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

Journal of Exposure Science & Environmental Epidemiology volume 23, pages 416–427 (2013)Cite this article

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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.

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Acknowledgements

The research reported in this study was funded by the US Federal Aviation Administration (FAA) Office of Aerospace Medicine through the National Air Transportation Center of Excellence for Research in the Intermodal Transport Environment, Aircraft Cabin Environment Research (ACER) under Cooperative Agreement 07-C-RITE-UMDNJ. Although the FAA has sponsored this project, it neither endorses nor rejects the findings of this research. This research was supported in part by the NIEHS sponsored Center for Environmental Exposure and Disease, Grant No. P30ES005022.

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Authors and Affiliations

  1. Environmental and Occupational Health Sciences Institute, A Joint Institute of Rutgers University and University of Medicine and Dentistry of New Jersey, Piscataway, 08854, New Jersey, USA

    Binnian Wei, Sastry S Isukapalli & Clifford P Weisel

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  1. Binnian Wei
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  2. Sastry S Isukapalli
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  3. Clifford P Weisel
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Correspondence to Clifford P Weisel.

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APPENDIX I

APPENDIX I

PBPK MODEL EQUATIONS

Q c :

cardiac output (l/h)

Q p :

alveolar ventilation rate (l/h)

C vt :

the tissue venous blood concentration (mg/l)

AV i :

venous amount in organ i

V i :

Volume of compartment i

A i :

amount of permethrin in the compartment i

Q i :

blood flow to the compartment i

P i: b :

tissue:blood partition coefficient for the compartment i

C i :

concentrations in the compartment i

PVF i :

blood volume fraction of compartment i

PA i :

permeability–surface area product of tissue (l/h)

Inhale_Conc :

inhaled airborne concentration of permethrin (mg/l)

M BLD :

amount of permethrin in blood (mg/h)

CA :

concentration in blood compartment (mg/l)

VB :

blood volume

ODRate :

oral dose rate (mg/h)

Stomach :

amount of permethrin in stomach (mg)

Intestine :

amount of permethrin in intestine (mg)

K s :

rate constant of absorption from stomach (h−1)

K i :

rate constant of absorption from intestine (h−1)

K si :

rate constant of transfer from stomach to intestine (h−1)

K fec :

fecal excretion rate constant (h−1).

A skin :

amount of permethrin in the skin compartment

Q skin :

blood flow to the skin compartment

P skin:b :

skin compartment:blood partition coefficient

C skin :

concentrations in skin compartment

derm_rate :

dose rate from dermal absorption

SL :

surface loading of permethrin (μg/cm2)

SA :

body surface area in direct contact with surface (cm2)

TF :

transferable surface residue of permethrin to exposed dermal

CABF :

cumulative absorbed dose fraction (%)

exp_time :

exposure duration (h).

met :

amount of metabolized permethrin in excretion compartment (mg)

RAM liver :

rate of metabolism in liver (mg/h)

RAM BLD :

rate of clearance in blood (mg/h)

RAM i :

rate of metabolism from compartment i (mg/h)

M BLD :

amount of permethrin in blood (mg)

:

amount of excreted permethrin through urine (mg)

K ur :

urinary excretion rate constant (h−1)

Model Equations

Rate of change in stomach (mg/h):

Rate of change in intestine (mg/h):

Rate of change in blood (mg/h):

Rate of clearance in blood (mg/h):

Permethrin concentration in blood (mg/l):

Distribution in flow-limited tissues (except liver and skin compartments):

Rate of change in liver compartment:

Rate of change in skin compartment:

Dermal absorption rate estimation:

Distribution in diffusion-limited tissues (fat, brain and slow perfused tissues):

Rate of change estimation for metabolized permethrin in excretion compartment (mg/h):

Excretion of metabolized permethrin through urine:

Urinary concentration:

where Conc is the urinary concentration for a specific metabolite of permethrin. is the cumulative mass of permethrin metabolite during two excretion time points (mg). is the cumulative urine volume at the same duration (l). As for flight attendants, the time duration from the last excretion time to the sampling time point was in the range from 1to 4 h, and the corresponding urine volume was in the range from 0.03 to 0.75 l.

Table a1 Correlation coefficient matrix for physiological parameters generated by 50,000 iterations in the Montel Carlo simulation.
Full size table

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Wei, B., Isukapalli, S. & Weisel, C. Studying permethrin exposure in flight attendants using a physiologically based pharmacokinetic model. J Expo Sci Environ Epidemiol 23, 416–427 (2013). https://doi.org/10.1038/jes.2013.12

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