLs for human adults were collected and reviewed and the 1-CoPK model was parametrized for an adult human to calculate HLB from HLT. Measured renal clearance and whole body total clearance data for 306 chemicals were used to calculate empirical HLB,emp. The HLB,emp values and other measured data were used to corroborate the 1-CoPK HLB model calculations. HLs span approximately 7.5 orders of magnitude from 0.05 h for nitroglycerin to 2 × 10(6) h for 2,3,4,5,2',3',5',6'-octachlorobiphenyl with a median of 7.6 h. The automated Iterative Fragment Selection (IFS) method was applied to develop and evaluate various quantitative structure-activity relationships (QSARs) to predict HLT and HLB from chemical structure and two novel QSARs are detailed. The HLT and HLB QSARs show similar statistical performance; that is, r(2) = 0.89, r(2-ext) = 0.72 and 0.73 for training and external validation sets, respectively, and root-mean-square errors for the validation data sets are 0.70 and 0.75, respectively.