H.M. Worth

Stimulation of hepatic drug-metabolizing enzymes by chlorophenothane (DDT); the relationship to liver enlargement and hepatotoxicity in the rat.

Abstract To study the relationship between induction of drug-metabolizing enzymes, liver enlargement and hepatotoxicity, we have administered DDT [1,1,1-trichloro-2,2-bis( p -chlorophenyl)ethane] to weanling male rats for 14 days. While administration of DDT at dietary concentrations of 0.5 or 2 ppm had no effect on the rate of p -nitroanisole ( p -NA) O -demethylation, concentrations of 4–750 ppm produced an increase in the rate of metabolism proportional to the log dose. Extrapolation of this portion of the dose-response curve to the abscissa provided a calculated no-effect level of 3.27 ± 1.02 ppm. At dietary concentrations greater than 750 ppm there was no further increase in p -NA metabolism. Liver weight increased in proportion to the dose when rats were maintained on diets containing 128–512 ppm DDT. Levels less than 128 ppm had no effect, and concentrations greater than 512 ppm produced a submaximal increase in liver weight. Although the total homogenate protein concentration (mg/g liver) was not affected by DDT administration, the microsomal protein concentration was increased by dietary concentrations above 16 ppm. Only in animals fed dietary levels above 750 ppm, in which there was no further increase in p -NA metabolism, were signs of neurotoxicity apparent. These results suggest that stimulation of drug-metabolizing enzymes, and the accompanying increase in liver weight and microsomal protein, are manifestations of a physiological adaptation.

Stimulation of hepatic microsomal drug-metabolizing enzymes by α,α-bis-(p-chlorophenyl)-3-pyridinemethanol and a method for determining no-effect levels in rats

Abstract The results of this study indicate that α,α-bis-( p -chlorophenyl)-3-pyridinemethanol (EL-241) is a potent inducer of EPN and p -nitroanisole metabolism in weanling male and female rats. Administration of 100 ppm of this compound via the diet results in a significant stimulation of p -nitroanisole O -demethylation within 4 days. Maximum stimulation occurs after 14 days. Removal of the test compound from the diet after 28 days results in the enzyme activities returing to control levels within 28 days. A method for determining no-effect levels for induction of EPN or p -nitroanisole metabolism is also presented. Using this method, the no-effect levels for EL-241 stimulation of p -nitroanisole demethylation in male rats were 26.8 ± 3.3 ppm, 22.3 ± 4.1 ppm, and 23.7 ± 4.0 ppm in three experiments. The no-effect level in female rats was 30.5 ± 3.9 ppm. Although EPN metabolism was stimulated to a greater extent than p -nitroanisole metabolism, the no-effect level for both pathways was the same.

The effects of long-term ingestion of methimazole on the thyroids of rats

Summary Harlan rats were fed methimazole in the diet at levels of 0, 5, 30 and 180 ppm for 2 yr. Survival was poor in the rats of the 180 ppm group and their growth was greatly retarded. Hypertrophy and hyperplasia of the thyroid occurred in rats of the 30 and 180 ppm groups but not in those of the 5 ppm group. In rats of the 30 and 180 ppm groups there was a high incidence of thyroid follicular adenoma and a lower incidence of follicular adenocarcinoma. A follicular adenoma was also found in one rat of the control group and one given 5 ppm methimazole, while one rat in the control group had a follicular adenocarcinoma. Incidence and induction time of neoplasias other than of the thyroid were similar in the treated and control groups. The no-effect dietary level of methimazole on the thyroids of rats was found to be 5 ppm.

THE TOXICITY OF CAPREOMYCIN IN LABORATORY ANIMALS

The chemical and biological properties of capreomycin have been described by Herr”’ and Stark et a l s Because of its antibiotic activity against Mycobacterium tuberculosis and because this compound was a polypeptide, differing in structure from other currently used antituberculous agents, it was of clinical interest. Studies were undertaken to determine its toxic effects in laboratory animals. Capreomycin was administered as the disulfate salt unless otherwise indicated. Dose values reported were expressed in terms of milligrams of antibiotic activity. The average lot of antibiotic assayed 620 mg. of activity per gram.

Toxicological studies on tylosin: its safety as a food additive.

Abstract Tylosin has been shown to be relatively non-toxic following oral administration of large single doses to mice, rats and dogs. Intravenous injection of solutions of various salts showed the acute lethal dose in mice and rats to be 580–695 mg/kg. The toxicity in guinea-pigs was of the same order as erythromycin and penicillin. Diets containing tylosin base up to 1% were well tolerated by rats for 2 yr. Growth was normal and no visceral or haematopoietic damage was produced. Reproduction and lactation studies through three generations showed no alterations in growth or viability at a concentration of 1% in the diet. In an attempt to produce toxic effects, diets containing levels of 2 and 5% tylosin were well tolerated for 2 yr. Lack of palatability of higher concentrations caused retardation of growth and death from malnutrition. Studies designed to demonstrate the possible toxicity of transformation products of tylosin formed during food processing revealed no effect on growth nor any visceral damage. 2-Yr studies in dogs showed that doses up to 100 mg/kg/day, equivalent to 4000 ppm of the diet, produced no visceral or haematopoietic damage. Two dogs had slight sulphobromophthalein retention that returned to normal within 2 wk after withdrawal of treatment. No alteration in the faecal flora was found. Higher daily doses of 200 mg/kg were well tolerated for 2 yr with one of four dogs showing mild pyelonephritis. Of the four dogs that received 400 mg/kg/day for over 2 yr, one revealed bilateral nephrosis, mild chronic pyelonephritis and mild chronic cystitis. Serum levels of tylosin in dogs were detectable at a dietary level of 10 mg/kg/day and were quite high after larger doses. There was no evidence of accumulation in the serum after 2 yr. The no-effect level in rats was 10,000 ppm or higher and in dogs, 4000 ppm. These studies have demonstrated the safety of tylosin and should justify a tolerance for the use of tylosin as a direct food additive.

Toxicological Studies on Carbutamide

In 1942, Janbon first observed the hypoglycemic action of certain sulfonamides when he was investigating the antibacterial action of sulfanilamido-isopropylthiadiazoles. Loubatieres showed that the compound was inactive in depancreatized dogs and postulated that it brought about hypoglycemia in normal animals by stimulating insulin secretion. In 1955, Achelis and Hardebeck and others 5 reported on the hypoglycemic action of /r-aminophenylsulfonyl butyl carbamide, carbutamide or BZ-55, in normal rabbits, in normal man and in some diabetic patients. Inasmuch as carbutamide has continued to lower the blood sugar of certain diabetics, long-term toxicity studies have been pursued.

Intragastric injection for toxicity studies with newborn rats

Abstract The results of this investigation show that the intragastric route of administration provides valid information about the toxic effects of drugs to newborn rats. Differences existing in the responses of young and aged rats to an oral preparation were demonstrated by data obtained from studies in which drugs were given by the intragastric and oral routes. Thus, the technique devised for this study appears to be useful for predicting unusual and unexpected toxicity in infants.

Comparison of 14- and 90-day tests in rats for liver enlargement and stimulation of drug-metabolizing enzymes induced by the agricultural fungicide EL 241.

Abstract The relationship between liver enlargement and stimulation of hepatic drug-metabolizing enzymes was studied after feeding various dietary concentrations of the agricultural fungicide EL 241 [α,α-bis( p -chlorophenyl)-3-pyridinemethanol] to weanling male rates for 14 or 90 days. The dietary concentrations of EL 241 ranged from 15 to 2500 ppm. Weight gain was not affected unless the dietary concentration exceeded 200 ppm. Concentrations of 30–200 ppm increased the rate of p -nitroanisole O -demethylation in proportion to the log dose. Above 200 ppm, there was no further increase. Liver weight was increased by dietary concentrations greater than 50 ppm. Although the absolute liver weight reached a maximum at 310 ppm, the relative liver weight (g liver/100 g body weight) increased in proportion to the log dose throughout the dose range. The concentration of microsomal protein was increased in all animals that had an increased rate of p -nitroanisole metabolism. Except for the magnitude of the changes, the doseresponse relationships for induction of liver enlargement and stimulation of drug-metabolizing enzymes were comparable after either a 14- or 90-day treatment period.

Microsomal drug-metabolizing enzyme activity in rats given α-(2,4-dichlorophenyl)-α-phenyl-5-pyrimidinemethanol for periods of 14 days to 2 years

The dose-response relationships for stimulation of hepatic drug-metabolizing enzymes were studied in rats given α-(2,4-dichlorophenyl)-α-phenyl-5-pyrimidinemethanol (EL-273) in the diet for periods of 2 weeks-2 years. The dietary concentrations ranged from 20 to 5000 ppm. p-Nitroanisole metabolism was not affected by EL-273 concentrations of 80 ppm or less. With dietary concentrations of 160–1250 ppm the rate of metabolism increased in proportion to the log of the dose. Concentrations greater than 1250 ppm produced no additional increase. Above a threshold of 80 ppm, EL-273 increased relative liver weight and microsomal protein. The effects of EL-273 on the liver at 2 weeks were reversible within 2 weeks on control diet. In chronic tests the increases in relative liver weight and p-nitroanisole metabolism reached maxima after 2 weeks of EL-273 administration and remained relatively constant throughout the remainder of the 2-year test.