Pharmacokinetics of Inhaled or Intraperitoneally Administered Styrene in Rats

Young, John; Ramsey, John C.; Blau, Gary; Karbowski, R.J.; NITSCHKE, K. D; Slauter, Richard; Braun, Werner

doi:10.1016/b978-0-444-00288-4.50034-7

Cited by 16 publications

(8 citation statements)

References 10 publications

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“…Due to saturation of styrene metabolism, AUCs under the concentration-time curves of atmospheric styrene resulting from administration of the high doses to rats (AUC: 380 ppm-h, dose: 205 mg/kg) and mice (AUC: 230 ppm.h, dose: 322 mg/kg) exceeded those determined from the lower doses (AUC: 9.1 ppm.h, dose: 23 mg/kg and AUC: 39 ppm .h, dose: 43 mg/kg in rats; AUC: 56 ppm .h, dose: 181 mg/kg in mice) disproportionately. Young et al (1979) measured blood concentration-time courses of styrene in rats after i.p. administration of 10, 50, 500 and 1000 mg styrene/kg.…”

Section: Kinetics Following I P and P O Administrationmentioning

confidence: 99%

“…Based on studies on the pharmacokinetics of styrene in Sprague-Dawley rats (Ramsey and Young 1978;Young et al 1979) and in Fischer 344 rats , Ramsey and Andersen (1984) developed a PBPK model in order to describe the behaviour of styrene in rats and to make interspecies extrapolations. Qualitatively, the conclusions and predictions reflect our findings presented here.…”

Section: Inhalation Kinetics In Rat and Mousementioning

confidence: 99%

“…The uncertainty of the evaluation of the carcinogenic potential of styrene in experimental animals may be due to species, strain, and route specific pharmacokinetics of styrene and its critical metabolite styrene oxide. Pharmacokinetics of styrene have been investigated in several rat strains (Withey 1976(Withey , 1978Collins 1977, 1979;Ramsey and Young 1978;Young et al 1979;Andersen et al 1984). However, up to now no such investigations have been performed in mice.…”

Section: Introductionmentioning

confidence: 97%

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Species-specific pharmacokinetics of styrene in rat and mouse

Filser¹,

Schwegler²,

Csanády

et al. 1993

Arch Toxicol

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The pharmacokinetics of styrene were investigated in male Sprague-Dawley rats and male B6C3F1 mice using the closed chamber technique. Animals were exposed to styrene vapors of initial concentrations ranging from 550 to 5000 ppm, or received intraperitoneal (i.p.) doses of styrene from 20 to 340 mg/kg or oral (p.o.) doses of styrene in olive oil from 100 to 350 mg/kg. Concentration-time courses of styrene in the chamber atmosphere were monitored and analyzed by a pharmacokinetic two-compartment model. In both species, the rate of metabolism of inhaled styrene was concentration dependent. At steady state it increased linearly with exposure concentration up to about 300 ppm; more than 95% of inhaled styrene was metabolized and only small amounts were exhaled unchanged. At these low concentrations transport to the metabolizing enzymes and not their metabolic capacity was the rate limiting step for metabolism. Pharmacokinetic behaviour of styrene was strongly influenced by physiological parameters such as blood flow and especially the alveolar ventilation rate. At exposure concentrations of styrene above 300 ppm the rate of metabolism at steady state was progressively limited by biochemical parameters of the metabolizing enzymes. Saturation of metabolism (Vmax) was reached at atmospheric concentrations of about 700 ppm in rats and 800 ppm in mice, Vmax being 224 mumol/(h.kg) and 625 mumol/(h.kg), respectively. The atmospheric concentrations at Vmax/2 were 190 ppm in rats and 270 ppm in mice. Styrene accumulates preferentially in the fatty tissue as can be deduced from its partition coefficients in olive oil:air and water:air which have been determined in vitro at 37 degrees C to be 5600 and 15. In rats and mice exposed to styrene vapors below 300 ppm, there was little accumulation since the uptake was rate limiting. The bioaccumulation factor body:air at steady state (K'st*) was rather low in comparison to the thermodynamic partition coefficient body:air (Keq) which was determined to be 420. K'st* increased from 2.7 at 10 ppm to 13 at 310 ppm in the rat and from 5.9 at 20 ppm to 13 at 310 ppm in the mouse. Above 300 ppm, K'st* increased considerably with increasing concentration since metabolism became saturated in both species. At levels above 2000 ppm K'st* reached its maximum of 420 being equivalent to Keq. Pretreatment with diethyldithiocarbamate, administered intraperitoneally (200 mg/kg in rats, 400 mg/kg in mice) 15 min prior to exposure of styrene vapours, resulted in effective inhibition of styrene metabolism, indicating that most of the styrene is metabolized by cytochrome P450-dependent monooxygenases.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Kinetics Following I P and P O Administrationmentioning

confidence: 99%

Section: Inhalation Kinetics In Rat and Mousementioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Species-specific pharmacokinetics of styrene in rat and mouse

Filser¹,

Schwegler²,

Csanády

et al. 1993

Arch Toxicol

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“…On the other hand, the total systemic clearance in rats exposed to the aromatic hydrocarbons except for styrene has scarcely been reported, although there were several reports on the systemic clearance in humans exposed to the substances. The average levels of the systemic clearance in humans Wigaeus et al, 1983Wigaeus et al, , 1984 and rats (Ramsey and Young, 1978;Young et al, 1979) exposed to styrene were 1.43 and 11.7 l h -1 kg -1 , respectively; that is, the level in humans was ca 12% of that in rats. This level was applied to the rat-to-human extrapolation of the clearance of the seven aromatic hydrocarbons, which resemble in chemical structure.…”

Section: Extrapolation Of Absorbed Amounts In Humans From Results Obtmentioning

confidence: 97%

Estimation of absorption of aromatic hydrocarbons diffusing from interior materials in automobile cabins by inhalation toxicokinetic analysis in rats

Yoshida

2010

J of Applied Toxicology

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Aromatic hydrocarbons, as well as aliphatic hydrocarbons, diffusing from interior materials in automotive cabins are the most common compounds contributing to interior air pollution. In this study, the amounts of seven selected aromatic hydrocarbons absorbed by a car driver were estimated by evaluating their inhalation toxicokinetics in rats. Measured amounts of these substances were injected into a closed chamber system containing a rat, and the concentration changes in the chamber were examined. The toxicokinetics of the substances were evaluated on the basis of the concentration-time course using a nonlinear compartment model. The amounts absorbed in humans at actual concentrations in automobile cabins without ventilation were extrapolated from the results obtained from rats. The absorbed amounts estimated for a driver during a 2 h drive were as follows (per 60 kg of human body weight): 30 microg for toluene (interior median concentration, 40 microg m(-3) in our previous study), 10 microg for ethylbenzene (12 microg m(-3)), 6 microg for o-xylene (10 microg m(-3)), 8 microg for m-xylene (11 microg m(-3)), 9 microg for p-xylene (11 microg m(-3)), 11 microg for styrene (11 microg m(-3)) and 27 microg for 1,2,4-trimethylbenzene (24 microg m(-3)). Similarly, in a cabin where air pollution was marked, the absorbed amount of styrene (654 microg for 2 h in a cabin with an interior maximum concentration of 675 microg m(-3)) was estimated to be much higher than those of other substances. This amount (654 microg) was approximately 1.5 times the tolerable daily intake of styrene (7.7 microg kg(-1) per day) recommended by the World Health Organization.

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“…The work of these investigators unveiled the extensive nonlinear behaviors associated with saturation of metabolism that frequently occurred at high-doses used in toxicology studies in test animals. Among the important classes of chemicals studied by these investigators were herbicides (Sauerhoff et al, 1976(Sauerhoff et al, , 1977, solvents (McKenna et al, 1982), industrial monomers (McKenna et al, 1978a,b), and hydrocarbons (Young et al, 1979;Ramsey et al, 1980). This work generally took the form of careful, detailed collection of biological data on time-course blood levels or excretion patterns at various dosage levels.…”

Section: A Historical Perspectivementioning

confidence: 99%