Thomas E. Hamm

A critical review of the literature on nitrobenzene toxicity

This literature review encompassing information available through 1980 and limited coverage in 1981, emphasizes results useful in assessing the potential toxic effects of nitrobenzene to man. Nitrobenzene exposure in man or experimental animals is most often associated with methemoglobinemia. Histopathologic changes also are observed in the hemato-lymphoreticular system, central nervous system, and liver. In addition, lesions have been reported in adrenals and testes. No information was found on carcinogenic or teratogenic potential, fertility, or reproductive effects of nitrobenzene. Results from Ames Salmonella assay are negative but test procedures are questionable; metabolites give positive results. Metabolism of nitrobenzene involves either oxidation or reduction yielding p-aminophenol and p-nitrophenol, and other reduced intermediates. From the foregoing, several aspects of nitrobenzene toxicity have been identified which warrant further study. Recommendations are made for chronic and subchronic exposure of test animals via inhalation to assess various toxicological endpoints. In addition, the relationship of nitrobenzene metabolism to its toxicity needs to be established. Genotoxic effects of nitrobenzene also need study.

Tumors in Control Hamsters, Rats, and Mice: Literature Tabulation

(1982). Tumors in Control Hamsters, Rats, and Mice: Literature Tabulation. CRC Critical Reviews in Toxicology: Vol. 10, No. 1, pp. 49-79.

Carcinogenicity and Toxicity of Inhaled Nitrobenzene in B6C3F1 Mice and F344 and CD Rats

The potential carcinogenicity and toxicity of inhaled nitrobenzene were evaluated following chronic (2-year) exposure in mice and rats. Male and female B6C3F1 mice were exposed to 0, 5, 25, or 50 ppm nitrobenzene, while male and female F344 rats and male CD rats were exposed to 0, 1, 5, or 25 ppm nitrobenzene. All exposures were for 6 hr/day, 5 days/week excluding holidays, for a total of 505 days over 2 years. Survival was not adversely affected by nitrobenzene exposure, and only mild exposure-related decreases in body weights (< 10% of control) were occasionally noted. Nitrobenzene exposure resulted in increased incidence of neoplasia in male B6C3F1 mice (pulmonary alveolar/bronchiolar and thyroid follicular cell neoplasms), female B6C3F1 mice (mammary gland neoplasms), male F344 rats (hepatocellular and renal neoplasms), female F344 rats (endometrial stromal neoplasms), and male CD rats (hepatocellular neoplasms). In addition, there were marginal increases in the incidence of hepatocellular neoplasia in female B6C3F1 mice and thyroid follicular neoplasia in male F344 rats. Groups of nitrobenzene-exposed mice and rats with increased incidence of renal and thyroid neoplasia also had increased incidences of hyperplasia in these tissues. Toxicity resulting from chronic inhalation of nitrobenzene was manifested by methemoglobinemia, anemia, and adaptive or degenerative changes in the nose, liver, and testis. The results indicate that inhaled nitrobenzene is carcinogenic and toxic in mice and rats, and that the spectrum of these responses in animals is dependent on species, sex, and genetic background.

Chronic toxicity and oncogenicity bioassay of inhaled ethylene in Fischer-344 rats☆

The toxicity and oncogenicity of inhaled ethylene was determined in Fischer-344 rats. Nine hundred and sixty animals were randomly divided into four groups of one hundred twenty animals of each sex and were exposed 6 hr/day, 5 days/week, for up to 24 months to concentrations of ethylene in air of 0, 300, 1000, or 3000 ppm. The maximum tolerated dose was not used as concentrations above 3000 ppm were considered hazardous because of the risks associated with ethylenes explosive properties. The calculated time-weighted average concentrations for the 24 months of exposure were 0.0, 301, 1003, and 3003 ppm, respectively. Randomly selected animals were necropsied and examined after 6, 12, and 18 months of exposure. All surviving rats were necropsied at 24 months. A complete selection of tissues and organs from all animals in the control and 3000-ppm groups were examined for microscopic lesions. All animals were examined for clinical changes throughout the course of the study and selected animals were used to determine ophthalmologic or hematologic effects and for clinical blood chemistry or urinalysis effects. There were 151 unscheduled deaths (15.7% of 960 animals). There was no difference in mortality between groups during the 2-year study. Gross examination of rats dying during the study, or of those that were sacrificed as scheduled, did not reveal any lesions attributable to ethylene exposure. Histologically, a variety of proliferative, degenerative, and inflammatory lesions were observed in both the control and 3000-ppm groups. These lesions were typical of those seen in this strain of animal and were considered unrelated to ethylene exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

One-year inhalation toxicity study of chlorine in rhesus monkeys (Macaca mulatta).

Chlorine (Cl2) gas is a potentially lung-damaging irritant which is used in the chemical, plastics, and paper industries. There are no data published using experimental animals on the chronic inhalation toxicity of chlorine. The purpose of this study was to investigate the chronic effects of Cl2 inhalation in Rhesus monkeys (Macaca mulatta). Rhesus monkeys were exposed to concentrations of 0, 0.1, 0.5, or 2.3 ppm Cl2 for 6 hr per day. 5 days per week for 1 year. Pulmonary physiology (pulmonary diffusing capacity and distribution of ventilation), body weights, urinalysis, electrocardiographs, hematology, and clinical chemistry were evaluated monthly during the study. Blood gas evaluations were performed at 3-month intervals during the study. Histopathologic, ophthalmologic, and neurologic parameters were evaluated after the 1-year exposure period. Monkeys exposed to 2.3 ppm Cl2 exhibited signs of ocular irritation during the daily exposures and a superficial conjunctival irritation was present in the 2.3 ppm group after the 1-year exposure regimen. Treatment-induced lesions revealed by histopathology were confined to the respiratory tract. Lesions associated with the nasal parasite Anatrichosoma spp. were present in the region of squamous epithelium of the nasal vestibule and did not interfere with interpretation of Cl2-induced effects. Treatment-induced histopathologic changes were found in the respiratory epithelium of the nasal passages and trachea and were limited to focal, concentration-related epithelial hyperplasia with loss of cilia and decreased numbers of goblet cells in affected areas. These changes in the nose and trachea were focal and mild in monkeys exposed to 2.3 ppm and were not found in all animals in these exposure groups. Tracheal lesions were confined to the 2.3 ppm group. The lesions observed at 2.3 ppm were not present in all animals. At the lower Cl2 concentrations, similar though less prominent respiratory epithelial lesions were observed. The latter changes were very minimal and were confined to the nasal passages of some treated monkeys and one male control animal. The results of this study indicate that 2.3 ppm chlorine acts as an upper respiratory irritant in monkeys, while 0.5 and 0.1 ppm induce changes of questionable clinical significance. Furthermore, the monkey appears to be less sensitive than the rat to chlorine toxicity.

Development of hepatic lesions in male Fischer-344 rats fed AIN-76A purified diet.

Abstract The suitability of the AIN-76A diet for Fischer-344 rats was investigated. This diet, proposed by the American Institute of Nutrition for use when a purified diet composed of refined ingredients and added vitamins and minerals is required, was tested in Sprague-Dawley rats. Male weanling Fischer-344 rats were fed three different lots of the AIN-76A diet from two suppliers. Increase in body weights and food consumption were compared to animals fed a cereal-based control diet. Animals were sacrificed at various intervals and tissues were taken for histopathological observation. By 8 weeks moderate to marked periportal lipidosis developed in livers of all rats fed the AIN-76A diet. Liver-body weight ratios over the 8-week period were significantly higher in rats fed AIN-76A diets compared to rats fed the control diet. However, growth rates of rats fed the AIN-76A diet were similar to growth rates of controls. Some rats fed the AIN-76A diet developed severe hemorrhagic lesions. The AIN-76A diet in its present form is not suitable for use with male Fischer-344 rats.

Regular articleOne-year inhalation toxicity study of chlorine in rhesus monkeys (Macaca mulatta)☆

Chlorine (Cl2) gas is a potentially lung-damaging irritant which is used in the chemical, plastics, and paper industries. There are no data published using experimental animals on the chronic inhalation toxicity of chlorine. The purpose of this study was to investigate the chronic effects of Cl2 inhalation in Rhesus monkeys (Macaca mulatta). Rhesus monkeys were exposed to concentrations of 0, 0.1, 0.5, or 2.3 ppm Cl2 for 6 hr per day. 5 days per week for 1 year. Pulmonary physiology (pulmonary diffusing capacity and distribution of ventilation), body weights, urinalysis, electrocardiographs, hematology, and clinical chemistry were evaluated monthly during the study. Blood gas evaluations were performed at 3-month intervals during the study. Histopathologic, ophthalmologic, and neurologic parameters were evaluated after the 1-year exposure period. Monkeys exposed to 2.3 ppm Cl2 exhibited signs of ocular irritation during the daily exposures and a superficial conjunctival irritation was present in the 2.3 ppm group after the 1-year exposure regimen. Treatment-induced lesions revealed by histopathology were confined to the respiratory tract. Lesions associated with the nasal parasite Anatrichosoma spp. were present in the region of squamous epithelium of the nasal vestibule and did not interfere with interpretation of Cl2-induced effects. Treatment-induced histopathologic changes were found in the respiratory epithelium of the nasal passages and trachea and were limited to focal, concentration-related epithelial hyperplasia with loss of cilia and decreased numbers of goblet cells in affected areas. These changes in the nose and trachea were focal and mild in monkeys exposed to 2.3 ppm and were not found in all animals in these exposure groups. Tracheal lesions were confined to the 2.3 ppm group. The lesions observed at 2.3 ppm were not present in all animals. At the lower Cl2 concentrations, similar though less prominent respiratory epithelial lesions were observed. The latter changes were very minimal and were confined to the nasal passages of some treated monkeys and one male control animal. The results of this study indicate that 2.3 ppm chlorine acts as an upper respiratory irritant in monkeys, while 0.5 and 0.1 ppm induce changes of questionable clinical significance. Furthermore, the monkey appears to be less sensitive than the rat to chlorine toxicity.

Reproduction in Fischer-344 rats exposed to methyl chloride by inhalation for two generations.

Male and female Fischer-344 rats were exposed to methyl chloride by inhalation (0, 150, 475, or 1500 ppm, 6 hr/day, 5 days/week, 40 males and 80 females per group). The only treatment-related clinical signs were a 10 to 20% body weight gain depression (BWGD) in both males and females exposed to 1500 ppm at all weekly weighings after 2 weeks of exposure and a 5-7% BWGD in 475-ppm exposed animals after Day 57. After 10 weeks the exposure schedule was changed to 6 hr/day, 7 days/week and each male was mated to two exposed females. The mating period was ended after 2 weeks, at which point 10 males/group were necropsied. The only treatment-related lesions found were severe bilateral testicular degeneration (10/10) and granulomas in the epididymis (3/10) in the 1500-ppm males. The remaining 30 males per group were then removed from exposure and mated during a 2-week period with 60 unexposed females. The exposed females were continued on exposure from the start of mating to Postnatal Day 28 (6 hr/day, 7 days/week). The females were not exposed from Gestation Day 18 to Postnatal Day 4, and the pups were never directly exposed prior to weaning. There were no significant differences between groups in the number of exposed or unexposed females that mated, as evidenced by copulation plugs. No litters were born to exposed or unexposed females mated to the 1500-ppm males. There was no significant difference in the number of litters produced by the 150-ppm groups when compared to the control groups. Fewer litters were born in the 475-ppm groups than in the control groups. No differences in litter size, sex ratio, pup viability, or pup growth were found among the 475-ppm, 150-ppm, or control F0 groups. When bred 10 weeks after the cessation of exposures, 5 to 20 1500-ppm F0 males had regained the ability to sire normal litters. The same number of 475-ppm F0 males proved as fertile (15/20) as control F0 males (13/20). After weaning, F1 pups from the 475-, 150-, and 0-ppm groups were exposed to the same concentrations of methyl chloride for 10 weeks and then mated. A trend toward decreased fertility was found in the 475-ppm F1 group.