Physiologically Based Pharmacokinetic Modeling of a Ternary Mixture of Alkyl Benzenes in Rats and Humans

Tardif, Robert; Charest‐Tardif, Ginette; Brodeur, Jean‐Paul; Krishnan, Kannan

doi:10.1006/taap.1996.8096

Cited by 155 publications

(148 citation statements)

References 16 publications

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“…Interactions between xenobiotics do occur and have been shown for several pairs of substances, see e.g. (10,84,85). Generally, however, interactions have been reported only at higher exposure levels than those used in the present study.…”

Section: Eliminationmentioning

confidence: 45%

Toxicokinetics of Inhaled Trimethylbenzenes in Man

Järnberg

Johanson

Löf

1996

Toxicology and Applied Pharmacology

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Section: Eliminationmentioning

confidence: 45%

Toxicokinetics of Inhaled Trimethylbenzenes in Man

Järnberg

Johanson

Löf

1996

Toxicology and Applied Pharmacology

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“…The three isomers of xylene were assumed to behave as m-xylene in the ®rst approximation. Metabolic parameters such as the maximum rate constants (Vmax), the Michaelis constants (Km), and the metabolic inhibition constants (Ki) for ethylbenzene and xylene were obtained from published data (Tardif et al 1993a(Tardif et al , 1997. Urinary excretion rate constants for mandelic (Sedivec et al 1983) and methylhippuric acid (Senczuk and Orlowski 1978) were obtained from experiments on humans (0.231 h )1 and 1.386 h )1…”

Section: Metabolite Of Substrate In Liver Compartmentmentioning

confidence: 99%

Biological monitoring of workers exposed to ethylbenzene and co-exposed to xylene

Jang¹,

Droz²,

Kim³

2000

International Archives of Occupational and Environmental Health

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“…Similar data obtained for m-XYL are presented in Figure 6. The PBPK models incorporating inhibition constants for competition of hepatic metabolism (13,14) adequately simulated the modulated kinetics of TOL and m-XYL in various binary mixtures (Figures 5, 6). The difference in kinetics between single and combined exposures is essentially a function of the modulated venous blood concentrations of both chemicals and the magnitude of the Ki.…”

Section: D-a D-b D-c) By Doing This the Modulatory Effect Of D Onmentioning

confidence: 93%

“…The validation of the PBPK modeling approach outlined above has been accomplished in a limited number of studies using mixtures of VOCs (12)(13)(14)(15)(16). The overall approach in these studies involved the characterization of the kinetics of chemicals present individually or in binary mixtures for identifying the occurrence and magnitude of binary interactions (e.g., competitive inhibition) as well as for determining the quantitative nature of the interaction mechanism (e.g., Ki).…”

Section: D-a D-b D-c) By Doing This the Modulatory Effect Of D Onmentioning

confidence: 99%

Physiological modeling and extrapolation of pharmacokinetic interactions from binary to more complex chemical mixtures.

Krishnan

Haddad

Béliveau

et al. 2002

Environ Health Perspect

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The available data on binary interactions are yet to be considered within the context of mixture risk assessment because of our inability to predict the effect of a third or a fourth chemical in the mixture on the interacting binary pairs. Physiologically based pharmacokinetic (PBPK) models represent a potentially useful framework for predicting the consequences of interactions in mixtures of increasing complexity. This article highlights the conceptual basis and validity of PBPK models for extrapolating the occurrence and magnitude of interactions from binary to more complex chemical mixtures. The methodology involves the development of PBPK models for all mixture components and interconnecting them at the level of the tissue where the interaction is occurring. Once all component models are interconnected at the binary level, the PBPK framework simulates the kinetics of all mixture components, accounting for the interactions occurring at various levels in more complex mixtures. This aspect was validated by comparing the simulations of a binary interaction-based PBPK model with experimental data on the inhalation kinetics of m-xylene, toluene, ethyl benzene, dichloromethane, and benzene in mixtures of varying composition and complexity. The ability to predict the kinetics of chemicals in complex mixtures by accounting for binary interactions alone within a PBPK model is a significant step toward the development of interaction-based risk assessment for chemical mixtures.

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Physiologically Based Pharmacokinetic Modeling of a Ternary Mixture of Alkyl Benzenes in Rats and Humans

Cited by 155 publications

References 16 publications

Toxicokinetics of Inhaled Trimethylbenzenes in Man

Toxicokinetics of Inhaled Trimethylbenzenes in Man

Biological monitoring of workers exposed to ethylbenzene and co-exposed to xylene

Physiological modeling and extrapolation of pharmacokinetic interactions from binary to more complex chemical mixtures.

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