Studying permethrin exposure in flight attendants using a physiologically based pharmacokinetic model

Abstract

Assessment of potential health risks to flight attendants from exposure to pyrethroid insecticides, used for aircraft disinsection, is limited because of (a) lack of information on exposures to these insecticides, and (b) lack of tools for linking these exposures to biomarker data. We developed and evaluated a physiologically based pharmacokinetic (PBPK) model to assess the exposure of flight attendants to the pyrethroid insecticide permethrin attributable to aircraft disinsection. The permethrin PBPK model was developed by adapting previous models for pyrethroids, and was parameterized using currently available metabolic parameters for permethrin. The human permethrin model was first evaluated with data from published human studies. Then, it was used to estimate urinary metabolite concentrations of permethrin in flight attendants who worked in aircrafts, which underwent residual and pre-flight spray treatments. The human model was also applied to analyze the toxicokinetics following permethrin exposures attributable to other aircraft disinsection scenarios. Predicted levels of urinary 3-phenoxybenzoic acid (3-PBA), a metabolite of permethrin, following residual disinsection treatment were comparable to the measurements made for flight attendants. Simulations showed that the median contributions of the dermal, oral and inhalation routes to permethrin exposure in flight attendants were 83.5%, 16.1% and 0.4% under residual treatment scenario, respectively, and were 5.3%, 5.0% and 89.7% under pre-flight spray scenario, respectively. The PBPK model provides the capability to simulate the toxicokinetic profiles of permethrin, and can be used in the studies on human exposure to permethrin.

Assessing exposure to tobacco-specific carcinogen NNK using its urinary metabolite NNAL measured in US population: 2011–2012

“…Other computational methods have been widely developed to address such issues—for example, physiologically based pharmacokinetic modeling combined with external exposure scenarios. 33 Further investigation is needed to characterize the dose variations and contributions of different tobacco exposure sources in population.…”

“…Within each iteration, a value of each parameter was randomly selected from its generated distribution. In order to avoid physiologically implausible values for the parameters involved in the simulation, we truncated the upper and lower bounds of each distribution at 1.96 times the SD above and below the mean, a method that includes 95% of the total distribution, following the methods used by Wei et al 33 The minimum, maximum, weighted means and variances for the measured urinary NNAL for each group were directly inputted into the MC simulations to obtain the distributions of daily absorption of NNK.…”

PBPK modeling of the cis- and trans-permethrin isomers and their major urinary metabolites in rats

“…In this paper, we propose to develop and calibrate a PBPK model for cis-and trans-permethrin in a Bayesian framework using data obtained from new in vivo experiments in rats exposed to the individual isomers. The PBPK model developed here is an extension of the PBPK models previously published Wei et al, 2013). The extended PBPK model includes the kinetic of the isomer of permethrin in additional organs and integrates the toxicokinetics of the three urinary metabolites that are commonly used as biomarkers of permethrin exposure (3-PBA, cis-and trans-DCCA) and the metabolite 4'OH-phenoxybenzoic acid (4'-OH-PBA) a major metabolite of permethrin (Takaku et al, 2011).…”

“…23 studies, the extended PBPK model can be also used in a reverse dosimetry context to assess the external exposure of human populations (Ulaszewska et al, 2012;Wetmore et al, 2012;Wei et al, 2013;Zeman et al, 2013;Cote et al, 2014;Huizer et al, 2014). These approaches are based on the interpretation of biomonitoring data using toxicokinetic models and individual characteristics to estimate the population or individual exposure (Clewell et al, 2008).…”

In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes

“…For non-persistent compounds such as pyrethroid insecticides, the metabolic clearances are model parameters that highly influence their internal levels in the body. Indeed, sensitivity analyses performed on a physiologically based pharmacokinetic (PBPK) model developed for permethrin in humans (Wei et al, 2013) showed that the hepatic intrinsic clearance was one of the most influential parameters for the blood concentration under several exposure scenarios, together with physiological parameters related to the absorption of the compound. The knowledge of the metabolic clearances is therefore a critical issue for the development of toxicokinetic models.…”