This research project will establish a strategy to evaluate potential health implications resulting from exposure to complex mixtures of organophosphate (OP) insecticides. OP insecticides are widely utilized in a variety of applications and potential exists for significant occupational exposure. The health implications of mixed chemical exposures are currently poorly understood, since the toxicological characterization of such complex mixtures is not practical due to the numerous potential combinations. To address this chemical mixture issue, an integrated approach is proposed involving the application of physiologically-based pharmacokinetic/ pharmacodynamic (PBPK/PD) modeling in conjunction with focused in vivo/ in vitro studies. The goal of this project is to provide a quantitative understanding of complex chemical interactions within biological systems, estimate tissue dosimetry, and quantitate pharmacodynamic response (i.e. esterase inhibition). This approach represents a reasonable application of limited resources (i.e. time and funding) to generate data which can be used to evaluate human health risk from occupational exposure to important agricultural chemicals. Specific research aims include: to develop a PBPK/PD model for diazinon (DZN) in the rat; to conduct focused in vitro experiments in rats to quantify critical metabolic interactions for mixtures of chlorpyrifos (CPF) and DZN that can readily be incorporated into a binary mixture PBPK/PD model; to conduct in vivo evaluations of the PBPK/PD model interactions for mixtures of CPF and DZN in the rat and to conduct focused in vitro experiments with human tissues to quantify critical metabolic interactions and to develop a human DZN and binary OP mixture PBPK/PD model.

Agency
National Institute of Health (NIH)
Institute
National Institute for Occupational Safety and Health (NIOSH)
Type
Research Project (R01)
Project #
5R01OH003629-02
Application #
6598152
Study Section
Safety and Occupational Health Study Section (SOH)
Program Officer
Robison, William
Project Start
2001-09-30
Project End
2004-09-29
Budget Start
2002-09-30
Budget End
2003-09-29
Support Year
2
Fiscal Year
2002
Total Cost
$246,279
Indirect Cost
Name
Battelle Pacific Northwest Laboratories
Department
Type
DUNS #
032987476
City
Richland
State
WA
Country
United States
Zip Code
99352
Smith, Jordan Ned; Wang, Jun; Lin, Yuehe et al. (2012) Pharmacokinetics and Pharmacodynamics of chlorpyrifos and 3,5,6-trichloro-2-pyridinol in rat saliva after chlorpyrifos administration. Toxicol Sci 130:245-56
Lee, S; Poet, T S; Smith, J N et al. (2011) Impact of repeated nicotine and alcohol coexposure on in vitro and in vivo chlorpyrifos dosimetry and cholinesterase inhibition. J Toxicol Environ Health A 74:1334-50
Smith, Jordan N; Wang, Jun; Lin, Yuehe et al. (2010) Pharmacokinetics of the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCPy) in rat saliva. Toxicol Sci 113:315-25
Lee, Sookwang; Poet, Torka S; Smith, Jordan N et al. (2010) Effect of in vivo nicotine exposure on chlorpyrifos pharmacokinetics and pharmacodynamics in rats. Chem Biol Interact 184:449-57
Busby-Hjerpe, Andrea L; Campbell, James A; Smith, Jordan Ned et al. (2010) Comparative pharmacokinetics of chlorpyrifos versus its major metabolites following oral administration in the rat. Toxicology 268:55-63
Lee, S; Busby, A L; Timchalk, C et al. (2009) Effects of nicotine exposure on in vitro metabolism of chlorpyrifos in male Sprague-Dawley rats. J Toxicol Environ Health A 72:74-82
Smith, Jordan Ned; Campbell, James A; Busby-Hjerpe, Andrea L et al. (2009) Comparative chlorpyrifos pharmacokinetics via multiple routes of exposure and vehicles of administration in the adult rat. Toxicology 261:47-58
Garabrant, David H; Aylward, Lesa L; Berent, Stanley et al. (2009) Cholinesterase inhibition in chlorpyrifos workers: Characterization of biomarkers of exposure and response in relation to urinary TCPy. J Expo Sci Environ Epidemiol 19:634-42
Timchalk, C; Poet, T S (2008) Development of a physiologically based pharmacokinetic and pharmacodynamic model to determine dosimetry and cholinesterase inhibition for a binary mixture of chlorpyrifos and diazinon in the rat. Neurotoxicology 29:428-43
Cole, Toby B; Walter, Betsy J; Shih, Diana M et al. (2005) Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism. Pharmacogenet Genomics 15:589-98

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