Neurotoxic effects of dichloroacetylene

In inhalation tests involving lethal as well as sublethal doses of dichloroacetylene (DCA) (126, 202 and 307 ppm/1 h; 17 ppm/6 h) its neurotoxic effect was examined in rabbits by means of histologic and neurofunctional methods. Histologic examination revealed chromatolysis, disintegration of Nissl bodies, and cell shrinkage in proportion to the doses employed in the nuclei of the unpaired brain stem, in the sensory cortical regions and especially in the sensory cranial nerve nuclei. The sensory trigeminal nucleus was involved most severely, followed in decreasing intensity by the facial and oculomotor nerves and the motor trigeminal nucleus; the least changes were observed in the acoustic nerve. By testing the protopathic sensitivity of the facial skin it was possible for the first time to produce evidence of a sensory loss in the distribution of the trigeminal nerve by animal experimentation. The neuropathological and functional deficits observed may explain the cranial nerve lesions in human DCA intoxication; however, these lesions seem to be less distinct in experimental animals.     

Prednisolon zur Therapie von Reizgaslungenödemen

Ohne Zusammenfassung     

Molecular mechanism of 1,1-dichloroethylene toxicity: excreted metabolites reveal different pathways of reactive intermediates.

The excretion and biotransformation of [14C] 1,1-dichloroethylene (vinylidene chloride, VDC) after administration of a single oral dose has been investigated in female rats. Seventy-two hours after a dose of 0.5, 5.0, and 50.0 mg/kg, 1.26, 9.70, 16.47%, respectively, are exhaled as unchanged VDC, and 13.64, 11.35, 6.13% as 14CO2. The main pathway of elimination is through renal excretion with 43.55, 53.88, 42.11% of the administered radioactivity. Through the biliary system, 15.74, 14.54, 7.65% of the activity are eliminated. The isolation of the main metabolites of VDC from 24 h urine is accomplished through the combined application of solvent extraction, ion exchange chromatography and thin layer chromatography. Then gas chromatography and mass spectrometry are used for their identification. Three metabolites have been identified: thiodiglycolic acid, N-acetyl-S-(2-carboxymethyl)cysteine and methyl-thio-acetylaminoethanol. In addition, three smaller unidentified radioactive peaks have been found. Thiodiglycolic acid is the main metabolite in VDC metabolism. The simultaneous formation of an ethanolamine- and a cysteine-conjugation product points to different reaction pathways of the postulated intermediate reactive epoxide; ethanolamine probably originates from membrane lipids, which react with VDC-epoxide and/or its derivatives. This pathway could explain, in part, the parenchyma damaging effect of VDC.     

Induction of unscheduled DNA synthesis in HeLa cells by allylic compounds

Thirteen allylic compounds, mostly with close structural relationship, were tested for their ability to induce unscheduled DNA synthesis (UDS) in HeLa cells and mutations in the Ames test; 11 induced UDS in dose dependence. Allyl isothiocyanate was negative in UDS (borderline in the Ames test) and acrolein (positive in the Ames test) proved toxic to HeLa cells, therefore UDS measurement was excluded. In general, positive qualitative and quantitative correlation between UDS, Ames test and alkylating properties 9as measured in the 4-nitrobenzyl-pyridine test, NBP) were found. Among structural analogs and typical allylic compounds with various leaving groups, the amount of induced DNA repair at equimolar concentrations decreased in the same order as the mutagenic and alkylating activities in the other 2 test systems: 1,3-dichloropropene (cis) > 1,3-dichloropropene (trans) > 2,3,-dichloro-1-propene; 1-chloro-2-butene > 3-chloro-1-butene > 3-chloro-2-methyl-1-propene > allyl chloride; allyl-methanesulfonate > -iodide > -bromide > -chloride.     

Metabolism of chlorinated alkenes and alkanes as related to toxicity

The chlorine substitution in aliphatic compounds results, by its electron attracting effect, in a destabilization in alkanes and a stabilization in alkenes. Thus, with alkanes the main pathways of metabolic transformation to reactive intermediates are radical formation by C-C break or dechlorination, or dehydrochlorination. In alkenes, the stability of the molecule increases with the number of chlorine substitutions. In the series of chlorinated ethylenes, the first step of metabolic transformation is the oxidation to electrophilic oxiranes which may be hydrolized enzymatically or non-enzymatically, react with cellular nucleophiles, or rearrange to either chlorinated aldehydes or acyl chlorides. With tetra-, 1,2-cis- and trans-di-, 1,1-di-, and monochloroethylene, the metabolites identified in in vivo experiments are identical with the thermal rearrangement products of the respective oxiranes. An important exception is found with trichloroethylene, where the thermal rearrangement product is dichloroacetyl chloride; the metabolites in vivo, however, are entirely derived from trichloroacetaldehyde (chloral). The reason for this peculiar behavior is most probably a Lewis acid catalysis by the oxidizing enzyme system. Mutagenic and carcinogenic activities in the series of chlorinated ethylenes are determined by the stability of their oxiranes, which is higher in symmetrical than in unsymmetrical chlorine substitution: the relatively unstable and unsymmetric oxiranes of trichloroethylene, 1, 1,-dichloro-, and monochloroethylene are mutagenic in the Ames test; the more stable symmetric oxiranes of tetra-, 1,2-cis- and trans-dichloroethylenes are inactive.     

To xikologische Untersuchungen an Trikresylphosphaten

Ohne Zusammenfassung     

Zur Spezifität einer Toleranzsteigerung bei wiederholter Einatmung von Lungenödem erzeugenden Gasen

Zusammenfassung Subletale Reizgasdosen schützen vor der Ausbildung tödlicher Lungenödeme bei nachfolgender Einatmung hochtoxischer Konzentrationen. Zur Prüfung der Spezifität dieser Toleranzsteigerung werden jeweils 20 Ratten 6 Std lang mit geringen Konzentrationen von Phosgen (1 ppm) oder Stickstoffdioxyd (20–40 ppm) oder Ozon (1,6–2 ppm) vorbehandelt und 4 Tage später 1/2 td lang einem der drei Gase Ausgesetzt in Konzentrationen, die für 50–100% gleichzeitig eingesetzter Kontrolltiere tödlich wirken. Vergleiche der Überlebensraten, Überlebenszeiten und relativen Lungengewichte von Vorbehandelten und Kontrollen dienen als Maßstab einer Schutzwirkung. Dabei schützt deutlichen Einfluß auf die Phosgenvergiftung. Da die Schutzwirkung demnach nicht spezifisch für ein und dieselbe Gasart ist, kann eine Antigen-Antikörperreaktion ausgeschlossen werden. Starke Unterschiede in Ausmaß und Dauer des Schutzes lassen vermuten, daß an seiner Ausbildung mehrere, noch unbekannte Vorgänge beteiligt sind.Zusammenfassung Subletale Reizgasdosen schützen vor der Ausbildung tödlicher Lungenödeme bei nachfolgender Einatmung hochtoxischer Konzentrationen. Zur Prüfung der Spezifität dieser Toleranzsteigerung werden jeweils 20 Ratten 6 Std lang mit geringen Konzentrationen von Phosgen (1 ppm) oder Stickstoffdioxyd (20–40 ppm) oder Ozon (1,6–2 ppm) vorbehandelt und 4 Tage später 1/2 Std lang einem der drei Gase ausgesetzt in Konzentrationen, die für 50–100% gleichzeitig eingesetzter Kontrolltiere tödlich wirken. Vergleiche der Überlebensraten, Überlebenszeiten und relativen Lungengewichte von Vorbehandelten und Kontrollen dienen als Maßstab einer Schutzwirkung. Dabei schützt Ozon wirksam gegenüber Ozon selbst, in geringerem Maße auch gegenüber Stickstoffdioxyd und Phosgen; Stickstoffdioxyd schützt gegen sich selbst und Ozon; Vorbehandlung mit Phosgen erzeugt die vergleichsweise stärksten Toleranzsteigerungen, in steigender Reihe gegen Phosgen selbst, Ozon und Stickstoffdioxyd. Vorbehandlung mit Stickstoffdioxyd bleibt aber selbst bei mehrfach variierten Versuchsbedingungen ohneMit 3 Textabbildungen