Effects of a thirteen-week inhalation exposure to ethyl tertiary butyl ether on fischer-344 rats and CD-1 mice.
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The 1990 Clean Air Act Amendments require that oxygenates be added to automotive fuels to reduce emissions of carbon monoxide and hydrocarbons. One potential oxygenate is the aliphatic ether ethyl tertiary butyl ether (ETBE). Our objective was to provide data on the potential toxic effects of ETBE. Male and female Fisher 344 rats and CD-1 mice were exposed to 0 (control), 500, 1750, or 5000 ppm of ETBE for 6 h/day and 5 days/wk over a 13-week period. ETBE exposure had no effect on mortality and body weight with the exception of an increase in body weights of the female rats in the 5000-ppm group. No major changes in clinical pathology parameters were noted for either rats or mice exposed to ETBE for 6 (rats only) or 13 weeks. Liver weights increased with increasing ETBE-exposure concentration for both sexes of rats and mice. Increases in kidney, adrenal, and heart (females only) weights were noted in rats. Degenerative changes in testicular seminiferous tubules were observed in male rats exposed to 1750 and 5000 ppm but were not seen in mice. This testicular lesion has not been reported previously for aliphatic ethers. Increases in the incidence of regenerative foci, rates of renal cell proliferation, and alpha2u-globulin containing protein droplets were noted in the kidneys of all treated male rats. These lesions are associated with the male rat-specific syndrome of alpha2u-globulin nephropathy. Increases in the incidence of centrilobular hepatocyte hypertrophy and rates of hepatocyte cell proliferation were seen in the livers of male and female mice in the 5000-ppm group, consistent with a mitogenic response to ETBE. These two target organs for ETBE toxicity, mouse liver and male rat kidney, have also been reported for methyl tertiary butyl ether and unleaded gasoline. (+info)
Physiologically based toxicokinetic modeling of inhaled ethyl tertiary-butyl ether in humans.
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A physiologically based toxicokinetic (PBTK) model was developed for evaluation of inhalation exposure in humans to the gasoline additive, ethyl tertiary-butyl ether (ETBE). PBTK models are useful tools to relate external exposure to internal doses and biological markers of exposure in humans. To describe the kinetics of ETBE, the following compartments were used: lungs (including arterial blood), liver, fat, rapidly perfused tissues, resting muscles, and working muscles. The same set of compartments and, in addition, a urinary excretion compartment were used for the metabolite tertiary-butyl alcohol (TBA). First order metabolism was assumed in the model, since linear kinetics has been shown experimentally in humans after inhalation exposure up to 50 ppm ETBE. Organ volumes and blood flows were calculated from individual body composition based on published equations, and tissue/blood partition coefficients were calculated from liquid/air partition coefficients and tissue composition. Estimates of individual metabolite parameters of 8 subjects were obtained by fitting the PBTK model to experimental data from humans (5, 25, 50 ppm ETBE, 2-h exposure; Nihlen et al., Toxicol. Sci., 1998; 46, 1-10). The PBTK model was then used to predict levels of the biomarkers ETBE and TBA in blood, urine, and exhaled air after various scenarios, such as prolonged exposure, fluctuating exposure, and exposure during physical activity. In addition, the interindividual variability in biomarker levels was predicted, in the eight experimentally exposed subjects after a working week. According to the model, raising the work load from rest to heavy exercise increases all biomarker levels by approximately 2-fold at the end of the work shift, and by 3-fold the next morning. A small accumulation of all biomarkers was seen during one week of simulated exposure. Further predictions suggested that the interindividual variability in biomarker levels would be higher the next morning than at the end of the work shift, and higher for TBA than for ETBE. Monte Carlo simulations were used to describe fluctuating exposure scenarios. These simulations suggest that ETBE levels in blood and exhaled air at the end of the working day are highly sensitive to exposure fluctuations, whereas ETBE levels the next morning and TBA in urine and blood are less sensitive. Considering these simulations, data from the previous toxicokinetic study and practical issues, we suggest that TBA in urine is a suitable biomarker for exposure to ETBE and gasoline vapor. (+info)
Biotransformation and kinetics of excretion of ethyl tert-butyl ether in rats and humans.
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Ethyl tert-butyl ether (ETBE) may be used in the future as an additive to gasoline to increase oxygen content and reduce tailpipe emissions of pollutants. Therefore, widespread human exposure may occur. To contribute to the characterization of potential adverse effects of ETBE, its biotransformation was compared in humans and rats after inhalation exposure. Human volunteers (3 males and 3 females) and rats (5 males and 5 females) were exposed to 4 (4.5+/-0.6) and 40 (40.6+/-3.0) ppm ETBE for 4 h in a dynamic exposure system. Urine samples from rats and humans were collected for 72 h at 6-h intervals, and blood samples were taken in regular intervals for 48 h. In urine, ETBE and the ETBE-metabolites tert-butanol (t-butanol), 2-methyl-1,2-propane diol, and 2-hydroxyisobutyrate were quantified; ETBE and t-butanol were determined in blood samples. After the end of the exposure period to inhalation of 40-ppm ETBE, blood concentrations of ETBE were found at 5.3+/-1.2 microM in rats and 12.1+/-4.0 microM in humans. The ETBE blood concentrations, after inhalation of 4-ppm ETBE, were 1.0+/-0.7 microM in rats and 1.3+/-0.7 microM in humans. ETBE was rapidly cleared from blood. After the end of the 40-ppm ETBE exposure period, the blood concentrations of t-butanol were 13.9+/-2.2 microM in humans and 21.7+/-4.9 microM in rats. After 4-ppm ETBE exposure, blood concentrations of t-butanol were 1.8+/-0.2 microM in humans and 5.7+/-0.8 microM in rats. t-Butanol was cleared from human blood with a half-life of 9.8+/-1.4 h in humans after 40-ppm ETBE exposure. In urine samples from controls and in samples collected from the volunteers and rats before the exposure, low concentrations of t-butanol, 2-methyl-1,2-propane diol, and 2-hydroxyisobutyrate were present. In the urine of both humans and rats exposed to ETBE, the concentrations of these compounds were significantly increased. 2-Hydroxy-isobutyrate was recovered in urine as the major excretory product formed from ETBE; t-butanol and 2-methyl-1,2-propane diol were minor metabolites. All metabolites of ETBE excreted with urine were rapidly eliminated in both species after the end of the ETBE exposure. Excretion half-lives for the different urinary metabolites of ETBE were between 10.2 and 28.3 h in humans and 2.6 and 4.7 h in rats. The obtained data indicate that ETBE biotransformation and excretion are similar for rats and humans, and that ETBE and its metabolites are rapidly excreted by both species. Between 41 and 53% of the ETBE retained after the end of the exposure was recovered as metabolites in the urine of both humans and rats. (+info)
Dual effects of ether on end-plate currents.
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1. The effects of diethyl ether (ether) on miniature end-plate currents (m.e.p.c.s) and on acetylcholine-activated end-plate channels were measured in toad sartorius muscle fibres with voltage-clamp and extracellular recording techniques. 2. At low concentrations (less than 20 mM) either made m.e.p.c.s decay faster than normal. At high concentrations (greaster than 40 mM), the decay of m.e.p.c.s was slower than normal. With all concentrations, the cecay remained exponential with single time constant, tau D. 3. At low concentrations ether did not affect the growth phase of m.e.p.c.s and only slightly reduced the amplitude of m.e.p.c.s. At the higher concentrations, the growth phase was slowed and m.e.p.c.s were significantly reduced in amplitude. 4. Ether at all concentrations (5--70 mM) reduced end-plate channel lifetime, the effect increasing with ether concentration. Ether did not significantly alter the elementary channel conductance or the actylcholine null (reversal) potential. 5. Curare reduced tau D which had been prolonged by high concentrations of ether. Ether itself at high concentrations caused a reduction in tau D increased by neostigmine. It is proposed that high concentrations of either inhibit acetylcholine hydrolysis by acetylcholinesterase. 6. The effect of ether in reducing end-plate channel lifetime and reducing m.e.p.c. amplitude, without significantly altering the normal voltage and temperature sensitivity of channel lifetime, is consistent with the proposal that either reduces the stability of open end-plate channels. (+info)
Intraocular pressures in children during isoflurane and halothane anesthesia.
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The effects of isoflurane and halothane on intraocular pressure (IOP) were studied in 28 children. Measurements were made during spontaneous ventilation and at a various levels of reduced PaCO2 achieved by controlled ventilation. Control IOP values were determined prior to anesthesia following premedication with chloral hydrate, pentobarbital, pentobarbital with meperidine. At roughly equivalent levels of anesthesia, mean IOP values during spontaneous ventilation ranged frm 16.3 to 17.6 torr for each anesthetic. These values were significantly less (P less than 0.01) than control values only in those patients receiving chloral hydrate who did not cooperate. In contrast, no significant change in IOP was found in more sedated and cooperative patients who received pentobarbital and meperidine. Moderate hypocarbia and hypercarbia over a range of PaCO2 greater than 42 torr had little influence on IOP. We conclude that IOP's during isoflurane and halothane anesthesia do not differ significantly from IOP in the sedated, cooperative, healthy pediatric patient. (+info)
Neuromuscular effects of enflurane, alone and combined with d-Tubocurarine, pancuronium, and succinylcholine, in man.
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The neuromuscular effects of d-tubocurarine (dTc), pacuronium, and succinylcholien (SCh) were studied in 37 unpremedicated adult surgical patients anesthetized with 1.25 MAC enflurance in oxygen. The relaxant doses that produced 50 per cent depression of twitch height (ED50) were 1.57, 0.29, and 4.9 mg/m2 for dTc, pancuronium, and SCh, respectively. These doses are approximately 3.1, 1.7, and 1.0 times less than the amount of dTc, pancuronium, and SCh required to produce 50 per cent depression of twitch height during halothane anesthesia but are the same as ED50 values during isoflurane anesthesia. In eight additional unpremedicated patients anesthesia was maintained at 0.71 MAC enflurane in oxygen (five patients) or 1.67 MAC enflurane in oxygen (three patients). Twitch depression following dTc, 1.5 mg/m2, was related directly to alveolar enflurane concentration. Ability to sustain tetanus decreased progressively with increasing tetanic frequencies and decreased with increasing alveolar enflurane concentrations. The authors concluded that smaller doses of dTc and pancuronium are needed for adequate relaxation during enflurane anesthesia than during equi-MAC halothane anesthesia, and that higher alveolar enflurane concentrations reduce the dose of dTc necessary to produce a given amount of paralysis. Also, neuromuscular effects of enflurane in combination with dTc or pancuronium are not significantly different from those seen suring equi-MAC isoflurane anesthesia. (+info)
Psychological studies of human performance as affected by traces of enflurane and nitrous oxide.
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Thirty human subjects were exposed for four hours to 500 ppm N-2O and 15 ppm enflurane in air and then, within five minutes, given a 35-minute battery of psychological tests. Performance of a divided-attention audiovisual task and a digit-span memory test were significantly decreased compared with control data following exposure to air. A tachistoscopic task, four tests from the Wechsler memory scale, and five others from the Wechsler Adult Intelligence Scale were unaffected. Thirty subjects exposed to 500 ppm N-2-O in air only scored significantly lower on the digit-span test only. (+info)
Comparative toxicities of halothane, isoflurane, and diethyl ether at subanesthetic concentrations in laboratory animals.
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Effects of 35-day exposures to subanesthetic concentrations of halothane, isoflurane, and diethyl ether were measured in mice, rats, and guinea pigs which were in a phase of rapid body growth. Halothane produced a greater decrement in weight gain and a greater incidence of hepatic degenerative changes than isoflurane or diethyl ether despite its administration at lower anesthetic concentrations. Isoflurane results were intermediate between those of halothane and diethyl ether. No consistent injury to any organ other than the liver was found. (+info)