UMLS:C0023380 - FACTA Search

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Query: UMLS:C0023380 (lethargy)
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Methacrylonitrile is an aliphatic nitrile used extensively in the preparation of homo- and copolymers, elastomers, and plastics and as a chemical intermediate in the preparation of acids, amides, esters, and other nitriles. This aliphatic nitrile is also used as a replacement for acrylonitrile in the manufacture of an acrylonitrile/butadiene/styrene-like polymer. Methacrylonitrile was nominated for toxicity and carcinogenicity testing by the National Cancer Institute due to its high production volume and extensive use, the lack of chronic or carcinogenicity data, and its structural resemblance to the known rat carcinogen acrylonitrile. The current 13-week studies were conducted as part of an overall effort by the NTP to assess the toxicity and carcinogenicity of methacrylonitrile. During the 13-week studies, groups of 20 male and 20 female F344/N rats were administered 0, 7.5, 15, 30, 60, or 120 mg methacrylonitrile/kg body weight in deionized, purified water by gavage. Groups of 20 male and 20 female B6C3F1 mice were administered 0, 0.75, 1.5, 3, 6, or 12 mg/kg methacrylonitrile. Ten male and ten female rats and mice from each group were evaluated on day 32. The results of these studies clearly revealed that male rats are more sensitive than females to methacrylonitrile treatment. In the rat study, 19 males and one female administered 120 mg/kg and two males administered 60 mg/kg died during the first week of the study. Males in the 60 mg/kg group at the 32-day interim evaluation and at 13 weeks and females in the 120 mg/kg group at 13 weeks had significantly lower final mean body weights and body weight gains than did the vehicle controls; the surviving male in the 120 mg/kg group also weighed less than the controls at the 32-day interim evaluation. Clinical findings of toxicity were dose dependent and included lethargy, lacrimation, tremors, convulsions, ataxia, and abnormal breathing. There was hematologic evidence indicating that administration of methacrylonitrile induced minimal, normocytic, normochromic anemia. At the 32-day interim evaluation, a minimal dose-related anemia was evidenced by decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts in male and female rats. The anemia ameliorated by week 13. Administration of methacrylonitrile resulted in dose-related increases in serum thiocyanate and blood cyanide concentrations of male and female rats. These changes were expected and would be consistent with the in vivo metabolism of methacrylonitrile to cyanide. Blood cyanide concentrations were generally higher in males than in females, which may explain the higher sensitivity of males to the lethal effect of methacrylonitrile. There was also biochemical evidence of increased hepatocellular leakage and/or altered function in dosed male rats, suggesting that the liver may be a target organ for toxic effects of methacrylonitrile. Minimal, but significant, decreases in absolute right kidney and thymus weights (32-day interim evaluation) and increases in liver and stomach weights (week 13) occurred in male rats that received 60 mg/kg compared to the vehicle controls. In female rats, stomach weights of the 60 and 120 mg/kg groups were significantly greater and thymus weights of the 120 mg/kg group were significantly less than those of the controls on day 32 and at week 13; liver weights were also significantly greater in females in the 120 mg/kg group than in the vehicle controls on day 32. Male and female rats administered 60 mg/kg and females administered 120 mg/kg had significantly greater incidences of metaplasia of the nasal olfactory epithelium on day 32 and at the end of the study than did the vehicle controls; incidences of olfactory epithelial necrosis were also significantly greater in females in the 60 and 120 mg/kg groups than in the vehicle controls on day 32. Incidence and/or severity increased with increasing dose in females; however, the mortality in male rats administered 120 mg/kg made it difficult to assess the dose-response relationship in males. The no-observed-adverse-effect level for the nasal cavity of rats was 30 mg/kg. Female rats administered 60 or 120 mg/kg methacrylonitrile had significantly longer estrous cycles than did the vehicle controls. Females in the 60 mg/kg group spent more time in diestrus than the vehicle controls. One male and one female mouse in the 12 mg/kg groups died early. Methacrylonitrile administration caused no significant differences in final mean body weights or body weight gains. Clinical findings included lethargy, tremors, ataxia, convulsions, and abnormal breathing. At the 32-day interim evaluation, stomach weights of males administered 3 mg/kg or greater were significantly greater and thymus weights of males in the 12 mg/kg group were significantly less than those of the vehicle controls. At week 13, however, the stomach weights of only males in the 12 mg/kg group were increased relative to the vehicle controls. No treatment-related histopathologic lesions occurred in mice. Methacrylonitrile did not induce mutations in any of several strains of Salmonella typhimurium, with or without S9 activation, and did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster fed methacrylonitrile during the larval stage. Results of in vivo bone marrow micronucleus tests with methacrylonitrile in male rats and mice were also negative. In summary, gavage administration of methacrylonitrile to rats and mice resulted in dose-dependent lethargy, tremors, lacrimation, convulsions, and abnormal breathing. However, these effects were more pronounced in rats than mice; these differences may be attributed to the higher doses of methacrylonitrile administered to rats. Body weight gain and survival data of rats demonstrated that males are more sensitive to methacrylonitrile dosing than females. There is an apparent correlation between blood cyanide concentrations and survival rates, with males having greater cyanide concentrations and lower survival rates than female rats administered methacrylonitrile. Microscopically, the only target of methacrylonitrile toxicity was the olfactory epithelium of the nasal cavity. Necrotic and metaplastic effects were induced in male and female rats that received 60 or 120 mg/kg per day. No similar lesions were observed in mice administered methacrylonitrile. The no-observed-adverse-effect level for olfactory epithelial lesions in male and female rats administered methacrylonitrile for 13 weeks was 30 mg/kg per day. No clear chemical-related effects were observed in male or female mice administered methacrylonitrile for 13 weeks by gavage at doses up to 12 mg/kg per day.
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PMID:NTP technical report on the toxicity studies of methacrylonitrile (CAS No. 126-98-7). Administered by gavage to F344/N rats and B6C3F1 mice. 1180 6

Many vertebrate animals have superior tolerance to environmental hypoxia compared to humans. For example, turtles tolerate an environment of 100% N2 for several hours, without apparent ill effect. This hypoxia tolerance is not limited to heterotherms, as some species of marine mammals, such as the northern elephant seal, may voluntarily dive for periods of up to 2 hours. Torpid bats exhibit prolonged periods of apnea and passive diffusion of oxygen down their trachea through an open glottis supplies a significant amount of the oxygen uptake. The Ruppell's griffon holds the known avian record of flight at 11,278 m, and other birds regularly migrate at altitudes over 8000m. These animals exhibit diverse adaptations for tolerating their hypoxic environment, many of which are poorly understood. Some of theses strategies include 1) the ability to lower metabolic rate when exposed to hypoxia 2) the ability to recruit alternate biochemical pathways for energy production 3) a left shifted oxy-hemoglobin dissociation curve 4) more efficient pulmonary gas exchange 5) the ability to alter blood flow distribution under hypoxic stress. Although there are common themes of animal adaptation to hypoxic stress, many animal solutions are unique.
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PMID:Common themes of adaptation to hypoxia. Insights from comparative physiology. 1195 Jan 36

Primidone is used alone or with other anticonvulsants in the control of grand mal, psychomotor, and focal epileptic seizures. It may control grand mal seizures refractory to other anticonvulsant therapy. Primidone was nominated by the National Cancer Institute for 2-year toxicology and carcinogenicity studies due to its human use as an anticonvulsant. Male and female F344/N rats and B6C3F1 mice received primidone (greater than 99% pure) in feed for 14 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 14-DAY STUDY IN RATS: Five male and five female rats were exposed to 0, 1,250, 2,500, 5,000, 10,000 or 20,000 ppm primidone (equivalent to average daily doses of approximately 120, 240, 500, 970, or 1,100 mg primidone/kg body weight to males and 120, 240, 500, or 900 mg/kg to females) in feed for 14 days. All 20,000 ppm females died before the end of the study as did one 10,000 ppm male and two 20,000 ppm males. The mean body weights of 10,000 ppm males and females and 20,000 ppm males were significantly less than those of the controls. Feed consumption by all exposed rats was generally similar to that by the controls. Males and females in the 10,000 and 20,000 ppm groups were observed to have eye discharge, ataxia, and abnormal posture and were thin and lethargic. 14-DAY STUDY IN MICE: Five male and five female mice were exposed to 0, 625, 1,250, 2,500, 5,000 or 10,000 ppm primidone (equivalent to average daily doses of approximately 100, 200, 400, or 800 mg/kg body weight to males and 100, 250, 500, or 900 mg/kg to females) in feed for 14 days. All mice in the 10,000 ppm groups and one male and one female mouse in the 5,000 ppm groups died on day 3 of the study. The mean body weights of mice in the 625, 1,250, 2,500, and 5,000 ppm groups were similar to those of the controls. Feed consumption by all exposed mice was generally similar to that by the controls. Males and females in the 10,000 ppm groups were observed to have abnormal posture, ataxia, and lethargy. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 300, 600, 1,300, 2,500, or 5,000 ppm primidone (equivalent to average daily doses of approximately 20, 40, 100, 200, or 400 mg/kg) in feed for 14 weeks. All rats survived to the end of the study. The mean body weights of male and female rats in the 2,500 and 5,000 ppm groups were significantly less than those of the controls. Feed consumption by all exposed rats was generally similar to that by the controls. A minimal to mild exposure-related thrombocytosis occurred on day 22 and at week 14 in all exposed groups of male rats and in females in the 1,300 ppm or greater groups. A minimal decrease in hemoglobin concentration occurred in 2,500 and 5,000 ppm male and female rats on day 22 and at week 14. The incidences of centrilobular hepatocyte hypertrophy in male rats exposed to 600 ppm or greater and in female rats exposed to 1,300 ppm or greater were significantly greater than those in the controls. The severity of chronic nephropathy in male rats exposed to 1,300 ppm or greater increased with increasing exposure concentration. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 300, 600, 1,300, 2,500, or 5,000 ppm primidone (equivalent to average daily doses of approximately 50, 100, 200, 400, or 1,000 mg/kg to males and 60, 120, 220, 440, or 1,100 mg/kg to females) in feed for 14 weeks. Three male and two female mice in the 5,000 ppm group died during week 1 of the study. The final mean body weights of all exposed groups were similar to those of the controls. Feed consumption by male mice in the 5,000 ppm group was slightly greater than that by the controls; this may have been due to feed spillage. Male and female mice in the 5,000 ppm groups were ataxic and lethargic. Compared to controls, the estrous cycle lengths of females exposed to 1,300, 2,500, or 5,000 ppm were significantly longer. The liver weights of male and female mice exposed to 600 po 600 ppm or greater were significantly greater than those of the controls. The incidences of centrilobular hepatocyte hypertrophy in all exposed males and in females exposed to 600 ppm or greater and the incidences of cytoplasmic alteration of the adrenal gland and hematopoietic cell proliferation of the spleen in 2,500 and 5,000 ppm males and in 5,000 ppm females were significantly greater than in the controls. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 600, 1,300, or 2,500 ppm primidone (equivalent to average daily doses of approximately 25, 50, or 100 mg/kg) in feed for 2 years. Survival, Body Weights, and Feed Consumption Survival of the 1,300 and 2,500 ppm males was sig nificantly less than that of the controls. The mean body weights of males and females in the 2,500 ppm groups were less than those of the controls, beginning at week 29 for males and week 17 for females; the mean body weights of 1,300 ppm males and females were less than those of the controls during the second year of the study. Feed consumption by all exposed groups of rats was generally similar to that by the controls. Pathology Findings Male rats exposed to primidone had increased inci dences of thyroid gland follicular cell neoplasms (adenoma and/or carcinoma). All exposed groups of male rats had follicular cell adenomas or carcinomas (combined) at incidences above the historical control range, with the highest incidence in the 1,300 ppm group. Hepatocyte cytoplasmic vacuolation and centrilobular hypertrophy were associated with primidone exposure in male and female rats. These changes were more severe in females than in males and the incidences in all exposed groups of females were significantly greater than those in the controls. Females in the 2,500 ppm group had an increased incidence of hepatocellular eosinophilic foci. In 2,500 ppm males, the incidence of renal tubule hyperplasia was greater than that in the controls in the standard evaluation. Additional hyperplasias were found in the extended evaluation, and the incidences in exposed groups of males were significantly greater than that in the controls. In the extended evaluation, the incidence of renal tubule adenoma in 2,500 ppm males was significantly increased. The incidence of adenoma or carcinoma (combined) in 2,500 ppm males in the combined standard and extended evaluations were marginally increased over those in the controls. Male rats had an exposure-related increase in the severity of chronic nephropathy, which probably accounted for the reduced survival in the 1,300 and 2,500 ppm groups. The incidences of kidney cysts were increased in 1,300 and 2,500 ppm males. Hyperparathyroidism, secondary to the loss of renal function, was present in many exposed male rats. The incidences of parathyroid gland hyperplasia in all groups of exposed males were significantly greater than that in the controls. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to dietary levels of 0, 300, 600, or 1,300 ppm primidone (equivalent to average daily doses of approximately 30, 65, or 150 mg/kg to males and 25, 50, or 100 mg/kg to females) in feed for 2 years. Survival, Body Weights, Feed Consumption, and Clinical Findings Survival of the 1,300 ppm males was significantly less than that of the controls. During the second year of the study, the mean body weights of 1,300 ppm male and female mice were less than those of the controls. The final mean body weights of 600 ppm males and females were less than those of the controls. Feed consumption by all exposed groups of mice was similar to that by the controls. During the latter part of the study, a treatment-related increase in the number of animals with swelling of the abdominal area was observed; necropsy revealed that the swelling was due to liver nodules/masses. Pathology Findings The liver was a target organ in both male and female mice. The incidences and multiplicities of hepatocellular neoplasms (hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma) in all exposed groups of males and females (except hepatoblastoma in females) were significantly greater than those in the controls. The incidences of hepatocellular adenoma or carcinoma (combined) and hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) in all exposed groups exceeded the historical control ranges in 2-year NTP studies. The incidences of centrilobular hepatocyte hypertrophy were increased in exposed groups of males and females, and the severities increased with increasing exposure concentration. The incidences of cytoplasmic vacuolization were increased in all exposed groups of females and in 300 ppm males. Incidences of eosinophilic focus in all exposed groups of females were significantly greater than those in the controls. Proliferative changes occurred in the thyroid gland in an exposure-related manner in male and female mice. Incidences of follicular cell hyperplasia were increased in all exposed groups of males and in 600 and 1,300 ppm females, but incidences of follicular cell adenomas were increased only in male mice. GENETIC TOXICOLOGY: Primidone was mutagenic in Salmonella typhimurium strain TA1535 in the absence of S9 activation only; no mutagenicity was detected in strain TA98, TA100, or TA1537, with or without S9. Primidone did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. The single in vivo study with primidone, a mouse bone marrow micronucleus test, also gave negative results. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of primidone in male F344/N rats based on a marginal increase in thyroid gland follicular cell neoplasms, primarily adenomas, and a marginal increase in renal tubule neoplasms. There was no evidence of carcinogenic activity of primidone in female F344/N rats exposed to 600, 1,300, or 2,500 ppm. There was clear evidence of carcinogenic activity of primidone in male B6C3F1 mice based on the increased incidences of hepatocellular neoplasms, and the increased incidence of thyroid gland follicular cell adenomas was also considered to be chemical related. There was clear evidence of carcinogenic activity of primidone in female B6C3F1 mice based on the increased incidences of hepatocellular neoplasms. Exposure of rats to primidone resulted in increased incidences of hepatocyte cytoplasmic vacuolization and centrilobular hypertrophy in males and females and eosinophilic foci in females. The increased severity of nephropathy and increased incidence of renal tubule hyperplasia in male rats were related to primidone exposure. Exposure of male mice to primidone resulted in hepatocyte centrilobular hypertrophy and thyroid gland follicular cell hyperplasia. Exposure of female mice to primidone resulted in hepatocyte centrilobular hypertrophy and cytoplasmic vacuolization, eosinophilic focus, and thyroid gland follicular cell hyperplasia. Synonyms: 5-Aethyl-5-phenyl-hexahydropyrimidin-4,6-dion; 2-deoxyphenobarbital; 2-desoxyphenobarbital; desoxyphenobarbitone; 5-ethyldihydro-5-phenyl-4,6 (1H,5H)-pyrimidinedione; 5-ethylhexahydro-4,6-dioxo-5-phenylphrimidine; 5-ethylhexahydro-5-phenylpyrimidine-4,6-dione; 5-ethyl-5-phenylhexahydropyrimidine-4,6-dione Trade names: Cyral; Hexadiona; Hexamidine; Lepimidin; Lepsiral; Majsolin; Midone; Milepsin; Misodine; Misolyne; Mizodin; Mizolin; Mylepsin; Mylepsinum; Mysedon; Mysoline; Prilepsin; Primacione; Primaclone; Primacone; Primakton; Primadon; Prysoline; Pyrimidone; ROE 101; Sertan
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PMID:NTP Toxicology and Carcinogenesis Studies of Primidone (CAS No. 125-33-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1257 87

p-Nitrobenzoic acid is produced in large volumes for organic synthesis and as an intermediate in the manufacture of pesticides, dyes, and industrial solvents. Groups of male and female F344/N rats and B6C3F1 mice were exposed to p-nitrobenzoic acid (>99% pure) in feed for 14 days, 13 weeks, or 2 years for toxicity and carcinogenicity studies. Genetic toxicology studies were conducted in in vitro assays with Salmonella typhimurium and cultured Chinese hamster ovary cells, and in studies of erythrocyte micronucleus formation in mice in the 13-week study. 14-DAY STUDY IN RATS: Groups of five male and five female rats were given 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid in feed for 14 days. All rats survived until the end of the study. Male and female rats given 20,000 and 40,000 ppm lost weight. The final mean body weights of 10,000, 20,000, and 40,000 ppm males were 82%, 60%, or 52% that of the controls, and the final mean body weights of 10,000, 20,000, and 40,000 ppm females were 87%, 68%, and 65% that of the controls. There were no clinical findings that were characteristic of organ-specific toxicity. Absolute and relative spleen weights were significantly increased in rats exposed to 10,000, 20,000, and 40,000 ppm. There were decreases in erythrocyte count and hemoglobin and hematocrit values and increases in reticulocyte count, nucleated erythrocytes, and methemoglobin concentration that were most pronounced in the 20,000 and 40,000 ppm groups. Congestion of the spleen occurred in 10,000 ppm males and in 20,000 and 40,000 ppm females. Hypertrophy of the follicular epithelium of the thyroid gland was present in male and female rats exposed to 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid, while follicular hyperplasia was observed in the 40,000 ppm males and females. Atrophy of the testis was observed in 20,000 and 40,000 ppm males. Other lesions observed in 20,000 and 40,000 ppm rats included atrophy of the thymus in males and atrophy of the ovary, bone marrow, and thymus in females. 14-DAY STUDY IN MICE: Groups of five male and five female mice were given 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid in feed for 14 days. Three males and two females given 40,000 ppm died during the study. All other animals survived until the end of the study. Male mice given 20,000 and 40,000 ppm and females given 20,000 ppm lost weight. Mean body weight gains of 20,000 and 40,000 ppm males and 10,000, 20,000, and 40,000 ppm females were significantly lower than those of the controls. There were no clinical findings related to organ-specific toxicity although lethargy and ataxia were observed in 40,000 ppm mice. Relative liver weights were significantly increased in 20,000 and 40,000 ppm males and females and in 10,000 ppm females. Absolute and relative thymus weights of 20,000 and 40,000 ppm males and of 10,000, 20,000, and 40,000 ppm females were reduced. No significant differences in hematology parameters occurred in exposed mice. Testicular degeneration was observed in three 20,000 ppm and two 40,000 ppm males. Bone marrow hemorrhage and atrophy occurred in 40,000 ppm females. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were given 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm pnitrobenzoic acid in feed for 13 weeks resulting in approximate daily doses of 40, 70, 160, 310, or 660 mg/kg to males and 40, 80, 170, 340, or 680 mg/kg to females. All rats survived until the end of the study. Mean body weight gains and final mean body weights were significantly less than those of the controls in 2,500, 5,000, and 10,000 ppm males and in 5,000 and 10,000 ppm females. There were no clinical findings related to organ-specific toxicity. Differences in spleen weights and hematology parameters characteristic of regenerative anemia were observed in males and females, primarily in groups given 10,000 ppm. The absolute and relative spleen weights were significantly increased in 10,000 ppm males and females and the relative spleen weights were significantly increased in 5,000 ppm males hts were significantly increased in 5,000 ppm males and females. Methemoglobin, Heinz bodies, and reticulocyte counts were increased and erythrocyte counts, hemoglobin, and hematocrit values were decreased in 10,000 ppm males and females. Congestion, pigmentation, and accumulation of macrophages in the spleen and pigmentation in the kidney occurred in 2,500, 5,000, and 10,000 ppm males. Congestion and pigmentation of the spleen occurred in 10,000 ppm females. A yellowish brown pigment (hemosiderin) in the spleen and kidney was associated with hemolytic anemia. Mild cytoplasmic hyaline droplet accumulation was present in renal tubule epithelial cells in 10,000 ppm males while karyomegaly was present in male and female rats exposed to 2,500, 5,000, and 10,000 ppm p-nitrobenzoic acid. A chemical-related testicular lesion, consisting of atrophy of the seminiferous tubules, occurred in 10,000 ppm males. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were given 0, 1,250, 5,000, 10,000, or 20,000 ppm pnitrobenzoic acid in feed for 13 weeks resulting in approximate daily doses of 170, 330, 670, 1,900, or 4,000 mg/kg body weight to males and 240, 460, 970, 2,500, or 4,900 mg/kg to females. All mice survived until the end of the study, except one 1,250 ppm female that was killed accidentally. Final mean body weights and mean body weight gains of all exposed males and of 5,000, 10,000, and 20,000 ppm females were significantly lower than those of the controls. No clinical findings or differences in organ weights or histopathology related to organ-specific toxicity were observed in exposed mice. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were given 0, 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid in feed for 2 years. Ten males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of 1,250 and 2,500 ppm males were similar to that of the controls. Two-year survival of 5,000 ppm males was marginally greater than that of the controls and was attributed in part to a decrease in the severity of nephropathy and a decrease in the incidence of mononuclear cell leukemia. Survival of exposed females was similar to that of the controls. Mean body weights of 5,000 ppm males were 2&percnt; to 8&percnt; lower than those of the controls through week 80. Final mean body weights of exposed males were similar to that of the controls. Mean body weights of 5,000 ppm females were 2&percnt; to 9&percnt; lower than those of the controls during the first year of the study and were 10&percnt; to 16&percnt; lower during the second year of the study. Final mean body weights of exposed females were 97&percnt; (1,250 ppm), 92&percnt; (2;500 ppm), and 84&percnt; (5,000 ppm) that of the controls. Feed consumption by exposed males and females was similar to that by the controls. Dietary levels of 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid delivered approximately 50, 100, or 210 mg/kg body weight per day to males and 60, 125, or 250 mg/kg per day to females. There were no clinical findings attributable to organ-specific toxicity. Pathology Findings: There were increases in the incidences of clitoral gland adenoma and of clitoral gland adenoma or carcinoma (combined) (4/50, 14/49, 15/49, 15/50) in exposed females. The incidences of clitoral gland adenoma or carcinoma (combined) in the exposed groups (29&percnt; to 31&percnt;) exceeded the historical control mean incidence (11&percnt;) and range (2&percnt; to 21&percnt;) in female F344/N rats in recent 2-year NTP feed studies. The increased incidences of clitoral gland neoplasms were considered to be some evidence of carcinogenic activity in female rats exposed to p-nitrobenzoic acid. The incidences of hyperplasia of the clitoral gland in exposed females were marginally lower than that of the controls (10/50, 6/49, 6/ 49, 7/50). There was a chemical-related decrease in the severity of nephropathy in male rats. Male rat kidneys were examined using both single and step-section analyses, and the incidences of renal tubule neoplasms were not statistically greater than those of the controls. Mild hyaline droplet accumulation was observed in renal tubule epithelial cells in 10,000 ppm males in the 13-week study, but this effect was not severe enough to lead to a chemical-related neoplastic response in the 2-year study as has been observed with other chemicals. At the 15-month interim evaluation, hematologic parameters characteristic of a mild regenerative anemia and significant differences in spleen weights were noted in 5,000 ppm females. These differences included decreases in erythrocyte count, hemoglobin, and hematocrit, increases in spleen weights, and hemosiderin accumulation in splenic macrophages. At 2 years, significant decreases in the incidences of mononuclear cell leukemia were observed in 5,000 ppm males and 2,500 and 5,000 ppm females (males: 29/50, 35/50, 26/50, 2/50; females: 17/50, 11/50, 3/50, 0/50). While the mechanism for this decrease is unknown, decreases in the incidence of mononuclear cell leukemia have also been observed in 2year studies with other amine/nitro compounds. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were given 0, 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid in feed for 2 years. Ten males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of exposed mice were similar to those of the controls. Mean body weights of 5,000 ppm males were 6&percnt; to 12&percnt; lower than those of the controls after week 17, and mean body weights of 5,000 ppm females were 12&percnt; to 24&percnt; lower than those of the controls after week 16. The final mean body weight of 5,000 ppm females was 19&percnt; less than that of the controls; final mean body weights of males were similar to that of the controls. Feed consumption by exposed mice was similar to that by the controls. Dietary levels of 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid delivered approximately 150, 300, or 675 mg/kg per day to males and 170, 365, or 905 mg/kg per day to females. There were no clinical findings of organ-specific toxicity. No chemical-related effects on hematology parameters were noted at the 15-month interim evaluation. Pathology Findings: There were no increases or decreases in neoplasms in male or female mice that were considered to be related to chemical administration. GENETIC TOXICOLOGY: p-Nitrobenzoic acid was mutagenic in Salmonella typhimurium strain TA100 with and without S9. No mutagenic activity was noted in strains TA98, TA1535, or TA1537, with or without S9. p-Nitrobenzoic acid induced sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells in the absence of S9; with S9, results of both tests were negative. In vivo, no increase in micronuclei was observed in peripheral blood erythrocytes of male or female mice administered p-nitrobenzoic acid in dosed feed for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of p-nitrobenzoic acid in male F344/N rats exposed to 1,250, 2,500, or 5,000 ppm. There was some evidence of carcinogenic activity of p-nitrobenzoic acid in female F344/N rats based on increases in the incidences of clitoral gland adenoma and of clitoral gland adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of p-nitrobenzoic acid in male or female B6C3F1 mice exposed to 1,250, 2,500, or 5,000 ppm. There were chemical-related decreases in the incidences of mononuclear cell leukemia in exposed male and female rats. p-Nitrobenzoic acid caused mild hematologic toxicity in female rats. Synonyms: 4-Nitrobenzoic acid; nitrodracylic acid; p-nitrobenzenecarboxylic acid; p-carboxynitrobenzene
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PMID:NTP Toxicology and Carcinogenesis Studies of p-Nitrobenzoic Acid (CAS No. 62-23-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1259 21

Late-onset hypogonadism (LOH) is defined by reduced serum testosterone levels (either total testosterone or free testosterone) and the careful exclusion of any form of classical hypogonadism. When the androgen decline associated with advancing age causes detrimental physiological and mental effects, the syndrome is known as symptomatic LOH (SLOH). A detailed medical history and physical examination are the bases of the diagnosis, and should always precede any biochemical investigations. A general screening of men above a certain age for testosterone deficiency is not feasible. Questionnaires may assist in identifying men who suffer from LOH. Common clinical symptoms of SLOH are lethargy, fatigue, decreased sense of well-being, reduced physical and mental activity, diminished libido, increased sweating, depressive mood, reduced muscle and bone mass or even osteoporosis, erectile dysfunction, and mild anemia. When clinical symptoms are present, the laboratory work-up should focus on total testosterone serum levels. Total testosterone levels <200 ng/dl indicate hypogonadism. In cases of testosterone levels between 200 and 400 ng/dl, measurement should be repeated and supplemented by determination of free testosterone, either by appropriate laboratory methods or the calculation of free testosterone index. In case of very low testosterone levels, classical secondary hypogonadism needs to be considered and excluded. For the safety reasons to exclude contraindications of therapy with androgens, and for follow-up investigations during therapy prostate-specific antigen (PSA), hemoglobin and hematocrit are of interest.
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PMID:Late-onset hypogonadism in the aging male (LOH): definition, diagnostic and clinical aspects. 1604 56

The Kidd blood group is clinically significant since the Jk antibodies can cause acute and delayed transfusion reactions as well as hemolytic disease of newborn (HDN). In general, HDN due to anti-Jk(b) incompatibility is rare and it usually displays mild clinical symptoms with a favorable prognosis. Yet, we apparently experienced the second case of HDN due to anti-Jk(b) with severe clinical symptoms and a fatal outcome. A female patient having the AB, Rh(D)-positive blood type was admitted for jaundice on the fourth day after birth. At the time of admission, the patient was lethargic and exhibited high pitched crying. The laboratory data indicated a hemoglobin value of 11.4 mg/dL, a reticulocyte count of 14.9% and a total bilirubin of 46.1 mg/dL, a direct bilirubin of 1.1 mg/dL and a strong positive result (+++) on the direct Coomb's test. As a result of the identification of irregular antibody from the maternal serum, anti-Jk(b) was detected, which was also found in the eluate made from infant's blood. Despite the aggressive treatment with exchange transfusion and intensive phototherapy, the patient died of intractable seizure and acute renal failure on the fourth day of admission. Therefore, pediatricians should be aware of the clinical courses of hemolytic jaundice due to anti-Jk(b), and they should be ready to treat this disease with active therapeutic interventions.
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PMID:A fatal case of severe hemolytic disease of newborn associated with anti-Jk(b). 1647 82

Side effects of interferon-ribavirin combination therapy limit the sustained viral response achievable in hepatitis C virus (HCV) patients. Coupling ribavirin to macromolecular carriers that target the drug to the liver would reduce systemic complications. The aim of this study was to evaluate the efficacy of a hemoglobin-ribavirin conjugate (HRC 203) in murine hepatitis virus strain 3 (MHV-3) induced viral hepatitis. HRC 203 had greater anti-viral activity on both isolated hepatocytes and macrophages, whereas both ribavirin and HRC 203 inhibited production of the pro-inflammatory cytokines interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) by macrophages. In vivo, untreated MHV-3-infected mice all developed clinical and biochemical signs of acute viral hepatitis and died by day 4 post infection. Livers recovered from untreated infected mice showed greater than 90% necrosis. In contrast, survival was enhanced in both ribavirin- and HRC 203-treated mice with a marked reduction in biochemical [ALT(max) 964 +/- 128 IU/L (ribavirin); 848 +/- 212 IU/L (HRC 203)] and histological evidence of hepatic necrosis (<10% in ribavirin/HRC 203 vs. 90% in untreated controls). Clinically, HRC 203-treated mice behaved normally, in contrast to ribavirin-treated mice, which developed lethargy and abnormal fur texture. In conclusion, targeted delivery of ribavirin to the liver alters the course of MHV-3 infection as demonstrated by prolonged survival, improved behavior, and reduced signs of histologically evident disease, as well as inhibition of viral replication and production of inflammatory cytokines in vitro.
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PMID:Targeted delivery of ribavirin improves outcome of murine viral fulminant hepatitis via enhanced anti-viral activity. 1649 40

Amongst toxic heavy metals, lead ranks as one of the most serious environmental poisons all over the world. Exposure to lead in the home and the workplace results in health hazards to many adults and children causing economic damage, which is due to the lack of awareness of the ill effects of lead. We report the case of a 22 year old man working in an unorganized lead acid battery manufacturing unit, complaining about a longer history of general body ache, lethargy, fatigue, shoulder joint pain, shaking of hands and wrist drop. Patient had blue line at gingivodental junction. Central nervous system (CNS) examination showed having grade 0 power of extensors of right wrist & fingers. Reflexes: Supinator- absent, Triceps- weak and other deep tendon reflexes- normal. Investigations carried out during the admission showed hemoglobin levels of 8.3 g/dl and blood lead level of 128.3 mug/dl. The patient was subjected to chelation therapy, which was accompanied by aggressive environmental intervention and was advised not to return to the same environmental exposure situation. After repeated course of chelation therapy he has shown the signs of improvement and is on follow up presently.
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PMID:Evaluation, diagnosis, and treatment of lead poisoning in a patient with occupational lead exposure: a case presentation. 1771 7

Oxcarbazepine is a commonly used antiepileptic and mood stabilizer medication with a considerably good safety profile. Medication-induced side effects are a common cause of morbidity in the geriatric population. We describe a patient presenting with hemolytic anemia attributed to oxcarbazepine that resolved after discontinuation of the drug. A 75-year-old male was brought into the hospital because of lethargy for the previous few days. His medical history included diet-controlled diabetes mellitus, mild essential hypertension, ischemic stroke with no residual deficit, seizure disorder, and dementia. He was taking only trileptal for the previous 3 months. His other history was insignificant. Physical examination was remarkable for generalized pallor and impaired memory. Laboratory results showed hemoglobin of 4.6 g/dL. Serum lactate dehydrogenase was 1314 u/L, and total bilirubin was 3.4 mg/dL, with indirect bilirubin of 2.9 mg/dL. Peripheral blood smear revealed microspherocytes, polychromasia, and a few nucleated red blood cells. Urinalysis showed 12RBCs/high power field (HPF), hemosiderinuria, and moderate bilirubin. Coombs test, cold agglutinins, antinuclear antibodies, and cultures were negative. Computerized tomographic scan of the chest, abdomen, and pelvis was also normal. After exclusion of other causes of hemolysis, drug-induced hemolytic anemia was suspected, and oxcarbazepine was discontinued. The patient's symptoms and laboratory parameters improved. He was in a usual state of health at 7 months follow-up. To our knowledge, this is the first reported case of oxcarbazepine-induced hemolytic anemia in the medical literature, and it was reported to the manufacturing pharmaceutical company.
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PMID:Oxcarbazepine-induced hemolytic anemia in a geriatric patient. 1835 42

It is well-established that total testosterone (TT) in men decreases with age and that bioavailable testosterone (bio-T) falls to an even greater extent. The clinical relevance of declining androgens in the aging male and use of testosterone replacement therapy (TRT) in this situation is controversial. Most studies have been short term and there are no large randomized placebo-controlled trials. Testosterone has many physiological actions in: muscles, bones, hematopoietic system, brain, reproductive and sexual organs, adipose tissue. Within these areas it stimulates: muscle growth and maintenance, bone development while inhibiting bone resorption, the production of red blood cells to increase hemoglobin, libido, enhanced mood and cognition, erectile function and lipolysis. Anabolic deficits in aging men can induce: frailty, sarcopenia, poor muscle quality, muscle weakness, hypertrophy of adipose tissue and impaired neurotransmission. The aging male with reduced testosterone availability may present with a wide variety of symptoms which in addition to frailty and weakness include: fatigue, decreased energy, decreased motivation, cognitive impairment, decreased self-confidence, depression, irritability, osteoporotic pain and the lethargy of anemia. In addition, testosterone deficiency is also associated with type-2 diabetes, the metabolic syndrome, coronary artery disease, stroke and transient ischemic attacks, and cardiovascular disease in general. Furthermore, there are early studies to suggest that TRT in men with low testosterone levels may improve metabolic status by: lowering blood sugar and HbA1C in men with type-2 diabetes, reducing abdominal girth, ameliorating features of the metabolic syndrome, all of which may be protective of the cardiovascular system. The major safety issue is prostate cancer but there is no evidence that supports the idea that testosterone causes the development of a de novo cancer. So on balance in a man with symptoms of hygonadism and low or lowish levels of testosterone with no evidence of prostate cancer such as a normal PSA a therapeutic (4-6 months) trial of TRT is justified. Treatment and monitoring of this duration will determine whether the patient is responsive.
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PMID:Testosterone and the aging male: to treat or not to treat? 2015 46

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