A novel toxicokinetic modeling of cypermethrin and permethrin and their metabolites in humans for dose reconstruction from biomarker data

Abstract

To assess exposure to pyrethroids in the general population, one of most widely used method nowadays consists of measuring urinary metabolites. Unfortunately, interpretation of data is limited by the unspecified relation between dose and levels in biological tissues and excreta. The objective of this study was to develop a common multi-compartment toxicokinetic model to predict the time courses of two mainly used pyrethroid pesticides, permethrin and cypermethrin, and their metabolites (cis-DCCA, trans-DCCA and 3-PBA) in the human body and in accessible biological matrices following different exposure scenarios. Toxicokinetics was described mathematically by systems of differential equations to yield the time courses of these pyrethroids and their metabolites in the different compartments. Unknown transfer rate values between compartments were determined from best fits to available human data on the urinary excretion time courses of metabolites following an oral and dermal exposure to cypermethrin in volunteers. Since values for these coefficients have not yet been determined, a mathematical routine was programmed in MathCad to establish the possible range of values on the basis of physiological and mathematical considerations. The best combination of parameter values was then selected using a statistic measure (reliability factor) along with a statistically acceptable range of values for each parameter. With this approach, simulations provided a close approximation to published time course data. This model allows to predict urinary time courses of trans-DCCA, cis-DCCA and 3-PBA, whatever the exposure route. It can also serve to reconstruct absorbed doses of permethrin or cypermethrin in the population using measured biomarker data.

Conflict of interest statement

Competing Interests: An employee from Infectopharm is a co-author on this manuscript, we declare that the company has had no involvement in model development or use of the model. The company has not provided any funding or consultant fees for this work. The company only provided the raw data allowing the validation of the model. The company has no patent or access to the model or its interpretation. Only the University of Montreal and Health Canada members have the PI on the modeling. Therefore, we declare that this does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Model conceptual representation.

Model conceptual representation of the kinetics of cis- and trans-permethrin and cypermethrin and their trans-DCCA, cis-DCCA and 3-PBA metabolites. Symbols are described in Table 1.

Figure 2. Algorithm.

Algorithm for the determination of parameters values of the model with experimental data of urine excretion profile.

Figure 3. Comparison of model simulations with experimental data for cis- and trans-DCCA (volunteers orally exposed).

Comparison of model simulations (lines) with experimental data of Woollen et al. (1992) (symbols) on the average time courses of cis- and trans-DCCA excretion rate (A) and cumulative excretion (B) (% of administered dose) in volunteers orally exposed to 3.3 mg of cypermethrin. Triangle and square symbols represent average experimental values for cis- and trans-DCCA, respectively, and vertical bars the experimental standard deviation (n = 6).

Figure 4. Comparison of model simulations with experimental data for 3-PBA (volunteers orally exposed).

Comparison of model simulations (lines) with experimental data of Woollen et al. (1992) (symbols) on the average time courses of 3-PBA excretion rate (A) and cumulative excretion (B) (% of administered dose) in volunteers orally exposed to 3.3 mg of cypermethrin. Symbols represent average experimental values and vertical bars the experimental standard deviation (n = 6).

Figure 5. Comparison of model simulations with experimental data for cis- and trans-DCCA (volunteers dermally exposed).

Comparison of model simulations (lines) with experimental data of Woollen et al. (1992) (symbols) on the average time courses of cis- and trans-DCCA excretion rate (A) and cumulative excretion (B) (% of applied dose) in volunteers dermally exposed to 31 mg of cypermethrin. Triangle and square symbols represent average experimental values for cis- and trans-DCCA, respectively, and vertical bars the experimental standard deviation (n = 6).

Figure 6. Comparison of model simulations with experimental data for 3-PBA (volunteers dermally exposed).

Comparison of model simulations (lines) with experimental data of Woollen et al. (1992) (symbols) on the average time courses of 3-PBA excretion rate (A) and cumulative excretion (B) (% of applied dose) in volunteers dermally exposed to 31 mg of cypermethrin. Symbols represent average experimental values and vertical bars the experimental standard deviation (n = 6).

Figure 7. Comparison of model simulations with experimental data for DCCA (volunteers dermally exposed).

Comparison of model simulations (lines) with experimental data of Tomalik-Scharte et al. (2005) (symbols) on the average time courses of DCCA excretion rate (A) and cumulative excretion (B) (% of applied dose) in healthy volunteers following a whole-body dermal application of a cream containing 3 g of permethrin. Diamond symbols represent average experimental values and vertical bars the experimental standard deviation (n = 6).

Figure 8. Comparison of model simulations with experimental data for DCCA (scabies patients dermally exposed).

Comparison of model simulations (lines) with experimental data of Tomalik-Scharte et al. (2005) (symbols) on the average time courses of DCCA excretion rate (A) and cumulative excretion (B) (% of applied dose) in scabies patients following a whole-body dermal application of a cream containing 3 g of permethrin. Diamond symbols represent average experimental values and vertical bars the experimental standard deviation (n = 6).

Figure 9. Comparison of model simulations with experimental data for DCCA (volunteers dermally exposed).

Comparison of model simulations (lines) with experimental data of Tomalik-Scharte et al. (2005) (symbols) on the average time courses of DCCA excretion rate (A) and cumulative excretion (B) (% of applied dose) in healthy volunteers following a dermal application of 215 mg of a permethrin solution on the scalp. Diamond symbols represent average experimental values and vertical bars the experimental standard deviation (n = 6).

Figure 10. Model simulations of cypermethrin and DCCA in blood, storage tissues and urine following repeated oral exposure.

Model simulations (lines) of the time courses of cypermethrin in blood (B(t)) (A) and storage tissues (S(t)) (B) as well as trans- and cis-DCCA in urine (U(t); solid and dotted lines, respectively) (C) following a repeated oral exposure, 3 times per day (at 7:30 am, 12: 30 am and 6:30 pm), during 10 consecutive days to a dose corresponding to 1/10 of the dose administered by Woollen et al. (1992) (0.33 mg/day).