Determination of biological reference values for chlorpyrifos metabolites in human urine using a toxicokinetic approach.

Urinary biomarkers of chlorpyrifos (CPF) exposure are often measured in field studies, although biological reference values (BRVs) are not yet available to assess health risks. This study aimed at proposing BRVs for CPF metabolites in workers' urine based on a toxicokinetic approach. As a first step, a toxicokinetic model was developed, using published human kinetic data, to link the absorbed dose of CPF under a variety of exposure routes and temporal scenarios to the urinary excretion of its major metabolites, 3,5,6-trichloro-2-pyridinol (3,5,6-TCP) and alkyl phosphates (AP). The model was then used to propose BRVs for CPF metabolites in urine below which workers should not experience adverse health effects. This was achieved by linking (1) a literature-reported, repeated CPF no-observed-effect level (NOEL) daily exposure dose for the inhibition of red-blood-cell acetylcholinesterase activity to a corresponding absorbed daily dose, and (2) this absorbed daily dose to the urinary excretion of CPF metabolites. Model simulations under a variety of exposure scenarios showed that the safest BRVs are obtained from a dermal exposure scenario with the slowest absorption rate compatible with available literature data rather than from respiratory or oral exposure scenarios. Also, model simulations showed that, for a given total absorbed dose, absorption over 8 hours results in smaller 3,5,6-TCP and AP urinary excretion rates than those obtained from the same dose absorbed over shorter durations. From these considerations, BRVs were derived by simulating an 8-hour dermal CPF exposure such that the total absorbed daily dose corresponds to the absorbed NOEL. The reference values are proposed in the form of total amounts of 3,5,6-TCP and AP metabolites excreted in urine over chosen time periods (24 and 48 hours).