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Title: The need for non- or minimally-invasive biomonitoring strategies and the development of pharmacokinetic/pharmacodynamic models for quantification

Abstract

Advancements in Exposure Science involving the development and deployment of biomarkers of exposure and biological response are anticipated to significantly (and positively) influence health outcomes associated with occupational, environmental and clinical exposure to chemicals/drugs. To achieve this vision, innovative strategies are needed to develop multiplex sensor platforms capable of quantifying individual and mixed exposures (i.e. systemic dose) by measuring biomarkers of dose and biological response in readily obtainable (non-invasive) biofluids. Secondly, the use of saliva (alternative to blood) for biomonitoring coupled with the ability to rapidly analyze multiple samples in real-time offers an innovative opportunity to revolutionize biomonitoring assessments. In this regard, the timing and number of samples taken for biomonitoring will not be limited as is currently the case. In addition, real-time analysis will facilitate identification of work practices or conditions that are contributing to increased exposures and will make possible a more rapid and successful intervention strategy. The initial development and application of computational models for evaluation of saliva/blood analyte concentration at anticipated exposure levels represents an important opportunity to establish the limits of quantification and robustness of multiplex sensor systems by exploiting a unique computational modeling framework. The use of these pharmacokinetic models will also enable predictionmore » of an exposure dose based on the saliva/blood measurement. This novel strategy will result in a more accurate prediction of exposures and, once validated, can be employed to assess dosimetry to a broad range of chemicals in support of biomonitoring and epidemiology studies.« less

Authors:
; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1361982
Report Number(s):
PNNL-SA-124528
Journal ID: ISSN 2468-2020; 453040220
DOE Contract Number:
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Current Opinion in Toxicology; Journal Volume: 4; Journal Issue: C
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Timchalk, Charles, Weber, Thomas J., and Smith, Jordan N.. The need for non- or minimally-invasive biomonitoring strategies and the development of pharmacokinetic/pharmacodynamic models for quantification. United States: N. p., 2017. Web. doi:10.1016/j.cotox.2017.03.003.
Timchalk, Charles, Weber, Thomas J., & Smith, Jordan N.. The need for non- or minimally-invasive biomonitoring strategies and the development of pharmacokinetic/pharmacodynamic models for quantification. United States. doi:10.1016/j.cotox.2017.03.003.
Timchalk, Charles, Weber, Thomas J., and Smith, Jordan N.. 2017. "The need for non- or minimally-invasive biomonitoring strategies and the development of pharmacokinetic/pharmacodynamic models for quantification". United States. doi:10.1016/j.cotox.2017.03.003.
@article{osti_1361982,
title = {The need for non- or minimally-invasive biomonitoring strategies and the development of pharmacokinetic/pharmacodynamic models for quantification},
author = {Timchalk, Charles and Weber, Thomas J. and Smith, Jordan N.},
abstractNote = {Advancements in Exposure Science involving the development and deployment of biomarkers of exposure and biological response are anticipated to significantly (and positively) influence health outcomes associated with occupational, environmental and clinical exposure to chemicals/drugs. To achieve this vision, innovative strategies are needed to develop multiplex sensor platforms capable of quantifying individual and mixed exposures (i.e. systemic dose) by measuring biomarkers of dose and biological response in readily obtainable (non-invasive) biofluids. Secondly, the use of saliva (alternative to blood) for biomonitoring coupled with the ability to rapidly analyze multiple samples in real-time offers an innovative opportunity to revolutionize biomonitoring assessments. In this regard, the timing and number of samples taken for biomonitoring will not be limited as is currently the case. In addition, real-time analysis will facilitate identification of work practices or conditions that are contributing to increased exposures and will make possible a more rapid and successful intervention strategy. The initial development and application of computational models for evaluation of saliva/blood analyte concentration at anticipated exposure levels represents an important opportunity to establish the limits of quantification and robustness of multiplex sensor systems by exploiting a unique computational modeling framework. The use of these pharmacokinetic models will also enable prediction of an exposure dose based on the saliva/blood measurement. This novel strategy will result in a more accurate prediction of exposures and, once validated, can be employed to assess dosimetry to a broad range of chemicals in support of biomonitoring and epidemiology studies.},
doi = {10.1016/j.cotox.2017.03.003},
journal = {Current Opinion in Toxicology},
number = C,
volume = 4,
place = {United States},
year = 2017,
month = 6
}
  • Chlorpyrifos (CPF)(O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate, CAS 2921-88-2), and diazinon (DZN)(O,O-diethyl-O-2-isopropyl-4-methyl-6-pyrimidyl thiophosphate, CAS 333-41-5) are commonly encountered organophosphorus insecticides whose oxon metabolites (CPF-oxon and DZN-oxon) have the ability to strongly inhibit acetylcholinesterase, an enzyme responsible for the breakdown of acetylcholine at nerve synapses. Chlorpyrifos-oxon and DZN-oxon are highly unstable compounds that degrade via hepatic, peripheral blood, and intestinal metabolism to the more stable metabolites, TCP (3,5,6-trichloro-2-pyridinol, CAS not assigned) and IMHP (2-isopropyl-6-methyl-4-pyrimidinol, CAS 2814-20-2), respectively. Studies have been performed to understand and model the chronic and acute toxic effects of CPF and DZN individually but little is known about their combined effects. The purposemore » of this study was to improve physiologically based pharmacokinetic/ pharmacodynamic (PBPK/PD) computational models by quantifying concentrations of CPF and DZN and their metabolites TCP and IMHP in whole rat blood, following exposure to the chemicals individually or as a mixture. Male Sprague-Dawley rats were orally dosed with 60 mg/kg of CPF, DZN, or a mixture of these two pesticides. When administered individually DZN and CPF were seen to reach their maximum concentration at ~3 hours post-dosing. When given as a mixture, both DZN and CPF peak blood concentrations were not achieved until ~6 hours post-dosing and the calculated blood area under the curve (AUC) for both chemicals exceeded those calculated following the single dose. Blood concentrations of IMHP and TCP correlated with these findings. It is proposed that the higher AUC obtained for both CPF and DZN as a mixture resulted from competition for the same metabolic enzyme systems.« less
  • Chlorpyrifos (CPF) and diazinon (DZN) are inhibitors of acetylcholinesterase due to the effects of their active oxon metabolites. The inhibition of acetylcholinesterase results in a buildup of acetylcholine within the nerve synapses leading to a variety of neurotoxic effects (Mileson et al., 1998). These effects are most clearly seen following acute high dose exposures but they can also be observed in lower dose chronic cases as well. Chlorpyrifos is the active ingredient in commonly used organophosphorous (OP) insecticides like DURSBAN and LORSBAN (Timchalk et. al, 2002). Chlorpyrifos and diazinon are used to eliminate pests in agricultural applications like cotton andmore » fruit crops. Every year globally there are approximately 3 million cases of organophosphate poisoning reported resulting in 200,000 deaths (Haywood et al., 2000). The public is exposed to these chemicals on a regular basis at chronic low levels from food and water contamination, dermal contact and inhalation. The United States National Health and Nutrition Examination Survey indicated that of approximately 3,600 persons from all 64 NHANES III locations, 70% tested positive for TCP in urine, suggesting exposure to chlorpyrifos (NHANES III, 1994). The chemical structures of chlorpyrifos, diazinon, and their major metabolites trichlorpyridinol (TCP), and isopropyl-methyl-hydroxypyrimidine (IMHP) are shown in Figure 1. The parent compounds, CPF and DZN, are metabolized to their potent inhibiting oxon forms via a desulfuration reaction initiated by cytochrome P450 (CYP)(Poet et al., 2003; Amitai et al., 1998). Competing with the formation of oxon is the detoxification metabolism of CPF to TCP and DZN to IMHP via a dearylation reaction utilizing the same enzymes. A-esterase (PON1) and other B-esterases also contribute to the production of TCP and IMHP through the metabolism of CPF-oxon and DZN-oxon, respectively (Poet et al., 2003; Ma et al., 1994). The ratio between the toxification/detoxification reactions determines the degree of enzyme inhibition and can be used to evaluate metabolism processes (Timchalk et al., 2002).« less
  • Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models have been developed and validated for the organophosphorus (OP) insecticides chlorpyrifos (CPF) and diazinon (DZN). Based on similar pharmacokinetic and mode of action properties it is anticipated that these OPs could interact at a number of important metabolic steps including: CYP450 mediated activation/detoxification, and blood/tissue cholinesterase (ChE) binding/inhibition. We developed a binary PBPK/PD model for CPF, DZN and their metabolites based on previously published models for the individual insecticides. The metabolic interactions (CYP450) between CPF and DZN were evaluated in vitro and suggests that CPF is more substantially metabolized to its oxon metabolite than ismore » DZN. These data are consistent with their observed in vivo relative potency (CPF>DZN). Each insecticide inhibited the other’s in vitro metabolism in a concentration-dependent manner. The PBPK model code used to described the metabolism of CPF and DZN was modified to reflect the type of inhibition kinetics (i.e. competitive vs. non-competitive). The binary model was then evaluated against previously published rodent dosimetry and ChE inhibition data for the mixture. The PBPK/PD model simulations of the acute oral exposure to single- (15 mg/kg) vs. binary-mixtures (15+15 mg/kg) of CFP and DZN at this lower dose resulted in no differences in the predicted pharmacokinetics of either the parent OPs or their respective metabolites; whereas, a binary oral dose of CPF+DZN at 60+60 mg/kg did result in observable changes in the DZN pharmacokinetics. Cmax was more reasonably fit by modifying the absorption parameters. It is anticipated that at low environmentally relevant binary doses, most likely to be encountered in occupational or environmental related exposures, that the pharmacokinetics are expected to be linear, and ChE inhibition dose-additive.« less
  • Sensitivity to chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to computationally predict disposition of CPF and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, age-dependent body weight was calculated from a generalized Gompertz function, and compartments (liver, brain, fat, blood, diaphragm, rapid, and slow) were scaled based on body weight from polynomial functions on a fractional body weight basis. Bloodmore » flows among compartments were calculated as a constant flow per compartment volume. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Model simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ≥ 0.55 mg/kg of chlorpyrifos (significantly higher than environmental exposure levels), 6 mo old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent oral doses of chlorpyrifos. At lower doses that are more relevant to environmental exposures, the model predicts that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict CPF disposition and biological response over various postnatal life-stages.« less
  • Abstract Non-invasive biomonitoring approaches are being developed using reliable portable analytical systems to quantify dosimetry utilizing readily obtainable body fluids, such as saliva. In the current study, rats were given single oral gavage doses (1, 10 or 50 mg/kg) of the insecticide chlorpyrifos (CPF), saliva and blood were collected from groups of animals (4/time-point) at 3, 6, and 12 hr post-dosing, and the samples were analyzed for the CPF metabolite trichlorpyridinol (TCP). Trichlorpyridinol was detected in both blood and saliva at all doses and the TCP concentration in blood exceeded saliva, although the kinetics in blood and saliva were comparable.more » A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for CPF incorporated a compartment model to describe the time-course of TCP in blood and saliva. The model adequately simulated the experimental results over the dose ranges evaluated. A rapid and sensitive sequential injection (SI) electrochemical immunoassay was developed to monitor TCP, and the reported detection limit for TCP in water was 6 ng/L. Computer model simulation in the range of the Allowable Daily Intake (ADI) or Reference Dose (RfD) for CPF (0.01-0.003 mg/kg/day) suggest that the electrochemical immunoassay had adequate sensitivity to detect and quantify TCP in saliva at these low exposure levels. To validate this approach further studies are needed to more fully understand the pharmacokinetics of CPF and TCP excretion in saliva. The utilization of saliva as a biomonitoring matrix, coupled to real-time quantitation and PBPK/PD modeling represents a novel approach with broad application for evaluating both occupational and environmental exposures to insecticides.« less