Pharmacokinetics of organic solvent vapors in relation to their toxicity.

Sato, Akio; Nakajima, Tamie

doi:10.5271/sjweh.2075

Cited by 58 publications

(32 citation statements)

References 50 publications

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“…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). In contrast, pretreatment of rats with phenobarbital (Ohtsuji and Ikeda 1971;Andersen et al 1984;Sato and Nakajima 1987;Elovaara et al 1991) and with acetone, 3-methylcholanthrene or with styrene itself (Elovaara et al 1991) resulted in an enhancement of the styrene biotransformation. These observations were made after administration of very high styrene doses at which according to this pharmacokinetic study the capacity of the enzymes was determining the rate of metabolism (Ohtsuji and Ikeda 1971;Andersen et al 1984;Elovaara et al 1991) or in vitro using liver preparations (Sato and Nakajima 1987;Elovaara et al 1991).…”

Section: Effects On Styrene Metabolizing Enzymesmentioning

confidence: 84%

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: 84%

Species-specific pharmacokinetics of styrene in rat and mouse

Filser¹,

Schwegler²,

Csanády

et al. 1993

Arch Toxicol

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“…For example, and similar to previous studies, we found that not all exposed gasoline workers developed abnormal menstrual characteristics or deranged reproductive hormone profiles. There are multiple interpretations for this finding, including inter-individual differences due to variations in the pulmonary absorption, distribution, action, metabolism and excretion of inhaled gasoline compounds, which further depend on blood gas values and the fat-blood partition coefficient [30].…”

Section: Discussionmentioning

confidence: 99%

Effects of Gasoline Inhalation on Menstrual Characteristics and the Hormonal Profile of Female Petrol Pump Workers

Ekpenyong¹,

Davies²,

Daniel³

2013

JEP

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Increasing numbers of young women are employed as gasoline station attendants in most developing countries despite the lack of empirical data on the adverse reproductive health effect of this solvent. This study therefore sought to assess the effects of gasoline inhalation on the serum sex hormone profile and menstrual characteristics of female gasoline station attendants in Nigeria, given the global increase in the rate of infertility and the existing evidence on the reproductive toxicity of gasoline constituents. A site-by-site cross-sectional study of 117 female gasoline pump attendants and 118 age-matched controls was carried out between September 2011 and November 2012. The following 3 instruments were used for data collection: a semi-structured questionnaire, a female sex hormone profile assay and exposure status measures. The prevalence of menstrual disorders among the exposed and unexposed women was 37.2% and 28.5% respectively. Exposure to gasoline was significantly associated with disorders in both menstrual cycle length and quantity of flow. Specifically, exposed women had a greater than threefold increased risk of a menstrual disorder, with an odds ratio (OR) of 3.25 for abnormal cycle length and OR of 4.16 for abnormal quantity of flow. In addition, longer duration of exposure (>1 year) was significantly associated with higher likelihood of menstrual disorders. There were also persistent low serum levels of estradiol, and fluctuating levels of other reproductive hormones. Gasoline inhalation may interfere with ovarian functions leading to disordered menstrual characteristics and female sex hormone profiles, as well as future reproductive impairment.

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“…The toxic nature of these chemicals are dependent on the type of toxicity as well as its potential, whereas the intensity and duration of toxic responses are dependent on the concentration in the target organ, which is determined by the quantitative description of absorption, distribution, metabolism, and excretion of the chemical 1) . Of these factors determined by pharmacokinetics, the metabolism is garnering more and more attention because i) it is essential as a biomarker for exposure in biological monitoring, ii) it determines the halflife of chemical substances inhaled into the body, and iii) metabolic activation often occurs during the metabolic process.…”

Section: Introductionmentioning

confidence: 99%

Polymorphism of Drug-Metabolizing Enzymes in Relation to Individual Susceptibility to Industrial Chemicals.

Nakajima¹,

Aoyama²

2000

INDUSTRIAL HEALTH

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Polymorphism and the induction/inhibition of drug-metabolizing enzymes, such as cytochrome P450, aldehyde dehydrogenase (ALDH), glutathione S-transferase (GST), Nacetyltransferase (NAT), and NAD(P)H-quinone oxidoreductase (NQO1), were reviewed in relation to susceptibility to disease and to inter-individual difference in biological monitorings. A number of genetic and acquired factors can influence the susceptibility of an individual to chemicals, creating a so-called predisposition. Most cases in which genetic factors were present resulted from polymorphism of drug-metabolizing enzymes. However, conflicting reports have appeared on the relationship between polymorphism and risk of disease; in some cases, biologically plausible mechanisms linking genotypes and disease are not yet in evidence. Current findings based on biological monitoring of chemicals are insufficient to evaluate the relationship between genetic polymorphism and acquired risk when exposure has occurred in an occupational area. Investigation of such situations has generated data implicating GSTT1, GSTM1, NAT2, and NQO1 polymorphisms in biological monitoring of some chemicals; the ALDH2 polymorphism is the likely link between the genotype and the metabolism of low molecular aliphatic aldehydes. Although this polymorphism is limited in the case of Japanese as well as other Asian subjects, the inhibitors of ALDH2 activity such as trichloroethylene may produce a false polymorphism of this gene. As to the effect of factors influencing acquired predisposition, such as ethanol intake, intake of low carbohydrate diet or diabetes, corroborative epidemiological studies may be further required.

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Pharmacokinetics of organic solvent vapors in relation to their toxicity.

Cited by 58 publications

References 50 publications

Species-specific pharmacokinetics of styrene in rat and mouse

Species-specific pharmacokinetics of styrene in rat and mouse

Effects of Gasoline Inhalation on Menstrual Characteristics and the Hormonal Profile of Female Petrol Pump Workers

Polymorphism of Drug-Metabolizing Enzymes in Relation to Individual Susceptibility to Industrial Chemicals.

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