Physiologically Based Pharmacokinetic Modeling of 1,4-Dioxane in Rats, Mice, and Humans

Sweeney, Lisa; Thrall, Karla D.; Poet, Torka S.; Corley, Richard A.; Weber, Thomas J.; Locey, Betty J.; Clarkson, Jacquelyn; Sager, Shawn L.; Gargas, Michael L.

doi:10.1093/toxsci/kfm251

Cited by 24 publications

(25 citation statements)

References 18 publications

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“…8,18) Parameter values for the physicochemical properties of compounds ( f u,p , log P, K p,h , and R b ) are shown in Table 1. Values of f u,p and log P were obtained by in silico estimation using SimCYP and ChemDrawBioUltra software, 19) K p,h was estimated from these two values (Appendix A), and R b was assumed to be 1.0 (blood and plasma concentrations are assumed to be equal).…”

Section: Estimation Of 14-dioxane Concentrations By Pbpk Modeling Wimentioning

confidence: 99%

“…Parameter values which represent physiological properties such as hepatic volumes and blood flow rates in rats or humans were taken from the literature. 8,18) Experimental plasma concentrations of 1,4-dioxane were analyzed by WinNonlin software (Professional version 5.01) with a one-compartment model and yielded primary k a , elimination constant (k el ). Values of total clearance (CL tot ), hepatic clearance (CL h ), CL h,int , and V 1 were also calculated (Appendix B).…”

Section: Estimation Of 14-dioxane Concentrations By Pbpk Modeling Wimentioning

confidence: 99%

“…2) However, although simple, inexpensive, and reliable methods are needed for evaluating the accurate toxic risk, only very complicated models have so far been established. 7,8) 1,4-Dioxane ( Fig. 1) is widely used, primarily as a solvent or as a solvent stabilizer, 9) but subchronic oral toxicity of 1,4-dioxane has been examined in rats by administering 1,4-dioxane in drinking water, suggesting hepatic and renal failures.…”

Section: Introductionmentioning

confidence: 99%

“…7,8) Kinetic models for 1,4-dioxane and its major metabolite (hydroxyethoxyacetic acid) were published in 1990; 11,12) however, the uncertainties and deficiencies of these models for use in a contemporary cancer risk assessment for 1,4-dioxane have been pointed out. 8) Therefore, the purpose of the present study was to carry out a forward dosimetry approach (shown in Fig. 2) using data from chemical doses administered to animals and from in vitro experiments with liver microsomes from humans and animals to predict 1,4-dioxane concentrations in humans.…”

Section: Introductionmentioning

confidence: 99%

“…13,16,17) 1,4-Dioxane Determinations in Biological Samples from Rats --Plasma and urine samples from individual rats were diluted 10 times with water. 1,4-Dioxane concentrations in these samples were measured by a gas chromatograph/mass spectrometer (GC/MS) with a head-space sampler system as reported previously (GCMS-QP2010, Shimadzu, Kyoto, Japan) 8) equipped with a CP-PORABOND Q column (25 m × 0.24 mm × 3 µm, Chrompack). To determine the concentrations, the intensities of the precursor ions for 1,4-dioxane (m/z = 88) and internal standard 1,4-dioxane-d 3 (m/z = 96) were used.…”

Section: Introductionmentioning

confidence: 99%

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Blood Concentrations of 1,4-Dioxane in Humans after Oral Administration Extrapolated from In Vivo Rat Pharmacokinetics, In Vitro Human Metabolism, and Physiologically Based Pharmacokinetic Modeling

Takano

Murayama

Horiuchi

et al. 2010

JOURNAL OF HEALTH SCIENCE

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The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for 1,4-dioxane in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a developed PBPK model in rats. The model consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for 1,4-dioxane. Evaluation of the rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after daily oral treatment with 1,4-dioxane (500 mg/kg, a noobserved-adverse-effect level) for 14 days. Elimination rates of 1,4-dioxane in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. 1,4-Dioxane was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for 1,4-dioxane is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses.

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Section: Estimation Of 14-dioxane Concentrations By Pbpk Modeling Wimentioning

confidence: 99%

Section: Estimation Of 14-dioxane Concentrations By Pbpk Modeling Wimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Blood Concentrations of 1,4-Dioxane in Humans after Oral Administration Extrapolated from In Vivo Rat Pharmacokinetics, In Vitro Human Metabolism, and Physiologically Based Pharmacokinetic Modeling

Takano

Murayama

Horiuchi

et al. 2010

JOURNAL OF HEALTH SCIENCE

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Ethers of Ethylene Glycol and Derivatives

Kelsey

2023

Patty's Toxicology

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E series Glycol ethers are alkyl ethers of ethylene glycol along with their acetate esters. They are commonly used in paints and cleaners and typically have a higher boiling point in conjunction with the favorable solvent properties of lower‐molecular weight ethers, esters, and alcohols. They are colorless liquids that have mild earthy or fruity odors. The ethers are miscible with water and/or with numerous organic solvents making them useful as solvents in oil‐water compositions. Their relatively slow rate of evaporation also makes them useful as solvents and coalescing agents in paints and inks. The surface tension and solvent properties of the ethers make them useful in cleaners. Other uses of the ethers include process solvents and deicers. The ethers of the higher glycols are used as hydraulic fluids. Occupational exposure to glycol ethers occurs dermally and by inhalation. Most glycol ethers have low acute, single‐dose toxicity to humans. The most notable and well‐known effect relevant to humans is toxicity to male fertility and developmental toxicity produced by those glycol ethers that can metabolize to produce significant amounts of methoxyacetic acid such as methoxy ethanol and the methyl glymes.

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Ethers of Ethylene Glycol and Derivatives

Cragg¹

2012

Patty's Toxicology

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There are seven U.S. manufacturers of ethers and other derivatives of ethylene glycol (EG), diethylene glycol (DEG), and higher glycols. Five of them are members of the American Chemistry Council (ACC) Glycol Ethers' Panel. The glycol ethers most commonly encountered industrially are colorless liquids that have mild ethereal odors. Alkyl glycol ethers are manufactured in a closed, continuous process by reacting ethylene oxide with an anhydrous alcohol in the presence of a suitable catalyst. Depending on the molar ratios of the reactants and other process parameters, the product mixtures obtained contain varying amounts of the monoethylene, diethylene, triethylene, and higher glycol ethers. Typically, the products in these mixtures are separated and purified by fractional distillation. The miscibility of most of these ethers with water and with a large number of organic solvents makes them especially useful as solvents in oil–water compositions. Their relatively slow rate of evaporation also makes them useful as solvents and coalescing agents in paints. Other uses include inks, cleaners, chemical intermediates, process solvents, brake fluids, and deicers. The ethers of the higher glycols are used as hydraulic fluids. An estimate of the U.S. production and use of representative ethylene glycol ethers is presented. Production of ethylene glycol ethers (total) in Western Europe amounted to 245 thousand metric tons in 1995. Occupational exposure to glycol ethers occurs dermally and by inhalation. Ingestion is not a concern in industrial exposure, although some cases of intentional ingestion of consumer products containing ethylene glycol ethers have been reported. A number of analytical methods have been published that are suitable for detecting glycol ethers in environmental air samples. Glycol ethers generally have low acute, single‐dose toxicity, and LD 50 values generally range from 1.0 to 4.0 g/kg of body weight. In animals and humans, high‐dose administrations (>350 mg/kg) result in central nervous system (CNS) depression, although the results from many studies show no specific damage to neural tissues. Other toxicological effects attributable to glycol ethers are associated with metabolism to the corresponding alkoxyacetic acids. In the case of EGME, EGEE, and certain other glycol ether derivatives, significant reproductive, developmental, hematologic, and immunologic effects have been associated with the formation of either methoxyacetic acid (MAA) or ethoxyacetic acids (EAA). For other glycol ether derivatives substituted with propyl, butyl, or higher homologues, both developmental effects secondary to maternal toxicity (without teratogenic effects) and hematologic effects are observed. Ethylene glycol ethers and acetates may enter the environment from manufacturing effluents and emissions and as a result of their use in commercial products.

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Physiologically Based Pharmacokinetic Modeling of 1,4-Dioxane in Rats, Mice, and Humans

Cited by 24 publications

References 18 publications

Blood Concentrations of 1,4-Dioxane in Humans after Oral Administration Extrapolated from In Vivo Rat Pharmacokinetics, In Vitro Human Metabolism, and Physiologically Based Pharmacokinetic Modeling

Blood Concentrations of 1,4-Dioxane in Humans after Oral Administration Extrapolated from In Vivo Rat Pharmacokinetics, In Vitro Human Metabolism, and Physiologically Based Pharmacokinetic Modeling

Ethers of Ethylene Glycol and Derivatives

Ethers of Ethylene Glycol and Derivatives

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