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J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Sep 1;1093-1094:119-127. doi: 10.1016/j.jchromb.2018.07.004. Epub 2018 Jul 5.

Determination of methyl isopropyl hydantoin from rat erythrocytes by gas-chromatography mass-spectrometry to determine methyl isocyanate dose following inhalation exposure.

Author information

1
Department of Chemistry and Biochemistry, South Dakota State University, Avera Health and Science, Box 2202, Brookings, SD 57007, United States of America. Electronic address: brian.logue@sdstate.edu.
2
Department of Chemistry and Biochemistry, South Dakota State University, Avera Health and Science, Box 2202, Brookings, SD 57007, United States of America.
3
MRIGlobal, 425 Volker Boulevard, Kansas City, MO 64110-2241, United States of America.
4
Pediatrics-Pulmonary Medicine, University of Colorado-Denver, Denver, CO, 80045, United States of America.

Abstract

Methyl isocyanate (MIC) is an important precursor for industrial synthesis, but it is highly toxic. MIC causes irritation and damage to the eyes, respiratory tract, and skin. While current treatment is limited to supportive care and counteracting symptoms, promising countermeasures are being evaluated. Our work focuses on understanding the inhalation toxicity of MIC to develop effective therapeutic interventions. However, in-vivo inhalation exposure studies are limited by challenges in estimating the actual respiratory dose, due to animal-to-animal variability in breathing rate, depth, etc. Therefore, a method was developed to estimate the inhaled MIC dose based on analysis of an N-terminal valine hemoglobin adduct. The method features a simple sample preparation scheme, including rapid isolation of hemoglobin, hydrolysis of the hemoglobin adduct with immediate conversion to methyl isopropyl hydantoin (MIH), rapid liquid-liquid extraction, and gas-chromatography mass-spectrometry analysis. The method produced a limit of detection of 0.05 mg MIH/kg RBC precipitate with a dynamic range from 0.05-25 mg MIH/kg. The precision, as measured by percent relative standard deviation, was <8.5%, and the accuracy was within 8% of the nominal concentration. The method was used to evaluate a potential correlation between MIH and MIC internal dose and proved promising. If successful, this method may be used to quantify the true internal dose of MIC from inhalation studies to help determine the effectiveness of MIC therapeutics.

KEYWORDS:

Gas-chromatography mass-spectrometry; Inhalation exposure; Liquid-liquid extraction; Methyl isocyanate

PMID:
30015309
PMCID:
PMC6218199
[Available on 2019-09-01]
DOI:
10.1016/j.jchromb.2018.07.004
[Indexed for MEDLINE]

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