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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The toxicity of 3,3',4,4'-tetrachloroazoxybenzene (TCAOB) was evaluated in 13-week gavage studies in male and female F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included clinical chemistry, hematology, thyroid hormone analyses, and effects on sperm morphology and estrous cycle length. Groups of 10 rats and 10 mice of each sex were exposed to TCAOB at dose levels of 0, 0.1, 1, 3, 10, or 30 mg/kg 5 days a week for 13 weeks. In the rat studies, the major effects included death in the 30 mg TCAOB/kg dose group; at lower exposure levels, a decrease in body weight gain, a decrease in thymus weight, an increase in liver weight, an increase in hematopoietic cell proliferation in the spleen and liver, a responsive anemia, a decrease in platelet counts, a chronic active inflammation of the vasculature in the lung, an increase in cardiomyopathy, hyperplasia of the forestomach, and a marked decrease in circulating thyroxine concentrations were observed. In male rats a decrease in sperm motility in the epididymides was observed. In addition, in female rats an increase in lung, spleen, kidney, and heart weights and nephropathy was observed. Furthermore, the estrous cycle length was increased. In the mouse studies, the major effects for males and females included a decrease in thymus weights, an increase in liver and kidney weights, centrilobular hypertrophy in the liver, hematopoietic cell proliferation, hyperplasia of the forestomach, and dilatation of hair follicles. The spectrum of effects in both rats and mice after exposure to TCAOB indicates that dioxin-like effects occur in addition to effects that have not been observed with dioxin-like compounds. No no-observed-adverse-effect level was reached in male or female rats or mice.
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PMID:Toxicity of 3,3',4,4'-tetrachloroazoxybenzene in rats and mice. 1022 13

Usual causes of intolerance to thyroxine sodium include coronary artery disease, advanced age, untreated adrenal insufficiency, and severe hypothyroidism. We describe 4 patients with iron deficiency anemia and primary hypothyroidism. After treatment with thyroxine sodium, these patients developed palpitations and feelings of restlessness, which necessitated discontinuation of the thyroid hormone. After the anemia was treated with ferrous sulfate for 4 to 7 weeks, they were able to tolerate thyroxine sodium therapy. Iron deficiency anemia coexisting with primary hypothyroidism results in a hyperadrenergic state. In such patients, we postulate that thyroid hormone administration causes palpitations, nervousness, and feelings of restlessness. Correction of any existing pronounced anemia in hypothyroid patients who are intolerant to thyroxine sodium therapy may result in tolerance to this agent.
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PMID:Anemia: a cause of intolerance to thyroxine sodium. 1068 60

The potential for sodium chlorite to produce reproductive toxicity, developmental neurotoxicity and alterations in hematology and thyroid hormones was evaluated in Sprague-Dawley rats administered sodium chlorite in the drinking water continuously for two generations. The F(0) generation animals (30 of each gender per group) and F(1) generation animals (25 of each gender per group) selected to rear the F(2) generation were allowed free access to drinking water containing 0, 35, 70 or 300 ppm sodium chlorite for a 10-week prebreed period, through mating for males and through mating, gestation and lactation for females. These drinking water concentrations corresponded to sodium chlorite doses of approximately 4, 8 and 30 mg kg(-1) day(-1) for males and 5, 10 and 39 mg kg(-1) day(-1) for females, respectively. Evaluations included standard reproductive and postnatal indices, sperm morphology and motility, estrous cyclicity, a functional observational battery, motor activity, auditory startle, swim maze, hematology, serum thyroid hormone analyses and histopathology of reproductive and nervous system tissues. Sodium chlorite resulted in a decrease in water consumption in all groups and a decrease in food consumption and body weights in the 70 and 300 ppm groups. There was no evidence of reproductive toxicity. Pup body weight was decreased in the 300 ppm group and small delays were observed in the time to preputial separation and vaginal opening. Mild anemia and mild methemoglobinemia were observed for animals in the 300 ppm group. Thyroid hormone levels were not affected by treatment. Changes to the nervous system were limited to small decreases in amplitude of auditory startle response for postnatal day (PND) 25 pups in the 70 and 300 ppm groups and a small decrease in absolute brain weight for PND 11 pups in the 300 ppm group. These effects were considered to be of questionable neurotoxicological significance. Based on the results of this study, the no-observed-effect level (NOEL) for effects on reproduction and thyroid hormones is 300 ppm. The no-observed-adverse-effect levels (NOAEL) for hematological toxicity and neurotoxicity are considered to be 70 and 300 ppm, respectively.
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PMID:Two-generation reproduction and developmental neurotoxicity study with sodium chlorite in the rat. 1094 4

Iron plays an important role in thyroid hormone metabolism; thus, iron deficiency anemia may lead to alterations in resting metabolic rate (RMR). Based on this premise, two iron-deficient-anemic female athletes, 18 (A1) and 21 (A2) years of age, were supplemented with 23 mg/day of elemental iron to assess its effects on iron and thyroid hormone status and RMR at 0, 8, and 16 weeks. Anemia was clinically corrected in both subjects (hemoglobin: A1 = 11.0 to 13.0 to 12.6 g/dL and A2 = 11.5 to 13.9 to 12.6 g/dL, 0 to 8 to 16 weeks, respectively). Serum ferritin (SF) concentration also improved in both subjects (A1: 5.0 to 11.0 to 15.0 ng/dL and A2: 5.0 to 16.0 to 20.0 ng/dL; 0 to 8 to 16 weeks, respectively); however, 16 weeks of iron supplementation did not fully replete iron stores. A2 increased dietary iron and ascorbic acid intakes from 8 to 16 weeks, possibly accounting for her higher SF concentrations. RMR and total thyroxine changed over time: A1 increased while A2 decreased in these variables. Although clinical correction of iron deficiency anemia occurred after 16 weeks of low-level iron supplementation, RMR and thyroid hormone metabolism were oppositely affected in the two subjects.
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PMID:Effect of iron supplementation on thyroid hormone levels and resting metabolic rate in two college female athletes: a case study. 1109 70

3,3',4,4'-Tetrachloroazobenzene is not commercially manufactured but is formed as an unwanted byproduct in the manufacture of 3,4-dichloroaniline and its herbicidal derivatives Propanil(R), Linuron(R), and Diuron(R). In addition, environmental contamination by 3,3',4,4'-tetrachloroazobenzene occurs from the degradation of chloranilide herbicides and the photolysis and biolysis of 3,4-dichloroaniline. 3,3',4,4'-Tetrachloroazobenzene was nominated by the United States Environmental Protection Agency for toxicity testing based on concerns over the potential for human exposure, the structural resemblance to 2,3,7,8-tetrachlorodibenzo-p-dioxin, and the reported dioxin-like effects of 3,3',4,4'-tetrachloroazobenzene. The toxicity of 3,3',4,4'- tetrachloroazobenzene was evaluated in 16-day and 13-week gavage studies in male and female F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included hematology (rats only), clinical chemistry, thyroid hormone analyses (rats only), cytochrome P(450)1A immunohistochemical staining in the liver (rats only), and assessments of male reproductive endpoints and estrous cycle length. Genetic toxicology studies included mutagenicity tests in Salmonella typhimurium and the determination of micronuclei in mouse bone marrow and peripheral blood erythrocytes. In the 16-day studies, groups of five male and five female rats received 3,3',4,4'-Tetrachloroazobenzene in corn oil by gavage 5 days a week at doses of 0, 12.5, 32, 80, 200, or 500 mg per kg body weight. Groups of five male and five female mice received 3,3',4,4'-Tetrachloroazobenzene in corn oil by gavage 5 days a week at doses of 0, 1, 3.2, 10, 32, or 100 mg/kg. Major effects included increases in liver, lung, and spleen weights of rats and liver and heart weights of mice and decreases in thymus weights of rats and mice. No effects were found on survival or mean body weight gains of rats or mice. Incidences of hematopoietic cell proliferation in the spleen were increased in all groups of dosed male rats, in female rats that received 32 mg/kg or greater, and in 100 mg/kg male and female mice. Renal tubule hyaline droplet accumulation in the cytoplasm of renal cortical epithelial cells and chronic nephropathy were observed microscopically in male rats in the 80, 200, and 500 mg/kg groups. Female mice in the 100 mg/kg group had atrophy of the thymus. In the 13-week studies, groups of 10 male and 10 female rats and mice received 3,3',4,4'-Tetrachloroazobenzene in corn oil by gavage 5 days a week at doses of 0, 0.1, 1, 3, 10, or 30 mg/kg. In the 13-week rat study, the major effects included a decrease in the mean body weight gain of 30 mg/kg females and final mean body weights of 30 mg/kg males and females, decreased thymus weights of males and females in the 10 and 30 mg/kg groups accompanied by thymic atrophy observed microscopically, increased incidences of hematopoietic cell proliferation in the spleen in 10 and 30 mg/kg males and females, a responsive anemia in 10 and 30 mg/kg males and females at week 13, and decreased platelet counts in 10 and 30 mg/kg males and females on day 21 and at week 13. Spleen weights were increased in 10 and 30 mg/kg males and females. Liver weights were increased in males that received 1 mg/kg or greater and in 10 and 30 mg/kg females. Furthermore, hepatic cytochrome P(450)1A staining presence and intensity were increased in 30 mg/kg males and females. Sharp decreases in circulating thyroxine concentrations were observed in males and females at all doses. In spite of this sharp decrease, thyroid-stimulating hormone concentrations were marginally increased. Incidences of hyperplasia of the forestomach were increased in males administered 3 mg/kg or greater and females administered 30 mg/kg. In the 13-week mouse study, the major effects included increases in liver and spleen weights of 10 and 30 mg/kg males and females and increased incidences of hyperplasia of the forestomach in males and females that received 1 mg/kg or greater. Furthermore, a decrease in thymus weight of 30 mg/kg males, an increase in centrilobular hypertrophy of hepatocytes in males that received 3 mg/kg or greater, and an increase in the incidences of hematopoietic cell proliferation in the spleen in males that received 3 mg/kg or greater were observed. A significant decrease in epididymal spermatozoal concentration was observed in 3 and 30 mg/kg males. 3,3',4,4'-Tetrachloroazobenzene was mutagenic in S. typhimurium strain TA97 in the presence of rat liver S9 activation enzymes; no mutagenic activity was detected in strain TA98, TA100, TA1535, or TA1537 with or without S9. In vivo, the frequency of micronucleated erythrocytes was significantly increased in peripheral blood samples from male and female mice given 3,3',4,4'-Tetrachloroazobenzene by gavage for 13 weeks. However, results of a 3-day exposure of up to 200 mg/kg by intraperitoneal injection did not demonstrate induction of micronuclei in bone marrow erythrocytes of male mice. In summary, 3,3',4,4'-Tetrachloroazobenzene caused typical dioxin-like effects, such as thymic atrophy, an increase in liver weights, induction of hepatic cytochrome P(450)1A, and decreased mean body weight gains. Furthermore, in the 13-week studies, a sharp decrease in circulating thyroxine concentrations was observed even at the lowest dose (0.1 mg/kg) tested in rats. Other effects included a decrease in epididymal spermatozoal concentration in mice, major effects on the hematopoietic system, and increased incidences of hyperplasia of the forestomach in 3 and 30 mg/kg males and 30 mg/kg females. A no-observable-adverse-effect-level (NOAEL) was not reached in rats. The NOAEL in mice was 0.1 mg/kg. Comparison of various dioxin-like effects in these studies with those reported in the literature indicate that 3,3',4,4'-Tetrachloroazobenzene is six to two orders of magnitude less potent than 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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PMID:NTP Technical Report on the Toxicity Studies of 3,3',4,4'-Tetrachloroazobenzene (CAS No. 14047-09-7) Administered by Gavage to F344/N Rats and B6C3F1 Mice. 1198 82

3,3',4,4'-Tetrachloroazoxybenzene is not commercially manufactured but is present as a contaminant of 3,4-dichloroaniline and its herbicidal derivative Diuron(R). In addition, environmental contamination occurs when 3,3',4,4'-tetrachloroazoxybenzene is formed by the photolysis and biolysis of 3,4-dichloroaniline. 3,3',4,4'-Tetrachloroazoxybenzene was nominated by the United States Environmental Protection Agency for toxicity testing based on concerns over the potential for human exposure, the structural resemblance to 2,3,7,8-tetrachlorodibenzo-p-dioxin, and the reported dioxin-like effects of 3,3',4,4'-tetrachloroazoxybenzene. The toxicity of 3,3',4,4'-tetrachloroazoxybenzene was evaluated in 16-day and 13-week gavage studies in male and female F344/N rats and B6C3F1 mice. In addition to histopathology, evaluations included hematology (rats only), clinical chemistry, thyroid hormone analyses (rats only), hepatic cell proliferation (rats only), cytochrome P(450)1A immunohistological staining in the liver (rats only), and assessments of male reproductive endpoints and estrous cycle length. Additional genetic toxicology studies included mutagenicity tests in Salmonella typhimurium and the determination of micronuclei in mouse bone marrow and peripheral blood erythrocytes. In the 16-day studies, groups of five male and five female rats received 3,3',4,4'-tetrachloroazoxybenzene in corn oil by gavage at doses of 0, 12.5, 32, 80, 200, or 500 mg per kg body weight, 5 days a week. Groups of five male and five female mice received 0, 1, 3.2, 10, 32, or 100 mg/kg in corn oil by gavage, 5 days a week. Major effects in rats included increases in liver and lung weights, and decreases in mean body weights and body weight gains, heart weights, and thymus weights. Effects in mice included increases in liver weights and decreases in thymus weights. No effects on survival were observed. Treatment-related lesions included cytoplasmic alteration of hepatocytes, splenic hematopoietic cell proliferation, thymic atrophy, and nephropathy in rats and thymic atrophy, splenic hematopoietic cell proliferation, and hepatic foci of inflammation and necrosis in mice. In the 13-week studies, groups of 10 male and 10 female rats and mice received 3,3',4,4'- tetrachloroazoxybenzene in corn oil by gavage at doses of 0, 0.1, 1, 3, 10, or 30 mg/kg, 5 days a week. In the 13-week rat study, all males and seven females in the 30 mg/kg groups died. Decreases in final mean body weights and body weight gains were observed in 3 and 10 mg/kg males and 10 and 30 mg/kg females. Decreased thymus weights, accompanied by thymic atrophy observed microscopically, were observed at doses of 1 mg/kg or greater in males and females. Increased liver weights were observed in males and females administered 1 mg/kg or greater, and hepatic cytochrome P(450)1A staining was increased in 1 and 3 mg/kg males and 3, 10, and 30 mg/kg females. In addition, a responsive anemia and decreases in platelet counts were observed in dosed male and female rats. A marked decrease in circulating thyroxine concentrations was observed in dosed males and females. In spite of this sharp decrease, thyroid-stimulating hormone concentrations were marginally increased. A decrease in epididymal spermatozoal motility was observed in all dosed groups tested. In 10 mg/kg females, the estrous cycle length was increased. Major effects included increased incidences of hyperplasia of the forestomach in 3, 10, and 30 mg/kg males and 10 and 30 mg/kg females. Increased incidences of centrilobular degeneration and hematopoietic cell proliferation were observed in the liver of dosed males and females. Furthermore, chronic active inflammation of the lung vasculature and hematopoietic cell proliferation in the spleen were observed in dosed males and females. The increased severities of cardiomyopathy and nephropathy in males and the incidences of cardiomyopathy and nephropathy and severity of cardiomyopathy in females were 3,3',4,4'-tetrachloroazoxybenzene related. In the 13-week mouse study, the major effects included increases in liver weights in males administered 3 mg/kg or greater and females administered 1 mg/kg or greater. Hyperplasia of the forestomach and dilatation of hair follicles were observed in 10 and 30 mg/kg males and 30 mg/kg females. Furthermore, thymus weights were decreased in males administered 3 mg/kg or greater and in 10 and 30 mg/kg females. Increased incidences of centrilobular hypertrophy of hepatocytes were observed in 10 and 30 mg/kg males and females. Increased incidences of hematopoietic cell proliferation in the spleen were observed in 30 mg/kg males and in 10 and 30 mg/kg females. Increases in the incidences of thymocyte necrosis were observed in 10 mg/kg males and in 10 and 30 mg/kg females. The incidences of splenic pigmentation were increased in all dosed groups of males, and the severity of pigmentation increased with increasing dose in males and females. 3,3',4,4'-Tetrachloroazoxybenzene was not mutagenic in S. typhimurium strain TA97, TA98, TA100, or TA1535 with or without induced S9 metabolic activation enzymes. It did not induce significant increases in micronucleated erythrocytes in a three-exposure male mouse bone marrow micronucleus test up to dose levels of 200 mg/kg, but results of a 13-week peripheral blood micronucleus test conducted in male and female mice were positive. In summary, 3,3',4,4'-tetrachloroazoxybenzene caused typical dioxin-like effects, including thymic atrophy, increased liver weights, induction of hepatic cytochrome P(450)1A, and decreased mean body weight gains. Furthermore, a marked decrease in circulating thyroxine concentrations was observed in male and female rats, even at the lowest dose (0.1 mg/kg) in female rats. A decrease in epididymal sperm motility was observed at all doses in rats. Effects on the hematopoietic system occurred at doses including and lower than those that caused histopathologic alterations in the liver. A no-observable-adverse-effect-level (NOAEL) was not reached in rats. In male and female mice, the NOAEL was 1 and 0.1 mg/kg, respectively. Furthermore, treatment-related effects included increased incidences of hyperplasia of the forestomach epithelium in rats and mice, chronic active inflammation of the vasculature of the lung in rats, increased incidences and/or severities of cardiomyopathy and nephropathy in rats, and dilatation of the hair follicles in mice. Comparison of various dioxin-like effects in these studies with those reported in the literature indicate that 3,3',4,4'- tetrachloroazoxybenzene is six to two orders of magnitude less potent than 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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PMID:NTP Technical Report on the Toxicity Studies of 3,3',4,4'-Tetrachloroazoxybenzene (CAS No. 21232-47-3) Administered by Gavage to F344/N Rats and B6C3F1 Mice. 1198 83

Table salt can now be fortified with iodine and iron without interaction and without loss of potency. According to Levente Diosady, professor of Food Engineering at the University of Toronto, the amounts of the two micronutrients available to the human body have been significantly reduced when the two interacted. In the new technology, the iodine is covered with a dextrin (a water soluble starch) capsule that serves as a physical barrier to the iron. Micronutrient Initiative (an international secretariat based at IDRC that works to eliminate health problems resulting from iron, iodine, and vitamin A deficiencies) and IDRC supported the development of the technology. The efficiency of absorption of the two micronutrients in the new double fortified salt in the human body is being tested at the Hospital for Sick Children in Toronto. Later testing will be conducted by University of Ghana scientists in IDRC-funded trials that will focus on women and their families in areas of Ghana where these deficiencies are endemic. Iodine is part of thyroid hormone, which contributes to brain development in the fetus and regulates human metabolism; iodine deficiency is the most frequent cause of preventable mental retardation. Related disorders include lethargy, physical disabilities, goiter, stillbirth, and neonatal death. Iron deficiency, the most common nutritional problem in the world (particularly among women, infants, and children), is associated with anemia, fatigue, learning problems, pregnancy complications, premature births, and maternal mortality. The two deficiencies together affect more than one-third of the world's population. Approximately 1.6 billion people, in more than 100 countries, live in areas where iodine is not available in sufficient amounts; those most at risk include about one-third of China's population. It is also a severe problem in the Himalayas, the Andes, India, and West Africa.
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PMID:Micronutrient deficiencies. Reports from the field -- Africa. 1229 Mar 27

Several minerals and trace elements are essential for normal thyroid hormone metabolism, e.g., iodine, iron, selenium, and zinc. Coexisting deficiencies of these elements can impair thyroid function. Iron deficiency impairs thyroid hormone synthesis by reducing activity of heme-dependent thyroid peroxidase. Iron-deficiency anemia blunts and iron supplementation improves the efficacy of iodine supplementation. Combined selenium and iodine deficiency leads to myxedematous cretinism. The normal thyroid gland retains high selenium concentrations even under conditions of inadequate selenium supply and expresses many of the known selenocysteine-containing proteins. Among these selenoproteins are the glutathione peroxidase, deiodinase, and thioredoxine reductase families of enzymes. Adequate selenium nutrition supports efficient thyroid hormone synthesis and metabolism and protects the thyroid gland from damage by excessive iodide exposure. In regions of combined severe iodine and selenium deficiency, normalization of iodine supply is mandatory before initiation of selenium supplementation in order to prevent hypothyroidism. Selenium deficiency and disturbed thyroid hormone economy may develop under conditions of special dietary regimens such as long-term total parenteral nutrition, phenylketonuria diet, cystic fibrosis, or may be the result of imbalanced nutrition in children, elderly people, or sick patients.
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PMID:The impact of iron and selenium deficiencies on iodine and thyroid metabolism: biochemistry and relevance to public health. 1248 69

Nitromethane is used as a rocket and engine fuel; as a synthesis intermediate for agricultural fumigants, biocides, and other products; as a solvent; and as an explosive in mining, oil-well drilling, and seismic exploration. It has been detected in air, in surface and drinking water, and in cigarette smoke. Nitromethane was studied because of the potential for widespread human exposure and because it is structurally related to the carcinogens 2-nitropropane and tetranitromethane. Male and female F344/N rats and B6C3F1 mice received nitromethane (purity 98% or greater) by inhalation for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and peripheral blood erythrocytes of mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 16 days. All rats survived until the end of the study. The mean body weight gain of male rats in the 1,500 ppm group was slightly but significantly less than that of the controls; the final mean body weights and mean body weight gains of exposed females were similar to those of the controls. Clinical findings in all male and female rats in the 1,500 ppm groups included increased preening, rapid breathing, hyperactivity early in the study, and hypoactivity and loss of coordination in the hindlimbs near the end of the study. The relative liver weights of all exposed groups of male rats and the absolute and relative liver weights of females exposed to 375 ppm or greater were significantly greater than those of the controls. Minimal to mild degeneration of the olfactory epithelium was observed in the nose of males and females exposed to 375 ppm or greater. Sciatic nerve degeneration was present in all male and female rats exposed to 375 ppm or greater; rats exposed to 750 or 1,500 ppm also had reduced myelin around sciatic axons. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 16 days. All mice survived to the end of the study. The final mean body weights and weight gains of exposed males and females were similar to those of the controls. Clinical findings included hypoactivity and tachypnea in male and female mice in the 1,500 ppm groups. Absolute and relative liver weights of male mice in the 750 and 1,500 ppm groups and female mice in all exposed groups and the relative liver weight of males in the 375 ppm group were significantly greater than those of the controls. Degeneration of the olfactory epithelium of the nose was observed microscopically in all males and females exposed to 375 ppm or greater; this lesion was of minimal severity in males and minimal to mild severity in females. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 13 weeks. All rats survived to the end of the study. The final mean body weight and weight gain of male rats in the 1,500 ppm group were significantly less than those of the controls. Clinical findings included hindlimb paralysis in rats in the 750 and 1,500 ppm groups. Inhalation exposure of rats to nitromethane resulted in an exposure concentration-dependent, microcytic, responsive anemia; anemia was most pronounced in males and females exposed to 375 ppm or greater. The presence of schistocytes, Heinz bodies, and spherocytes and increased mean cell hemoglobin concentration and methemoglobin concentration were evidence that a hemolytic process was occurring; this hemolytic process could have accounted, in part, for the anemia. Thrombocytosis accompanied the anemia and would be consistent with a reactive bone marrow or could have been due to the erroneous inclusion of small erythrocyte fragments as part of the platelet count. On day 23, transient decreases in serum triiodothyronine, thyroxine, and fr and free thyroxine were observed in male rats exposed to 375 ppm or greater and female rats exposed to 750 or 1,500 ppm. There was little or no pituitary response to the thyroid hormone decreases, as evidenced by the lack of significantly increased concentrations of thyroid-stimulating hormone in exposed rats. No biologically significant differences in organ weights were observed. The forelimb and hindlimb grip strengths of males in the 1,500 ppm group were significantly less than those of the controls. The hindlimb grip strengths of females in the 750 and 1,500 ppm groups were also significantly less than the control value. Minimal to mild hyperplasia of the bone marrow was observed microscopically in male rats in the 750 and 1,500 ppm groups and in females exposed to 188 ppm or greater. Nasal lesions in exposed males and females included olfactory epithelial degeneration in males and females exposed to 375 ppm or greater and in one female exposed to 188 ppm and respiratory epithelial hyaline droplets and goblet cell hyperplasia in males and females in the 750 and 1,500 ppm groups; the severity of nasal lesions in males and females was minimal to mild. Males and females exposed to 375 ppm or greater had minimal to mild degeneration of the sciatic nerve and the lumbar spinal cord. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 94, 188, 375, 750, or 1,500 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 13 weeks. All mice survived to the end of the study. The final mean body weights and weight gains of exposed mice were generally similar to those of the controls. There were no treatment-related clinical findings. The absolute right kidney weights of all groups of exposed male mice except the 1,500 ppm group and of females exposed to 188 ppm or greater and the relative right kidney weights of all groups of exposed males and of females in the 750 and 1,500 ppm groups were significantly greater than those of the controls. The absolute liver weight of male mice in the 750 ppm group and the relative liver weights of males exposed to 375 ppm or greater were significantly greater than those of the controls. Olfactory epithelial degeneration and respiratory epithelial hyaline droplets were observed microscopically in all male and female mice exposed to 375 ppm or greater. Degeneration also occurred in females in the 188 ppm group, and hyaline droplets occurred in females in the 94 and 188 ppm groups. The average severity of the nasal lesions ranged from minimal to mild in males. In females, the average severity of olfactory epithelial degeneration ranged from minimal to mild and the severity of respiratory epithelial hyaline droplets ranged from minimal to moderate. All males and nine females in the 1,500 ppm groups also had minimal extramedullary hematopoiesis of the spleen. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 0, 94, 188, or 375 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 103 weeks. Survival,Body Weights, and Clinical Findings: There were no significant differences in survival rates between exposed and control male or female rats. The mean body weight of females in the 375 ppm group was slightly greater than that of the control group; the mean body weights of exposed males were generally similar to the mean body weight of the controls throughout the study. Clinical findings were consistent with incidences of mammary gland neoplasms in females exposed to 188 or 375 ppm; no hindlimb paralysis, as occurred in rats in the 13-week study, was observed in male or female rats in the 2-year study. Pathology Findings: The incidences of mammary gland fibroadenoma and fibroadenoma, adenoma, or carcinoma (combined) in female rats in the 188 and 375 ppm groups were significantly greater than those in the controls. Additionally, the incidences of mammary gland carcinoma in the 375 ppm group were significantly greater than those in the controls. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to 0, 188, 375, or 750 ppm nitromethane by inhalation, 6 hours per day, 5 days per week, for 103 weeks. Survival,Body Weights, and ClinicalFindings The survival rate of females in the 750 ppm group was marginally greater than that of the controls. The mean body weights of exposed females were generally slightly greater than the mean body weights of the controls during the study but were generally similar to the mean body weight of the controls at the end of the study. The mean body weights of exposed males were similar to those of the controls throughout the study. Clinical findings included swelling around the eyes and exophthalmos in exposed males and females; these findings were coincident with harderian gland neoplasms. Pathology Findings: The incidences of harderian gland adenoma and adenoma or carcinoma (combined) in exposed mice increased with increasing exposure concentration and were significantly greater in males and females in the 375 and 750 ppm groups than those in the controls. The incidences of harderian gland carcinoma in males and females in the 375 and 750 ppm groups were also slightly greater than those in the controls. Female mice in the 188 and 750 ppm groups had significantly greater incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) than the controls. The incidences of liver eosinophilic focus increased with increasing exposure concentration, and the incidences in the 375 and 750 ppm groups were significantly greater than the control incidence. The incidences of alveolar/bronchiolar carcinoma in male mice in the 750 ppm group and female mice in the 375 ppm group were significantly greater than those in the controls. Females in the 750 ppm group also had a significantly greater incidence of alveolar/bronchiolar adenoma or carcinoma (combined) and a slightly greater incidence of alveolar/bronchiolar adenoma than the controls. Females in the 375 ppm group had a significantly greater incidence of cellular infiltration of histiocytes in the lung than the controls. The incidences of degeneration and metaplasia of the olfactory epithelium and hyaline degeneration of the respiratory epithelium were significantly greater in exposed male and female mice than those in the controls. Additionally, males in the 375 and 750 ppm groups had significantly greater incidences of inflammation of the nasolacrimal duct than did the controls. GENETIC TOXICOLOGY: Nitromethane was not mutagenic in any tests performed by the NTP. It did not induce mutations in Salmonella typhimurium, with or without S9 metabolic activation, and no induction of sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells exposed to nitromethane was noted with or without S9. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples of male and female mice at the end of the 13-week inhalation study of nitromethane. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of nitromethane in male F344/N rats exposed to 94, 188, or 375 ppm. There was clear evidence of carcinogenic activity of nitromethane in female F344/N rats based on increased incidences of mammary gland fibroadenomas and carcinomas. There was clear evidence of carcinogenic activity of nitromethane in male B6C3F1 mice based on increased incidences of harderian gland adenomas and carcinomas. There was clear evidence of carcin ogenic activity in female B6C3F1 mice, based on increased incidences of liver neoplasms (primarily adenomas) and harderian gland adenomas and carcinomas. Increased incidences of alveolar/bronchiolar adenomas and carcinomas in male and female mice exposed to nitromethane were also considered to be related to chemical administration. Exposure to nitromethane by inhalation for 2 years resulted in increased incidences of nasal lesions including degeneration and metaplasia of the olfactory epithelium and degeneration of the respiratory epithelium in male and female mice. Synonym: Nitrocarbol
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PMID:NTP Toxicology and Carcinogenesis Studies of Nitromethane (CAS No. 75-52-5) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1258 15

Salicylazosulfapyridine is widely used for the treatment of ulcerative colitis and Crohn's disease. It has been beneficial in the treatment of psoriasis and rheumatoid arthritis, and it has been used in veterinary medicine for the treatment of granulomatous colitis. Salicylazosulfapyridine was nominated for toxicity and carcinogenicity testing by the National Cancer Institute on the basis of its widespread use in humans and because it is a representative chemical from a class of aryl sulfonamides. Salicylazosulfapyridine is a suspect carcinogen because reductive cleavage of the azo linkage yields a p-amino aryl sulfonamide (sulfapyridine), and a related p-amino aryl sulfonamide (sulfamethoxazole) has been shown to produce thyroid neoplasms in rats. Toxicology and carcinogenicity studies were conducted in F344/N rats and B6C3F1 mice. Rats and mice were administered salicylazosulfapyridine (96% to 98% pure) in corn oil by gavage for 16 days, 13 weeks, or 2 years. The gavage route of administration was selected for these studies because it approximates the typical route of human exposure to the chemical. Genetic toxicology studies were conducted in vitro in Salmonella typhimurium and cultured Chinese hamster ovary cells and in vivo in rat and mouse bone marrow and mouse peripheral blood cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 16 days excluding weekends. All rats survived to the end of the study. With the exception of the 675 mg/kg male group, the final mean body weights of all dosed groups of males and females were significantly lower than those of controls. Mean body weight gains of all dosed groups were less than those of controls. Clinical findings included ruffled fur and distended abdomens in male and female rats receiving 2,700 mg/kg. Hypothyroidism, evidenced by decreased serum triiodothyronine and thyroxine concentrations and increased thyroid-stimulating hormone concentrations, occurred in 2,700 mg/kg male and female rats. The absolute and relative thymus weights of male rats receiving,350 or 2,700 mg/kg and female rats receiving 2,700 mg/kg were significantly lower than those of controls. At necropsy, all dosed rats had enlarged cecae/large intestines. Male rats receiving 1,350 mg/kg and male and female rats receiving 2,700 mg/kg had red, enlarged thyroid glands. Chemical-related microscopic lesions were present in the forestomach, thymus, thyroid gland, and pituitary gland. Minimal to mild hyperplasia of the forestomach mucosa was present in the 1,350 and 2,700 mg/kg male and female groups. Lymphoid depletion was observed in the thymus of three male and three female rats in the 2,700 mg/kg groups. Male and female rats receiving 1,350 and 2,700 mg/kg had thyroid gland follicular cell hyperplasia and an increase in thyroid-stimulating hormone producing cells in the pars distalis of the pituitary gland. 16-DAY STUDY IN MICE: Groups of five male and five female mice were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 16 days excluding weekends. There were no chemical-related deaths, and final mean body weights of dosed mice were similar to those of controls. No chemical-related clinical findings were noted for male or female mice. There were no differences in triiodothyronine, thyroxine, or thyroid-stimulating hormone concentrations between dosed and control mice. There were no biologically significant differences in absolute or relative organ weights between dosed and control male and female mice. At necropsy, male mice receiving 2,700 mg/kg had enlarged cecae/large intestines. There were no biologically significant histopathologic lesions attributed to salicylazosulfapyridine administration. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 84, 168.8, or 337.5 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 13 weeks. All rats survived to the end of the study. The finaludy. The final mean body weights of dosed male rats were similar to those of controls; the final mean body weights and body weight gains of dosed females were significantly lower than those of controls. No chemical-related clinical findings were noted in dosed male or female rats during the 13-week study. No significant differences in hematology or urinalysis parameters between control and dosed rats were observed. The absolute and relative right kidney weights of 337.5 mg/kg females were significantly greater than those of controls. At necropsy, some 337.5 mg/kg male rats had red, enlarged thyroid glands. Histopathologic changes were noted primarily in the thyroid gland and pituitary gland of males and females in the 337.5 mg/kg groups. The thyroid gland lesions observed were similar to those present in the 16-day study. Nine male rats receiving 168.8 mg/kg and ten male and seven female rats receiving.5 mg/kg had minimal but consistent changes in thyroid gland follicular cells. In the pituitary gland of 337.5 mg/kg males and females, the thyroid-stimulating hormone producing cells were enlarged and contained pale-staining cytoplasm and prominent Golgi complexes. Decreased serum triiodothyronine and thyroxine concentrations and increased thyroid-stimulating hormone concentration, similar to differences observed in the 16-day study, occurred in 337.5 mg/kg male rats; thyroid hormone concentrations were not affected in female rats. Sperm motility of all dosed groups of males was significantly lower than that of controls. Vaginal cytology parameters of dosed groups of females were similar to those of controls. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for 13 weeks. All mice survived to the end of the study. The final mean body weights of dosed male and female mice were similar to those of controls. The mean body weight gains of 1,350 and 2,700 mg/kg male mice were less than that of controls. No chemical-related clinical findings were noted in dosed male or female mice during the 13-week study. There was minimal evidence of a responsive anemia in mice in the 13-week study. The anemia was probably related to a methemoglobinemia. There were minimal decreases in thyroxine concentration in all dosed groups of male and female mice in the -week study. There were, however, no differences in triiodothyronine and thyroid-stimulating hormone concentrations between dosed and control animals. Absolute and relative liver weights of all groups of dosed male and female mice were significantly greater than those of controls. There were no chemical-related gross lesions. Microscopic evaluation of the liver revealed centrilobular hypertrophy in five 1,350 mg/kg and all 2,700 mg/kg male mice. The right cauda weight of the 1,350 mg/kg group and the right epididymis weights of all dose groups were significantly lower than those of controls. There was no evidence of chemical-related alteration in the vaginal cytology parameters of female mice. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were administered 84, 168, or 337.5 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for up to 105 weeks. Groups of 70 male and 60 female rats were administered the corn oil vehicle by gavage for up to 105 weeks. A stop-exposure group of 70 male rats was administered 337.5 mg/kg salicylazosulfapyridine in corn oil by gavage for 6 months, after which animals received the corn oil vehicle by gavage for the remainder of the 2-year study. Ten animals from the vehicle control male group and 10 animals from the 337.5 mg/kg stop-exposure group were evaluated at 6 months; animals from each core-study group were evaluated at 15 months. Survival, Body Weights, and Clinical Chemistry: Survival of 337.5 mg/kg male core-study rats was significantly lower than that of controls; survival of 84 and 168 mg/kg core-study males, all groups of dosed females, and the stop-exposure male group was similar to controls. Mean body weights of core-study males and stop-exposure males were similar to controls throughout the study. From week 45 to the end of the study, females in the 337.5 mg/kg group had mean body weights that were lower than those of controls. The serum thyroxine concentration in 337.5 mg/kg core-study males at study termination was minimally lower than that of controls; the serum thyroid-stimulating hormone, triiodothyronine, and reverse triiodothyronine concentrations of dosed males and females were similar to those of controls. Pathology Findings: Administration of salicylazosulfapyridine for 2 years was associated with transitional epithelial papilloma in the urinary bladder of male rats and may have been associated with transitional epithelial papilloma of the kidney and of the urinary bladder of female rats. Nonneoplastic effects in the urinary bladder and kidney of male and female rats and in the spleen of male rats were also observed. Dosed male and female rats had increased incidences of grossly and microscopically observed urinary bladder concretions (diagnosed grossly as calculi at necropsy); male and female rats that developed transitional epithelial papillomas of the urinary bladder had grossly observed concretions (calculi) in the urinary bladder at necropsy. The microscopic neoplastic and nonneoplastic urinary bladder and kidney effects observed in dosed male rats during the 2-year continuous study did not occur in dosed rats during the 2-year stop-exposure study, nor were there gross observations of concretions (calculi) at necropsy. The incidences of mononuclear cell leukemia in male and female rats were decreased. The thyroid gland hyperplasia seen in the -week study was not observed in the 2-year study, and there was no evidence of chemical-related thyroid gland follicular cell adenomas or carcinomas. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were administered 0, 675, 1,350, or 2,700 mg salicylazosulfapyridine/kg body weight in corn oil by gavage for up to 104 weeks. Ten animals from each group were evaluated at 15 months. Survival, Body Weights,and Clinical Chemistry: Survival of all the dosed groups of male and female mice was similar to that of controls. Mean body weights of 675 and 1,350 mg/kg male and female mice were similar to controls throughout the study. From week 12 to the end of the study, 2,700 mg/kg male mice had mean body weights that were lower than those of controls. From week 14 to the end of the study, the 2,700 mg/kg female mice had mean body weights that were lower than those of controls. There were no chemical-related differences in triiodothyronine, reverse triiodothyronine, thyroxine, or thyroid-stimulating hormone concentrations between dosed and control mice at the 15-month evaluation. Pathology Findings: Exposure of mice to salicylazosulfapyridine in corn oil by gavage for 2 years was associated with increased incidences of hepatocellular neoplasms in males and females. Nonneoplastic effects in the liver and spleen were also observed in male and female mice. The incidences of forestomach squamous cell papilloma in females and forestomach hyperplasia in males and females were decreased. GENETIC TOXICOLOGY: Salicylazosulfapyridine was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro assays were performed with and without S9 metabolic activation enzymes. Results from in vivo mouse bone marrow chromo somal aberration tests were uniformly negative, while results of micronucleus assays performed on male or female mice exposed to salicylazosulfapyridine for periods ranging from 3 days to weeks were positive. Micronucleus tests in male mice for shorter exposure times (1 to 2 days) yielded negative or very weakly positive results. A three-treatment (72-hour exposure time) micronucleus test performed in male rats yielded equivocal results. Overall, results of these in vivo assays indicate that salicylazosulfa pyridine is capable of inducing chromosomal damage, possibly in the form of aneuploidy, in mouse bone marrow cells after multiple administrations. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of salicylazosulfapyridine in male and female F344/N rats based on increased incidences of neoplasms in the urinary tract. There was an increased incidence of transitional epithelial papilloma of the urinary bladder in males and a low incidence of rare transitional epithelial papillomas of the kidney and of the urinary bladder in females. There was clear evidence of carcinogenic activity of salicylazosulfapyridine in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Increased incidences of nonneoplastic lesions of the urinary bladder and kidney in male and female rats and of the spleen in male rats were observed. Increased incidences of nonneoplastic lesions of the liver and spleen in male and female mice were observed. Decreased incidences of mononuclear cell leukemia in male and female rats were related to salicylazosulfapyridine administration. Decreased incidences of forestomach squamous cell papilloma in female mice and forestomach hyperplasia in male and female mice were related to salicylazosulfapyridine administration. Synonyms: 2-Hydroxy-5-[[4-[2-(pyridinylamino)sulfonyl]phenyl]azo]benzoic acid; 5-[p- (2-pyridylsulfamoyl)phenylazo]salicylic acid; sulfasalazine; salazosulfapyridine; 5-[4-(2-pyridylsulfamoyl)phenylazo]-2-hydroxybenzoic acid; 4-(pyridyl-2-amidosulfonyl)-3'-carboxy-4'-hydroxyazobenzene; sulphasalazine Trade names: Azopyrin, Azulfidine, Benzosulfa, Colo-Pleon, Reupirin, Salazopyrin
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PMID:NTP Toxicology and Carcinogenesis Studies of Salicylazosulfapyridine (CAS No. 599-79-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1258 19


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