Determination of Biological Reference Values for Chlorpyrifos Metabolites in Human Urine Using a Toxicokinetic Approach

Abstract

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).

Keywords:

• 3,5,6-trichloro-2-pyridinol
• alkyl phosphates
• biological reference values
• biomarkers
• chlorpyrifos
• toxicokinetics

ACKNOWLEDGMENT

The authors wish to thank the Institut de Recherche Robert-Sauvé en Santé et Sécurité du Travail (IRSST) for providing financial support for this study.

Notes

^A The description of parameters is given in Table I.

^B The oral absorption fraction and rate are known to vary according to the mode of administration. ^(12,14) These oral absorption fraction and rate values were determined from the oral data of Nolan et al. ⁽¹²⁾ on the average blood time profile of 3,5,6-TCP along with the average time course of 3,5,6-TCP cumulative urinary excretion calculated from the urinary excretion rate data presented by these authors.

^C The dermal absorption fraction and rate are known to vary according to the site of application. ⁽³¹⁾ These dermal absorption rate and fraction values were determined from the dermal data of Nolan et al. ⁽¹²⁾ on the average blood and urinary time courses of 3,5,6-TCP in volunteers exposed to CPF on the forearm.

^D Determined from the data of Drevenkar et al. ⁽²⁴⁾ on both the blood time courses of chlorpyrifos and alkyl phosphates (AP).

^E Based on the available human data, ^(12—14) excretion of metabolites from the body was taken to occur through the renal route.

^F Determined from the average blood time course of 3,5,6-TCP reported by Nolan et al. ⁽¹²⁾ and accuracy was verified from the average urinary excretion time profile of 3,5,6-TCP reported by these authors.

^G Determined from the blood time course of AP reported by Drevenkar et al. ⁽²⁴⁾ and accuracy was verified from the urinary excretion time profile of AP reported by these authors.

^A , where I₁ is the estimated value of the parameter as given in Table II, I₂ is its locally modified value, O₁ is the predicted 12-, 24-, or 48-hour cumulative urinary excretion using the estimated parameter value, and O₂ is the predicted value with the modified parameter value. The cumulative urinary O₁ and O₂ were obtained by model simulations of an 8-hour dermal exposure to chlorpyrifos, where the daily absorbed dose corresponds to a unit dose.

^B k_BS and k_BM are varied simultaneously but such as to maintain a constant partitioning ratio between storage and biotransformation (k_BS/k_BM).

^A For comparison of urinary metabolite measurements to the proposed biological reference values, workers should collect all urines from the beginning of a workshift for either of the proposed periods: 24 or 48 hours, preferably at the end of a workweek to capture, for safety, noneliminated doses from previous days.

^B Obtained using model simulations of an 8-hour dermal exposure, where the daily absorbed dose corresponds to the estimated human absorbed no-observed-effect level (NOEL) dose of 0.08 mg/kg of body weight and where the dermal absorption rate is equal to 0.04 hour^{− 1}. The absorbed NOEL dose was obtained by multiplying the oral exposure dose NOEL of 0.1 mg/kg determined by Coulston et al. ⁽²⁹⁾ by the oral absorption fraction of 0.798. This latter value was determined from the data of Nolan et al. ⁽¹²⁾ where volunteers were administered chlorpyrifos in the form of tablets as in the study of Coulston et al. ⁽²⁹⁾