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Title: The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments

Abstract

The ILSI Health and Environmental Sciences Institute (HESI) formed the Agricultural Chemical Safety Assessment (ACSA) Technical Committee in the year 2000 to design a toxicity testing scheme that would incorporate current understanding of pesticide toxicology and exposure and recognize the specificity of agricultural products. The purpose of and background for the ACSA project are described in detail in the companion paper by Carmichael et al. (2006). As the proposed tiered testing approach for agricultural chemical safety assessment evolved, the ACSA Technical Committee and its task forces (Carmichael et al., 2006; Cooper et al., 2006; Doe et al., 2006) worked toward the following objectives: (1) Provide information that can be applied to a range of relevant human exposure situations. (2) Characterize effects that have the potential to damage human health at exposure levels approximating those that might be encountered in the use of these compounds. (3) Avoid high doses that cause unnecessary public concern (e.g., safety assessments should focus on doses that are relevant to realistic human exposures while maintaining adequate power for the experimental studies to detect toxicity). (4) Use the minimum number of animals necessary to produce a thorough safety assessment of the chemicals of interest. (5) Inflict themore » minimum amount of distress on animals. (6) Minimize excessive and unnecessary use of resources by regulatory authorities and industry, which could be used to address other issues of concern. (7) Increase both the efficiency and relevance of the current safety assessment process.« less

Authors:
; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
881938
Report Number(s):
PNNL-SA-49404
Journal ID: ISSN 1040-8444; CRTXB2; TRN: US200613%%126
DOE Contract Number:
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Critical Reviews in Toxicology; Journal Volume: 36; Journal Issue: 1
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ABSORPTION; ANIMALS; DISTRIBUTION; EXCRETION; METABOLISM; PESTICIDES; SAFETY ANALYSIS; SPECIFICITY; TESTING; TOXICITY; AGRICULTURE; HEALTH HAZARDS; agricultural chemicals, ADME

Citation Formats

Barton, H. A., Pastoor, Timothy P., Baetcke, Karl, Chambers, Janice E., Diliberto, Janet, Doerrer, Nancy G., Driver, Jeffrey H., Hastings, Charles E., Iyengar, Seshadri, Krieger, Robert, Stahl, Bernhard, and Timchalk, Chuck. The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments. United States: N. p., 2006. Web. doi:10.1080/10408440500534362.
Barton, H. A., Pastoor, Timothy P., Baetcke, Karl, Chambers, Janice E., Diliberto, Janet, Doerrer, Nancy G., Driver, Jeffrey H., Hastings, Charles E., Iyengar, Seshadri, Krieger, Robert, Stahl, Bernhard, & Timchalk, Chuck. The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments. United States. doi:10.1080/10408440500534362.
Barton, H. A., Pastoor, Timothy P., Baetcke, Karl, Chambers, Janice E., Diliberto, Janet, Doerrer, Nancy G., Driver, Jeffrey H., Hastings, Charles E., Iyengar, Seshadri, Krieger, Robert, Stahl, Bernhard, and Timchalk, Chuck. Sun . "The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments". United States. doi:10.1080/10408440500534362.
@article{osti_881938,
title = {The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments},
author = {Barton, H. A. and Pastoor, Timothy P. and Baetcke, Karl and Chambers, Janice E. and Diliberto, Janet and Doerrer, Nancy G. and Driver, Jeffrey H. and Hastings, Charles E. and Iyengar, Seshadri and Krieger, Robert and Stahl, Bernhard and Timchalk, Chuck},
abstractNote = {The ILSI Health and Environmental Sciences Institute (HESI) formed the Agricultural Chemical Safety Assessment (ACSA) Technical Committee in the year 2000 to design a toxicity testing scheme that would incorporate current understanding of pesticide toxicology and exposure and recognize the specificity of agricultural products. The purpose of and background for the ACSA project are described in detail in the companion paper by Carmichael et al. (2006). As the proposed tiered testing approach for agricultural chemical safety assessment evolved, the ACSA Technical Committee and its task forces (Carmichael et al., 2006; Cooper et al., 2006; Doe et al., 2006) worked toward the following objectives: (1) Provide information that can be applied to a range of relevant human exposure situations. (2) Characterize effects that have the potential to damage human health at exposure levels approximating those that might be encountered in the use of these compounds. (3) Avoid high doses that cause unnecessary public concern (e.g., safety assessments should focus on doses that are relevant to realistic human exposures while maintaining adequate power for the experimental studies to detect toxicity). (4) Use the minimum number of animals necessary to produce a thorough safety assessment of the chemicals of interest. (5) Inflict the minimum amount of distress on animals. (6) Minimize excessive and unnecessary use of resources by regulatory authorities and industry, which could be used to address other issues of concern. (7) Increase both the efficiency and relevance of the current safety assessment process.},
doi = {10.1080/10408440500534362},
journal = {Critical Reviews in Toxicology},
number = 1,
volume = 36,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 2006},
month = {Sun Jan 01 00:00:00 EST 2006}
}
  • A scientific workshop was held in 2006 to discuss the use of in vitro Absorption, Distribution, Metabolism, and Excretion (ADME) data in chemical bioaccumulation assessments for fish. Computer-based (in silico) modeling tools are widely used to estimate chemical bioaccumulation. These in silico methods have inherent limitations that result in inaccurate estimates for many compounds. Based on a review of the science workshop participants concluded that two factors, absorption and metabolism, represent the greatest sources of uncertainty in current bioaccumulation models. Both factors can be investigated experimentally using in vitro test systems.
  • The disposition and metabolism of a single oral 10 mg/kg (LD50) of uniformly phenyl-labeled (/sup 14/C)EPN (O-ethyl O-4-nitrophenyl (/sup 14/C)phenylphosphonothioate) were studied in adult hens. The birds were protected from acute toxicity with atropine sulfate. Three treated hens were killed at each time interval (days): 0.5, 2, 4, 8, 12. Radioactivity was adsorbed from the gastrointestinal tract and distributed in all tissues. Most of the dose was excreted in the combined urinary-fecal excreta (74%). Only traces of the radioactivity (0.2%) were detected in expired CO/sub 2/. Most of the excreted radioactive materials were identified as phenylphosphonic acid (PPA), O-ethyl phenylphosphonicmore » acid (EPPA), and O-ethyl phenylphosphonothioc acid (EPPTA). Radioactivity in tissues reached a peak of 11.8% in 12 days. The highest concentration of radioactivity was present in the liver followed by bile, kidney, adipose tissue, and muscle. EPN was the major compound identified in brain, spinal cord, sciatic nerve, kidney, and plasma. Most of the radioactivity in the liver was identified as EPPA followed by EPPTA and PPA. Kinetic studies showed that EPN disappeared exponentially from tissues. The half-life of the elimination of EPN from plasma was 16.5 days corresponding to a constant rate value of 0.04 day-1. Relative residence (RR) of EPN relative to plasma was shortest in liver and longest in adipose tissue followed by sciatic nerve and spinal cord.« less
  • With /sup 14/C-potassium cyanate as the starting material, 2-/sup 14/C-1-allyl-3,5-diethyl-6-chlorouracil was synthesized for in vitro and in vivo absorption studies in human skin and for metabolic studies in rats and rabbits. The radioactivity in the horny layer, epidermis, and dermis of the human skin was determined after different intervals of time, and the radioactivity excreted in the urine was measured by collecting samples for 5 days from a patient and also under occlusion conditions. Almost 90% of the radioactivity remained on the surface and approximately 6.28% penetrated and was systemically absorbed. Over a 5-day period, a total of 3.25% wasmore » excreted. Almost 3% was systemically absorbed and cumulated in the system. After intraperitoneal application in male and female rats, most of the radioactivity was excreted in the feces and urine, with female rats excreting more in the urine than male rats. The radioactivity rose in the organs in the first 3 hr and then decreased. At the end of 144 hr, no appreciable radioactivity could be found in the organs and tissues, except in the carcass where the cumulation was maximum (1%). After intravenous injection in rabbits, most of the radioactivity (80%) was excreted in the urine and only 4% in the feces. At the end of 96 hr, approximately 3% was cumulated in the body. The drug was quantitatively metabolized in both rats and rabbits: Metabolite 1 (70-85%), Metabolite 2 (10-15%), Metabolite 3 (5-10%), and Metabolite 4 (0.3%).« less