Estimating
Screening-Level Organic Chemical Half-Lives
in Humans
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Abstract
Relatively
few measured data are available for the thousands of
chemicals requiring hazard and risk assessment. The whole body, total
elimination half-life (<i>HL</i><sub>T</sub>) and the whole
body, primary biotransformation half-life (<i>HL</i><sub>B</sub>) 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 <i>HL</i><sub>B</sub> from measured <i>HL</i><sub>T</sub> data in
mammals. Approximately 1900 <i>HL</i>s for human adults
were collected and reviewed and the 1-CoPK model was parametrized
for an adult human to calculate <i>HL</i><sub>B</sub> from <i>HL</i><sub>T</sub>. Measured renal clearance and whole body
total clearance data for 306 chemicals were used to calculate empirical <i>HL</i><sub>B,emp</sub>. The <i>HL</i><sub>B,emp</sub> values and other measured data were used to corroborate the 1-CoPK <i>HL</i><sub>B</sub> model calculations. <i>HL</i>s
span approximately 7.5 orders of magnitude from 0.05 h for nitroglycerin
to 2 × 10<sup>6</sup> 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 <i>HL</i><sub>T</sub> and <i>HL</i><sub>B</sub> from
chemical structure and two novel QSARs are detailed. The <i>HL</i><sub>T</sub> and <i>HL</i><sub>B</sub> QSARs show similar
statistical performance; that is, <i>r</i><sup>2</sup> =
0.89, <i>r</i><sup>2‑ext</sup> = 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
