To evaluate the effect of pretreatment of rats with CCL, on tolerance development to subsequent exposures, rats were exposed 25-7500 ppm of CC& vapor or given Ccl, orally, 3.25 mg/g body weight. Forty-eight hours later these rats were rcexposed to a normally lethal 7500 ppm Ccl0 concentration. Mortality, blood clotting time, serum bilirubin, serum and liver triglycerides, and CC& and CHC& concentrations in tissues and in the whole rat were used as a measure of the response to Ccl, exposure. Conversion of Ccl., to CHCl3 in vitro was also determined in normal and pretreated animals. It was found that animals exposed to 4000 ppm for 6 hr or given 3.25 mg/g of CC& orally developed tolerance to subsequent normally lethal CC& exposures. Serum bilirubin levels in animals protected by CCI, pretreatment were significantly lower than in those receiving only a single exposure to Ccl,. Blood clotting times in protected animals were normal, while in those not protected by pretreatment, they were greatly prolonged. Serum triglyceride levels in protected animals were normal whereas they were considerably depressed in the nonprotected animals. Liver triglycerides were elevated in both protected and nonprotected, but were not as high in the protected animals. Carbon tetrachloride conversion to CHC& was slower in protected than in the nonprotected animals. Tolerance to CCI, developed in animals whose ability to metabolize Ccl, had been depressed by pretreatment with the same compound. This suggests that the toxicity of CC& is related to its metabolic pathway or to the production of toxic intermediates.

No abstract

A commercial polychlorinated biphenyl mixture (PCBs), Aroclor 1242, was administered to rats po by intubation in order to determine toxic manifestations of acute and subacute ingestion. In addition, the effect of PCBs on hepatic microsomal enzyme systems in rats was evaluated. The oral, 14day LD50 was determined to be approximately 4.25 g/kg. Major toxic signs observed upon administration of high doses of PCBs included diarrhea, chromodacryorrhea, loss of body weight, unusual stance and gait, lack of response to pain stimuli, and terminal ataxia. Progressive dehydration and CNS depression appeared to be contributing factors in each fatality. Histopathologic alterations were evident only in the liver and kidneys, manifest as foci of sudanophilic vacuolation. Rats maintained on an oral dosage regimen of 100 mg/kg every other day for 3 weeks exhibited similar histopathologic changes, but no overt signs of toxicity. Serum GOT activities were elevated over controls in both the acute and subacute groups. A single ip injection (100 mg/kg) increased liver weight, total hepatic microsomal enzyme activity (measured as hydroxylation of acetanilide and N-demethylation of aminopyrine), and hepatic cytochrome P.,5,, and b5 levels. Hepatic microsomal enzyme activity remained elevated 10 days after a single dose of PCBs, suggesting that PCBs may play an important role in altering biologic responses of mammals subjected to environmental chemical stress. Polychlorinated biphenyls (PCBs) have experienced widespread industrial usage and are now widely distributed throughout the environment (Gustafson, 1970; Peakall and Lincer, 1970). These compounds have been found in the livers of dying pelagic birds (Bourne and Mead, 1969), in fish, mussels, and birds (Koeman et al., 1969), and even in human adipose tissues (Biros et al., 1970). Humans have been inadvertently exposed to PCBs in several instances, including ingestion of PCB-contaminated rice oil in Japan (Kuratsune, 1969), and poultry products in the United States (Pichirallo, 1971). Data on the precise chemical composition and the toxicity of PCBs is at present incomplete. Commercial PCB products are known to consist of mixtures of isomers, differing from one another in the degree of chlorination. Vos and co-workers (1970) reported 2 such products, Clophen and Phenoclor, to be contaminated by trace amounts of chlorinated naphthalenes and highly poisonous chlorinated dibenzofurans. Chlorinated dibenzofurans have been implicated in the toxic action of Clophen and Phenoclor,

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No abstract

Serum enzyme levels and isozyme profile were utilized as a measure of hepatotoxic response to carbon tetrachloride, mercuric chloride, diethanolamine and thioacetamide. The sensitivity of these measurements was compared with the degree of morphological damage to the liver or kidney as assessed by light and electron microscopy. Morphological damage was present at dosage levels considerably below those necessary to induce detectable enzyme alterations. Generally, advanced degenerative change, including necrosis, had occurred in both the liver and kidney before enzyme alterations were seen.

Within recent years hydrazine and the methyl substituted hydrazines have come into considerable use as rocket fuels. As a result of this increased production of hydrazines, the possibility of accidental human exposure is of considerable interest. Obvious concern results from the fact that hydrazine had been used as an experimental means of producing fatty liver in experimental animals for many years. On an acute toxicity basis, O'Brien and coworkers (1964) reported comparative lethal dosebo ( LDSo) values for hydrazine 64 mg/ kg ( 2 mmoles/kg) , rnonomethylhydrazine (MMH) 28 mg/kg (0.61 mmoles/ kg), 1,l-dimethylhydrazine (unsymmetrical dimethylhydrazine, UDMH) 102 mg/kg ( 1.7 mmoles/ kg) , and 1 ,Zdimethylhydrazine (symmetrical dimethylhydrazine, SDMH) essentially nontoxic even at dosages of 500 mg/kg. The structures of these four compounds are shown in FIGURE 1, and it appears that a free amino group is essential for biological activity in this group of compounds. Barth and associates ( 1967) have previously reported the diuretic effect induced by UDMH, and it is interesting to note that of the four hydrazines shown in FIGURE 1, only SDMH is without diuretic effect, again emphasizing the biological activity of the free amino groups in this series of compounds. Killam and Bain reported in 1957 that thiosemicarbazide, furoyl hydrazide, and isonicotinic acid hydrazide would inhibit, in vitro, enzyme systems catalyzed by vitamin Bg. Thus it was suggested

and 0 rats, respectively, in each group of 10. All deaths occurred within the first 3 days. Animals surviving the first 3 days began to gain weight even though daily dosing was continued. Animals receiving more than 10 mg/kg/day were markedly diuretic throughout the 21-day experimental period. Blood urea nitrogen and serum glutamic-oxaloacetic transaminase (SGOT) levels were significantly elevated in the 50 mg/kg dose group at 21 days. SGOT also appeared somewhat elevated in the 30 mg/kg/ day group. Histopathologic studies showed some evidence of early lipid infiltration in the tubular epithelium of the kidney. Thus, although some animals appear to adjust to relatively high daily doses of UDMH, biochemical and histologic evidence indicates mild kidney damage in these animals.