Grantee Research Project Results
2004 Progress Report: Reducing Uncertainty in Children’s Risk Assessment: Development of a Quantitative Approach for Assessing Internal Dosimetry Through Physiologically-Based Pharmacokinetic Modeling
EPA Grant Number: R830800Title: Reducing Uncertainty in Children’s Risk Assessment: Development of a Quantitative Approach for Assessing Internal Dosimetry Through Physiologically-Based Pharmacokinetic Modeling
Investigators: Bruckner, J. V. , Delp, Michael D. , Bartlett, Michael G. , Fisher, Jeffrey W.
Current Investigators: Bruckner, J. V. , Bartlett, Michael G.
Institution: University of Georgia , Texas A & M University
Current Institution: University of Georgia
EPA Project Officer: Hahn, Intaek
Project Period: February 1, 2003 through January 31, 2007 (Extended to January 31, 2008)
Project Period Covered by this Report: February 1, 2004 through January 31, 2005
Project Amount: $749,991
RFA: Children's Vulnerability to Toxic Substances in the Environment (2002) RFA Text | Recipients Lists
Research Category: Human Health , Children's Health
Objective:
The objectives of the research project are to develop and validate a systematic quantitative approach (i.e., a physiologically based toxicokinetic [PBTK] model) for predicting internal dosimetry of deltamethrin (DLT), a representative pyrethroid insecticide, in maturing rats (as a model for children).
Progress Summary:
One of the major accomplishments during the past year has been to delineate the metabolism of DLT in adult rats. Previous investigators have shown that DLT is biotransformed in male rats by ester cleavage and by cytochrome (CY) P450-catalyzed hydroxylation, with subsequent glucuronidation and sulfation. There is little information on the identity of the esterases or CYP450s. More importantly for PBTK modeling, there is no information on the relative contributions of liver and plasma metabolism to the systemic clearance of DLT. We found that DLT is hydrolyzed by carboxylesterases (CaEs) in plasma and liver microsomes of adult, male Sprague-Dawley (S-D) rats. A-esterases do not appear to catalyze this reaction. Genetically engineered individual rat CYP450s (Supersomes ®) were utilized to demonstrate that CYP1A1, CYP1A2, and CYP2C11 (in decreasing order of importance quantitatively) metabolized DLT in liver microsomes. Intrinsic clearance (V max/K m) was most efficient by liver CYP450s, followed in turn by liver CaEs and plasma CaEs. These metabolic indices are being used in development of a PBTK model for DLT in the adult male S-D rat. The DLT biotransformation data may be generally applicable to systemic metabolism of other pyrethroid insecticides.
Another accomplishment was identification of a solvent or diluent for DLT. DLT and other pyrethroids are extremely lipid-soluble compounds. Solubilizing them in aqueous in vitro systems and administering them in vivo for absorption into the aqueous blood is very problematic. We commonly have utilized Emulphor ®/Alkamuls ®, a polyethoxylated vegetable oil, to emulsify lower molecular weight halocarbons and hydrocarbons for dosing animals. Rats given DLT in Emulphor ® orally or intravenously exhibited very low arterial blood and tissue DLT levels, as a result of physical trapping of micelles containing DLT in the alveolar capillaries. Glycerol formal, however, proved to be quite suitable for in vivo and in vitro experiments. It is quite likely that glycerol formal also may be suitable for toxicokinetic and toxicology studies of DDT, PCBs, dioxins, and other polyaromatic hydrocarbons.
Results of toxicokinetic experiments in immature and adult rats were consistent with the hypothesis that preweanling animals are particularly sensitive to acute DLT neurotoxicity, as a result of to inefficient DLT metabolism/detoxification. In one experiment, blood DLT and 3-phenoxybenzoic acid (PBA) levels were monitored for up to 48 hours after gavage of 10-, 21-, 40-, and 90-day-old S-D rats with 10 mg DLT/kg. PBA is a major hydrolysis product of DLT. Blood DLT levels and the areas under the curve varied inversely with age. The youngest animals exhibited signs of acute neurotoxicity and died within 7 to 8 hours of dosing. Their blood DLT concentrations were the highest and their blood PBA concentrations were the lowest of any age group. These time-course data are being used for PBTK model development and validation.
Future Activities:
Work during the next reporting period will be focused primarily on comprehensive toxicokinetic studies and upon development of a PBTK model for DLT. Blood and tissue (brain, liver, kidney, muscle, and fat) time profiles will be obtained for 2 to 3 DLT doses in 5- 10-, 21-, 28-, 40-, and 90-day-old rats and used for model construction and validation. Another goal will be to obtain physiological and metabolic parameters needed for PBTK modeling of DLT kinetics in immature rats. Body and organ weights/volumes will be ascertained in male and female rats from birth to sexual maturity. The age-dependency of cardiac output and organ blood flows also will be assessed.
Journal Articles on this Report : 2 Displayed | Download in RIS Format
Other project views: | All 29 publications | 12 publications in selected types | All 12 journal articles |
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Ding Y, White CA, Muralidhara S, Bruckner JV, Bartlett MG. Determination of deltamethrin and its metabolite 3-phenoxybenzoic acid in male rat plasma by high-performance liquid chromatography. Journal of Chromatography B 2004;810(2):221-227. |
R830800 (2003) R830800 (2004) R830800 (2005) R830800 (2006) R830800 (Final) R830900 (2004) |
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Ding Y, White CA, Bruckner JV, Bartlett MG. Determination of deltamethrin and its metabolites, 3-phenoxybenzoic acid and 3-phenoxybenzyl alcohol, in maternal plasma, amniotic fluid, and placental and fetal tissues by HPLC. Journal of Liquid Chromatography & Related Technologies 2004;27(12):1875-1892. |
R830800 (2003) R830800 (2004) R830800 (2005) R830800 (2006) R830800 (Final) R830900 (2004) |
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Supplemental Keywords:
modeling, internal exposure, pharmacokinetics, toxicokinetics, metabolism, toxicology, health effects, human health, risk assessment, susceptible populations, children, pesticides, insecticides, pyrethroids, toxics,, RFA, Health, Scientific Discipline, PHYSICAL ASPECTS, ENVIRONMENTAL MANAGEMENT, Toxics, PESTICIDES, Toxicology, Genetics, Health Risk Assessment, Risk Assessments, Environmental Microbiology, Susceptibility/Sensitive Population/Genetic Susceptibility, Biochemistry, Physical Processes, Environmental Monitoring, Children's Health, genetic susceptability, Pesticide Types, Risk Assessment, health effects, pesticide exposure, pharmacodynamic model, sensitive populations, detoxification, biomarkers, age-related differences, gene-environment interaction, exposure, animal model, developmental effects, metabolic study, children, pharmacokinetic models, insecticides, toxicity, genetic polymorphisms, PBPK modeling, pharmacokinetc model, metabolism, biological markers, risk based model, exposure assessment, organophosphate pesticides, biochemical research, environmental hazard exposures, human health riskRelevant Websites:
http://www.rx.uga.edu/index.html Exit
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.