A Physiologically Based Pharmacokinetic and Pharmacodynamic (PBPK/PD) Model for the Organophosphate Insecticide Chlorpyrifos in Rats and Humans

The objective of this study was to evaluate the quantitative relation between measured red blood cell acetylcholinesterase (RBC AChE) and plasma butyrylcholinesterase (BuChE) activities with exposure to chlorpyrifos (CPF) as assessed by measurement of urinary 3,5,6-trichloro-2-pyridinol (TCPy) in a study group of workers occupationally exposed in the manufacture of CPF and a referent group of chemical manufacturing workers. Measures of plasma BuChE and RBC AChE activity and urinary TCPy concentration collected over a year-long study (1999)(2000) in CPF-exposed workers (n ¼ 53) and referents (n ¼ 60) were analyzed using linear mixed models to characterize exposure-response relationships. Intraindividual variability in cholinesterase measures was compared between CPF-exposed workers and referents. Urinary TCPy concentrations in CPF workers were substantially elevated compared to referents, with median and 95th percentile concentrations during typical employment conditions 10-fold and more than 30-fold higher, respectively, than corresponding measures in the referents. Intraindividual variability in cholinesterase activities was substantial, with 17% of unexposed referents experiencing one or more plasma BuChE measures more than 20% below baseline over a year of repeated, periodic measurements. RBC AChE activity, an early biomarker of effect, was unrelated to urinary TCPy concentration over the entire range of exposure, up to 1000 mg TCPy/g creatinine (Cr). Plasma BuChE activity, a non-adverse biomarker of exposure, was negatively related to urinary TCPy concentrations above approximately 110 mg TCPy/g Cr. No-effect levels for inhibition of plasma BuChE and RBC AChE corresponding to absorbed doses of CPF of approximately 5 and greater than 50 mg/kg/day, respectively, were identified. These findings are consistent with previous no-effect level determinations for ChE inhibition in humans and suggest that general population CPF exposure levels are substantially below the identified no-effect levels. The doseresponse relationships observed in this study are consistent with predictions from the previously published physiologically based pharmacokinetic/ pharmacodynamic model for CPF. Intraindividual variability in measured cholinesterase activities in referents was substantial, suggesting that ongoing monitoring programs may have a substantial rate of false positives.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cholinesterase inhibition in chlorpyrifos workers: Characterization of biomarkers of exposure and response in relation to urinary TCPy

Garabrant

Aylward

Berent

et al. 2008

“…It was found that by using the exposure estimates from Pang et al (2002) as inputs to the PK model (using both steady-state and time-variant assumptions) the TCPy biomarker levels are significantly under-predicted (Figure 4). This under-prediction is likely to be even more severe when the variability in the CPF absorption, which can be as low as 18% (Timchalk et al, 2002b), is taken into account. This leads to the conclusion that the NHEXAS-MDderived exposure estimates are inadequate for use as "prior" exposure information in this particular case.…”

Section: Analysis Of the Linked Pk/biomarker Approach Using Forward Mmentioning

confidence: 99%

Reconstructing population exposures to environmental chemicals from biomarkers: Challenges and opportunities

Georgopoulos

Sasso

Isukapalli

et al. 2008

A conceptual/computational framework for exposure reconstruction from biomarker data combined with auxiliary exposure-related data is presented, evaluated with example applications, and examined in the context of future needs and opportunities. This framework employs physiologically based toxicokinetic (PBTK) modeling in conjunction with numerical "inversion" techniques. To quantify the value of different types of exposure data "accompanying" biomarker data, a study was conducted focusing on reconstructing exposures to chlorpyrifos, from measurements of its metabolite levels in urine. The study employed biomarker data as well as supporting exposure-related information from the National Human Exposure Assessment Survey (NHEXAS), Maryland, while the MENTOR-3P system (Modeling ENvironment for TOtal Risk with Physiologically based Pharmacokinetic modeling for Populations) was used for PBTK modeling. Recently proposed, simple numerical reconstruction methods were applied in this study, in conjunction with PBTK models. Two types of reconstructions were studied using (a) just the available biomarker and supporting exposure data and (b) synthetic data developed via augmenting available observations. Reconstruction using only available data resulted in a wide range of variation in estimated exposures. Reconstruction using synthetic data facilitated evaluation of numerical inversion methods and characterization of the value of additional information, such as study-specific data that can be collected in conjunction with the biomarker data. Although the NHEXAS data set provides a significant amount of supporting exposurerelated information, especially when compared to national studies such as the National Health and Nutrition Examination Survey (NHANES), this information is still not adequate for detailed reconstruction of exposures under several conditions, as demonstrated here. The analysis presented here provides a starting point for introducing improved designs for future biomonitoring studies, from the perspective of exposure reconstruction; identifies specific limitations in existing exposure reconstruction methods that can be applied to population biomarker data; and suggests potential approaches for addressing exposure reconstruction from such data.

“…By physiologic-based pharmaco-kinetic modeling. One can estimate the equilibrium or ''biological equivalent'' blood serum contaminant concentration (mg/dl), which would result from a constant daily dietary intake at the RfD level (Timchalk et al, 2002;Hays et al, 2007). With a physiologic-based pharmaco-kinetic (PBPK) submodel of renal clearance and an assumption of the daily fluid intake (l/day), estimate the average daily urinary contaminant concentration, mg/l, which would be excreted in equilibrium with the calculated blood serum contaminant concentration.…”

Section: Introductionmentioning

confidence: 99%

Creatinine corrections for estimating children's and adult's pesticide intake doses in equilibrium with urinary pesticide and creatinine concentrations

Mage

Allen

Kodali

2007

150

149

A urine contaminant concentration per se has uncertain meaning for human health because of dilution by hydration. However, the estimation of the health-related daily intake dose of pollutant (mg/kg/day) that equilibrates with a spot urinary concentration of a pesticide residue or metabolite, or other analyte, can be made using creatinine-corrected toxicant levels (mg analyte/mg creatinine) multiplied by an estimate of the subjects' expected creatinine excretion rates (mg creatinine/kg/day). The objective was to develop a set of equations predicting a person's expected daily creatinine excretion (mg/kg) as a function of age, gender, race and morphometry, from birth to old age. We review the creatinine excretion literature where infants, children and adults provided 24 h total urine samples for creatinine analysis. Equations are developed for infants (r3 years), children (3-18 years) and adults (Z18 years) that match at 3 and 18 years. A series of equations that estimate daily creatinine excretion (mg/day) are developed that are piecewise continuous from birth through infancy through adolescence and through adulthood for males and females, and Black and White races. Complicating factors such as diet, health status and obesity are discussed. We propose that these equations, with caveat, can now be used with measured urine concentrations to consistently estimate the corresponding equilibrium intake doses of toxicants at ages from birth to 92 years for the healthy non-obese. We recommend that this system of equations be considered for future development and reporting of applied doses in mg/kg/day of pollutants and toxicants that are measured in urine samples, as in the National Health and Nutrition Examination Survey.