Acute target organ toxicity of 1-nitronaphthalene in the rat.

1-Nitronaphthalene (1-NN) produced respiratory distress and centrilobular liver necrosis in male Sprague-Dawley rats after a single intraperitoneal injection (100 mg kg-1). Microscopic examination of the lungs of rats killed 24 h after the injection revealed a highly selective non-ciliated bronchiolar (Clara) cell necrosis as the only remarkable lesion. Pretreatment of animals with phenobarbital offered complete protection from the respiratory distress induced by 1-NN, but increased the severity of the hepatotoxicity. Pretreatment with SKF-525A protected against 1-NN-induced liver necrosis, but did not alter the incidence or severity of the respiratory distress. Under similar conditions, this pattern of toxicity was not seen with the structural analogue 2-nitronaphthalene.

Comparative theobromine metabolism in five mammalian species.

Biotransformation of theobromine (TBR) was compared in rats, mice, hamsters, rabbits, and dogs by assaying urinary metabolites using HPLC after oral administration of a 5 mg/kg dose containing 8-14C-TBR. Recovery of radioactivity ranged from 60-89% of the dose in urine, and from 2-38% of the dose in feces, with most material being excreted during the first 48 hr after dosing. TBR was most extensively metabolized by rabbits and male mice. The primary metabolite excreted by rats and mice was 6-amino-5-[N-methylformylamino]-1-methyluracil (6-AMMU); male mice converted TBR to this metabolite more extensively than did female mice. Rabbits and dogs metabolized TBR primarily to 7-methylxanthine (7-MX) and 3-methylxanthine (3-MX), respectively; the major metabolites excreted by hamsters were 6-AMMU and 7-MX. Overall N-demethylase activity yielding monomethyl metabolites was greatest in rabbits and lowest in rats. Ring N-demethylation at position 3 predominated over 7-N-demethylation in all species except the rat and dog. In dogs, TBR was N-demethylated primarily at position 7, while N-demethylase activity in rats was without apparent positional specificity. Oxidation of methylated xanthines to the corresponding uric acids was a relatively minor metabolic pathway in all species, but had greatest activity in mice. Oxidation of TBR to 3,7-dimethyluric acid was significantly greater in female rats than in male rats. In summary, excretion patterns of TBR and its metabolites were qualitatively similar among species, indicating that TBR is metabolized along similar pathways. Except for the excretion of small quantities of an unidentified but apparently unique metabolite by dogs, only quantitative species- and sex-related differences were observed in the metabolic disposition of TBR.

Modification of methanol potentiation of CCl4 toxicity in rats by chloramphenicol and salicylate.

The mechanisms by which methanol potentiates CCl4 hepatotoxicity was studied in rats. Chloramphenicol, an inhibitor of cytochrome P-450, blocked the increase of serum glutamate-oxaloacetate transaminase activity enhanced by methanol pretreatment of rats exposed to CCl4. Chloramphenicol also decreased microsomal lipid peroxidation in both CCl4 and methanol-pretreated, CCl4-intoxicated animals when measured 30 minutes after exposure. Chloramphenicol prevented the loss of glucose 6-phosphatase activity after CCl4 and methanol. Sodium salicylate, which lowers the level of NADPH in the hepatocyte, blocked methanol potentiation of CCl4 damage as measured by the elevation of serum GOT activity. Therefore, methanol may potentiate CCl4 hepatotoxicity by stimulation of CCl4 bioactivation by cytochrome P-450 via an increase in the level of reduced NAD(P)H in the liver.

Possible mechanism of rubidium-induced hyperactivity in the rat.

This study suggests that replacement of intracellular potassium by rubidium ions might lower the resting membrane potential. Thus rubidium-treated rats were more responsive to depolarizing influences and generated more cyclic AMP in the brainstem and consequently the behavioral changes.

Mutagenicity of alkyl-(omega-hydroxyalkyl) nitrosamines related to dibutylnitrosamine.

Various alkyl-(omega-hydroxyalkyl) derivatives related to dibutylnitrosamine (DBN) were investigated for mutagenicity in the absence of liver-activation system. Butyl-(4-hydroxybutyl)-, butyl-(3-hydroxypropyl)-, and butyl-(2-hydroxyethyl)-nitrosamines were so tested and found to be mutagenic for TA 1535 strain of Salmonella typhimurium. In all cases, a simple dose-response relationship was observed. Furthermore, no significant (p less than 0.05) differences in the mutagenicity of the various test compounds were observed as the alkyl sidechain possessing the OH group increased in length. From these results it is siggested that mutagenesis in S. typhimurium by the higher dialkylnitrosamines is partially due to the formation of omega-hydroxylated derivatives in addition to the major mutagenic metabolite derived from alpha-carbon dealkylation.

Influence of aliphatic alcohols on the hepatic response to halogenated olefins.

The role of alcohols in potentiating the toxicity of halogenated hydrocarbon solvents has been reviewed. The toxicity of carbon tetrachloride and chloroform can be markedly potentiated by prior treatment with ethanol or phenobarbital. Trichloroethylene toxicity may also be potentiated by ethanol ingestion. Prior ethanol ingestion acts by altering biochemical parameters that result in an increased response to subsequent solvent exposure. Simultaneous exposure to both ethanol and trichloroethylene allows for competitive substrate inhibition of metabolism since these compounds share several common enzymatic pathways. Thus the toxic response to multiple exposures varies depending upon the time sequence and the comparative levels of the individual components. Phenobarbital apparently potentiates solvent toxocity by induction of the microsomal mixed function oxidase system. Ethanol, either on a chronic or single dose basis, also has the ability to stimulate this enzyme system. Although alteration of the microsomal mixed function oxidase system by chronic ethanol ingestion may play an important role in potentiation of solvent toxicity, the potentiation seen following a single dose of ethanol cannot be fully accounted for by the known effects of ethanol on the mixed function oxidase system. In addition to ethanol a large number of other alcohols will markedly potentiate the hepatotoxic response to solvents such as carbon tetrachloride and chloroform. The mechanisms involved in such potentiation are not known at the present time.

Experimental toxicology of pyrolysis and combustion hazards.

Data are presented on the acute toxicity (mortality only) of the thermal degradation products of polymers obtained by two methods of degradation. One system utilized a slowly increasing temperature (5 degrees C/min) and gradual degradation of the polymer with the rats being exposed to degradation products as they were evolved. In this system the more toxic polymers included wool, polypropylene, poly(vinyl chloride), and urethane foam. The second system utilized conditions of rapid combustion and exposure of rats to the total products of combustion for a period of 4 hr. In this system the more toxic materials included red oak, cotton, acrylonitrile-butadiene-styrene (ABS), and styrene-acrylonitrile. It is of interest to note that the natural product wool is among the least toxic under these rapid combustion conditions and among the most toxic under slow pyrolysis conditions. Other materials also vary in the comparative toxicity of their thermal degradation products, depending upon the conditions of degradation and animal exposure. The two experimental techniques presented here may well represent the two extreme conditions of rapid combustion versus slow pyrolysis. Intermediate types of fire situations might be expected to result in relative acute toxicities somewhere between these two extremes. This report deals with acute toxicity on the basis of mortality data only and does not include other parameters of toxicity such as organ weights and histopathology.