%0 Journal Article %J Xenobiotica %D 2011 %T Organophosphorus pesticide degradation product in vitro metabolic stability and time-course uptake and elimination in rats following oral and intravenous dosing. %A Norman D Forsberg %A Rodriguez-Proteau, R %A Ma, L %A Morré, J %A Christensen, J M %A Maier, C S %A Jeffrey J Jenkins %A Kim A Anderson %K Administration, Oral %K Animals %K Environmental Monitoring %K Humans %K Injections, Intravenous %K Male %K Mass Spectrometry %K Organophosphorus Compounds %K Pesticides %K Rats %K Rats, Sprague-Dawley %K Time Factors %X

Levels of urinary dialkylphosphates (DAPs) are currently used as a biomarker of human exposure to organophosphorus insecticides (OPs). It is known that OPs degrade on food commodities to DAPs at levels that approach or exceed those of the parent OP. However, little has been reported on the extent of DAP absorption, distribution, metabolism and excretion. The metabolic stability of O,O-dimethylphosphate (DMP) was assessed using pooled human and rat hepatic microsomes. Time-course samples were collected over 2 h and analyzed by LC-MS/MS. It was found that DMP was not metabolized by rat or pooled human hepatic microsomes. Male Sprague-Dawley rats were administered DMP at 20 mg kg(-1) via oral gavage and i.v. injection. Time-course plasma and urine samples were collected and analyzed by LC-MS/MS. DMP oral bioavailability was found to be 107 ± 39% and the amount of orally administered dose recovered in the urine was 30 ± 9.9% by 48 h. The in vitro metabolic stability, high bioavailability and extent of DMP urinary excretion following oral exposure in a rat model suggests that measurement of DMP as a biomarker of OP exposure may lead to overestimation of human exposure.

%B Xenobiotica %V 41 %P 422-9 %8 05/2011 %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/21446834?dopt=Abstract %R 10.3109/00498254.2010.550656 %0 Journal Article %J Toxicol Appl Pharmacol %D 2011 %T Preliminary physiologically based pharmacokinetic models for benzo[a]pyrene and dibenzo[def,p]chrysene in rodents. %A Crowell, Susan Ritger %A Amin, Shantu G %A Kim A Anderson %A Krishnegowda, Gowdahalli %A Sharma, Arun K %A Soelberg, Jolen J %A Williams, David E %A Corley, Richard A %K Administration, Oral %K Algorithms %K Animals %K Benzo(a)pyrene %K Benzopyrenes %K Environmental Pollutants %K Female %K Injections, Intravenous %K Mice %K Models, Biological %K Rats %K Rats, Sprague-Dawley %K Tissue Distribution %X

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated as byproducts of natural and anthropogenic combustion processes. Despite significant public health concern, physiologically based pharmacokinetic (PBPK) modeling efforts for PAHs have so far been limited to naphthalene, plus simpler PK models for pyrene, nitropyrene, and benzo[a]pyrene (B[a]P). The dearth of published models is due in part to the high lipophilicity, low volatility, and myriad metabolic pathways for PAHs, all of which present analytical and experimental challenges. Our research efforts have focused upon experimental approaches and initial development of PBPK models for the prototypic PAH, B[a]P, and the more potent, albeit less studied transplacental carcinogen, dibenzo[def,p]chrysene (DBC). For both compounds, model compartments included arterial and venous blood, flow limited lung, liver, richly perfused and poorly perfused tissues, diffusion limited fat, and a two compartment theoretical gut (for oral exposures). Hepatic and pulmonary metabolism was described for both compounds, as were fractional binding in blood and fecal clearance. Partition coefficients for parent PAH along with their diol and tetraol metabolites were estimated using published algorithms and verified experimentally for the hydroxylated metabolites. The preliminary PBPK models were able to describe many, but not all, of the available data sets, comprising multiple routes of exposure (oral, intravenous) and nominal doses spanning several orders of magnitude.

%B Toxicol Appl Pharmacol %V 257 %P 365-76 %8 12/2011 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22001385?dopt=Abstract %R 10.1016/j.taap.2011.09.020