PBPK Model for Atrazine and Its Chlorotriazine Metabolites in Rat and Human

Campbell, Jerry L.; Andersen, Melvin E.; Hinderliter, Paul M.; Yi, Kun; Pastoor, Timothy P.; Breckenridge, Charles B.; Clewell, Harvey J.

doi:10.1093/toxsci/kfw014

Cited by 28 publications

(26 citation statements)

References 30 publications

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“…Exposure was determined by using TCT chemographs along with daily surveys of individual human water consumption ( Barraj et al , 2009 ). The resulting temporal pattern of human exposure was converted to estimated, time-dependent, internal human plasma TCT concentrations using a PBPK model ( Campbell et al , 2016 ). The human POD was established by using the PBPK model to convert an administered TCT-POD dose to the TCT-POD plasma concentration ( Figure 1 ).…”

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confidence: 99%

PBPK-Based Probabilistic Risk Assessment for Total Chlorotriazines in Drinking Water

et al. 2016

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The risk of human exposure to total chlorotriazines (TCT) in drinking water was evaluated using a physiologically based pharmacokinetic (PBPK) model. Daily TCT (atrazine, deethylatrazine, deisopropylatrazine, and diaminochlorotriazine) chemographs were constructed for 17 frequently monitored community water systems (CWSs) using linear interpolation and Krieg estimates between observed TCT values. Synthetic chemographs were created using a conservative bias factor of 3 to generate intervening peaks between measured values. Drinking water consumption records from 24-h diaries were used to calculate daily exposure. Plasma TCT concentrations were updated every 30 minutes using the PBPK model output for each simulated calendar year from 2006 to 2010. Margins of exposure (MOEs) were calculated (MOE = [Human Plasma TCTPOD] ÷ [Human Plasma TCTEXP]) based on the toxicological point of departure (POD) and the drinking water-derived exposure to TCT. MOEs were determined based on 1, 2, 3, 4, 7, 14, 28, or 90 days of rolling average exposures and plasma TCT Cmax, or the area under the curve (AUC). Distributions of MOE were determined and the 99.9th percentile was used for risk assessment. MOEs for all 17 CWSs were >1000 at the 99.9th percentile. The 99.9th percentile of the MOE distribution was 2.8-fold less when the 3-fold synthetic chemograph bias factor was used. MOEs were insensitive to interpolation method, the consumer’s age, the water consumption database used and the duration of time over which the rolling average plasma TCT was calculated, for up to 90 days. MOEs were sensitive to factors that modified the toxicological, or hyphenated appropriately no-observed-effects level (NOEL), including rat strain, endpoint used, method of calculating the NOEL, and the pharmacokinetics of elimination, as well as the magnitude of exposure (CWS, calendar year, and use of bias factors).

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PBPK-Based Probabilistic Risk Assessment for Total Chlorotriazines in Drinking Water

et al. 2016

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“…The tolerance of maize to chlorotriazines has been linked to higher levels of expression and activity of GST (Timmerman, 1989) and that when weeds develop resistance to ATR, it is often attributed to increased expression/activity of GST in the resistant weed (Anderson & Gronwald, 1991;Evans et al, 2017). In a pharmacokinetic model of ATR (Campbell et al, 2016), it has been demonstrated that the clearance of chlorotriazines from plasma was most sensitive to the rate of elimination of the ATR metabolite, DACT (Breckenridge et al, 2016). Thus, the rate of the clearance of ATR and its metabolites from plasma is directly dependent on GSH levels and GST expression and activity in the liver and kidney.…”

Section: Discussionmentioning

confidence: 99%

“…In mammals, ATR is rapidly absorbed, dealkylated in the liver by CYP P450 liver enzymes (Lang et al, 1996) and eliminated in urine and feces, predominantly as glutathione (GSH) conjugated chlorotriazine mercapturates. ATR has a terminal half-life of elimination of approximately 31 h in humans (Campbell et al, 2016) and plasma clearances of 2.4, 6.9, 6.0 and 8.1 h for ATR and its three chlorotriazine (DEA, DIA and DACT) metabolites, respectively, in female rats administered ATR by gavage (McMullin et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Changes in hepatic phase I and phase II biotransformation enzyme expression and glutathione levels following atrazine exposure in female rats

Zimmerman

Breckenridge

et al. 2017

Xenobiotica

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1. To determine the effects of repeated atrazine (ATR) treatment on hepatic phase I and II enzymes, adult female rats were treated with vehicle or 100 mg/kg of ATR for 1, 2, 3 or 4 days. Glutathione-s-transferases (GST) mRNA expression, protein levels (mu, pi, alpha, omega), and activity (cytosolic and microsomal), along with bioavailable glutathione (GSH) were assayed. 2. GST expression, concentrations and activity were increased, along with GSH levels, in animals treated with ATR for 3 and 4 days. 3. A subsequent study was performed with animals treated with vehicle, 6.5, 50 or 100 mg/kg/day for 4, 8 or 14 days. Expression of hepatic phase I CYP 450 enzymes was evaluated in conjugation with GST expression, protein and activity. Nineteen of the 45 CYP enzymes assayed displayed increased mRNA levels after eight days of treatment in animals treated with 50 or 100 mg/kg/day. After 14 days of treatment, all CYP expression levels returned to control levels except for CYP2B2, CYP2B3, CYP2C7, CYP2C23, CYP2E1, CYP3A9, CYP4A3 and CYP27A1, which remained elevated. 4. Results indicate that there may be a habituation or adaptation of liver phase I and phase II expression following repeated ATR treatment.

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“…Human exposure to atrazine or terbuthylazine results in a relatively fast urinary excretion of the parent compounds and their dealkylated and conjugated metabolites (104,105). The half-life of atrazine, for example, is only 24-31 h (106,107). The parent compound is, therefore, generally detected only in minor amounts in the urine, usually after continuous occupational exposure.…”

Section: Epidemiological Studiesmentioning

confidence: 99%

Oxidative stress in triazine pesticide toxicity: a review of the main biomarker findings

Semren

Žunec

Pizent

2018

Archives of Industrial Hygiene and Toxicology

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This review article provides a summary of the studies relying on oxidative stress biomarkers (lipid peroxidation and antioxidant enzymes in particular) to investigate the effects of atrazine and terbuthylazine exposure in experimental animals and humans published since 2010. In general, experimental animals showed that atrazine and terbuthylazine exposure mostly affected their antioxidant defences and, to a lesser extent, lipid peroxidation, but the effects varied by the species, sex, age, herbicide concentration, and duration of exposure. Most of the studies involved aquatic organisms as useful and sensitive bio-indicators of environmental pollution and important part of the food chain. In laboratory mice and rats changes in oxidative stress markers were visible only with exposure to high doses of atrazine. Recently, our group reported that low-dose terbuthylazine could also induce oxidative stress in Wistar rats. It is evident that any experimental assessment of pesticide toxic effects should take into account a combination of several oxidative stress and antioxidant defence biomarkers in various tissues and cell compartments. The identified effects in experimental models should then be complemented and validated by epidemiological studies. This is important if we wish to understand the impact of pesticides on human health and to establish safe limits.

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PBPK Model for Atrazine and Its Chlorotriazine Metabolites in Rat and Human

Cited by 28 publications

References 30 publications

PBPK-Based Probabilistic Risk Assessment for Total Chlorotriazines in Drinking Water

PBPK-Based Probabilistic Risk Assessment for Total Chlorotriazines in Drinking Water

Changes in hepatic phase I and phase II biotransformation enzyme expression and glutathione levels following atrazine exposure in female rats

Oxidative stress in triazine pesticide toxicity: a review of the main biomarker findings

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