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.

2,4‐dinitroanisole transformation during advanced oxidation with ultraviolet light emitting diodes and hydrogen peroxide

“…DNAN is present in the wastewaters generated from munitions manufacturing and training ranges (Thiboutot et al, 2012). DNAN toxicity can inhibit the activities of multiple bacterial groups (Dodard et al, 2013; Liang et al, 2013), and it is associated with neurotoxicity in rats (Sweeney et al, 2015). DNAN must be removed from wastewater.…”

Mitochondrial DNA Haplogroups and Frailty in Adults Living with HIV

“…22 Race and ethnicity were by self-report. 29 Variables that were significantly associated ( p < .1) with at least one outcome were included in the final models, which were all adjusted for age (continuous, per year), gender at birth, education level (continuous, per year), smoking (never, prior, and current), hepatitis C antibody positivity, and any prior use of didanosine or stavudine. Additional variables that were considered but not included in the final models were BMI, current or prior use of efavirenz or an integrase strand transferase inhibitor, and CD4 + T cell count nadir.…”

Toxicokinetic Model Development for the Insensitive Munitions Component 3-Nitro-1,2,4-Triazol-5-One

“…25 For the structurally related compound DNAN, partition coefficients estimated in vivo, in vitro, and in silico were found to be similar. 27…”

“…25 For the structurally related compound DNAN, partition coefficients estimated in vivo, in vitro, and in silico were found to be similar. 27 The relationships between external and internal doses, shown in Figure 6, can be used to convert a wide range of rat doses to equivalent human doses. As an example, the rat BMDL 10 of 38 mg/kg/d is predicted to yield the same average blood concentration as a human bolus dose of 5.6 mg/kg/d or continuous (12 hours) dose of 6.1 mg/kg/d.…”

“…The preliminary model structure (Figure 1) and anatomical parameter values (Table 1) were taken from PBPK models developed for the structurally related, nitrogen rich compounds RDX [24][25][26] and 2,4dintiroanisole (DNAN). 27 Briefly, equilibrium between tissue and venous blood was assumed for all tissues, and metabolism was assumed to take place in the liver. Based on initial modeling efforts and evaluation of key data sets, urinary clearance and saturable reabsorption of NTO from glomerular urinary filtrate to the kidney (richly perfused tissues) were added to the model structure, per Loccisano et al 22,23 Models were developed and simulations conducted using acslX version 3.0.2.1 (AEgis Technologies Group, Inc, Huntsville, AL), and Gear algorithm for stiff equations.…”