Influence of simultaneous exposure to acrylonitrile and styrene on the toxicity and metabolism of styrene in rats

Normandeau, Jacques; Chakrabarti, Swapan; Brodeur, Jean‐Paul

doi:10.1016/0041-008x(84)90217-5

Cited by 10 publications

(1 citation statement)

References 16 publications

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“…It was also decreased by co-administration of toluene (Ikeda et al 1972) which is also metabolized via cytochrome P450-dependent monooxygenases. Furthermore, metabolic interactions between styrene and ethanol (Elovaara et al 1979) and styrene and acrylonitrile (Normandeau et al 1984) have been reported. Simultaneous exposure to 1,3-butadiene and styrene resuited in an inhibition of the metabolism of 1,3-butadiene only whereas 1,3-butadiene had no effect on the rate of styrene metabolism (Laib et al 1992).…”

Section: Effects On Styrene Metabolizing Enzymesmentioning

confidence: 95%

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: Effects On Styrene Metabolizing Enzymesmentioning

confidence: 95%

Species-specific pharmacokinetics of styrene in rat and mouse

Filser¹,

Schwegler²,

Csanády

et al. 1993

Arch Toxicol

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Pharmacokinetic interaction between 1,3-butadiene and styrene in Sprague-Dawley rats

Laib¹,

Tucholski²,

Filser

et al. 1992

Arch Toxicol

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Gas uptake studies were carried out to evaluate kinetic interactions between 1,3-butadiene and styrene in Sprague-Dawley rats. The animals were co-exposed by inhalation to a mixture of 1,3-butadiene between 20 and 6000 ppm (v/v) and styrene between 0 and 500 ppm. The data demonstrate that metabolism of 1,3-butadiene was partially inhibited by styrene. The inhibition was competitive at atmospheric concentrations of styrene up to 90 ppm. Higher concentrations of styrene resulted in a small additional inhibition only. The apparent Michaelis-Menten constant for 1,3-butadiene, related to the average concentration in the organism of the animals, was Kmapp = 1.17 +/- 0.37 (mumol/l of tissue) and the corresponding atmospheric concentration at steady state was 560 ppm. The inhibition constant of styrene was found to be Ki = 0.23 +/- 0.30 (mumol/l of tissue). The maximal metabolic rate for 1,3-butadiene was 230 +/- 10 (mu/kg/h).

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