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This work is part two of a three-part series in this issue of a Sweden-United States collaborative effort towards the understanding of the chemical attribution signatures of Russian VX (VR) in synthesized samples and complex food matrices. In this study, we describe the sourcing of VR present in food based on chemical analysis of attribution signatures by liquid chromatography-tandem mass spectrometry (LC-MS/MS) combined with multivariate data analysis. Analytical data was acquired from seven different foods spiked with VR batches that were synthesized via six different routes in two separate laboratories. The synthesis products were spiked at a lethal dose into seven food matrices: water, orange juice, apple purée, baby food, pea purée, liquid eggs and hot dog. After acetonitrile sample extraction, the samples were analyzed by LC-MS/MS operated in MRM mode. A multivariate statistical calibration model was built on the chemical attribution profiles from 118 VR spiked food samples. Using the model, an external test-set of the six synthesis routes employed for VR production was correctly identified with no observable major impact of the food matrices to the classification. The overall performance of the statistical models was found to be exceptional (94%) for the test set samples retrospectively classified to their synthesis routes., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Organophosphorus pesticides acephate and chlorpyrifos in foods have potential to impact human health. The aim of the current study was to investigate the pharmacokinetics of acephate and chlorpyrifos orally administered at lowest-observed-adverse-effect-level doses in chimeric mice transplanted with human hepatocytes. Absorbed acephate and its metabolite methamidophos were detected in serum from wild type mice and chimeric mice orally administered 150mg/kg. Approximately 70% inhibition of cholinesterase was evident in plasma of chimeric mice with humanized liver (which have higher serum cholinesterase activities than wild type mice) 1day after oral administrations of acephate. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated plasma concentrations of acephate and chlorpyrifos in humans were consistent with reported concentrations. Acephate cleared similarly in humans and chimeric mice but accidental/incidental overdose levels of chlorpyrifos cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in mice. The data presented here illustrate how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of toxicological potential of organophosphorus pesticides., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The biomarkers acetylcholinesterase (AChE) and glutathione S-transferase (GST) were measured in fourth-instar Chironomus riparius Meigen larvae exposed to the organophosphate insecticide pirimiphos methyl (0, 5, 10, and 50ng/g) for 48 or 96h, and at high or low food ration. Larvae exposed to 50ng/g pirimiphos methyl died within 48h. The weight of larvae exposed to 10ng/g pirimiphos methyl was significantly lower than those exposed to 0 and 5ng/g. AChE activity was significantly reduced in larvae exposed to 10ng/g, but GST activity remained unaffected. Lower food ration reduced larval weights across all treatments but did not affect biomarker measurements. Insecticide exposure was associated with a longer time to adult emergence and oviposition, fewer egg masses, a greater proportion of deformed egg masses, and fewer eggs.

Fourth-instar Chironomus riparius Meigen larvae were exposed to the organophosphate (OP) insecticide pirimiphos methyl (0, 0.1, 1.0, and 10 microg/L) for 48, 72, or 96 h at three temperatures (3, 12, or 22 degrees C). Two biochemical biomarkers, acetylcholinesterase (AChE) and glutathione S-transferase (GST), were measured in individual larvae from each treatment. AChE activity was inhibited by the OP in a dose-responsive fashion. This response remained similar at all three temperatures, demonstrating that AChE is a robust and specific biomarker. Exposure duration had little effect on AChE activity. In contrast, GST activity was induced at the highest OP insecticide concentration, but induction was also evident at 3 degrees C. There was a significant effect of exposure duration, with an overall decline in GST activity over time. This result agrees with previous work suggesting that GSTs are not particularly suitable for use as a biomarker of pesticide exposure or effect in Chironomus., ((c) 2002 Elsevier Science (USA).)

The U.S. Army has estimated acute lethality guideline levels for inhalation of the chemical warfare agents mustard, GB, and VX. These levels are expressed as dosages measured in milligram-minutes per cubic meter (mg-min/m(3)). The National Advisory Council has also proposed acute emergency guideline levels (AEGLs) for the agents. The AEGLs are threshold exposure limits for the general public for mild effects, serious adverse effects, and lethality. They are expressed as air concentrations (in units of mg/m(3)) and are applicable to emergency exposure periods ranging from 10 min to 8 h. The report discusses strengths and deficiencies in the levels, important parameters (i.e., exposure time, breathing rate) that need to be explicitly addressed in deriving the guideline levels, and possible impacts that could result from using AEGLs instead of guideline dosages in future assessments., (Copyright 2002 Elsevier Science (USA))

Discrepancies in the aging reaction between neuropathy target esterase (NTE) inhibited in vitro and in vivo by racemic mixtures of O-alkyl O-2,5-dichlorophenyl phosphoramidates have been observed. It suggested the existence of differences in the interactions (inhibition and aging) between NTE and each stereoisomers of the above mentioned compounds. In order to verify this hypothesis, stereoisomers of O-hexyl O-2,5-dichlorophenyl phosphoramidate (HDCP) were isolated by chiral column chromatography, followed by the evaluation of NTE inhibition and aging for each stereoisomers. The loss of reactivation capacity by KF was used as criterion of aging. The stereoisomer S-(-)-HDCP inhibited hen brain NTE with an I50 of 7.6 nM for 30 min of incubation, this being similar to the value obtained for the racemic mixture (I50 = 6.2 nM), and much lower than that recorded for R-(+)-HDCP (I50 = 191 nM). NTE inhibited by HDCP racemic mixture and the stereoisomer S-(-)-HDCP was reactivated by KF after 20 h of incubation at 37 degrees C. The NTE inhibited by R-(+)-HDCP could not be fully reactivated after inhibition.

Thirty-five workers became ill after they entered a cauliflower field contaminated with residues of three different insecticides, the organophosphates oxydemeton-methyl (Metasystox-R) and mevinphos (Phosdrin), and a carbamate, methomyl (Lannate). One crew member was pregnant with a 4-week-old fetus. At birth, the 3200-g female infant had multiple cardiac defects, bilateral optic nerve colobomas, microphthalmia of the left eye, cerebral and cerebellar atrophy, and facial anomalies. The cardiac defects included ventricular and atrial septal defects, stenosis of the pulmonary artery, and a patent ductus arteriosus. The child died at 14 days of age. There was no family history of birth defects, nor any maternal risk factor present, except that doxylamine (Bendectin) had been prescribed at 9 weeks fetal age. It is unlikely that doxylamine was responsible for the observed anomalies. Of the three chemicals involved, reproductive effects in test organisms have been observed only with oxydemeton-methyl. This case represents the first report of human malformations associated with prenatal exposure to this chemical. Further studies may be warranted to determine if a causal relationship exists.