title: Toxicokinetic Model Development for the Insensitive Munitions Component 2,4-Dinitroanisole.
abstract: The Armed Forces are developing new explosives that are less susceptible to unintentional detonation (insensitive munitions [IMX]). 2,4-Dinitroanisole (DNAN) is a component of IMX. Toxicokinetic data for DNAN are required to support interpretation of toxicology studies and refinement of dose estimates for human risk assessment. Male Sprague-Dawley rats were dosed by gavage (5, 20, or 80 mg DNAN/kg), and blood and tissue samples were analyzed to determine the levels of DNAN and its metabolite 2,4-dinitrophenol (DNP). These data and data from the literature were used to develop preliminary physiologically based pharmacokinetic (PBPK) models. The model simulations indicated saturable metabolism of DNAN in rats at higher tested doses. The PBPK model was extrapolated to estimate the toxicokinetics of DNAN and DNP in humans, allowing the estimation of human-equivalent no-effect levels of DNAN exposure from no-observed adverse effect levels determined in laboratory animals, which may guide the selection of exposure limits for DNAN.
authors.affiliation: Henry M. Jackson Foundation for the Advancement of Military Medicine, Naval Medical Research Unit Dayton (NAMRUD), Wright Patterson Air Force Base, OH, USA lisa.sweeney.3.ctr@us.af.mil.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sweeney
authors.affiliation: CAMRIS, NAMRUD, Wright Patterson Air Force Base, OH, USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Goodwin
authors.affiliation: Oak Ridge Institute for Science and Education, NAMRUD, Wright Patterson Air Force Base, OH, USA.
authors.forename: Angela D
authors.initials: AD
authors.lastname: Hulgan
authors.affiliation: CAMRIS, NAMRUD, Wright Patterson Air Force Base, OH, USA.
authors.forename: Chester P
authors.initials: CP
authors.lastname: Gut
authors.affiliation: US Army Public Health Command, Institute of Public Health, Toxicology Portfolio, Aberdeen Proving Ground, MD, USA.
authors.forename: Desmond I
authors.initials: DI
authors.lastname: Bannon
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000840:Anisoles / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D053834:Explosive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D019055:No-Observed-Adverse-Effect Level; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D066007:Toxicokinetics
chemical_list: D000840:Anisoles; D053834:Explosive Agents; C539360:2,4-dinitroanisole
keywords: 2, 4-dinitroanisole; 2, 4-dinitrophenol; insensitive munitions; physiologically based pharmacokinetic (PBPK) model; toxicokinetics