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Toxicokinetics of methyl tert-butyl ether and its metabolites in humans after oral exposure.

Methyl tert-butyl ether (MTBE) is widely used as an additive to gasoline, to increase oxygen content and reduce tailpipe emission of pollutants. Widespread human exposure to MTBE may occur due to leakage of gasoline storage tanks and a high stability and mobility of MTBE in ground water. To compare disposition of MTBE after different routes of exposure, its biotransformation was studied in humans after oral administration in water. Human volunteers (3 males and 3 females, identical individuals, exposures were performed 4 weeks apart) were exposed to 5 and 15 mg 13C-MTBE dissolved in 100 ml of water. Urine samples from the volunteers were collected for 96 h after administration in 6-h intervals and blood samples were taken in intervals for 24 h. In urine, MTBE and the MTBE-metabolites tert-butanol (t-butanol), 2-methyl-1,2-propane diol, and 2-hydroxyisobutyrate were quantified, MTBE and t-butanol were determined in blood samples and in exhaled air in a limited study of 3 male volunteers given 15 mg MTBE in 100 ml of water. MTBE blood concentrations were 0.69 +/- 0.25 microM after 15 mg MTBE and 0.10 +/- 0.03 microM after 5 mg MTBE. MTBE was rapidly cleared from blood with terminal half-lives of 3.7 +/- 0.9 h (15 mg MTBE) and 8.1 +/- 3.0 h (5 mg MTBE). The blood concentrations of t-butanol were 1.82 +/- 0.63 microM after 15 mg MTBE and 0.45 +/- 0.13 microM after 5 mg MTBE. Approximately 30% of the MTBE dose was cleared by exhalation as unchanged MTBE and as t-butanol. MTBE exhalation was rapid and maximal MTBE concentrations (100 nmol/l) in exhaled air were achieved within 10-20 min. Clearance of MTBE by exhalation paralleled clearance of MTBE from blood. T-butanol was cleared from blood with half-lives of 8.5 +/- 2.4 h (15 mg MTBE) and 8.1 +/- 1.6 h (5 mg MTBE). In urine samples, 2-hydroxyisobutyrate was recovered as major excretory product, t-butanol and 2-methyl-1,2-propane diol were minor metabolites. Elimination half-lives for the different urinary metabolites of MTBE were between 7.7 and 17.8 h. Approximately 50% of the administered MTBE was recovered in urine of the volunteers after both exposures, another 30% was recovered in exhaled air as unchanged MTBE and t-butanol. The obtained data indicate that MTBE-biotransformation and excretion after oral exposure is similar to inhalation exposure and suggest the absence of a significant first-pass metabolism of MTBE in the liver after oral administration.

Adult↗

Skin-test reactivity to egg protein--exposure by inhalation compared with ingestion.

Of two hundred and sixty-seven subjects exposed to egg by ingestion only, forty-eight were skin (prick)-test positive to egg material. All forty-eight subjects also reacted to other allergens on skin testing, forty-seven (98%) to allergens associated with respiratory allergy. Of thirteen subjects exposed to egg by inhalation in their workplace (and ingestion) two were skin-test-positive to egg, both also reacting to respirable allergens. Thus, inhalation of egg antigen does not greatly influence skin-test reactivity to eggs as determined by comparing the ratio of egg skin-test-positives to total skin-test-positives in the egg groups ingesting and inhaling egg antigen, i.e. 48:218 vs 2:6. In terms of the pulmonary response to inhaled eggs there were equal numbers of symptomatics with positive skin tests to common allergens as there were symptomatics with negative skin tests. Thus, an allergic predisposition shown by a positive skin test to common allergens does not predict nor preclude development of a pulmonary reaction to inhaled egg material.

Allergens↗

Endothelin-1 and nitric oxide synthase in short rebound reaction to short exposure to inhaled nitric oxide.

On withdrawal of inhalation of nitric oxide (INO) administered after lung injury, pulmonary artery pressure (PAP) and arterial oxygen tension (Pa(O(2))) may deteriorate more than before INO (rebound response). In this study, we investigated the possible roles of endothelin (ET)-1 and nitric oxide (NO) synthase (NOS) activity in the short rebound reaction to short-term inhalation of NO. Twenty-six anesthetized mechanically ventilated piglets were given endotoxin infusion. Twelve animals then received INO (30 parts per million) for two 30-min periods. Nine controls were not given NO. Measurements were made of blood gases and hemodynamic parameters, lung tissue ET-1 expression and NOS activity, and plasma ET-1 concentration. INO decreased PAP and increased Pa(O(2)), but INO withdrawal caused a short rebound reaction with an increase in PAP. Lung tissue expression and plasma concentration of ET-1 increased during INO, and plasma ET-1 increased further after its withdrawal. Activity of constitutive NOS decreased during INO, whereas that of inducible NOS was unchanged. Upregulation of ET-1 and downregulation of NOS activity may have influenced the short rebound reaction to short-term INO.

Administration, Inhalation↗

Pulmonary effects of acute vanadium pentoxide inhalation in monkeys.

An experimental study was conducted to investigate the hypothesis that changes in pulmonary function induced by vanadium pentoxide (V2O5) inhalation would be accompanied by evidence of pulmonary inflammation. Sixteen adult, male cynomolgus monkeys were acutely exposed by whole-body inhalation of V2O5 dust at aerosol concentrations of 0.5 mg V2O5/m3 and 5.0 mg V2O5/m3, conducted at a 1-wk interval. Comprehensive pulmonary function tests were performed 1 day after each inhalation exposure to detect functional changes in the airways and pulmonary parenchyma. Pulmonary inflammation was assessed by cytologic analysis of respiratory cells recovered from the lower respiratory tract by bronchoalveolar lavage (BAL). Postexposure values for pulmonary function and BAL were compared with the baseline values determined for each monkey prior to V2O5 exposure. Acute V2O5 dust inhalation produced significant air-flow limitation in both central and peripheral airways without producing any detectable changes in parenchymal function. These functional changes were accompanied by a significant increase in the total cell counts recovered from the lungs by BAL. The increase in total cell count occurred through a dramatic increase in absolute number and relative percentage of polymorphonuclear leukocytes (PMN). These findings suggest that pulmonary inflammatory changes involving PMN may play an important role in the occurrence of air-flow limitation after acute inhalation of V2O5 dust.

Air Pollutants, Occupational↗

Trichloroethylene health risk assessment: a new and improved process.

Trichloroethylene (TCE), an environmental contaminant of National concern, is the focus of a new health risk assessment process incorporating the Proposed Cancer Risk Assessment Guidelines. This paper describes not only how TCE became an environmental problem for the Air Force, but also details the new Risk Assessment process envisioned by the Environmental Protection Agency's (EPA) National Center for Environmental Assessment (NCEA). Insights on epidemiological evaluations, both past and future, and their impact on the cancer classification of TCE are discussed. Examples of how physiologically based pharmacokinetics and dose-response characterization described in the new Cancer Guidelines are applied to TCE are provided. In addition, a variety of modeling techniques are discussed for the development of reference doses (oral exposure) and reference concentrations (inhalation exposures) for TCE. Finally, the role of risk communication is included. This new process provides an example of how interagency (EPA, Department of Defense. Department of Energy) and extramural (industry, academia) partnerships can provide greater gains to the nation, as a whole, than any of the parts on their own.

Animals↗

Reactive airways dysfunction syndrome following metal fume fever.

Metal fume fever (MFF) is an acute response to the inhalation of heavy metals used in industry. The patient typically experiences symptoms of cough, fever, chills, malaise, and myalgia that are self-limited and of short duration. Wheezing may occur and pulmonary function may be acutely impaired with a decrease in lung volumes and diffusing capacity of carbon monoxide. Nevertheless, respiratory function quickly returns to normal, and persistent pulmonary insufficiency is unusual. Irritant-induced asthma is a non-immunogenic form of airway injury that may be associated with industrial inhalation exposure. In this situation, the direct toxic effect on the airways causes persistent airway inflammation and bronchial hyperreactivity. The two conditions are considered distinct entities, but we report a previously healthy worker who had classic MFF and was left with irritant-induced asthma or reactive airways dysfunction syndrome (RADS).

Adrenal Cortex Hormones↗