Comparative Pharmacokinetics of High and Low Doses of the Herbicide Propanil in Mice

Schafer, Rosana; Ognibene, Ted J.; Malfatti, Michael A.; Turteltaub, Kenneth W.; Barnett, John B.

doi:10.1021/acs.chemrestox.8b00151

Title: Comparative Pharmacokinetics of High and Low Doses of the Herbicide Propanil in Mice

Abstract

We have documented that the herbicide propanil is immunotoxic in mice, and our in vitro tissue culture experiments largely recapitulate the in vivo studies. Laboratory studies on environmental contaminants are the most meaningful when these studies are conducted using concentrations that approximate levels in the environment. Many techniques to measure the distribution and pharmacokinetics (PK) on compounds rely on techniques, such as liquid scintillation counting (LSC) of radio-labeled starting compound, that require concentrations higher than environmental levels. The aim of this study was to compare tissue PK after exposure to propanil concentrations more relevant to levels of exposure to agricultural workers and the general population to concentrations previously reported for laboratory studies. To this end, we conducted a study to measure propanil distribution in three immune organs, using ultrasensitive accelerator mass spectrometry (AMS). Here, we used two doses: the lower dose modeled levels expected in the environment or long-term occupational exposure to low doses, while the higher dose was to model the effects of an accidental exposure. Our results showed that the distribution and PK profiles from these two different concentrations was markedly different. The profile of the high dose (concentration) exposure was indicative of saturation of the detoxifying capabilitymore »« less

Authors:

Schafer, Rosana ^[1]; Ognibene, Ted J. ^[2]; Malfatti, Michael A. ^[2]; Turteltaub, Kenneth W. ^[2];

^[1]

West Virginia Univ., Morgantown, WV (United States). Dept. of Microbiology, Immunology, and Cell Biology
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Center for Accelerator Mass Spectrometry

Publication Date:: Wed Sep 19 00:00:00 EDT 2018

Research Org.:: Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

Sponsoring Org.:: USDOE National Nuclear Security Administration (NNSA)

OSTI Identifier:: 1479060

Report Number(s):: LLNL-JRNL-752574
Journal ID: ISSN 0893-228X; 938884

Grant/Contract Number:: AC52-07NA27344

Resource Type:: Accepted Manuscript

Journal Name:: Chemical Research in Toxicology

Additional Journal Information:: Journal Volume: 31; Journal Issue: 10; Journal ID: ISSN 0893-228X

Publisher:: American Chemical Society (ACS)

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats


                    Schafer, Rosana, Ognibene, Ted J., Malfatti, Michael A., Turteltaub, Kenneth W., and Barnett, John B. Comparative Pharmacokinetics of High and Low Doses of the Herbicide Propanil in Mice.  United States: N. p., 2018. 
Web.  doi:10.1021/acs.chemrestox.8b00151.

Copy to clipboard


                    Schafer, Rosana, Ognibene, Ted J., Malfatti, Michael A., Turteltaub, Kenneth W., & Barnett, John B. Comparative Pharmacokinetics of High and Low Doses of the Herbicide Propanil in Mice.  United States.  https://doi.org/10.1021/acs.chemrestox.8b00151

Copy to clipboard


                    Schafer, Rosana, Ognibene, Ted J., Malfatti, Michael A., Turteltaub, Kenneth W., and Barnett, John B. Wed .  
"Comparative Pharmacokinetics of High and Low Doses of the Herbicide Propanil in Mice".  United States.  https://doi.org/10.1021/acs.chemrestox.8b00151.  https://www.osti.gov/servlets/purl/1479060.

Copy to clipboard


                    
@article{osti_1479060,

  title        = {Comparative Pharmacokinetics of High and Low Doses of the Herbicide Propanil in Mice},

  author       = {Schafer, Rosana and Ognibene, Ted J. and Malfatti, Michael A. and Turteltaub, Kenneth W. and Barnett, John B.},

  abstractNote = {We have documented that the herbicide propanil is immunotoxic in mice, and our in vitro tissue culture experiments largely recapitulate the in vivo studies. Laboratory studies on environmental contaminants are the most meaningful when these studies are conducted using concentrations that approximate levels in the environment. Many techniques to measure the distribution and pharmacokinetics (PK) on compounds rely on techniques, such as liquid scintillation counting (LSC) of radio-labeled starting compound, that require concentrations higher than environmental levels. The aim of this study was to compare tissue PK after exposure to propanil concentrations more relevant to levels of exposure to agricultural workers and the general population to concentrations previously reported for laboratory studies. To this end, we conducted a study to measure propanil distribution in three immune organs, using ultrasensitive accelerator mass spectrometry (AMS). Here, we used two doses: the lower dose modeled levels expected in the environment or long-term occupational exposure to low doses, while the higher dose was to model the effects of an accidental exposure. Our results showed that the distribution and PK profiles from these two different concentrations was markedly different. The profile of the high dose (concentration) exposure was indicative of saturation of the detoxifying capability of the animal. In contrast, at the lower environmentally relevant concentration, in vivo concentrations of propanil in spleen, liver, and blood dropped to a very low level by 720 min. In conclusion, these studies highlight the differences in PK of propanil at these two doses, which suggests that the toxicity of this chemical should be re-investigated to obtain better data on toxic effects at doses relevant for humans.},

  doi          = {10.1021/acs.chemrestox.8b00151},

  journal      = {Chemical Research in Toxicology},

  number       = 10,

  volume       = 31,

  place        = {United States},

  year         = {Wed Sep 19 00:00:00 EDT 2018},

  month        = {Wed Sep 19 00:00:00 EDT 2018}

}

Copy to clipboard

Journal Article:

Free Publicly Available Full Text

Accepted Manuscript (DOE)

Publisher's Version of Record

https://doi.org/10.1021/acs.chemrestox.8b00151

Other availability

Search WorldCat to find libraries that may hold this journal

Citation Metrics:

Cited by: 3 works

Citation information provided by
Web of Science

Figures / Tables:

Figure 1: Outline of the experimental design. C57Bl/6 mice were injected with propanil at time zero. At 1, 10, 20, 40, 80, 120, 240, 360, 720 minutes after propanil injection, blood was collected into a capillary tube and then the animal was euthanized and the liver and spleen removed bymore »

All figures and tables (6 total)

Save / Share:

Export Metadata

Save to My Library

Figures / Tables found in this record:

Figures/Tables have been extracted from DOE-funded journal article accepted manuscripts.

Similar Records in DOE PAGES and OSTI.GOV collections:

Immunomodulatory effects of the herbicide propanil on cytokine production in humans: In vivo and in vitro exposure

Journal Article Corsini, Emanuela ; Codeca, Ilaria ; Mangiaratti, Simona ; ... - Toxicology and Applied Pharmacology

Propanil, 3,4-dichloropropionanilide, a commonly used herbicide, has been shown to induce effects on the mouse immune system. The aim of this study was to assess the immunotoxicity of propanil in occupationally exposed agricultural workers and to characterize its molecular mechanism of action. Seven agricultural workers intermittently exposed to propanil and 7 healthy matched controls entered the study. Data were collected through physical examination, and laboratory investigations addressed at the main serum, cellular, and functional immune parameters. The levels of exposure were assessed by determining the urine concentration of the major propanil metabolite, 3,4-dichloroaniline. The investigation of serum, cellular, and functionalmore »« less
https://doi.org/10.1016/j.taap.2007.04.017
The biodistribution and pharmacokinetics of the oxime acetylcholinesterase reactivator RS194B in guinea pigs

Journal Article Malfatti, Michael A. ; Enright, Heather A. ; Be, Nicholas A. ; ... - Chemico-Biological Interactions

Organophosphorus-based (OP) nerve agents represent some of the most toxic substances known to mankind. The current standard of care for exposure has changed very little in the past decades, and relies on a combination of atropine to block receptor activity and oxime-type acetylcholinesterase (AChE) reactivators to reverse the OP binding to AChE. Although these oximes can block the effects of nerve agents, their overall efficacy is reduced by their limited capacity to cross the blood-brain barrier (BBB). RS194B, a new oxime developed by Radic et al. (J. Biol. Chem., 2012) has shown promise for enhanced ability to cross the BBB.more »« less
Cited by 13
https://doi.org/10.1016/j.cbi.2017.09.016

Full Text Available
Metabolism and toxicological evaluation of the aromatic amide herbicide propanil and its derivatives

Miscellaneous McMillian, D C

Since propanil is structurally similar to other carcinogenic arylamides, the potential chronic toxicity of propanil and its derivatives were examined in short-term assays for genotoxicity. Propanil, 3,4-dichloroaniline, and their N-oxidized derivatives were inactive in the Salmonella typhimurium reversion, Chinese hamster ovary/hypoxanthine guanine phosphoribosyl transferase (CHO/HGPRT), and rat hepatocyte/DNA repair assays. The metabolism of propanil and 3,4-dichloroaniline was subsequently examined in liver microsomes from males Sprague-Dawley rats to identify metabolites that may be involved in the acute toxicity of propanil. The major pathway of propanil metabolism was acylamidase-catalyzed hydrolysis to 3,4-dichloroaniline. Oxidized metabolites were isolated by high performance liquid chromatography, andmore »« less
A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models

Journal Article Singh, Dharaminder ; Deosarkar, Sudhir P. ; Cadogan, Elaine ; ... - PLoS Biology (Online)

Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its ability to reproduce in vivo PK profiles of different oncology compoundsmore »« less
https://doi.org/10.1371/journal.pbio.3001624
Estimation of placental and lactational transfer and tissue distribution of atrazine and its main metabolites in rodent dams, fetuses, and neonates with physiologically based pharmacokinetic modeling

Journal Article Lin, Zhoumeng ; Interdisciplinary Toxicology Program, University of Georgia, Athens, GA 30602 ; Fisher, Jeffrey W. ; ... - Toxicology and Applied Pharmacology

Atrazine (ATR) is a widely used chlorotriazine herbicide, a ubiquitous environmental contaminant, and a potential developmental toxicant. To quantitatively evaluate placental/lactational transfer and fetal/neonatal tissue dosimetry of ATR and its major metabolites, physiologically based pharmacokinetic models were developed for rat dams, fetuses and neonates. These models were calibrated using pharmacokinetic data from rat dams repeatedly exposed (oral gavage; 5 mg/kg) to ATR followed by model evaluation against other available rat data. Model simulations corresponded well to the majority of available experimental data and suggest that: (1) the fetus is exposed to both ATR and its major metabolite didealkylatrazine (DACT) atmore »« less
https://doi.org/10.1016/J.TAAP.2013.08.010

Similar Records