Protein binding of isofluorophate in vivo after coexposure to multiple chemicals.
Full toxicologic profiles of chemical mixtures, including dose-response extrapolations to realistic exposures, is a prohibitive analytical problem, even for a restricted class of chemicals. We present an approach to probing in vivo interactions of pesticide mixtures at relevant low doses using a monitor compound to report the response of biochemical pathways shared by mixture components. We use accelerator mass spectrometry (AMS) to quantify [14C]-diisopropylfluorophosphate as a tracer at attomole levels with 1-5% precision after coexposures to parathion (PTN), permethrin (PER), and pyridostigmine bromide separately and in conjunction. Pyridostigmine shows an overall protective effect against tracer binding in plasma, red blood cells, muscle, and brain that is not explained as competitive protein binding. PTN and PER induce a significant 25-30% increase in the amount of tracer reaching the brain with or without pyridostigmine. The sensitivity of AMS for isotope-labeled tracer compounds can be used to probe the physiologic responses of specific biochemical pathways to multiple compound exposures.
Vogel
John S
JS
University of California, Lawrence Livermore National Laboratory, Livermore, California, USA. jsvogel@llnl.gov
Keating
Garrett A
GA
Buchholz
Bruce A
BA
D000818:Animals; D001921:Brain; D002250:Carbon Radioisotopes; D002800:Cholinesterase Inhibitors / Q000009:adverse effects* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007306:Insecticides / Q000009:adverse effects* / Q000493:pharmacokinetics; D007531:Isoflurophate / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D010278:Parathion / Q000009:adverse effects* / Q000493:pharmacokinetics; D026023:Permethrin / Q000009:adverse effects* / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000378:metabolism*; D011485:Protein Binding; D011729:Pyridostigmine Bromide / Q000009:adverse effects* / Q000493:pharmacokinetics; D012680:Sensitivity and Specificity
D002250:Carbon Radioisotopes; D002800:Cholinesterase Inhibitors; D007306:Insecticides; D011480:Protease Inhibitors; D007531:Isoflurophate; D026023:Permethrin; D010278:Parathion; D011729:Pyridostigmine Bromide