PBTK model for assessment of operator exposure to haloxyfop using human biomonitoring and toxicokinetic data

Alexander B. Cooper*, Manoj Aggarwal, Michael J. Bartels, Alistair Morriss, Claire Terry, Gwyn A. Lord, Timothy Gant

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Physiologically-based toxicokinetic (PBTK) models are mathematical representations of chemical absorption, distribution, metabolism and excretion (ADME) in animals. Each parameter in a PBTK model describes a physiological, physicochemical or biochemical process that affects ADME. Distributions can be assigned to the model parameters to describe population variability and uncertainty. In this study to assess potential crop sprayer operator exposure to the herbicide haloxyfop, a permeability-limited PBTK model was constructed with parameter uncertainty and variability, and calibrated using Bayesian analysis via Markov chain Monte Carlo methods. A hierarchical statistical model was developed to reconstruct operator exposure using available measurement data: experimentally determined octanol/water partition coefficient, mouse and human toxicokinetic data as well as human biomonitoring data from seven operators who participated in a field study. A chemical risk assessment was performed by comparing the estimated systemic exposure to the acceptable operator exposure level (AOEL). The analysis suggested that in one of the seven operators, the model estimates systemic exposure to haloxyfop of 49.04 ± 10.19 SD μg/kg bw in relation to an AOEL of 5.0 μg/kg bw/day. This does not represent a safety concern as this predicted exposure is well within the 100-fold uncertainty factor applied to the No Observed Adverse Effect Level (NOAEL) in animals. In addition, given the availability of human toxicokinetic data, the 10x uncertainty factor for interspecies differences in ADME could be reduced (EFSA, 2006). Thus the AOEL could potentially be raised tenfold from 5.0 to 50.0 μg/kg bw/day.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalRegulatory Toxicology and Pharmacology
Publication statusPublished - Mar 2019

Bibliographical note

Funding Information:
The research was funded by the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Health Impact of Environmental Hazards at King's College London in partnership with Public Health England and Imperial College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, the Department of Health and Social Care or Public Health England .

Publisher Copyright:
© 2018

Copyright 2019 Elsevier B.V., All rights reserved.


  • Bayesian analysis
  • Haloxyfop
  • PBTK model
  • Pesticides
  • Risk assessment


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