Anneliese Eben

Metabolism, excretion and toxicology of trichloroethylene after inhalation

Each of 8 subjects was exposed to a concentration of approx. 40 ppm trichloroethylene for 4 h and each of 4 subjects to a concentration of approx. 50 ppm for 4 h/day on 5 successive days. The concentrations of trichloroethylene and the metabolites trichloroethanol and trichloroacetic acid were determined in the blood, urine and the expired breath. Repeated exposures were followed by a slight increase of trichloroethylene and trichloroethanol in the blood. After a short time, the urinary excretion of trichloroethanol reached a maximal level and then remained constant. During the exposure the trichloroacetic acid-concentration increased continuously from one day to the other.Zusammenfassung8 Personen wurden einmal 4 Std lang einer Trichloroäthylenkonzentration von ca. 40 ppm und weitere 4 Personen täglich 4 Std lang einer Konzentration von ca. 50 ppm an 5 aufeinanderfolgenden Tagen exponiert.In Atemluft, Blut und Harn wurden die Konzentrationen von Trichloräthylen und den Metaboliten Trichloräthanol und Trichloressigsäure bestimmtAls Folge der wiederholten Exposition zeichnete sich die Tendenz zu einem leichten Anstieg des Trichloräthylen- und Trichloräthanolspiegels im Blut ab.Die Trichloräthanolkonzentration im Harn erreichte nach kurzer Zeit ein konstant bleibendes Niveau. Die Trichloressigsäureausscheidung nahm kontinuierlich von Tag zu Tag zu.

Metabolism, excretion and toxicology of trichloroethylene after inhalation. 1. Experimental exposure on rats.

In acute and subchronic inhalation studies rats were exposed to trichloroethylene. During the 4-h exposures the concentration was about 50 ppm to 3160 ppm and more, and in the 14-week study (8 h/day) within the range of the MAC (50 ppm). The behavior of trichloroethylene and its metabolites (chloral hydrate, trichloroethanol and trichloroacetic acid) in the expired air, blood and urine was investigated. For this purpose, analytical methods were developed.With the exception of elevated liver weights, the exposure to a trichloroethylene concentration of 55 ppm over a period of 14 weeks did not cause any pathological changes. The liver enlargement as a consequence of an enzyme induction is discussed. Trichloroethylene was not detectable in the blood, and the concentrations of trichloroethanol and chloral hydrate were not altered significantly. The urinary trichloroethanol excretion increased until the 10th week and then decreased slowly. In contrast, the trichloroacetic acid remained fairly constant. Corresponding results of the ratio TCE:TCA were found.ZusammenfassungRatten wurden in akuten und subchronischen Inhalationsversuchen Trichloräthylen exponiert. Bei den 4stündigen Expositionen waren die Konzentrationen ca. 50 ppm bis 3160 ppm, im 14-Wochenversuch (täglich 8 Std) im MAK-Bereich (50 ppm). Das Verhalten von Trichloroäthylen und seiner Metabolite (Chloralhydrat, Trichloräthanol, Trichloressigsäure) in Atemluft, Blut und Harn wurde untersucht. Dazu wurden Methoden zur analytischen Bestimmung ausgearbeitet. Mit Ausnahme erhöhter Lebergewichte ergaben sich bei Ratten nach Inhalation einer TRI-Konzentration von ca. 55 ppm über 14 Wochen keine pathologischen Veränderungen. Die Lebervergrößerung als Folge einer Enzyminduktion wird diskutiert. Trichloroäthylen konnte im Blut nicht nachgewiesen werden, die Trichloräthanol- und Chloralhydrakontzentrationen veränderten sich nicht wesentlich. Die Trichloräthanolmenge im Harn stieg bis zur 10. Woche an, um dann allmählich abzunehmen. Dagegen blieb die Trichloressigsäurekonzentration ziemlich unverändert. Entsprechend verhielt sich das Verhältnis Trichloräthanol/Trichlor-essigsäure.

Zur Toxicität von Methylisocyanat und dessen quantitativer Bestimmung in der Luft

ZusammenfassungDie Inhalationstoxicität und das Verhalten von Methylisocyanat an der Haut werden tierexperimentell untersucht. Methylisocyanat verursacht noch in starken Verdünnungen bei Einatmung Lungenödem. Diese Verbindung besitzt in hohem Grade haut- und schleimhautschädigende Wirkungen. Über eine praktische Handhabung dieser Verbindung in Labor und Fabrik wird diskutiert. Eine Analysenmethode zur Bestimmung von Methylisocyanat in der Luft wird angegeben.

Metabolism studies of N,N-dimethylformamide. I. Studies in rats and dogs.

SummaryIn acute and subacute inhalation studies rats and dogs were exposed to N,N-dimethylformamide. In addition dogs were subjected to subchronic inhalation tests.The rats were subjected to N,N-dimethylformamide concentrations of 21, 146 or 2005 ppm during the 3-hr trial. During the 6-hr exposure they were subjected to 29 or 170 ppm.In the case of repeated exposures on rats the average concentration was 350 ppm.In the 6-hr test dogs were exposed to 20, 32, 143 or 172 ppm. In the 5-day test (6 hrs/day) they were exposed to 23 or 59 ppm, and in the 4-week test (6 hrs/day) the concentration was 20 ppm (MAC).The metabolisation of N,N-dimethylformamide was studied in rats and dogs. Methods for the analytical determination of the unchanged active substance and its metabolites (N-methylformamide and formamide) in blood and urine were developed.In addition to the already known metabolite N-methylformamide, a further metabolite, formamide, was found in the urine of rats and dogs. The elimination rate of N-methylformamide and formamide differed in dogs and rats. The elimination rate in dogs was much slower. In the group of dogs subjected to repeated inhalation of 59 ppm an accumulation of N-methylformamide was determined in the blood and urine. In the case of rats exposed to substantially higher subacute N,N-dimethylformamide concentration (350 ppm) this phenomenon was not observed.In the MAC-range (20 ppm) the dogs of the subacute and subchronic group showed no signs of accumulation.The results of the liver and kidney function studies in dogs exposed to 20 ppm N,N-dimethylformamide for 4 weeks were normal.

Metabolism, Excretion and Toxicology of Methylchloroform in Acute and Subacute Exposed Rats*

In acute and subacute inhalation studies rats were exposed to methylchloroform. In the 4-h exposure the concentrations were approximately 220 and 440 ppm, and in the 3-month study (5×8 h/week) approximately 204 ppm (MAC= 200 ppm).The behavior of methylchloroform and its metabolites (trichloroethanol and trichloroacetic acid) in the expired air, blood, and urine was investigated. A gaschromatographic method for the determination of methylchloroform is described. Most of the methylchloroform is eliminated unchanged via the lungs.In the subchronic inhalation studies, methylchloroform concentrations within the range of the MAC were tolerated with no symptoms. During this time, the concentrations of methylchloroform and trichloroethanol in the blood and the concentration of trichloroacetic acid in the urine remained constant. The urinary trichloroethanol excretion increased until the 10th week, then it fell and remained constant at a level somewhat below the maximum concentration. Methylchloroform was not detectable in organ tissue. The results of the metabolic studies are discussed.ZusammenfassungIn akuten und subakuten Inhalationsversuchen wurden Ratten Methylchloroform exponiert. Bei den 4stündigen Expositionen waren die Konzentrationen ca. 220 und 440 ppm, im 3 Monateversuche (wöchentlich 5×8 Std) ca. 204 ppm (MAK-Wert: 200 ppm). Das Verhalten von Methylchloroform und seiner Metabolite (Trichloräthanol und Trichloressigsäure) in Atemluft, Blut und Harn wurde untersucht. Eine gaschromatographische Methode zur Methylchloroformbestimmung wird angegeben. Methylchloroform wird hauptsächlich unverändert abgeatmet. Als Metabolite wurden Trichloroäthanol und Trichloressigsäure nachgewiesen. In den subchronischen Inhalationsversuchen wurden von den Ratten Methylchloroformkonzentrationen im MAK-Bereich symptomlos toleriert.Während dieser Zeit blieben die Konzentrationen von Methylchloroform und Trichloräthanol im Blut- und von Trichloressigsäure im Harn konstant. Die Trichloräthanolmenge im Harn stieg bis zur 10. Woche an und stellte sich dann auf einem Niveau etwas unterhalb der maximalen Konzentration ein. Im Organgewebe konnte Methylchloroform nicht nachgewiesen werden. Die Ergebnisse der Stoffwechseluntersuchungen werden diskutiert.

Toxicological and metabolic studies of methyl n-butylketone, 2,5-hexanedione, and 2,5-hexanediol in male rats

Abstract Comparative studies with repeated oral administration (400 mg/kg/day) of methyl n-butylketone, 2,5-hexanedione, or 2,5-hexanediol were carried out on male rats. The neurotoxic effects of these compounds as well as their metabolism were studied. Repeated oral doses of 2,5-hexanedione and 2,5-hexanediol caused paresis after 5 and 10 weeks, respectively. However, after repeated doses of methyl n-butylketone only a weakness of the hindlimbs was observed after 17 weeks. In the further course of the study, this symptom disappeared and the animals recovered. It was shown that there was a relationship between the concentration of the 2,5-hexanedione excreted with the urine and the onset of the neuropathy.

Altered lung function in rats after subacute exposure to n-butyl isocyanate

The objectives of this study were to use pulmonary function tests, blood gas measurements and bronchoalveolar lung lavage (BAL) to characterize lesions in the respiratory tract of young adult male Wistar rats as a result of a 5-day exposure (6 h/day) to 0, 1.1, 6.2, 15 or 26 mg n-butyl isocyanate (n-BIC)/m3 air. Further objectives were to probe the diagnostic sensitivities of these procedures in comparison with more traditional evaluations (clinical observation, lung weight, histopathology). Measurements were performed during post-exposure weeks 2 and 5. Most rats exposed to 26 mg/m3 died or were sacrificed in a moribund state during post-exposure week 2. All other rats survived the exposure regimen. In rats exposed to 15 and 26 mg/m3 a significant decrease in body weight, laboured breathing, hypoactivity, nasal discharge, cyanosis, and hypothermia were observed. Pulmonary function measurements revealed increased total lung capacity (TLC) and residual volume (RV), decreased forced expiratory flow rates and quasistatic compliance in rats exposed to 26 mg/m3. At the end of the observation period rats exposed to 6.2 and 15 mg/m3 air were hyperresponsive to an acetylcholine bronchoprovocation aerosol. Arterial blood gas measurements revealed an arterial hypoxia and an increase in venous admixture, suggesting a severe mismatch of the ventilation-perfusion relationship, Biochemical and cellular components in BAL fluid (BALF) indicated a concentration dependent and protracted increase of polymorphonuclear leucocytes and further inflammatory parameters. In the 1.1 mg/m3 group BALF parameters were not significantly elevated. The major histopathological lesions of the lung were thickening of septa, emphysema, and intra-alveolar oedema in rats exposed to 26 mg/m3. Collectively, these results demonstrate obstructive and progressive lung disease with associated gas trapping and severe disturbance of the ventilation perfusion relationship which is considered to be the cause of delayed mortality. In terms of variability and sensitivity the increase in BALF parameters was most sensitive in indicating the diseased state of the lung.

Acute toxicity of bicyclic phosphorus esters.

The acute toxicity of 4-ethyl-1-phospha-2,6,7-trioxabicyclo (2.2.2) octane-1-oxide and 4-ethyl-1-phospha-2,6,7-trioxabicyclo (2.2.2) octane has been determined by different routes of application in various species of animals. The compounds stimulate the activity of the central nervous system and are highly toxic. They showed no toxic cumulative effects. The presence of the bicyclic phosphate ester in the combustion products of specific rigid polyurethane foams is dicussed. The question is raised whether there may be an additional hazard caused by this combustion product in a real fire situation.ZusammenfassungDie akute Toxicität von 4-Äthyl-1-phospha-2,6,7-trioxabicyclo-(2,2,2)-octan-1 -oxid und 4-Äthyl-1-phospha-2,6,7-trioxabicyclo-(2,2,2)-octan wurde bei verschiedenen Tierarten mittels verschiedener Applikationsarten bestimmt. Die Verbindungen stimulieren die Aktivität des Zentralnervensystems und sind hoch toxisch. Sie zeigen keine kumulativ-toxischen Wirkungen. Das Vorhandensein des bicyclischen Phosphatesters in den Verbrennungsprodukten von spezifischen Polyurethan-Hartschäumen wird diskutiert. Es wird in Frage gestellt, ob dieses Produkt in einer Brandsituation eine zusätzliche Gefahrenquelle darstellt.

Die gleichzeitige Bestimmung der beiden Acetylcholinesterasen im Rattenvollblut bei zwei verschiedenen pH-Werten

SummaryA thorough study on the two specific acetylcholine esterases of rat blood resulted in the development of a method for differential assays of both enzymes. 0.08 ml of whole blood are required, the incubation period is 4 hours. Comparisons between the new method and the Warburg andΔ pH methods were performed in numerous animal experiments with identical results. Thus, the new method may be recommended for routine assays.ZusammenfassungAuf Basis einer grundlegenden Untersuchung über die beiden spezifischen Acetylcholinesterasen der Ratte wurde eine Methode ausgearbeitet, mit der es möglich ist, bei einer Blutentnahme von 0,08 ml Vollblut und einer Bebrütungszeit von 4 Std die Aktivität beider Acetylcholinesterasen nebeneinander zu bestimmen. Die Methode wurde in umfangreichen Tierversuchen (von denen nur ein Teil wiedergegeben ist) mit der klassischen, aber sehr aufwendigen Methode nachWarburg und derΔ pH-Methode verglichen. Die Resultate stimmen sehr gut überein, so daß die vorgelegte Methode als Routinemethode empfohlen werden kann.

Abhängigkeit der Acetylcholinesteraseaktivität in Plasma und Erythrocyten von Alter und Geschlecht der Ratte

SummaryActivity of acetylcholine esterase in plasma and erythrocytes of rats, male and female, was checked at pH 7.1 and 8.1, at 2, 4, 5, 7, 8, 11, 15, 25, and 30 weeks post partum. In the plasma of males, there is a decrease in activity up to week 11, in the plasma of females an increase coinciding with maturity (at week 6–7) is seen. At week 25, the plasma values in females exceed those in males by a factor of 3.2 at pH 7.1, and 3.4 at pH 8.1, respectively, the differences being statistically significant. In contrast, the activities of erythrocyte acetyloholine esterases are independent of sex and age.ZusammenfassungBei männlichen und weiblichen Ratten untersuchten wir 2, 4, 5, 7, 8, 11, 15, 25 und 30 Wochen nach der Geburt den Verlauf der Acetylcholinesteraseaktivität in Plasma und Erythrocyten bei pH 7,1 und pH 8,1. Während bei Männchen im Plasma bis zur 11. Woche ein Absinken beobachtet wird, steigt die Aktivität bei den Weibchen mit beginnender Geschlechtsreife (nach 6–7 Wochen) stark an. Nach 25 Wochen liegen die Werte bei pH 7,1 um das 3,2fache und bei pH 8,1 um das 3,4fache höher als bei den männlichen Tieren. Die Unterschiede sind signifikant. Demgegenüber zeigen die Acetylcholinesterasen der Erythrocyten ein von Geschlecht und Alter weitgehend unabhängiges Verhalten.