The pharmacokinetics of inhaled chlorobenzene in the rat

Sullivan, Timothy M.; Born, Christa; Carlson, Gary P.; Kessler, Wayne V.

doi:10.1016/0041-008x(83)90336-8

Cited by 22 publications

(12 citation statements)

References 12 publications

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“…A comparison of the shape of the series of uptake curves reveals that the slopes of the curves decreased progressively with increasing chamber concentration. This behavior is representative of a saturable metabolic pathway, and is in agreement with observations of metabolic saturation reported by Sullivan et al (1983) for chlorobenzene inhalation exposure in the rat. An optimal fit of the family of uptake curves was obtained by adjusting Michaelis-Menten metabolic constants, K m (affinity) and V max (capacity), using the PBPK model.…”

Section: Gas Uptake Studiessupporting

confidence: 87%

Development Of A Physiologically Based Pharmacokinetic Model For Chlorobenzene In F-344 Rats

Thrall

Woodstock

Kania

2004

Journal of Toxicology and Environmental Health, Part A

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A physiologically based pharmacokinetic (PBPK) model to describe the absorption, distribution, metabolism, and elimination of chlorobenzene in rats was developed. Partition coefficients were experimentally determined in rat tissues and blood samples using an in vitro vial equilibration technique. These solubility ratios were in agreement with previous reports. The in vivo metabolism of chlorobenzene was evaluated using groups of three F344 male rats exposed to initial chlorobenzene concentrations ranging from 82 to 6750 ppm in a closed, recirculating gas uptake system. An optimal fit of the family of uptake curves was obtained by adjusting Michaelis-Menten metabolic constants, K(m) (affinity) and Vmax (capacity), using the PBPK model. At the highest chamber concentration, the uptake curve could not be modeled without the addition of a first-order (Kfo) metabolic pathway. Pretreatment with pyrazole, an inhibitor of oxidative microsomal metabolism, had no impact on the slope of the uptake curve. The completed PBPK model was evaluated against real-time exhaled breath data collected from rats receiving either an intraperitoneal (i.p.) injection or oral gavage dose of chlorobenzene in corn oil. Exhaled breath profiles were evaluated and absorption rates were determined. Development of the chlorobenzene PBPK model in rats is the first step toward future extrapolations to apply to humans.

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Section: Gas Uptake Studiessupporting

confidence: 87%

Development Of A Physiologically Based Pharmacokinetic Model For Chlorobenzene In F-344 Rats

Thrall

Woodstock

Kania

2004

Journal of Toxicology and Environmental Health, Part A

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“…In the urine the amount of the mercapturic acid conjugate decreases relative to that of 4-chlorophenol or 4-chlorophenol sulfate and glucuronic acid conjugates; the amount of unmetabolized chlorobenzene eliminated via the lungs is increased. Such a saturation of metabolism is seen, for example, in rats exposed once or several times to a chlorobenzene concentration of 400 ml/m 3 (BUA 1990, Sullivan et al 1983.…”

Section: Eliminationmentioning

confidence: 99%

“…In animal studies it was demonstrated that the distribution of chlorobenzene in the organism depended largely on the fat content of the various organs (Shimada 1988, Sullivan et al 1983. In mice, 2 hours after the end of a 1-hour exposure to 500 ml/m 3 , the highest concentration of chlorobenzene was found in the adipose tissue followed by the kidneys, liver, brain and blood (Shimada 1988).…”

Section: Distributionmentioning

confidence: 99%

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Chlorobenzene [MAK Value Documentation, 1999]

2012

The MAK‐Collection for Occupational Health and Safety

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Published in the series Occupational Toxicants , Vol. 12 (1999) The article contains sections titled: Toxic Effects and Mode of Action Mechanism of Action Toxicokinetics and Metabolism Absorption Distribution Metabolism Elimination Effects in Man Single exposures Repeated exposure Effects on skin and mucous membranes Animal Experiments and in vitro Studies Acute toxicity Subacute, subchronic and chronic toxicity Effects on skin and mucous membranes Allergenic effects Reproductive and developmental toxicity Genotoxicity Carcinogenicity Other effects Manifesto (MAK value, classification)

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“…The compounds are being used in industrial chemistry and are considered important pollutants 1 -26 . They can be absorbed readily in the gastrointestinal tract and lungs 27 and metabolized in the liver to one or more toxic compounds 28 " 29 . In the body, there is a mixture of cells with different functions and interactions making the interpretation of in vivo studies difficult. In contrast, in vitro, cells react more uniformly and the system is easy to handle and is suitable for short-term studies.…”

Section: Introductionmentioning

confidence: 99%

Genetic toxicology of benzene and its derivatives in rat bone marrow cell cultures

Khalil

Odeh

1994

Toxicological & Environmental Chemistry

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The cytogenetic effects of short-term in vitro exposure of rat bone marrow cells to benzene and its derivatives were studied. The used benzene concentrations ranged from 0.001 to 200 mM, while those of phenol, chlorobenzene and bromobenzene ranged from 0.001 to 100 mM. Each chemical was individually added for either 24 or 36 hr. No dividing cells were encountered in cultures treated with 200 mM benzene, 100 mM chlorobenzene or bromobenzene as well as with 10 mM phenol.The four derivatives of benzene, at both exposure periods, resulted in concentration-dependent elevations in the incidence of sister-chromatid exchanges. The relative potency was in the following order: Phenol > chlorobenzene = bromobenzene > benzene. Similarly, concentration-and time-related depressions in the mitotic and cell proliferation indices were observed. These data suggest that, under the present experimental conditions, phenol, chlorobenzene and bromobenzene might be genotoxic. Therefore, excessive exposure to these compounds is not recommended.

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The pharmacokinetics of inhaled chlorobenzene in the rat

Cited by 22 publications

References 12 publications

Development Of A Physiologically Based Pharmacokinetic Model For Chlorobenzene In F-344 Rats

Development Of A Physiologically Based Pharmacokinetic Model For Chlorobenzene In F-344 Rats

Chlorobenzene [MAK Value Documentation, 1999]

Genetic toxicology of benzene and its derivatives in rat bone marrow cell cultures

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