Development of a physiologically based pharmacokinetic (PBPK) model for methyl iodide in rats, rabbits, and humans

Abstract

Methyl iodide (MeI) has been proposed as an alternative to methyl bromide as a pre-plant soil fumigant that does not deplete stratospheric ozone. In inhalation toxicity studies performed in animals as part of the registration process, three effects have been identified that warrant consideration in developing toxicity reference values for human risk assessment: nasal lesions (rat), acute neurotoxicity (rat), and fetal loss (rabbit). Uncertainties in the risk assessment can be reduced by using an internal measure of target tissue dose that is linked to the likely mode of action (MOA) for the toxicity of MeI, rather than the external exposure concentration. Physiologically based pharmacokinetic (PBPK) models have been developed for MeI and used to reduce uncertainties in the risk assessment extrapolations (e.g. interspecies, high to low dose, exposure scenario). PBPK model-derived human equivalent concentrations comparable to the animal study NOAELs (no observed adverse effect levels) for the endpoints of interest were developed for a 1-day, 24-hr exposure of bystanders or 8 hr/day exposure of workers. Variability analyses of the PBPK models support application of uncertainty factors (UF) of approximately 2 for intrahuman pharmacokinetic variability for the nasal effects and acute neurotoxicity.

Keywords::

• Methyl iodide
• physiologically based pharmacokinetic (PBPK) modeling
• iodide
• glutathione

Acknowledgments

Financial support was provided by Arysta LifeScience Corporation. We are grateful to Drs. Rick Corley, Jim Morris, and Torka Poet (PNNL), Drs. Matt Himmelstein, Ray Kemper, and Mike DeLorme (DuPont-Haskell Laboratory), Ed Kaiser (Exygen) and Dr. Eddie Sloter (WIL Laboratories) for providing preliminary data to expedite modeling. We also thank Elaine Merrill (Geo-Centers), who provided the perchlorate/iodide model code. We appreciate valuable discussions with Drs. Paul Schlosser and Hugh Barton (US EPA) regarding model parameter values and application of the model in risk assessment.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.