Filser J G, Schwegler U, Csanády G A, Greim H, Kreuzer P E, Kessler W
GSF-Forschungszentrum für Umwelt und Gesundheit, Institut für Toxicologie, Neuherberg, Germany.
Arch Toxicol. 1993;67(8):517-30. doi: 10.1007/BF01969264.
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)
采用密闭箱技术，在雄性斯普拉格 - 道利大鼠和雄性B6C3F1小鼠中研究了苯乙烯的药代动力学。动物暴露于初始浓度范围为550至5000 ppm的苯乙烯蒸气中，或接受20至340 mg/kg的苯乙烯腹腔注射剂量，或100至350 mg/kg的苯乙烯橄榄油口服剂量。通过药代动力学二室模型监测和分析箱内空气中苯乙烯的浓度 - 时间过程。在这两个物种中，吸入苯乙烯的代谢速率均与浓度有关。在稳态时，其随暴露浓度线性增加，直至约300 ppm；超过95%的吸入苯乙烯被代谢，只有少量未改变地呼出。在这些低浓度下，转运至代谢酶而非其代谢能力是代谢的限速步骤。苯乙烯的药代动力学行为受生理参数如血流量，尤其是肺泡通气率的强烈影响。在苯乙烯暴露浓度高于300 ppm时，稳态时的代谢速率逐渐受到代谢酶生化参数的限制。大鼠在大气浓度约700 ppm、小鼠在800 ppm时达到代谢饱和（Vmax），Vmax分别为224 μmol/(h·kg)和625 μmol/(h·kg)。Vmax/2时的大气浓度在大鼠中为190 ppm，在小鼠中为270 ppm。从其在橄榄油与空气以及水与空气之间的分配系数可以推断，苯乙烯优先在脂肪组织中蓄积，在37℃体外测定其分配系数分别为5600和15。在暴露于低于300 ppm苯乙烯蒸气的大鼠和小鼠中，蓄积很少，因为摄取是限速的。与热力学分配系数体：气（Keq）相比，稳态时的生物蓄积因子体：气（K'st*）相当低，Keq测定为420。大鼠中K'st从10 ppm时的2.7增加到310 ppm时的13，小鼠中从20 ppm时的5.9增加到310 ppm时的13。高于300 ppm时，由于两个物种的代谢均达到饱和，K'st随浓度增加而显著增加。在高于2000 ppm的水平，K'st*达到其最大值420，等同于Keq。在暴露于苯乙烯蒸气前15分钟腹腔注射二乙基二硫代氨基甲酸盐（大鼠200 mg/kg，小鼠400 mg/kg）进行预处理，可有效抑制苯乙烯代谢，表明大部分苯乙烯由细胞色素P450依赖性单加氧酶代谢。（摘要截短于400字）
