Acute, short-term, and subchronic oral toxicity of 1,1,1-trichloroethane in rats.

1,1,1-Trichloroethane (TRI) is a widely used solvent that has become a frequent contaminant of drinking water supplies in the U.S. There is very little information available on the potential for oral TRI to damage the liver or to alter its P450 metabolic capacity. Thus, a major objective of this investigation was to assess the acute, short-term, and subchronic hepatotoxicity of oral TRI. In the acute study, male Sprague-Dawley (S-D) rats were gavaged with 0, 0.5, 1, 2, or 4 g TRI/kg bw and killed 24 h later. No acute effects were apparent other than CNS depression. Other male S-D rats received 0, 0.5, 5, or 10 g TRI/kg po once daily for 5 consecutive days, rested for 2 days, and were dosed for 4 additional days. Groups of the animals were sacrificed for evaluation of hepatotoxicity 1, 5, and 12 days after initiation of the short-term experiment. This dosage regimen caused numerous fatalities at 5 and 10 g/kg, but no increases in serum enzymes or histopathological changes in the liver. For the subchronic study, male S-D rats were gavaged 5 times weekly with 0, 0.5, 2.5, or 5.0 g TRI/kg for 50 days. The 0 and 0.5 g/kg groups were dosed for 13 weeks. A substantial number of rats receiving 2.5 and 5.0 g/kg died, apparently due to effects of repeated, protracted CNS depression. There was evidence of slight hepatocytotoxicity at 10 g/kg, but no progression of injury nor appearance of adverse effects were seen during acute or short-term exposure. Ingestion of 0.5 g/kg over 13 weeks did not cause apparent CNS depression, body or organ weight changes, clinical chemistry abnormalities, histopathological changes in the liver, or fatalities. Additional experiments did reveal that 0.5 g/kg and higher doses induced hepatic microsomal cytochrome P450IIE1 (CYP2E1) in a dose- and time-dependent manner. Induction of CYP2E1 activity occurred sooner, but was of shorter duration than CYP2B1/2 induction. CYP1A1 activity was not enhanced. In summary, 0.5 g/kg po was the acute, short-term, and subchronic NOAEL for TRI, for effects other than transient CYP2E1 induction, under the conditions of this investigation. Oral TRI appears to have very limited capacity to induce P450s or to cause liver injury in male S-D rats, even when administered repeatedly by gavage in near-lethal or lethal dosages under conditions intended to maximize hepatic effects.

Metastatic Staphylococcus aureus endophthalmitis: a case report.

A case of bilateral metastatic Staphylococcus aureus endophthalmitis is presented. It evolved over a two-week period, causing some diagnostic confusion. Treatment with fusidic acid and benzylpenicillin resulted in the retention of useful vision in one eye and good vision in the other.

Oral toxicity of carbon tetrachloride: acute, subacute, and subchronic studies in rats.

This investigation was conducted to characterize the acute, subacute, and subchronic toxic potency of ingested carbon tetrachloride (CCl4). In the first acute and subacute toxicity study, male Sprague-Dawley rats of 300-350 g were gavaged with 0, 20, 40, or 80 mg CCl4/kg once daily for 5 consecutive days, rested for 2 days, and dosed once daily for 4 additional days. Rats of 200-250 g were gavaged with 0, 20, 80, or 160 mg CCl4/kg according to the same dosage regimen in the second acute and subacute study. In the first and second studies one group of rats at each dosage level was sacrificed for clinical chemistry and histopathological evaluation at 24 hr, 4 days, and 11 days after initiation of dosing. Single 20- and 40-mg/kg doses had no apparent toxic effect at 24 hr, although 80 mg/kg caused mild hepatic centrilobular vacuolization and significant increases in some serum enzyme levels. In general, there was progressively severe hepatic injury at each dosage level over the 11-day period. CCl4 was more hepatotoxic to the 200-250-g rats than to the 300-350-g rats. In the subchronic study, rats initially 200-250 g were gavaged 5 times weekly for 12 weeks with 0, 1, 10, or 33 mg CCl4/kg. Body weight and clinical chemistry indices were monitored during the 12 weeks of dosing and 2 weeks after cessation of dosing. A dose of 1 mg/kg had no apparent adverse effect; 10 mg/kg produced slight, but statistically significant increases in sorbitol dehydrogenase activity and mild hepatic centrilobular vacuolization; 33 mg/kg caused marked hepatotoxicity. Serum enzyme levels remained elevated during the 12-week dosing period, but returned toward normal within 13 days of cessation of CCl4 exposure. Microscopic examination of livers of the 33-mg/kg rats revealed cirrhosis, characterized by bile duct proliferation, fibrosis, lobular distortion, parenchymal regeneration, hyperplastic nodules, and single-cell necrosis. The fibrosis was not reversed within the 13-day recovery period.

Acquired Brown's syndrome: an unusual cause.

A 62-year-old man with acquired Brown's syndrome is presented. This was due to an orbital metastatic deposit, a cause not previously reported. Other causes of this disorder and its treatment are discussed.

Assessment of functional, morphological, and enzymatic tests for acute nephrotoxicity induced by mercuric chloride.

The relative merits of a comprehensive series of contemporary methods for detection of acute nephrotoxicity were evaluated. Male Sprague-Dawley rats were given 0, 0.25, 0.5, 1.0, or 3.0 mg mercuric chloride (HgCl2)/kg body weight by ip injection. Indices of nephrotoxicity were examined 8, 24, 48, 72, and 96 h later. Alterations in urine osmolality, volume, and protein levels were seen within 24 h in response to 1 mg/kg or more of HgCl2. Administration of 0.5-3.0 mg/kg produced dose-dependent increases in urinary excretion of maltase activity and glucose by 24 h, the period of peak effect. There was no increase in maltase or alkaline phosphatase (AP) activity in the serum of these animals. Enzymuria was not apparent in rats that had marked elevations in serum AP, argininosuccinate lyase, and ornithine carbamyl transferase activities as a result of physical (i.e., dichlorodifluoromethane-frozen) or chemical (carbon tetrachloride-induced) damage of the liver. Morphological alterations, in the proximal tubular epithelium of perfusion-fixed kidneys from HgCl2-dosed rats, paralleled the changes in enzyme excretion with respect to time of onset and dose-effect. There was a dose-dependent inhibition of tetraethylammonium (TEA) and p-aminohippurate (PAH) uptake by renal cortical slices at 24 h. Interestingly, increases in uptake of TEA and PAH were seen 8 h after a 1-mg/kg dose. Clearance of inulin and PAH in vivo were altered at 8 h by 0.5 and 1 mg/kg. Marked depression of these functional indices was seen at 24 h, by which time blood urea nitrogen (BUN) levels were increased. The 0.5- and 1.0-mg/kg doses also produced time- and dose-dependent increases in intracellular Na+ content which were maximal at 24 h. These results illustrate the importance of using a combination of biochemical and functional tests to elucidate the sequence of events in the kidney following toxic insult. Nevertheless, some of the simpler, traditional techniques (e.g., histopathology, urinalyses, BUN) were sensitive and organ-specific, and should continue to be very useful in nephrotoxicity testing/screening.