Toxicokinetics and tolerance of a high energy material 3,4,5-trinitropyrazole (TNP) in mice.
Toxicol Appl Pharmacol
; 355: 103-111, 2018 09 15.
Article
en En
| MEDLINE
| ID: mdl-29959026
ABSTRACT
The high-energy compound 3,4,5-trinitropyrazole (TNP) was developed as an alternative to other less energetic and more sensitive explosive materials, in particular 1-methyl-2,4,6-trinitrobenzene (TNT). However, the level of toxicity of TNP remains understudied. Here using an in vivo CD1 mouse model, we mimicked an acute exposure (24â¯h) to TNP, given either orally or intravenously, and determined the maximum administrable doses (190â¯mg/kg and 11â¯mg/kg, respectively), as well as the lethal dose for 50% (LD50) of female or male mice (390â¯mg/kg for both) treated intravenously with TNP alone. Several metabolites including nitroso-dinitro-pyrazole, hydroxylamino-dinitro-pyrazole, hydroxyl-dinitro-pyrazole and amino-dinitro-pyrazole were identified in urine. TNP is quickly metabolized and eliminated via urine as two main amino-dinitro-pyrazole metabolites. A comparison of the transcriptomic effects of TNP and TNT after 10â¯days exposure enabled us to demonstrate no major induction of transcripts involved both in cell death mechanisms (apoptosis, necrosis, autophagy) and physiological pathways (glycolysis, ATP production). Finally, subchronic exposure to TNP was replicated in female mice, fed 16.8-52.8â¯mg/kg/day of TNP for one month, to study the impact on cellular functions. Although blood TNP levels remained high, a lower rate of TNP accumulation in the liver and lungs were observed than during an acute exposure. Conversely, cellular stress functions explored using the RT2 Profiler™ PCR Array Mouse Molecular Toxicology PathwayFinder remained unaltered after this chronic exposure. These findings demonstrate that TNP can be rapidly eliminated in vivo without accumulating in vital organs.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sustancias Explosivas
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Toxicol Appl Pharmacol
Año:
2018
Tipo del documento:
Article
País de afiliación:
Francia