Pulmonary carcinogenic effects of ozone.
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Biomedical subjects
Publications and source records attributed to G W Newell.
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The single-dose and repeated-exposure toxicity of a synthetic mixture of 30 nitrotoluene analogs, representative of a complex industrial wastewater termed condensate water, was evaluated in dogs, rats, and mice. The single-dose oral LD50s for the synthetic condensate water (CW) were 447 and 295 mg/kg in male and female rats, respectively. In the repeated-exposure studies, dogs were given 0, 0.05, 0.5, or 5 mg of CW per kilogram of body weight by capsule daily for 26 wk. Rats and mice received 0, 0.001, 0.01, or 0.1% of this mixture in their diet for 4 or 13 wk. Groups of each rodent species were set aside for 4 wk to assess recovery. The most notable findings were a compensatory anemia with reticulocytosis (severe in rats), Heinz body formation, and related blood cell abnormalities and hemosiderin in the spleen; pigmentation in the liver cells; atrophy and aspermia in the testes; hyperplasia and inflammation in the female reproductive organs; and neurotoxic signs at the high doses. Rats and mice also experienced food intake and body weight depression and exhibited some alterations in organ weights (spleen, testes, and liver). The findings were referable principally to the two major components 2,4,- and 2,6-dinitrotoluene, but the "no observable effects" levels were lower for the mixture.
The short-term oral toxicity of 2,4,6-trinitrotoluene (alpha-TNT) was determined in dogs, rats, and mice. Single-dose oral LD50s for alpha-TNT in corn oil were 1320 and 794 mg/kg in male and female rats, respectively, and 660 mg/kg in both male and female mice. For multiple-dose studies, dogs were dosed daily for up to 13 wk with alpha-TNT at 0, 0.2, 2.0, or 20 mg/kg by capsule; rats received 0, 0.002, 0.01, 0.05, or 0.25% and mice received 0, 0.001, 0.005, 0.025, or 0.125% alpha-TNT in their diets over the same period. All species receiving the highest doses exhibited anemia, with reduced erythrocytes, hemoglobin, and hematocrit. Alterations were observed in organ weights, including enlarged spleens (accompanied by hemosiderosis) and livers, and depressed body weight and/or body weight gain (temporary in dogs and mice). Alterations in clinical chemistry values included elevated cholesterol and depressed serum glutamicpyruvic transaminase activity in dogs and rats; no effect on serum glutamic-oxaloacetic transaminase activity was observed. Some effects, such as SGPT depression in rats, appeared after 13 wk, suggesting a cumulative toxicity. Reduced testes size was observed in rats at the highest dose regardless of length of exposure. Most of the toxic effects were reversible, but testicular atrophy was not in rats allowed a 4-wk recovery period after treatment. Signs of anemia were present at intermediate dose levels. "No observable effects" levels for alpha-TNT were: dogs, 0.20; rats, 1.42; and mice, 7.76 mg/kg . d.
The oral toxicity of a mixture of 2,4,6-trinitrotoluene and hexahydro-1,3,5-trinitro-1,3,5-triazine (1:0.62, w/w) compounds typically found in munitions plant effluents, was evaluated in mammalian species. Single-dose oral LD50s of the mixture were 574 and 594 mg/kg in male and female rats and 947 and 1130 mg/kg in male and female mice, respectively. Long dispersion periods during preparation or ultraviolet irradiation of the mixture lowered the LD50s. In repeated-exposure studies, dogs were given 0.50, 5.0 or 50 mg/kg X d by capsule for up to 90 d. Rats and mice were fed the mixture in the diet at 0.005, 0.05, or 0.5% for 90 d; mice were also fed at 0.25%. Mortality resulted at the highest dose level in each species. All three species showed depression of body weight or body weight gain, depressed food intake, moderate to severe anemia, and alterations in the spleen (hemosiderosis), liver (hepatomegaly), and testes (atrophy) at the highest dose levels. Cholesterol was elevated in rats and dogs after 90 d. Several species differences were also noted. Uric acid values were elevated in rats but not in dogs, serum glutamic-pyruvic transaminase (SGPT) activity was low in dogs but unchanged in rats, and rats developed hypoplasia of the uterus but dogs did not. Signs of anemia were present at the intermediate dose levels. The lowest dose level in all three species was designated at a "no observable effects" level, based on the absence of clearly treatment-related effects. In a 4-wk study, the irradiated mixture fed to rats at 0.003, 0.03, or 0.3% in the diet was less toxic than the unirradiated mixture.
The status of the heritable-translocation test in mice with respect to its usefulness in practical testing was evaluated by using information available in the open literature. A total of 47 reports were evaluated; 29 were judged to contain adequate information to classify whether or not a given chemical induced heritable translocations. Heritable-translocation data were available for 32 compounds; data were not adequate for 15 compounds. Of the remaining 17 compounds, clear-cut determination of positive or negative effects was made for 14 compounds, while data for 3 compounds were only suggestive of either negative or positive effects. 10 chemicals have been shown to induce heritable translocations. These chemicals are either direct or indirect alkylating agents. The heritable-translocation test needs to be improved before it can be used in wide-scale practical testing. The most important question is whether or not historical controls can be used in tests for significance; the cost of concurrent controls is prohibitive. There is a need to standardize methods used in testing laboratories with respect to the size of error involved in classifying translocation heterozygotes and the power of the test. There is also a need to study in the effectiveness of non-alkylating clastogens in inducing heritable translocations in mice.
A water quality standard for laboratory rodents has not been established nor given serious consideration. Yet many studies have shown on occasion the presence of heavy metals, polycyclic hydrocarbons (some known to be carcinogens) as well as microscopic organisms. All of these materials may have significant impacts upon the outcome of an experiment if proper attention is not given to their presence and control. Several methods and systems for the control of these extraneous factors are discussed.
Various aziridine derivatives derived from diamines were studied in several biological systems to evaluate their effects on reproduction and as potential mutagens. Considerable variations in the biological activities of these compounds were seen among animal species and among the varied chemical structures. In general, mutagenic responses paralleled the antifertility effects in mice and houseflies and the anticancer effects in mice. The lack of an antifertility effect by N,N'-bis(aziridinylacetyl)-1,8-octamethylenediamine in the rat was quite unexpected in view of its chemosterilant activity in houseflies and mice.
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