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Toxicological evaluations of some brominated biphenyls.

Extensive toxicological studies were carried out to define the probable hazard of octabromobiphenyl (OBB) to workers, users, and the environment. OBB had low acute toxicity in mammals and birds by various routes of administration. It was essentially non-irritating to rabbit eyes, non-irritating to human skin and caused only mild skin irritation and no sensitization in the guinea pig. OBB caused equivocal effects in the rat fetus. OBB was stored in the body fat of rats and caused liver enlargement at high single doses or low repeated doses. The studies indicate probable low safety factors in application and use and probable bioaccumulation. Hexabromobiphenyl (HBB) was more acutely toxic than OBB by skin absorption in the rabbit and caused liver enlargement at lower single doses.

Abnormalities, Drug-Induced

Toxicological evaluation of arsenic in edible seaweed, Hizikia species.

Young male Wistar rats were fed with chows containing marketed Hizikia preparation. Hizikia-arsenic could be absorbed at the rate comparable to arsenic trioxide, and accumulated primarily in blood. Intake and excretion of arsenic from Hizikia-diet reached a steady state within 4 days of administration as was the case of arsenic trioxide. Biological half-life in blood and urine was also essentially the same in the 2 groups. Rats kept for 3 weeks on the chows containing up to 20% Hizikia did not show significant growth retardation as compared with the controls, while those on 50% Hizikia-diet were markedly emaciated. In a 38-week feeding experiment, 4 groups of rats were given 20% Hizikia-diets made from various Hizikia preparations (final arsenic concentrations; 9, 16, 21 and 21 ppm, respectively). For positive controls, 2 groups were given arsenic trioxide diets (24 and 50 ppm as arsenic). Growth retardation was minimum both in Hizikia and arsenic groups with no relation to the arsenic dose. Changes in hematology, blood biochemistry and pathology of major organs and skin were also essentially negative in all groups. The maximum no-effect level observed in the present study was compared with the possible amount of arsenic taken via seaweed in mankind.

Animal Feed

[Toxicological evaluation of ethyl acetate in conditions of sealed cabin atmospheres].

Ethyl acetate was studied as an atmosphere contaminant in an enclosed environment. A 90-day continuous experiment on 160 white rats and 120 white mice with three concentrations of the compound (43, 10 and 2 mg/m3) was carried out. Ethyl acetate used in the first two concentrations caused functional disturbances in the state of animals and morphological changes in their viscera. Ethyl acetate at a concentration of 2 mg/m3 was ineffective. The data obtained allow recommendations of permissible concentrations of ethyl acetate vapours in an enclosed atmosphere in relation to a different time of man's exposure.

Acetates

Toxicological evaluation of new calcium antagonists: 2-substituted 3-dimethylamino-5,6-methylenedioxyindenes.

The 2-n-propyl (pr) and 2-n-butyl (bu) methylenedioxyindenes (MDIs) developed in our laboratories are intracellular calcium antagonists with coronary dilating and antiarrhythmic actions. Acute toxicity studies resulted, in mice, in an iv LD50 of 40 and 32 mg/kg for pr-MDI and bu-MDI, respectively, and an ip LD50 of 185 mg/kg for both MDIs. In rats, the ip LD50 was 175 and 240 mg/kg for pr-MDI and bu-MDI, respectively. An iv dose of 16 mg/kg decreased motor activity and prolonged barbiturate sleeping time in mice, but did not affect conditioned avoidance behavior or motor coordination tests. In sub-acute toxicity studies, rats received daily for 4 weeks 26.25 or 52.5 mg/kg ip of either MDIs, while mice received 23.13 or 46.25 mg/kg ip of either MDIs. No alterations were observed in serum alkaline phosphatase, glutamic-pyruvic transaminase, glutamic-oxalacetic transaminase, creatine phosphokinase, bilirubin, chloride, cholesterol, uric acid, prothrombin time, and bromsulphalein retention. Blood glucose was slightly lowered. Serum calcium was slightly lowered in male mice. The higher dose of pr-MDI elevated serum lactate dehydrogenase in rats. Both MDIs elevated serum isocitric dehydrogenase in male rats. Light microscopic examination of brain, kidney, liver, spleen, intestine, stomach, and myocardium showed no anomalies resulting from the 4-week MDI treatment, and electron microscopic examination of hepatocytes revealed no deleterious effects of either MDIs.

Animals

Subacute toxicological evaluation of sclerotia of Sclerotinia sclerotiorum in rats.

Weanling Wistar rats of both sexes were fed diets containing 0 (control), 1% and 5% ground sclerotia of Sclerotinia sclerotiorum derived from infected rapeseed (Brassica napus). Body weight, feed consumption and clinical appearance were monitored over an 84-day period. Blood samples were collected on days 41 and 84 and necropsies performed on day 84. Weight gain and feed consumption were similar in the control and 1% groups. In the 5% group, weight gain was depressed, feed wastage was greater and at termination more than half the rats were in poor body condition with alopecia and hyperkeratosis of the tail. These effects were probably nutritional and due to unpalatability of the diet. Blood urea nitrogen and blood glucose concentrations did not vary consistently among the groups. Serum glutamic-pyruvic transaminase activity was significantly depressed (p less than 0.001) by consumption of sclerotia. This depression was dose-related and consistent on days 41 and 84. There were no significant differences (p greater than 0.05) between groups in the ratios of liver weight and kidney weight to body weight.

Alanine Transaminase

Use of the uricase-inhibited rat as an animal model in toxicology.

An accessible, reproducible, and inexpensive animal model for toxicologic evaluation of hyperuricemic conditions has been required for some time. A number of authors have tried to develop such a model by administering high doses of uric acid to various animal species (dog, rabbit, rat) but the potent liver uricase in these species prevented development of sustained hyperuricemia. Johnson et al. [4], Stavric et al. [5], and a number of other investigators [72, 75] successfully used potassium oxonate [63] to block the effect of hepatic uricase and to produce hyperuricemia in rats [4, 5, 68, 69, 72, 74, 76, 80], rabbits [66], mongrel dogs [67], mice [65], and pigs [64]. The oxonate-treated rat can serve as a useful animal model not only in investigation of the uric acid nephropathy, but also in a number of other toxicologic evaluations connected with uric acid. This model has been used to evaluate drugs that affect uric acid excretion, to determine which dietary factors affect serum urates, or to evaluate possible therapeutic agents in certain disorders associated with uric acid. The same model could also be used by behavioral scientists, for whom research on uric acid has become increasingly popular in recent years [33, 137]. The ideal uricase inhibitor for induction of hyperuricemia would be one which is irreversible, noncompetitive, and relatively nontoxic, so that its activity would be independent of high levels of uric acid, and effective inhibition could be attained at low dosage levels. Oxonic acid is not an ideal uricase inhibitor, because it is competitive and is eliminated from the body relatively rapidly. Although relatively nontoxic, oxonic acid and its salts are foreign substances that could interfere with some other metabolic systems. The possibility exists that an ideal, or at least a better inhibitor, could be developed by appropriate substitutions on the molecule of oxonic acid or by introducing different types of compounds such as derivatives of diazohypoxanthines, barbiturates, or similar substances. Until such improvements on the uricase-inhibited rat models are available, potassium oxonate, which is easily obtainable, can be used as an effective inhibitor of uricase in vivo.

Aggression

Problems associated with the application of short-term tests for mutagenicity in mass-screening programs.

The application of short-term tests for toxicological evaluation of environmental chemicals is certainly a reality in the near future as a result of the Toxic Substances Control Act, as well as other regulations under development [de Serres, 1977]. Many of the problems associated with this testing in the area of genetic toxicology are under study at the National Institute of Environmental Health Sciences in our National Toxicology Program and at the Environmental Protection Agency in their Gene-Tox Program. The other problems that I have discussed in connection with standardization of protocols, protocol review and modification, and training of personnel are not being pursued aggressively. Perhaps with their definition and acceptance as meaningful problems, mechanisms will be established for their resolution. It is in these latter areas that I hope that this society can provide the forceful leadership that will result in their resolution in the near future.

Animals