Status epilepticus after C-4 ingestion: using liquid chromatography to quantify toxicity.

Context: C-4, a commonly used explosive in military operations, is sometimes consumed by soldiers as a rite of passage. The primary component of C-4 is cyclotrimethylenetrinitramine, or Research Department Explosive (RDX), which causes euphoria along with nausea, vomiting, renal injury, encephalopathy and convulsions when consumed in toxic amounts. We present a case of status epilepticus caused by known ingestion of C-4, in which serum levels of the compound were measured with high-performance liquid chromatography (HPLC). Case details: A 22-year-old active-duty male with no prior medical history was brought to the ED with convulsions that only minimally improved traditional anti-epileptic treatment. EEG showed persistent epileptiform activity despite initial management. Continuous propofol infusion, lacosamide and levitiracetam eventually broke the seizures. The patient eventually reported consuming a piece of C-4 four hours prior to the start of his seizure activity. Results: HPLC showed a peak RDX concentration of 3.06 µg/ml. RDX concentration at cessation of seizure activity was 2.43 µg/ml. Conclusion: Per our review of the literature, this is the first case where the explosive's toxicity could directly be measured over time in a human patient. C-4 poisoning must be considered when assessing sudden onset epileptiform activity in soldiers with access to this substance.

Development of a microextraction by packed sorbent with gas chromatography-mass spectrometry method for quantification of nitroexplosives in aqueous and fluidic biological samples.

A new method for quantification of 12 nitroaromatic compounds including 2,4,6-trinitrotoluene, its metabolites and 2,4,6-trinitrophenyl-N-methylnitramine with microextraction by packed sorbent followed by gas chromatography and mass spectrometric detection in environmental and biological samples is developed. The microextraction device employs 4 mg of C18 silica sorbent inserted into a microvolume syringe for sample preparation. Several parameters capable of influencing the microextraction procedure, namely, number of extraction cycles, washing solvent, volume of washing solvent, elution solvent, volume of eluting solvent and pH of matrix, were optimized. The developed method produced satisfactory results with excellent values of coefficient of determination (R2  > 0.9804) within the established calibration range. The extraction yields were satisfactory for all analytes (> 89.32%) for aqueous samples and (> 87.45%) for fluidic biological samples. The limits of detection values lie in the range 14-828 pg/mL.

Toxicokinetic Model Development for the Insensitive Munitions Component 2,4-Dinitroanisole.

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.

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

3-Nitro-1,2,4-triazol-5-one (NTO) is a component of insensitive munitions that are potential replacements for conventional explosives. Toxicokinetic data can aid in the interpretation of toxicity studies and interspecies extrapolation, but only limited data on the toxicokinetics and metabolism of NTO are available. To supplement these limited data, further in vivo studies of NTO in rats were conducted and blood concentrations were measured, tissue distribution of NTO was estimated using an in silico method, and physiologically based pharmacokinetic models of the disposition of NTO in rats and macaques were developed and extrapolated to humans. The model predictions can be used to extrapolate from designated points of departure identified from rat toxicology studies to provide a scientific basis for estimates of acceptable human exposure levels for NTO.

Acute barium toxicity from ingestion of "snake" fireworks.

INTRODUCTION: Ingestion of fireworks has been infrequently reported in the medical literature. We describe a case of acute barium poisoning following firework ingestion. CASE REPORT: A 35-year-old male with a history of severe mental retardation presented with vomiting and diarrhea following ingestion of 16 small fireworks ("color snakes" and "black snakes"). His condition rapidly deteriorated and he developed obtundation, wide complex dysrhythmias, and respiratory failure. Approximately 12 hours following ingestion, his serum potassium level was 1.5 mmol/L with a serum barium level of 20,200 microg/mL (reference range <200 microg/L). The patient eventually recovered with ventilatory support and potassium supplementation. DISCUSSION: Although firework ingestion is uncommon, clinicians should be prepared for potentially severe complications. In the case of barium poisoning, treatment consists of potassium supplementation, along with respiratory and hemodynamic support.

Physiologically based pharmacokinetic modeling of cyclotrimethylenetrinitramine in male rats.

A physiologically based pharmacokinetic (PBPK) model for simulating the kinetics of cyclotrimethylene trinitramine (RDX) in male rats was developed. The model consisted of five compartments interconnected by systemic circulation. The tissue uptake of RDX was described as a perfusion-limited process whereas hepatic clearance and gastrointestinal absorption were described as first-order processes. The physiological parameters for the rat were obtained from the literature whereas the tissue : blood partition coefficients were estimated on the basis of the tissue and blood composition as well as the lipophilicity characteristics of RDX (logP = 0.87). The tissue : blood partition coefficients (brain, 1.4; muscle, 1; fat, 7.55; liver, 1.2) obtained with this algorithmic approach were used without any adjustment, since a focused in vitro study indicated that the relative concentration of RDX in whole blood and plasma is about 1 : 1. An initial estimate of metabolic clearance of RDX (2.2 h(-1) kg(-1)) was obtained by fitting PBPK model simulations to the data on plasma kinetics in rats administered 5.5 mg kg(-1) i.v. The rat PBPK model without any further change in parameter values adequately simulated the blood kinetic data for RDX at much lower doses (0.77 and 1.04 mg (-1) i.v.), collected in this study. The same model, with the incorporation of a first order oral absorption rate constant (K(a) 0.75 h(-1)), reproduced the blood kinetics of RDX in rats receiving a single gavage dose of 1.53 or 2.02 mg kg(-1). Additionally, the model simulated the plasma and blood kinetics of orally administered RDX at a higher dose (100 mg kg(-1)) or lower doses (0.2 or 1.24 mg kg(-1)) in male rats. Overall, the rat PBPK model for RDX with its parameters adequately simulates the blood and plasma kinetic data, obtained following i.v. doses ranging from 0.77 to 5.5 mg kg(-1) as well as oral doses ranging from 0.2 to 100 mg kg(-1).

Analysis of acetylene in blood and urine using cryogenic gas chromatography-mass spectrometry.

A method for quantitative analysis of acetylene in blood and urine samples was investigated. Using cryogenic gas chromatography-mass spectrometry (GC-MS), acetylene was measured with isobutane as the internal standard in the headspace method, which revealed a linear response over the entire composite range with an excellent correlation coefficient, both in blood (R = 0.9968, range = 5.39-43.1 microg/ml) and urine (R = 0.9972, range = 2.16-10.8 microg/ml). The coefficients of variation (CV) for blood ranged from 2.62 to 11.6% for intra-day and 4.55 to 10.4% for inter-day. The CV for urine ranged from 2.38 to 3.10% for intra-day and 4.83 to 11.0% for inter-day. The recovery rate as an index of accuracy ranged from 83 to 111%. The present method showed good reliability, and is also simple and rapid. In actual samples from a charred cadaver due to acetylene explosion, the measured concentrations of acetylene by this method were 21.5 microg/ml for femoral vein blood, 17.9 microg/ml for right atrial blood, 25.5 microg/ml for left atrial blood and 7.49 microg/ml for urine. Quantification of acetylene provides important information, because the acetylene concentration is a vital reaction or sign. For example, when acetylene is filled in a closed space and then explodes, in antemortem explosion, the blood acetylene concentration of the cadaver might be significant. On the other hand, in postmortem explosion, acetylene is not detected in blood. Furthermore, when several victims are involved in one explosion, comparison of the sample concentrations can also provide useful information to establish the conditions at the accident scene; therefore, the present method is useful in forensics.

Biomonitoring of workers cleaning up ammunition waste sites.

2,4,6-Trinitrotoluene (TNT) is an important occupational and environmental pollutant. In TNT-exposed humans, notable toxic manifestations have included aplastic anaemia, toxic hepatitis, cataracts, hepatomegaly and liver cancer. Therefore, it is important to develop protection measures and to monitor workers involved in the clean-up of ammunition sites. Haemoglobin (Hb) adducts of TNT, 4-amino-2,6-dinitrotoluene (4ADNT) and 2-amino-4,6-dinitrotoluene (2ADNT), and the urine metabolites of TNT, 4ADNT and 2ADNT were found in 22-50% of the exposed workers, but not in the control group. The exposed workers were wearing protective equipment. The levels of erythrocytes, haemoglobin, creatinine, serum glutamic pyruvic transaminase and lymphocyte levels were significantly lower in the exposed workers than in the non-exposed workers. The levels of blood urea and reticulocytes were significantly higher in the exposed workers than in the non-exposed workers. Headache (26%), mucous membrane irritation (16%), sick leave (18%), lassitude (8%), anxiety (6%), shortness of breath (3%), nausea (5%) and allergic reactions (8%) were reported by the exposed workers. In a further analysis the U-4ADNT levels and the Hb-adduct levels were compared to the blood parameter and the health effects. The blood parameters were not significantly different between the U-4ADNT positive and U-4ADNT-negative group. Headache, mucous membrane irritation, sick leave, lassitude, anxiety, shortness of breath and allergic reactions were statistically not different between the two groups. Also in the workers with Hb-4ADNT adducts no significant negative changes were seen in regards to the changes of the blood parameters or the health effects. According to the results of the present study, it appears that the blood parameter changes and the health effects are more influenced by other factors than by the internal exposure to TNT.