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Archives of Toxicology (v.68, #8)

1,N ²-Cyclic deoxyguanosine adducts and guanine adducts of 2-haloacroleins. Isolation, characterization, isomerization and stability by Erwin Eder; Christian Hoffman (pp. 471-479).

The reaction of the mutagenic 2-haloacroleins, 2-fluoroacrolein, 2-chloroacrolein and 2-bromoacrolein, with nucleosides and 5′-mononucleotides was studied. We found two different regioisomers of 1,N ²-cyclic deoxyguanosine adducts of 2-chloroacrolein and 2-bromoacrolein: type A, the 6-hydroxy, 7-haloadduct in which the OH-substituent is vicinal to the N ²-atom of the guanine moiety and type B, the 8-hydroxy, 7-haloadduct in which the OH-group is adjacent to the N¹-atom of the guanine moiety. The major adducts were the trans pairs of diastereomers of type A and type B in which the 6,7-substituents as well as the 7,8-substituents are in the energetically favoured diaxial position of the newly formed tetrahydropyrimidine ring. In the case of the type A regioisomers, the cis pairs of diastereomers (traces with chloroacrolein and about 4% with bromoacrolein) were also found in which the halosubstituent probably takes the equatorial position. Due to the anomeric effect, the OH-group takes the axial position in both regioisomers. No cis isomers of the type B regioisomers could be isolated. Acid hydrolysis of the deoxyguanosine adducts released deoxyribose, and the respective guanine adducts were isolated and characterized. Besides the vicinal halo, hydroxy adducts, trace amounts of the corresponding dihydroxy adducts were formed by hydrolysis of the chlorine or bromine substituents. The dihydroxy compounds possess the same structures and conformations in the newly formed tetrahydropyrimidine ring as do the halo, hydroxy adducts. Under our conditions no adducts other than those with deoxyguanosine and guanine could be identified. We found, however, indication for the formation of deoxyadenosine adducts when using dimethylsulfoxide as a solvent. No adducts in substantical amounts could be isolated with fluoroacrolein due to its rapid polymerization.

Keywords: Deoxyguanosine adducts of 2-halo-substituted acroleins

Pharmacokinetics of the oximes HI 6 and HLö 7 in dogs after i.m. injection with newly developed dry/wet autoinjectors by U. Spöhrer; H. Thiermann; R. Klimmek; P. Eyer (pp. 480-489).

The rapid onset of cholinergic crisis after intoxication with highly toxic organophosphorus compounds calls for pre-clinical administration of effective antidotes as early as possible. For this purpose, i.m. administration of the antidotes by autoinjectors is desired to allow early treatment also in the absence of a physician. Besides atropine, oximes with broad antidotal spectrum are considered valuable adjuncts that should be included in antidotal mixtures. To circumvent the problem of limited stability of the new-generation oximes, dry/wet autoinjectors were developed in which the unstable solid is dissolved by a diluent in an adjacent chamber upon activation of the device. In this study the tolerance, bioavailability and pharmacokinetics of 500 mg HI 6 [1-(((4-(aminocarbonyl) pyridinio)methoxy) methyl)-2-((hydroxyimino)methyl) pyridinium dichloride monohydrate] or 200 mg HLö 7 [1-(((4-(aminocarbonyl) pyridinio)methoxy)methyl)-2,4-bis ((hydroxyimino)methyl)pyridinium dimethanesulfonate] in combination with 2 mg atropine sulfate versus atropine alone, delivered by two dry/wet autoinjector types, were investigated in eight male beagle dogs (16 kg) in a complete cross-over design. The dogs tolerated the six injections with 3-week intervals without any symptoms of discomfort. Nonetheless, CPK activity increased, peaking at 6 h after injection. In contrast to atropine which merely led to a marginal increase, HI 6 plus atropine increased the baseline CPK activity about 10-fold, and HLö 7 plus atropine about 20-fold, regardless of the injector type. The HI 6 autoinjectors from Astra Tech were from an irregular production batch which did not deliver the declared HI 6 dose. The HLö 7 autoinjectors from Astra Tech and both Binjaect autoinjectors from STI functioned well: the bioavailability was complete with t_max values of about 25 min as observed after conventional i.m. injection. The absorption half-time was about 8 min, elimination t_1/2 about 50 min, and V_app 0.26 l/kg. The urinary recovery of unchanged oximes was 70–80%, the renal clearance being the same as for inulin. Unexpectedly, hematocrit and hemoglobin content of blood decreased by about 15% within 2 h and reached pre-treatment values after 6–24 h. This decrease was observed with all three drug treatments and could not be accounted for by blood loss (<4%), thus pointing to an atropine effect. In conclusion, the newly developed dry/wet autoinjectors appear suitable for the administration of atropine and an oxime stored in solid form.

Keywords: Oximes; HI 6 (CAS reg. No. 34 433-31-231); HLö 7 (CAS reg. No. 120 103-35-7); Atropine; Autoinjectors; Pharmacokinetics; Creatine phosphokinase; Hematocrit; Dogs

Computer assisted recognition and quantitation of the effects of airborne chemicals acting at different areas of the respiratory tract in mice by R. Vijayaraghavan; M. Schaper; R. Thompson; M. F. Stock; L. A. Boylstein; J. E. Luo; Y. Alarie (pp. 490-499).

The pattern and timing of a normal breath in unanesthetized mice was analyzed from measurement of inspiratory and expiratory airflows (VI and VE). Airflow was measured via a differential pressure transducer, attached to a pneumotachograph, which itself was attached to a body plethysmograph into which a mouse was placed. The analog voltage from the differential pressure transducer was digitized and stored for analysis on a microcomputer. Criteria were developed to classify each breath as normal (N) or belonging into one of seven abnormal categories. The abnormal categories were arrived at by computer analysis, recognizing specific modifications of the normal pattern into patterns of: sensory irritation of the upper respiratory tract (S), airflow limitation within the conducting airways of the lungs (A) or pulmonary irritation at the alveolar level (P). Combinations of these effects, i.e., S+A, P+A, P+S and P+S+A were also recognized. Computer analysis of each breath also permitted quantitative evaluation of the degree of S, A or P abnormalities. To induce each type of effect we used inhalation exposures to 2-chlorobenzylchloride, carbamylcholine or propranolol. We propose that this approach will permit rapid evaluation of the possible effects of airborne chemicals at three levels of the respiratory tract, with the classification of the type of effect easily obtained in an objective way using well defined criteria, followed by quantitation of the degree of each effect.

Keywords: Sensory irritation; Pulmonary irritation; Airflow limitation; Mice; Airborne chemicals; Propranolol; Carbamylcholine; 2-Chlorobenzylchloride; Trigeminal nerve endings; Vagal nerve endings

Identification of four metabolites of 3-(phenylamino)alanine, a constituent in l-tryptophan products implicated in eosinophiliamyalgia syndrome, in rats by Junko Adachi; Takaya Mio; Yasuhiro Ueno; Takeaki Naito; Akiyoshi Nishimura; Satoshi Fujiwara; Kimiaki Sumino; Yoshitsugu Tatsuno (pp. 500-505).

3-(Phenylamino)alanine (PAA), a contaminant found in l-tryptophan tablets, has been discussed as a possible cause of eosinophilia-myalgia syndrome (EMS). We administered PAA (100 mg/kg) by gastric gavage to Wistar rats to determine its distribution and metabolism. We developed a purification procedure, using Bond Elut SCX cartridges followed by high performance liquid chromatography (HPLC) in order to determine levels of PAA. The level of PAA in blood was 4.22 μg/ml at 5 h and urinary excretion was 21.7 μg for 5 h and 84.6 μg between 5 and 24 h. The amount of PAA in the contents of the large intestine at 5 h was 0.76 μg, indicating poor transfer of PAA to the large intestine. However, the highest concentration of PAA was 12.3 μg/g in the brain, indicating the passage of PAA through the blood-brain barrier. In addition to detecting PAA in the blood and organs, we also detected four metabolites of PAA in urine. We used gas chromatography mass spectrometry to identify PAA in rat liver, as well as N-(hydroxyphenyl)glycine, N-phenylglycine, 3-(pheylamino)lactic acid, and 3-(hydroxyphenylamino)-lactic acid in rat urine. These results suggest that the degradation pathway of PAA is similar to that of phenylalanine.

Keywords: 3-(Phenylamino)alanine; l-Tryptophan; Eosinophilia-myalgia syndrome; Rat urine

Effects of clofibric and beclobric acid in rat and monkey hepatocyte primary culture: influence on peroxisomal and mitochondrial β-oxidation and the activity of catalase, glutathione S-transferase and glutathione peroxidase by W. C. Mennes; H. M. Wortelboer; G. A. M. Hassing; K. van Sandwijk; A. Timmerman; B. P. Schmid; U. Jahn; B. J. Blaauboer (pp. 506-511).

The effect of hypolipidaemic compounds on peroxisomal fatty acid β-oxidation and on peroxisome morphology in the liver differs widely between rodent and primate species. We studied the relative importance of peroxisomal and mitochondrial β-oxidation of palmitate in primary cultures of hepatocytes isolated from rat and monkey liver in the absence or presence of clofibric acid or beclobric acid. It was demonstrated that it is possible to differentiate between peroxisomal and mitochondrial β-oxidation activities in intact cells. Overall β-oxidation of palmitate was ca. 30% higher in rat hepatocytes than in monkey liver cells. In both monkey and rat cell cultures the mitochondrial component was over 90% of the total palmitate β-oxidation. In rat hepatocyte culture clofibric acid and beclobric acid caused a 5- to 8-fold stimulation of peroxisomal β-oxidation, while in monkey cells this activity was not significantly increased. However, in cells derived from both species mitochondrial palmitate β-oxidation was increased (rat 2.5-fold; monkey 1.5-fold). These results indicate that the species differences in the increase in peroxisomal fatty acid oxidation are not a result of an inability to metabolize fatty acids in rat liver cell mitochondria. A comparison of the activity of enzymes involved in the detoxification of hydrogen peroxide showed that catalase and glutathione-S-transferase activity is 2.9-fold higher in monkey hepatocytes than in rat liver cells, while glutathione peroxidase activity was 1.6-fold higher in rat cells. When a comparison between both species is made for the ratio of hydrogen peroxide production over catalase activity, it can be concluded that this peroxide will have much smaller possibilities to escape from the peroxisomal compartment in monkey hepatocytes. These findings suggest that species differences in these enzyme activities can contribute to differences in susceptibility for peroxisome proliferator-induced carcinogenicity between rodents and primates.

Keywords: Peroxisome proliferators; Rat and monkey hepatocyte cultures; Antioxidant enzyme activities

Acute effects of methylmercury on hepatic and renal glutathione metabolisms in mice by Akira Yasutake; Kimiko Hirayama (pp. 512-516).

Because of its high affinity to the sulfhydryl group, the in vivo fate of methylmercury (MeHg) is closely related to the glutathione (GSH) metabolism. Here, to examine the possible effects of MeHg on the GSH metabolism, C57BL female mice were challenged by this heavy metal at a marginal dose level to induce slight renal dysfunction. Liver and blood GSH levels decreased by 16% and 20%, respectively, 24 h after MeHg (160 μmol/kg) administration, whereas kidney and plasma levels drastically increased. The GSH half-lives obtained using l-buthionine-(S,R)-sulfoximine were shortened by 17% in the liver, but lengthened by 28% in the kidney. The accelerated secretion of GSH from the liver and/or blood cells might have caused increased plasma levels of the tripeptide, which in turn could increase the supply of the constituent amino acids for GSH synthesis to the kidney. Furthermore, renal γ-glutamylcysteine synthetase activity, a rate-determining enzyme in GSH biosynthesis, was found to be enhanced in the MeHg-treated group. The marked increase in the renal GSH levels induced by MeHg could be due to the increased synthesis and the decreased efflux of the tripeptide in this tissue. The MeHg-induced alterations of GSH metabolism described here might reflect one of the defense mechanisms of bioorganisms against the challenge by MeHg.

Keywords: Mouse; Methylmercury; Glutathione; γ-Glutamylcysteine synthetase; Renal failure

Pulmonary elimination of methyl tertiary-butyl ether after intraperitoneal administration in mice by M. Yoshikawa; K. Arashidani; T. Katoh; T. Kawamoto; Y. Kodama (pp. 517-519).

The pulmonary elimination after intraperitoneal administration at three different doses (50, 100, and 500 mg/kg) of methyl tertiary-butyl ether (MTBE) was studied using mice. There were two exponential curves with an initial rapid decrease of the elimination ratio followed by a slow decrease at the doses of 100 mg/kg and 500 mg/kg. The calculated half-lives of the two elimination curves obtained by the least squares method were approximately 45 min and 80 min. The pulmonary elimination ratios at the three different doses were from 23.2% to 69.0%. Most of the excreted MTBE was eliminated within 3 h. It is suggested in this paper that MTBE in exhaled air can be used as a biological exposure index for the exposure assessment of MTBE.

Keywords: Methyl tertiary-butyl ether; Pulmonary elimination; Half-life; Mouse

Biliary excretion of exogenous cadmium and manganese in Long-Evans Cinnamon (LEC) rats characterized by an inherently gross amount of copper-metallothionein in the liver by Naoki Sugawara; Dan Li; Chieko Sugawara (pp. 520-523).

Long-Evans Cinnamon (LEC) rats are characterized by the sudden onset of hepatitis around 4 months after birth and the gross accumulation of hepatic copper (Cu) accompanied by metallothionein (MT). The biliary excretion of manganese (Mn) and cadmium (Cd) injected intravenously was studied in 3-month-old LEC rats without signs of hepatitis. Injected Mn was excreted into the bile in LEC and Fischer rats used for comparison. However, increased biliary excretion of Cd was found not in the LEC rat but in the Fischer rat. Excretion of horseradish peroxidase (HRP) injected along with the metal mixture was significantly lower in the LEC group than in the Fischer group. Our results suggest that Mn excretion is not related to the existence of a gross amount of Cu-MT. Reduced excretion of Cd may be partly due to binding to Cu-MT in the liver. Decreased excretion of HRP implies the existence of an inherent defect in the bile excretion route for endo-and exogenous substances.

Keywords: Cadmium; Manganese; Metallothionein; Biliary excretion; Long-Evans Cinnamon (LEC) rat

Styrene-7,8-oxide in blood of workers exposed to styrene by M. Korn; W. Gfrörer; J. G. Filser; W. Kessler (pp. 524-527).

A field study was carried out on 13 workers exposed to styrene vapors at time-weighted average concentrations between 10 and 73 ppm. The reactive intermediate styrene-7,8-oxide was determined in blood samples using a direct gas chromatographic method. Styrene-7,8-oxide concentrations were in the range between 0.9 and 4.1 μg/l blood. Linear correlations were found between styrene-7,8-oxide in blood and styrene in ambient air and blood. For an exposure concentration of 20 ppm styrene (German MAK value) a steady-state level of about 1 μg styrene-7,8-oxide/l blood was calculated.

Keywords: Styrene; Styrene-7,8-oxide; Blood concentration; Man; Field study; Capillary gas chromatography

Styrene-7,8-oxide in blood of workers exposed to styrene by M. Korn; W. Gfrörer; J. G. Filser; W. Kessler (pp. 524-527).

Keywords: Styrene; Styrene-7,8-oxide; Blood concentration; Man; Field study; Capillary gas chromatography

Cobalt bioavailability from hard metal particles by D. Lison; R. Lauwerys (pp. 528-531).

Hard metal is an alloy of tungsten carbide (WC) in a matrix of cobalt metal (Co). The inhalation of hard metal dust can cause an alveolitis which may progress to interstitial fibrosis. This study was undertaken to compare, both in vivo and in vitro, the bioavailability of cobalt metal when mixed or not with WC and to assess whether this factor had any influence on the cellular toxicity of hard metal particles. In vivo, non-toxic doses of cobalt metal were administered intratracheally in the rat, alone (Co, 0.03 mg/100 g) or mixed with tungsten carbide (WC-Co, 0.5 mg/100 g containing 6.3% of cobalt metal particles). Sequential measurements of cobalt in the lung and in urine demonstrated that the retention time of the metal in the lung was longer in Co- than in WC-Co-treated animals. In vitro, the cellular cobalt uptake was higher when the metal was presented to the macrophages as WC-Co. However, there was no relationship between the cellular uptake of cobalt and the occurrence of toxicity, since the intracellular concentration of cobalt associated with the occurrence of a cytotoxic effect of WC-Co particles was insufficient to exert the same effect when resulting from exposure to Co alone. This clearly indicates that increased bioavailability of cobalt is not the mechanism by which hard metal particles exhibit their cellular toxicity. These observations confirm and extend our previous findings supporting the view that cobalt is not the only component responsible for the toxicity of hard metal particles which should be considered as a specific toxic entity.

Keywords: Cobalt; Hard metal; Bioavailability; Particles

Effects of deltamethrin on catecholamine secretion of bovine chromaffin cells by Ulf Bickmeyer; Frank Weinsberg; Herbert Wiegand (pp. 532-534).

The effects of the pyrethroid deltamethrin (D) on catecholamine secretion of cultured bovine chromaffin cells were investigated in vitro using high performance liquid chromatography (HPLC). Spontaneous release of catecholamines was increased by 10 μM and 100 μM D. This increase could partially be prevented by the simultaneous use of 2 μM tetrodotoxin (TTX), which reduced the increase by 10 μM D of catecholamine secretion by 90% and that of 100 μM D by 50%. TTX 2 μM alone did not alter the spontaneous release in comparison to controls. Medullary chromaffin cells consist of two cell groups, one secreting mainly epinephrine (E), the other norepinephrine (NE). The ratio between the spontaneously secreted catecholamines E and NE was increased after treatment with D, indicating a dominant effect on E secreting cells.

Keywords: Pyrethroids; Deltamethrin; Bovine chromaffin cells; HPLC

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Archives of Toxicology (v.68, #8)