Acute, pharmacokinetic, and subchronic toxicological studies of 2,4-dichlorophenoxyacetic acid*1, *2

Gorzinski, S.J.; Kociba, R.J.; Campbell, R. A.; Smith, F.A.; Nolan, R.J.; Eisenbrandt, David L.

doi:10.1016/0272-0590(87)90025-x

Cited by 68 publications

(13 citation statements)

References 13 publications

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“…In part because of its lengthy history and widespread use, the toxicity and potential human health effects of 2,4-D have been extensively studied and reviewed (Bus and Hammond, 2007; Garabrant and Philbert, 2002; Munro et al , 1992). Subchronic and chronic rat toxicity studies have identified the kidney as a primary target organ (Charles et al , 1996a, b; Gorzinski et al , 1987), consistent with the observation that 2,4-D is accumulated in renal proximal tubules through the action of a saturable, metabolically active renal organic anion transporter, OAT1 (Berndt and Koschier, 1973; Hasegawa et al , 2003; Hook et al , 1974). The OAT1 transporter plays a critical role in the dose-dependent systemic renal clearance of 2,4-D in rats and is saturated at oral gavage and dietary doses of approximately 50mg/kg, resulting in distinct nonlinear toxicokinetic (TK) behavior (Gorzinski et al , 1987; Saghir et al , 2006; Timchalk, 2004; van Ravenzwaay et al , 2003).…”

supporting

confidence: 69%

“…Subchronic and chronic rat toxicity studies have identified the kidney as a primary target organ (Charles et al , 1996a, b; Gorzinski et al , 1987), consistent with the observation that 2,4-D is accumulated in renal proximal tubules through the action of a saturable, metabolically active renal organic anion transporter, OAT1 (Berndt and Koschier, 1973; Hasegawa et al , 2003; Hook et al , 1974). The OAT1 transporter plays a critical role in the dose-dependent systemic renal clearance of 2,4-D in rats and is saturated at oral gavage and dietary doses of approximately 50mg/kg, resulting in distinct nonlinear toxicokinetic (TK) behavior (Gorzinski et al , 1987; Saghir et al , 2006; Timchalk, 2004; van Ravenzwaay et al , 2003). Importantly, OAT1 is the primary transporter responsible for renal clearance of 2,4-D in humans (Nozaki et al , 2007), and thus, 2,4-D would be expected to exhibit analogous dose-dependent nonlinear TK in humans.…”

supporting

confidence: 69%

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Life-Stage-, Sex-, and Dose-Dependent Dietary Toxicokinetics and Relationship to Toxicity of 2,4-Dichlorophenoxyacetic Acid (2,4-D) in Rats: Implications for Toxicity Test Dose Selection, Design, and Interpretation

Saghir

Marty

Zablotny

et al. 2013

Toxicological Sciences

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Life-stage-dependent toxicity and dose-dependent toxicokinetics (TK) were evaluated in Sprague Dawley rats following dietary exposure to 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D renal clearance is impacted by dose-dependent saturation of the renal organic anion transporter; thus, this study focused on identifying inflection points of onset of dietary nonlinear TK to inform dose selection decisions for toxicity studies. Male and female rats were fed 2,4-D-fortified diets at doses to 1600 ppm for 4-weeks premating, <2 weeks during mating, and to test day (TD) 71 to parental (P1) males and to P1 females through gestation/lactation to TD 96. F1 offspring were exposed via milk with continuing diet exposure until postnatal day (PND) 35. As assessed by plasma area under the curve for the time-course plasma concentration, nonlinear TK was observed ≥1200 ppm (63mg/kg/day) for P1 males and between 200 and 400 ppm (14–27mg/kg/day) for P1 females. Dam milk and pup plasma levels were higher on lactation day (LD) 14 than LD 4. Relative to P1 adults, 2,4-D levels were higher in dams during late gestation/lactation and postweaning pups (PND 21–35) and coincided with elevated intake of diet/kg body weight. Using conventional maximum tolerated dose (MTD) criteria based on body weight changes for dose selection would have resulted in excessive top doses approximately 2-fold higher than those identified incorporating critical TK data. These data indicate that demonstration of nonlinear TK, if present at dose levels substantially above real-world human exposures, is a key dose selection consideration for improving the human relevance of toxicity studies compared with studies employing conventional MTD dose selection strategies.

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supporting

confidence: 69%

supporting

confidence: 69%

Life-Stage-, Sex-, and Dose-Dependent Dietary Toxicokinetics and Relationship to Toxicity of 2,4-Dichlorophenoxyacetic Acid (2,4-D) in Rats: Implications for Toxicity Test Dose Selection, Design, and Interpretation

Saghir

Marty

Zablotny

et al. 2013

Toxicological Sciences

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“…Electron microscopy in this study has shown that the height of these cells was diminished, the cytoplasm of the altered cells was markedly reduced in volume, and there was a prominent decrease in the number and volume of mitochondria (Ozaki et al 2001). Treatment-related cytoplasmic alterations (described as increased homogenicity) were observed in the renal proximal tubules of rats given 60 mg/kg/day and higher of 2,4-D for 13 weeks (Gorzinski et al 1987). Furthermore, subchronic exposure of male and female rats to 300 mg/kg/ day 2,4-D for 2 years has resulted in brush border loss and vacuolization of proximal tubular cells in the kidney (Charles et al 1996).…”

Section: Resultsmentioning

confidence: 95%

“…The lower no-observable-adverse-effect level (NOAEL) for 2,4-D in rats subchronically exposed to the herbicide for 13 weeks was reported as 15 mg/kg/day (Gorzinski et al 1987;Charles et al 1996); therefore, a slightly higher dose of NOAEL (20 mg/kg) and its multiples were chosen as the test doses in this study. Apart from a dose-dependent decrease in body and kidney weights, changes in the kidney morphology at light microscopical level (Table 2) was observed distinctly in this dose range, indicating the congruity of the dose range selected.…”

Section: Resultsmentioning

confidence: 99%

Immunohistochemical and Histopathological Evaluation of 2,4-Dichlorophenoxyacetic Acid-Induced Changes in Rat Kidney Cortex

Uyanıkgil

Ateş

Baka

et al. 2009

Bull Environ Contam Toxicol

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This study aims to investigate the effect of 2,4-dichlorophenoxyacetic acid (2,4-D) on rat kidney cortex histology. Oral exposure of rats to 2,4-D for 28 days resulted in decreases in body weight gain and kidney weight. Histological examination showed degeneration in renal corpuscles and podocytes; vacuolization in the glomerulus with disintegration of the basal membrane; tissue edema; vacuolization, cystic dilation and invagination of the basal laminae in the tubular structures; dilation and congestion in renal corpuscular vessels and marked decrease in glomerular and stromal fibronectin reaction; suggesting that subacute 2,4-D administration induces dose-dependent histopathological degenerative effects in rat kidney cortex.

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“…Gorzinski et al (1987) evaluated the oral pharmacokinetics of 2,4-D in rats. Groups of animals were administered single oral doses ranging from 10 to 150 mg 14 C-2,4-D/kg.…”

Section: Example E Dose-dependent Kinetics Associated With the Saturmentioning

confidence: 99%

The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments

Barton

Pastoor

Baetcke

et al. 2006

Critical Reviews in Toxicology

127

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A proposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. Incorporation of pharmacokinetic studies describing absorption, distribution, metabolism, and excretion is an essential tool for improving the design and interpretation of toxicity studies and their application for safety assessment. A tiered approach is described in which basic pharmacokinetic studies, similar to those for pharmaceuticals, are conducted for regulatory submission. Subsequent tiers provide additional information in an iterative manner, depending on pharmacokinetic properties, toxicity study results, and the intended uses of the compound.

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Acute, pharmacokinetic, and subchronic toxicological studies of 2,4-dichlorophenoxyacetic acid1, 2

Cited by 68 publications

References 13 publications

Life-Stage-, Sex-, and Dose-Dependent Dietary Toxicokinetics and Relationship to Toxicity of 2,4-Dichlorophenoxyacetic Acid (2,4-D) in Rats: Implications for Toxicity Test Dose Selection, Design, and Interpretation

Life-Stage-, Sex-, and Dose-Dependent Dietary Toxicokinetics and Relationship to Toxicity of 2,4-Dichlorophenoxyacetic Acid (2,4-D) in Rats: Implications for Toxicity Test Dose Selection, Design, and Interpretation

Immunohistochemical and Histopathological Evaluation of 2,4-Dichlorophenoxyacetic Acid-Induced Changes in Rat Kidney Cortex

The Acquisition and Application of Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Agricultural Chemical Safety Assessments

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