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Title: Time course of cholinesterase inhibition in adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl or propoxur

Abstract

To compare the toxicity of seven N-methyl carbamates, time course profiles for brain and red blood cell (RBC) cholinesterase (ChE) inhibition were established for each. Adult, male, Long Evans rats (n = 4-5 dose group) were dosed orally with either carbaryl (30 mg/kg in corn oil); carbofuran (0.5 mg/kg in corn oil); formetanate HCl (10 mg/kg in water); methomyl (3 mg/kg in water); methiocarb (25 mg/kg in corn oil); oxamyl (1 mg/kg in water); or propoxur (20 mg/kg in corn oil). This level of dosing produced at least 40% brain ChE inhibition. Brain and blood were taken from 0.5 to 24 h after dosing for analysis of ChE activity using two different methods: (1) a radiometric method which limits the amount of reactivation of ChE activity, and (2) a spectrophotometric method (Ellman method using traditional, unmodified conditions) which may encourage reactivation. The time of peak ChE inhibition was similar for all seven N-methyl carbamate pesticides: 0.5-1.0 h after dosing. By 24 h, brain and RBC ChE activity in all animals returned to normal. The spectrophotometric method underestimated ChE inhibition. Moreover, there was a strong, direct correlation between brain and RBC ChE activity (radiometric assay) for all seven compounds combined (rmore » {sup 2} = 0.73, slope 1.1), while the spectrophotometric analysis of the same samples showed a poor correlation (r {sup 2} = 0.09). For formetanate, propoxur, methomyl, and methiocarb, brain and RBC ChE inhibitions were not different over time, but for carbaryl, carbofuran and oxamyl, the RBC ChE was slightly more inhibited than brain ChE. These data indicate (1) the radiometric method is superior for analyses of ChE activity in tissues from carbamate-treated animals (2) that animals treated with these N-methyl carbamate pesticides are affected rapidly, and recover rapidly, and (3) generally, assessment of RBC ChE is an accurate predictor of brain ChE inhibition for these seven pesticides.« less

Authors:
 [1];  [2];  [3];  [4]
  1. Cellular and Molecular Toxicology Branch, Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States). E-mail: Padilla.Stephanie@epa.gov
  2. Cellular and Molecular Toxicology Branch, Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States). E-mail: Marshall.renee@epa.gov
  3. Cellular and Molecular Toxicology Branch, Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States). E-mail: Hunter.deborah@epa.gov
  4. Office of Pesticide Programs, OPPTS, U.S. Environmental Protection Agency, Washington, DC 20460 (United States). E-mail: Lowit.anna@epa.gov
Publication Date:
OSTI Identifier:
20976886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 219; Journal Issue: 2-3; Other Information: DOI: 10.1016/j.taap.2006.11.010; PII: S0041-008X(06)00425-X; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BLOOD CELLS; BRAIN; CARBAMATES; CHOLINESTERASE; CORN OIL; CORRELATIONS; HYDROCHLORIC ACID; IN VIVO; INHIBITION; PESTICIDES; RATS; SPECTROPHOTOMETRY; TOXICITY

Citation Formats

Padilla, S., Marshall, R.S., Hunter, D.L., and Lowit, A. Time course of cholinesterase inhibition in adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl or propoxur. United States: N. p., 2007. Web. doi:10.1016/j.taap.2006.11.010.
Padilla, S., Marshall, R.S., Hunter, D.L., & Lowit, A. Time course of cholinesterase inhibition in adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl or propoxur. United States. doi:10.1016/j.taap.2006.11.010.
Padilla, S., Marshall, R.S., Hunter, D.L., and Lowit, A. Thu . "Time course of cholinesterase inhibition in adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl or propoxur". United States. doi:10.1016/j.taap.2006.11.010.
@article{osti_20976886,
title = {Time course of cholinesterase inhibition in adult rats treated acutely with carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl or propoxur},
author = {Padilla, S. and Marshall, R.S. and Hunter, D.L. and Lowit, A.},
abstractNote = {To compare the toxicity of seven N-methyl carbamates, time course profiles for brain and red blood cell (RBC) cholinesterase (ChE) inhibition were established for each. Adult, male, Long Evans rats (n = 4-5 dose group) were dosed orally with either carbaryl (30 mg/kg in corn oil); carbofuran (0.5 mg/kg in corn oil); formetanate HCl (10 mg/kg in water); methomyl (3 mg/kg in water); methiocarb (25 mg/kg in corn oil); oxamyl (1 mg/kg in water); or propoxur (20 mg/kg in corn oil). This level of dosing produced at least 40% brain ChE inhibition. Brain and blood were taken from 0.5 to 24 h after dosing for analysis of ChE activity using two different methods: (1) a radiometric method which limits the amount of reactivation of ChE activity, and (2) a spectrophotometric method (Ellman method using traditional, unmodified conditions) which may encourage reactivation. The time of peak ChE inhibition was similar for all seven N-methyl carbamate pesticides: 0.5-1.0 h after dosing. By 24 h, brain and RBC ChE activity in all animals returned to normal. The spectrophotometric method underestimated ChE inhibition. Moreover, there was a strong, direct correlation between brain and RBC ChE activity (radiometric assay) for all seven compounds combined (r {sup 2} = 0.73, slope 1.1), while the spectrophotometric analysis of the same samples showed a poor correlation (r {sup 2} = 0.09). For formetanate, propoxur, methomyl, and methiocarb, brain and RBC ChE inhibitions were not different over time, but for carbaryl, carbofuran and oxamyl, the RBC ChE was slightly more inhibited than brain ChE. These data indicate (1) the radiometric method is superior for analyses of ChE activity in tissues from carbamate-treated animals (2) that animals treated with these N-methyl carbamate pesticides are affected rapidly, and recover rapidly, and (3) generally, assessment of RBC ChE is an accurate predictor of brain ChE inhibition for these seven pesticides.},
doi = {10.1016/j.taap.2006.11.010},
journal = {Toxicology and Applied Pharmacology},
number = 2-3,
volume = 219,
place = {United States},
year = {Thu Mar 15 00:00:00 EDT 2007},
month = {Thu Mar 15 00:00:00 EDT 2007}
}
  • The bioavailability of bound residues from radishes treated with (/sup 14/C)dieldrin and (/sup 14/C)carbofuran was investigated by feeding the rats /sup 14/C material obtained after exhaustive solvent extraction. For comparison, nonextracted radishes were also fed to rats. The /sup 14/C residues were predominantly excreted in feces. Urinary excretion of /sup 14/C from rats fed nonextracted material was relatively greater than from those fed extracted radishes. The excreted material from rats fed dieldrin-treated radishes contained mainly parent compounds as residue. However, carbofuran and two of its metabolites, 3-hydroxycarbofuran and 3-ketocarbofuran, were present in feces and urine samples of rats fed carbofuran-treatedmore » radishes. These data demonstrated that bound residues in radishes treated with dieldrin and carbofuran have a low degree of bioavailability in rats. The results also show that bound residues in dieldrin-treated radishes would be more bioavailable than in the carbofuran-treated samples.« less
  • We evaluated the inhibition of striatal cholinesterase activity following intracerebral administration of paraoxon assaying activity either in tissue homogenates ex vivo or by substrate hydrolysis in situ. Artificial cerebrospinal fluid (aCSF) or paraoxon in aCSF was infused unilaterally (0.5 {mu}l/min for 2 h) and ipsilateral and contralateral striata were harvested for ChE assay ex vivo. High paraoxon concentrations were needed to inhibit ipsilateral striatal cholinesterase activity (no inhibition at < 0.1 mM; 27% at 0.1 mM; 79% at 1 mM paraoxon). With 3 mM paraoxon infusion, substantial ChE inhibition was also noted in contralateral striatum. ChE histochemistry generally confirmed thesemore » concentration- and side-dependent effects. Microdialysates collected for up to 4 h after paraoxon infusion inhibited ChE activity when added to striatal homogenate, suggesting prolonged efflux of paraoxon. Since paraoxon efflux could complicate acetylcholine analysis, we evaluated the effects of paraoxon (0, 0.03, 0.1, 1, 10 or 100 {mu}M, 1.5 {mu}l/min for 45 min) administered by reverse dialysis through a microdialysis probe. ChE activity was then monitored in situ by perfusing the colorimetric substrate acetylthiocholine through the same probe and measuring product (thiocholine) in dialysates. Concentration-dependent inhibition was noted but reached a plateau of about 70% at 1 {mu}M and higher concentrations. Striatal acetylcholine was below the detection limit at all times with 0.1 {mu}M paraoxon but was transiently elevated (0.5-1.5 h) with 10 {mu}M paraoxon. In vivo paraoxon (0.4 mg/kg, sc) in adult rats elicited about 90% striatal ChE inhibition measured ex vivo, but only about 10% inhibition measured in situ. Histochemical analyses revealed intense AChE and glial fibrillary acidic protein staining near the cannula track, suggesting proliferation of inflammatory cells/glia. The findings suggest that ex vivo and in situ cholinesterase assays can provide very different views into enzyme-inhibitor interactions. Furthermore, the proliferation/migration of cells containing high amounts of cholinesterase just adjacent to a dialysis probe could affect the recovery and thus detection of extracellular acetylcholine in microdialysis studies.« less
  • The degree of interaction between mercury and cholinesterase inhibiting pesticides was determined by comparing enzyme responses to sublethal dosages of parathion or carbofuran in quail fed 0.05, 0.5, or 5.0 ppM morsodren for 18 weeks. A statistically significant interaction was defined as greater brain cholinesterase inhibition in morsodren-fed than in clean-fed birds following pesticide dosage. The tissue residues of mercury that accumulated before significant mercury-parathion interactions occurred were higher than levels that might be expected in natural populations, but significant mercury-carbofuran interactions occurred in birds that had only accumulated 1.0 ppM liver mercury. The results indicate that indiscriminate usage ofmore » cholinesterase inhibiting pesticides is dangerous, since natural populations of fish-eating birds oftentimes contain this magnitude of mercury.« less
  • Time course of /sup 3/H-physostigmine (Phy) concentration and cholinesterase (ChE) activity in plasma and tissues was studied in rats pretreated with Phy and then soman. Rats were dosed with Phy (100 ..mu..g/kg, i.v.), 5 or 15 min prior to soman (105 ..mu..g/kg, 1.5 LD/sub 50/, s.c.) treatment and were sacrificed at various times; Phys conc. and ChE activity were determined. BuChE activity in plasma was 5% of control from 7-30 min after Phy i.v. pretreatment and soman or soman alone treatment. Plasma Phy conc. steadily declined (32.6 ng/ml at 7 min) to 15 ng/ml at 30 min. ChE activity inmore » muscle was 60-50% of control for Phy pretreated but soman alone gave 85-72% activity from 2-30 min. Brain ChE activity was about 5% of control within 2 min after soman treatment; however, with Phy pretreatment, the activity was about 52% at 7 min, 40% at 22 min, which recovered to 45% of control at 35 min, indicating that Phy protected brain ChE. Brain Phy conc. steadily declined (58.6 ng/g at 7 min) to 11.7 ng/g at 30 min. However, pretreatment of rat with a higher dose of Phy and then soman showed BuChE in plasma and ChE in brain and muscle to be about 25, 35 and 51%, in comparison to about 5% in plasma and brain with soman alone treatment, indicating higher protection of ChE enzyme with higher conc. of Phy in plasma and brain.« less
  • No abstract prepared.