Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cholestasis in early infancy produces reactive alterations of liver parenchyma within the first weeks of life; histological examination of liver biopsy specimens may give hints as to the underlying disease. Differentiation of bile duct atresia and giant cell hepatitis at an early stage is especially important. Hyperplasia of the intrahepatic bile duct system can be due to rather different diseases. Congenital abnormalities of the duct system can be distinguished from reactive alterations only by early liver biopsy. Certain histological changes may give evidence of congenital or other metabolic disorders. Hemochromatosis of the neonatal period has been characterized morphologically but not as yet biochemically.
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PMID:[Cholestasis in early infancy - histological findings (author's transl)]. 44 71

Transmissible ileal hyperplasia (TIH) was experimentally induced in weanling hamsters, and the development of lesions was characterized. Ileal lesions developed in two phases: a hyperplastic phase which was detected by Day 10 and an inflammatory phase which began by Day 20. Hyperplasia began as focal lengthening of villi with expansion of crypt-type epithelium onto villus walls. Diffuse hyperplasia of distal ileum developed; dilated, tortuous crypts penetrated subjacent supporting tissues; but metastases were not seen. Inflammation began in association with focal or segmental necrosis of crypt epithelium, and crypt abscesses developed. Severe pyogranulomatous inflammation of the ileal wall, focal peritonitis, mesenteric lymphadenitis, and portal hepatitis were common in advanced lesions. Development of ileal lesions was closely correlated with accumulation of particulate antigen, detectable by immunofluorescence, in the cytoplasm of mucosal epithelial cells. Antigen was also detected in ileal granulomas, mesenteric lymph nodes, and liver. There was simultaneous development of serum antibody specific for intracytoplasmic antigen. These studies comfirm that mucosal hyperplasia is the primary lesion in TIH.
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PMID:Transmissible ileal hyperplasia of hamsters. I. Histogenesis and immunocytochemistry. 65 59

An overview about drug-induced liver injury is presented. The most frequent changes of the hepatocytes are those of the organelles, which are adaptive at the beginning, but in later stages they can develop to degenerative alterations leading to necrosis. Cases of drug-induced hepatitis simulating all types of non-suppurative hepatitis are a major problem of diagnosis. Bile duct lesions can include pure cholestasis, cholangiolitis and destruction of intrahepatic ducts. Drug-induced vascular lesions including tumours can be found as isolated phenomenon or in association with other signs of drug-induced liver damage. Hyperplasia (focal or diffuse) and neoplasia of the liver can develop in the course of a longstanding application of some drugs.
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PMID:[Drug-induced liver damage from the morphologic viewpoint]. 220 23

Sodium xylenesulfonate is used as a hydrotrope, an organic compound that increases the ability of water to dissolve other molecules. Sodium xylenesulfonate is a component in a variety of widely used shampoos and liquid household detergents where it can constitute up to 10% of the total solution. Because of its widespread use, the potential for human exposure to sodium xylenesulfonate is great. Male and female F344/N rats and B6C3F1 mice were administered sodium xylenesulfonate in water or 50% ethanol dermally for 17 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, and cultured Chinese hamster ovary cells. 17-DAY STUDY IN RATS: Groups of five male and five female rats were administered 300 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in distilled water by dermal application 5 days per week for 17 days. All rats survived to the end of the study. Final mean body weights and body weight gains of dosed rats were similar to those of the control groups. Dermal applications of 300 mL of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately 10, 30, 90, 260, and 800 mg sodium xylenesulfonate/kg body weight to males and 13, 40, 120, 330, and 1,030 mg/kg to females. Clinical findings generally involved the skin of dosed animals and included tan or brown skin discoloration and crusty white deposits (presumed to be dried chemical) at the site of application. Neither of these observations were considered significant findings. The relative liver weights of 133 and 400 mg/mL male and female rats were significantly greater than those of the control groups, but the absolute liver weights were not increased and the biological significance of the relative differences in liver weight was unclear. In males and females, the few lesions observed grossly and microscopically were generally attributed to repeated clipping and were not considered related to chemical administration. 17-DAY STUDY IN MICE: Groups of five male and five female mice were administered 100 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in distilled water by dermal application 5 days per week for 17 days. All mice survived to the end of the study. Final mean body weights and body weight gains of dosed mice were similar to those of the controls. Dermal applications of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately, 20, 60, 190, 540, and 1,600 mg sodium xylenesulfonate/kg body weight to males and 26, 80, 220, 680, and 2,000 mg/kg to females. Clinical findings included crusty white deposits (presumed to be dried chemical) at the site of application in two 133 mg/mL males and in all 400 mg/mL males and females. The absolute and relative liver weights of 15 and 44 mg/mL males and 400 mg/mL males and females were significantly greater than those of the control groups, but the biological significance of these differences was unclear. The few skin lesions observed grossly and microscopically in males and females were generally attributed to repeated clipping and were not considered related to chemical administration. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 300 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in 50% ethanol by dermal application for 14 weeks. For special hematology and clinical pathology studies, additional groups of 10 male and 10 female rats were administered 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in 50% ethanol by dermal application for 14 weeks. All rats survived to the end of the study. Final mean body weights and body weight gains of dosed male and female rats were similar to those of the control groups. Dermal applications of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately 6, 20, 60, 170, and 500 mg sodium xylenesulfonate/kg body weight to males and 10, 30, 90, 260, and 800 mg/kg to females. The only notable clinical finding was brown discoloration of the skin at the site of application in dosed animals. Hemaation in dosed animals. Hematology and clinical chemistry parameters of dosed groups of males and females were significantly different from those of the controls in several instances, but these differences were sporadic and did not demonstrate a treatment relationship. The absolute and relative liver weights of males receiving 44, 133, or 400 mg/mL were significantly less than those of the control group, but the biological significance of these differences was unclear, and there were no treatment-related histopathologic effects in the liver. There were no significant differences in liver weights in female rats. Minimal hyperplasia of the epidermis at the site of application occurred in both male and female rats in the control group as well as most dosed groups. The incidence of epidermal hyperplasia in 400 mg/mL males was possibly chemical related. 14-Week Study in Mice: Groups of 10 male and 10 female mice were administered 100 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in 50% ethanol by dermal application for 14 weeks. There were no chemical-related deaths. The mean body weight gain of the 400 mg/mL males was significantly greater than that of the control group. Dermal applications of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately 17, 40, 140, 440, and 1,300 mg sodium xylenesulfonate/kg body weight to males and 20, 60, 170, 530, and 1,630 mg/kg to females. There were no clinical findings related to sodium xylenesulfonate administration. Epidermal hyperplasia occurred in one 44 mg/mL female, two 133 mg/mL males, five 400 mg/mL males, and four 400 mg/kg females. Hyperplasia of the epidermis in 400 mg/mL males and females was probably related to chemical administration. Chronic inflammation of the skin occurred primarily in the control groups of males and females. These lesions consisted of mononuclear inflammatory cells in the dermis. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were dermally administered 0, 60, 120, or 240 mg sodium xylenesulfonate/kg body weight in 50% ethanol for 104 weeks. Survival, Body Weights, and Clinical Findings: Survival of dosed males and females was similar to that of the control groups. Mean body weights of dosed males and females were similar to those of the controls throughout the study. In male groups, there were no clinical findings considered treatment related. In females, clinical findings were limited to irritation at the site of application in one control female, four 120 mg/kg females, and two 240 mg/kg females. Pathology Findings: There were no neoplasms at any site (including the skin) that were considered treatment related.Low incidences of hyperplasia of the epidermis at the site of application occurred in males in the 60, 120, and 240 mg/kg groups. Low incidences of hyperplasia of the epidermis at the site of application also occurred in females in the 120 and 240 mg/kg groups, and they occurred with a significant positive trend. Low incidences of hyperplasia of the sebaceous gland occurred in control and 60 mg/kg males and in control, 120 mg/kg, and 240 mg/kg females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were dermally administered 0, 182, 364, or 727 mg sodium xylenesulfonate/kg body weight in 50% ethanol for 104 to 105 weeks. Survival, Body Weights, and Clinical Findings: Survival of dosed males and females was similar to that of the control groups. Mean body weights of dosed males and females were generally similar to those of the controls throughout the study; however, the mean body weights of 727 mg/kg females were greater than those of the control group from week 85 to week 97. With the exception of irritation at the site of application in one 364 mg/kg female, there were no clinical findings related to sodium xylenesulfonate administration. Pathology Findings: There were no neoplasms at any site (including the skin) that were considered treatment related.Hyperplasia of the epidermis occurred in control,364 mg/kg, and 727 mg/kg males and in control and dosed females. In male mice, the incidences occurred with a significant positive trend. Focal ulceration occurred in one 727 mg/kg male and in one female in each dose group. In males and females from control and dosed groups, the incidences of hepatocellular adenoma, hepatocellular carcinoma, and hepato- cellular adenoma or carcinoma (combined) were generally higher than those expected by spontaneous occurrence. The incidences of hepatocellular neoplasms in some groups of males and females exceeded the NTP historical control range. Male mice had a pattern of nonneoplastic liver lesions along with silver stained positive helical organisms within the liver which suggests an infection with Helicobacter hepaticus. The findings in this study of sodium xylenesulfonate were not considered to have been significantly impacted by the infection with H. hepaticus or its associated hepatitis. GENETIC TOXICOLOGY: Sodium xylenesulfonate was not mutagenic in Salmonella typhimurium strain TA98, TA100, TA1535, or TA1537 with or without induced liver S9. Equivocal results were obtained in a mutation assay with mouse lymphoma cells in the presence of induced S9; no evidence of mutagenicity was noted without S9 in this assay. In cytogenetic tests with sodium xylenesulfonate in cultured Chinese hamster ovary cells, significant increases in sister chromatid exchanges were observed in the absence of S9 only, and no increases in chromosomal aberrations were observed with or without S9. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of sodium xylenesulfonate in male or female F344/N rats administered 60, 120, or 240 mg/kg or in male or female B6C3F1 mice administered 182, 364, or 727 mg/kg. Increased incidences of epidermal hyperplasia in female rats and male mice may have been related to exposure to sodium xylenesulfonate. Synonyms: Benzenesulfonic acid, dimethyl-, sodium salt; xylenesulfonic acid, sodium salt; sodium dimethylbenzenesulfonate; xylenesulfonic acid, sodium salt Trade names: Conco SXS; Cyclophil; SXS 30; Eletesol SX 30; Naxonate; Naxonate G; Richonate SXS; Stepanate SXS; Stepanate X; SXS 40; Ultrawet 40SX
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PMID:NTP Toxicology and Carcinogenesis Studies of Technical Grade Sodium Xylenesulfonate (CAS No. 1300-72-7) in F344/N Rats and B6C3F1 Mice (Dermal Studies). 1257

Cobalt sulfate is used in the electroplating and electro chemical industries. It is also used as a coloring agent for ceramics and as a drying agent in inks, paints, varnishes, and linoleum. Cobalt sulfate may be added to animal feed as a mineral supplement and has been used as a top dressing on pasture lands. Cobalt sulfate was nominated by the National Cancer Institute for study based on a lack of information on the toxicity of soluble salts. Male and female F344/N rats and B6C3F1 mice were exposed to cobalt sulfate heptahydrate (approximately 99% pure) by inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium. The results of prechronic inhalation toxicity studies were reported previously (Bucher et al., 1990; NTP, 1991). 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to aerosols containing 0, 0.3, 1.0, or 3.0 mg/m3 cobalt sulfate heptahydrate 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights Survival of exposed males and females was similar to that of the chamber controls. Mean body weights of exposed male and female rats were similar to those of the chamber controls throughout the study. Pathology Findings The incidences and severities of proteinosis, alveolar epithelial metaplasia, granulomatous alveolar inflammation, and interstitial fibrosis were markedly greater in all exposed groups of male and female rats than in the chamber controls. The incidences of alveolar epithelial hyperplasia in all groups of exposed males and in females exposed to 3.0 mg/m3 were significantly greater than those in the chamber control groups, as were the incidences of squamous metaplasia in 1.0 mg/m3 females and atypical alveolar epithelial hyperplasia in 3.0 mg/m3 females. In 3.0 mg/m3 males, the combined incidence of alveolar/ bronchiolar neoplasms (adenoma and/or carcinoma) was significantly greater than in the chamber controls. In female rats exposed to 1.0 or 3.0 mg/m3, the incidences of alveolar/bronchiolar neoplasms were significantly greater than those in the chamber control group and exceeded the NTP historical control ranges. A squamous cell carcinoma was observed in one 1.0 mg/m3 and one 3.0 mg/m3 female. The incidences of benign, complex, or malignant pheochromocytoma (combined) in 1.0 mg/m3 males and in 3.0 mg/m3 females were significantly greater than those in the chamber controls and exceeded the historical control ranges. Hyperplasia of the lateral wall of the nose, atrophy of the olfactory epithelium, and squamous metaplasia of the epiglottis were observed in all exposed groups of males and females, and the severities of these lesions increased with increasing exposure concentration. The incidences of squamous metaplasia of the lateral wall of the nose and metaplasia of the olfactory epithelium were increased in 3.0 mg/m3 males and females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to aerosols containing 0, 0.3, 1.0, or 3.0 mg/m3 cobalt sulfate heptahydrate 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights Survival of exposed males and females was similar to that of the chamber controls. Mean body weights of 3.0 mg/m3 male mice were less than those of the chamber controls from week 96 until the end of the study. The mean body weights of all exposed groups of female mice were generally greater than those of the chamber controls from week 20 until the end of the study. Pathology Findings The incidences of diffuse histiocytic cell infiltration in 3.0 mg/m3 males and of focal histiocytic cell infil tration in 3.0 mg/m3 females were significantly greater than those in the chamber controls. The incidences of alveolar/bronchiolar neoplasms in 3.0 mg/m3 males and females were significantly greater than those in the chamber control groups. The combined incidences of alveolar/bronchiolar adenoma or carcinoma and the incidences of alveolar/bronchiolar carcinoma in 3.0 mg/m3 males and females and the incidence of alveolar/bronchiolar adenoma in 3.0 mg/m3 females exceeded the NTP historical crical control ranges for inhalation studies. The incidences of atrophy of the olfactory epithelium in 1.0 and 3.0 mg/m3 males and females and hyper plasia of the olfactory epithelium in 3.0 mg/m3 males and females were significantly greater than in the chamber controls. Squamous metaplasia of the larynx was observed in all exposed groups of males and females. Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms within the liver, characteristic of an infection with Helico bacter hepaticus. In NTP studies with H. hepaticus- associated hepatitis, increased incidences of hemangiosarcoma were seen in the liver of male mice. In this study of cobalt sulfate heptahydrate, incidences of hemangiosarcoma were increased in exposed groups of male mice. Because of the above association, interpretation of the increased incidences of hemangiosarcoma in the livers of male mice was confounded. Incidences of lesions at other sites in this study of cobalt sulfate heptahydrate were not considered to have been significantly impacted by the infection with H. hepaticus or its associated hepatitis. GENETIC TOXICOLOGY: Cobalt sulfate heptahydrate was mutagenic in S. typhimurium strain TA100 with and without liver S9 metabolic activation enzymes; no mutagenic activity was detected in strain TA98 or TA1535, with or without S9. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of cobalt sulfate heptahydrate in male F344/N rats based on increased incidences of alveolar/bronchiolar neoplasms. Marginal increases in incidences of pheochromocytomas of the adrenal medulla may have been related to exposure to cobalt sulfate heptahydrate. There was clear evidence of carcinogenic activity in female F344/N rats based on increased incidences of alveolar/bronchiolar neo-plasms and pheochromocytomas of the adrenal medulla in groups exposed to cobalt sulfate heptahydrate. There was clear evidence of carcinogenic activity of cobalt sulfate heptahydrate in male and female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. Exposure to cobalt sulfate heptahydrate caused a spectrum of inflammatory, fibrotic, and proliferative lesions in the respiratory tract of male and female rats and mice. Synonyms: Bieberite; cobalt(II) sulfate (1:1) heptahydrate; cobalt monosulfate heptahydrate; cobalt(II) sulphate heptahydrate; sulfuric acid, cobalt(2+) salt (1:1) heptahydrate
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PMID:NTP Toxicology and Carcinogenesis Studies of Cobalt Sulfate Heptahydrate (CAS No. 10026-24-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1257 2

3'-Azido-3'-deoxythymidine (AZT) is the most widely used and evaluated chemotherapeutic agent for the treatment of persons with acquired immune deficiency syndrome (AIDS) and persons seropositive for human immunodeficiency virus (HIV). The National Cancer Institute nominated AZT for toxicity and carcinogenicity studies because of the impending large-scale use of AZT in the treatment of adult patients with AIDS or AIDS-related complex. alpha-Interferon A/D, which displays antiviral activity in mice, is a hybrid molecule composed of the N-terminal portion of human alpha-interferon A and the C-terminal portion of human alpha-interferon D. AZT and alpha-interferon A/D combination studies were conducted because in vitro studies of AZT and alpha-interferon have demonstrated that the combination is more effective in blocking HIV infection than either agent alone. Male and female B6C3F1 mice received AZT (approximately 98% pure) in 0.5% aqueous methylcellulose by gavage for 14 weeks or 2 years. In addition, male and female B6C3F1 mice received alpha-interferon A or alpha-interferon A/D by subcutaneous injection for 2 years, and male and female B6C3F1 mice received AZT in 0.5%% aqueous methylcellulose by gavage in combination with alpha-interferon A/D by subcutaneous injection for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow erythrocytes, and mouse peripheral blood erythrocytes. 14-WEEK AZT STUDY: Groups of 10 male and 10 female mice received AZT in 0.5% methylcellulose by gavage at doses of 0, 50, 100, 200, 800, or 2,000 mg/kg daily for 14 weeks. Additional groups of 10 male and 10 female mice received AZT in 0.5% methylcellulose by gavage at doses of 0, 100, 800, or 2,000 mg/kg daily for 14 weeks and then were held without treatment for an additional 4 weeks before necropsy. One female receiving 100 mg/kg and two females receiving 200 mg/kg died during week 1 as a result of gavage trauma; one female receiving 2,000 mg/kg also died prior to the end of the 14-week dosing period. One female receiving 2,000 mg/kg in the recovery study also died from gavage trauma during week 1. The final mean body weights of dosed mice were similar to those of the vehicle control groups at the end of the dosing period and at the end of the recovery period. Female mice receiving 200, 800, or 2,000 mg/kg gained less weight than the vehicle controls during the 14-week dosing period. Exposure to AZT was toxic to the bone marrow, resulting in significant changes in the peripheral blood (decreased hematocrit values, erythrocyte counts, and hemoglobin concentrations, and increased mean cell volume and mean cell hemoglobin) and bone marrow (erythroid hypoplasia) characteristic of a dose- and time-dependent, minimal to moderate, poorly regenerative macrocytic anemia. At the end of the 4-week recovery period, the hematology parameters had returned to normal, indicating that the hematotoxicity was reversible. 2-YEAR STUDIES: AZT Groups of 95 male and 95 female mice received AZT in 0.5% methylcellulose by gavage at daily doses of 0, 30, 60, or 120 mg/kg body weight, administered as two equal doses at least 6 hours apart, 5 days per week for 105 weeks. Each group of 95 animals was composed of a core group of 50 animals for evaluation of carcinogenic response, a group of 30 animals for evaluation of hematology and bone marrow cellularity, and a group of 15 animals from which blood was drawn for determination of plasma AZT concentrations at week 54. alpha-Interferon A/D and AZT/alpha-Interferon A/D Studies Groups of 80 male and 80 female mice received AZT in 0.5% aqueous methylcellulose by gavage at daily doses of 0, 30, 60, or 120 mg/kg body weight, given in two equal doses, 5 days per week for 105 weeks. Those groups receiving AZT also received sub-cutaneous injections of 500 or 5,000 U alpha-interferon A/D three times per week for 105 weeks. Additional groups of 80 male and 80 female mice received subcutaneous injections of the vehicle, 500 U alpha-interferon A/D, 5,000 Uutaneous injections of the vehicle, 500 U α-interferon A/D, 5,000 U α-interferon A/D, or 5,000 U α-interferon A, three times per week for 105 weeks. Each group of 80 animals was composed of a core group of 50 animals for evaluation of carcinogenic response and a group of 30 animals for evaluation of hematology and bone marrow cellularity. Because of the large number of animals involved, the 2-year studies were started in four phases and, for clarity, are presented as follows: the AZT study, the α-interferon A/D study, the AZT/500 U α-interferon A/D study, and the AZT/5,000 U α-interferon A/D study. Design of the 2-year AZT, AZT/α-Interferon A/D, and α-Interferon A/D Studies AZT Dose AZT Study AZT/500 U α-Interferon A/D Study AZT/5,000 U α-Interferon A/D Study 500 or 5,000 U α-Interferon A/D or 5,000 U α-Interferon A Study Vehicle Control 95 male and 95 female micea 80 male and 80 female miceb 80 male and 80 female miceb 80 male and 80 female miceb 30 mg/kg AZT 95 male and 95 female mice 80 male and 80 female mice 80 male and 80 female mice none 60 mg/kg AZT 95 male and 95 female mice 80 male and 80 female mice 80 male and 80 female mice none 120 mg/kg AZT 95 male and 95 female mice 80 male and 80 female mice 80 male and 80 female mice none aFor the AZT study, there were 95 male and 95 female mice; these were divided into 50 males and 50 females in the core groups, 30 males and 30 females in the clinical pathology groups (hematology and bone marrow analyses only), and 15 males and 15 females for plasma AZT concentration determinations. bFor the α-interferon A/D study and the AZT/α-interferon A/D studies, there were 80 male and 80 female mice for each study; these were divided into 50 males and 50 females in the core groups and 30 males and 30 females in the clinical pathology groups (hematology and bone marrow analyses only). Survival and Body Weights Survival and mean body weights of mice exposed to AZT, α-interferon A, α-interferon A/D, or AZT plus α-interferon A/D were generally similar to those of the vehicle control groups. Hematology and Bone Marrow Analyses All groups of male and female mice receiving AZT exhibited changes in peripheral blood and bone marrow characteristic of a dose- and time-dependent, minimal to mild, macrocytic, nonresponsive anemia. In females, these changes were evident throughout the study. In males, the macrocytic anemia had resolved by week 80 in the 30 mg/kg group; at study termination erythrocyte macrocytosis was present only in males receiving 60 or 120 mg/kg AZT or AZT plus α-interferon A/D. There were no treatment-related alterations in hematology or bone marrow parameters in groups that received only α-interferon A or A/D. Pathology Findings Incidences of squamous cell carcinoma and squamous cell papilloma or carcinoma (combined) of the vagina occurred with a positive trend and were significantly increased in groups of female mice receiving 60 or 120 mg/kg AZT alone or in combination with α-interferon A/D. Epithelial hyperplasia was observed in all dosed groups of females, and the incidence was significantly increased in the 120 mg/kg AZT group. Three renal tubule adenomas and one renal tubule carcinoma were observed in male mice receiving 120 mg/kg AZT; the combined incidence in this group exceeded the range in historical controls. A renal tubule adenoma was observed in one male receiving 60 mg AZT/kg and 500 U α-interferon A/D; how ever, none were observed in other groups. Evaluation of step sections revealed a few more renal tubule hyperplasias but no additional neoplasms. The incidence of harderian gland adenoma was increased in male mice receiving 120 mg/kg AZT and exceeded the range in historical controls. Harderian gland neoplasms were observed in other groups but did not follow a treatment-related pattern. Overall Incidences of Vaginal Neoplasms and Hyperplasia of the Vaginal Epithelium in Female Mice in the 2-Year Gavage Studies of AZT and AZT/α-Interferon A/Da Vehicle Control 30 mg AZT/kg 60 mg AZT/kg 120 mg AZT/kg AZT alone 2/197 (1%)b 1/197 0/49 (0%) 3/49 5/45 (11%%) 4/45 11/49 (22%%) 11/49 500 U α-Interferon A/D 0/49 (0%%) 0/49 0/44 (0%) 4/44 5/48 (10%) 8/48 6/48 (13%) 12/48 5,000 U α-Interferon A/D 1/50 (2%) 1/50 1/48 (2%) 4/48 5/48 (10%) 8/48 4/50 (8%) 15/50 aData are presented as number of vaginal neoplasms/number of animals microscopically examined (first line) and number of vaginal hyperplasias/number of animals microscopically examined (second line) bCombined incidences of controls from the AZT alone study and the AZT/α-interferon A/D studies; incidences in the vehicle control group from the AZT alone study are 0/50 (0%%) (neoplasms) and 0/50 (hyperplasia) Overall Incidence of Harderian Gland Neoplasms in Male Mice in the 2-Year Gavage Studies of AZT and AZT/α-Interferon A/Da Vehicle Control 30 mg AZT/kg 60 mg AZT/kg 120 mg AZT/kg AZT alone 13/200 (6%%)b 5/50 (10%%) 2/50 (4%) 10/50 (20%%) 500 U α-Interferon A/D 3/50 (6%) 3/50 (6%) 1/50 (2%%) 4/50 (8%%) 5,000 U α-Interferon A/D 3/50 (6%) 9/50 (18%%) 4/50 (8%%) 4/50 (8%) aData are presented as number of harderian gland neoplasms/number of animals necropsied bCombined incidences of controls from the AZT alone study and the AZT/α-interferon A/D studies; incidence in the vehicle control group from the AZT alone study is 3/50 (6%) Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms within the liver consistent with an infection with Helicobacter hepaticus. An organism compatible with H. hepaticus was confirmed by polymerase chain reaction-restriction fragment length polymorphism-based assays. Detection of dose-related differences in neoplasm incidences in these studies was not considered to have been significantly impacted by the infection with H. hepaticus or its associated hepatitis. GENETIC TOXICOLOGY: AZT is mutagenic in vitro and in vivo. It induced gene mutations in Salmonella typhimurium strain TA102, with and without S9; no increases in mutations were noted in the other tested strains of S. typhimurium. AZT induced sister chromatid exchanges, but not chromosomal aberrations, in cultured Chinese hamster ovary cells, with and without S9. In vivo studies with male mice administered AZT by gavage showed highly significant increases in micronucleated erythrocytes in bone marrow and peripheral blood after exposure periods that ranged from 72 hours to 14 weeks. CONCLUSIONS: Under the conditions of these 2-year gavage studies there was equivocal evidence of carcinogenic activity of AZT in male mice based on increased incidences of renal tubule and harderian gland neoplasms in groups receiving AZT alone. There was clear evidence of carcinogenic activity of AZT in female mice based on increased incidences of squamous cell neoplasms of the vagina in groups that received AZT alone or in combination with α-interferon A/D. Hematotoxicity occurred in all groups that received AZT. Treatment with AZT alone and AZT in combination with α-interferon A/D resulted in increased incidences of epithelial hyperplasia of the vagina in all dosed groups of females. Synonyms: AZT; 3'-azido-2',3'-dideoxythymidine; azidodeoxythymidine; azidothymidine; 3'-azidothymidine; 3'-deoxy-3'-azidothymidine; 3'-deoxy-(8CI) (9CI); BW A509U; Compound S; ZDV; zidovudine Trade name: Retrovir®
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PMID:NTP Toxicology and Carcinogenesis Studies of AZT (CAS No. 30516-87-1) and AZT/alpha-Interferon A/D B6C3F1 Mice (Gavage Studies). 1257 4

Triethanolamine is widely used as an ingredient in emulsifiers, thickeners, wetting agents, detergents, and alkalinizing agents in cosmetic products; as a chemical intermediate for anionic and nonionic surfactants and surface active agents in household cleaning agents, textiles, herbicides, pharmaceutical ointments, and other products; as a vulcanization accelerator in the manufacture of rubber; and in many other industrial applications. The National Cancer Institute nominated triethanolamine for study because of its widespread use in cosmetics and other consumer products, its high potential for worker exposure due to its many industrial uses, and its potential for conversion to the carcinogen N -nitrosodiethanolamine. Dermal application was chosen as the route of exposure to mimic the principal means of human exposure to triethanolamine and because considerable systemic exposure is achieved with this route. Male and female F344/N rats and B6C3F1 mice received triethanol amine (purity 98% or greater) by dermal application for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melano gaster, and mouse peripheral blood erythrocytes. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were topically administered 0, 125, 250, 500, or 1,000 mg triethanolamine per kilogram body weight in acetone or 2,000 mg/kg neat triethanolamine, 5 days per week, for 13 weeks. All rats survived to the end of the study. Final mean body weights and weight gains of males and females administered 2,000 mg/kg and the mean body weight gain of females administered 1,000 mg/kg were significantly less than those of the vehicle controls. Clinical observations included irritation, scaliness, and crustiness of the skin at the site of application for males and females. Males also had discoloration, and two males administered 2,000 mg/kg had ulceration at the site of application. Changes in clinical pathology parameters were minor and consistent with inflammation at the site of application. Kidney weights were generally greater in males and females administered 500, 1,000, or 2,000 mg/kg than in the vehicle controls. Microscopic lesions attributed to triethanolamine administration included acanthosis and inflammation at the site of application, nephropathy in females, and hypertrophy of the pituitary gland pars intermedia in males and females. These lesions generally occurred with dose-related increases in incidence and severity in males and females. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were topically administered 0, 250, 500, 1,000, or 2,000 mg triethanolamine per kilogram body weight in acetone or 4,000 mg/kg neat triethanolamine, 5 days per week, for 13 weeks. All mice survived to the end of the study. The final mean body weight and weight gain of males in the 250 mg/kg group were less than those of the vehicle controls. Clinical findings were observed only in mice in the 4,000 mg/kg groups and included scaliness, irritation, and discoloration at the site of triethanolamine application for males and females and skin erosion at this site in one male. The absolute kidney and liver weights of males and females administered 4,000 mg/kg were greater than those of the vehicle controls; relative kidney weights of males administered 1,000 mg/kg or greater and females in all dosed groups were also greater than those of the vehicle controls. Microscopic examination of the skin of dosed mice indicated acanthosis and inflammation at the site of application. Acanthosis occurred in all dosed groups and in one vehicle control female; the severity increased with increasing dose in males and females. Inflammation was observed in males and females in the 4,000 mg/kg groups and in one female in the 2,000 mg/kg group. 2-YEAR STUDY IN RATS: Based on the presence of acanthosis and inflammation at the site of application at the higher doses in the 13-week study, triethanolamine doses selected for the 2-year study in rats were 32, 63, and 125 mg/kg for malesr males and 63, 125, and 250 mg/kg for females. Groups of 60 male and 60 female rats were topically administered triethanolamine in acetone 5 days per week for 103 weeks. Ten male and ten female rats from each group were evaluated at 15 months for organ weights and histopathology. Survival, Body Weights, Clinical Findings, and Organ Weights: The survival rate of females in the 250 mg/kg group was slightly less than that of the vehicle controls. The mean body weight of females administered 250 mg/kg ranged from 9% to 12% less than that of the vehicle controls between weeks 73 and 93. Male and female rats receiving triethanolamine had irritated skin at the site of application; in dosed females, the site of application also had a crusty appearance. The number of animals in which these findings were observed increased with increasing dose. At the 15-month interim evaluation, the absolute left and right kidney weights and relative right kidney weight of females administered 250 mg/kg were significantly greater than those of the vehicle controls. Pathology Findings: The incidence of acanthosis at the site of application in males administered 125 mg/kg and the incidences of acanthosis, inflammation, and ulceration in dosed females were greater than in the vehicle controls at the 15-month interim evaluation and at the end of the 2-year study. Males in the 125 mg/kg group also had greater incidences of inflammation and ulceration than the vehicle controls, and females receiving 125 or 250 mg/kg had greater incidences of epidermal erosion than the vehicle controls at 2 years. There were no skin neoplasms at or away from the site of application that were considered related to treatment with triethanolamine. At the end of the study, renal tubule adenomas were observed in seven dosed males and in one vehicle control female and one female in the 63 mg/kg group. One male in the 125 mg/kg group and one female in the 250 mg/kg group had renal tubule hyperplasia. Extended (step-section) evaluation of the kidneys of all male rats revealed additional renal tubule adenomas in one vehicle control male, one male in the 32 mg/kg group, two males in the 63 mg/kg group, and three males in the 125 mg/kg group (including one male from the 15-month interim evaluation). An oncocytoma was also identified in one male in the 32 mg/kg group. Hyperplasia was identified in eight additional vehicle control males and in 19 additional dosed males. The total incidences (combined standard and extended evaluations) of renal tubule adenoma in dosed male rats were slightly greater than the vehicle control incidence (vehicle control, 1/50; 32 mg/kg, 2/50; 63 mg/kg, 6/49; 125 mg/kg, 4/50). The total incidence of hyperplasia in dosed and vehicle control males was similar (9/50, 8/50, 7/49, 6/50). The severity of hyperplasia in males in the 32 and 125 mg/kg groups was greater than that in the vehicle controls. 2-YEAR STUDY IN MICE: Based on dose-related inflammation at the site of application in the 13-week study, triethanolamine doses selected for the 2-year study in mice were 200, 630, and 2,000 mg/kg for males and 100, 300, and 1,000 mg/kg for females. Groups of 60 male and 60 female mice were topically administered triethanolamine in acetone 5 days per week for 103 weeks. Ten male and ten female mice from each group were evaluated at 15 months for organ weights and histopathology. Survival, Body Weights, Clinical Findings, and Organ Weights: Survival rates of all dosed groups of males and females were similar to those of the vehicle controls. The mean body weight of males administered 2,000 mg/kg ranged from 8% to 10% less than that of the vehicle controls from week 69 through the end of the study. Clinical findings included irritation and discoloration of the skin at the site of application for most males in the 2,000 mg/kg group and a few females in the 1,000 mg/kg group; males administered 200 or 630 mg/kg also had skin irritation. At the 15-month interim evaluation, the right kidney weights of male mice that received 630 or 2,000 mg/kg and the left kidney weights of males that received 2,000 mg/kg were significantly greater than those of the vehicle controls. Pathology Findings: Acanthosis and inflammation of the skin were observed at the site of application in male and female mice at the 15-month interim evaluation and at the end of the 2-year study. In males in the 2,000 mg/kg group, the incidences of both lesions were significantly greater than those in the vehicle controls at both time points; however, the severities of acanthosis and inflammation did not increase with dose. At the end of the study, the incidence of inflammation in females in the 1,000 mg/kg group was significantly greater than that in the vehicle controls. One vehicle control male and two males in each of the 630 and 2,000 mg/kg groups had ulcers at the site of application. At the 15-month interim evaluation, hepatocellular carcinomas were observed in dosed and vehicle control males and hepatocellular adenomas in dosed and vehicle control males and females; however, the incidences were not dose related. Nonneoplastic lesions observed at 15 months included foci of cellular alteration in a few dosed males and females; eosinophilic foci were also observed in two vehicle control females. At the end of the 2-year study, females in the 1,000 mg/kg group had significantly greater incidences of hepatocellular adenoma and multiple adenomas and a greater combined incidence of hepatocellular adenoma and carcinoma than the vehicle controls (adenoma: vehicle control, 22/50; 100 mg/kg, 22/50; 300 mg/kg, 24/50; 1,000 mg/kg, 40/50; multiple adenomas: 11/50, 9/50, 13/50, 29/50; combined adenoma and carcinoma: 23/50, 26/50, 28/50, 41/50). Females in the 300 mg/kg group had significantly greater incidences of hepatocellular carcinoma (1/50, 4/50, 7/50, 5/50) and eosinophilic foci (9/50, 10/50, 18/50, 16/50) than the vehicle controls. Incidences of hepatocellular adenoma and multiple adenomas in males in the 2,000 mg/kg group were significantly greater than those in the vehicle controls (adenoma: vehicle control, 27/50; 200 mg/kg, 27/50; 630 mg/kg, 29/50; 2,000 mg/kg, 37/50; multiple adenomas: 17/50, 18/50, 17/50, 29/50). Three males in the 2,000 mg/kg group had hepatoblastomas, and males in this group also had significantly greater incidences of hepatocellular neoplasms (combined) (adenoma, carcinoma, and hepatoblastoma: 31/50, 34/50, 33/50, 42/50) and eosinophilic foci (10/50, 17/50, 11/50, 23/50) than the vehicle controls. Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms within the liver which suggested an infection with Helicobacter hepaticus. With polymerase chain reaction-based assays and culture, the presence of an organism compatible with H. hepaticus was confirmed. An increased incidence of hepatocellular neoplasms in male mice has been shown to be associated with H. hepaticus infection when hepatitis is also present. Therefore, interpretation of the increased incidence of hepatocellular neoplasms in mice was confounded. GENETIC TOXICOLOGY: Triethanolamine was not mutagenic in any of the in vitro or in vivo short-term tests performed by the NTP. It did not induce mutations in Salmonella typhimurium, and no induction of sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells exposed to triethanolamine was noted. These in vitro tests were conducted with and without S9 metabolic activation. Triethanolamine did not induce sex-linked recessive lethal mutations in germ cells of adult male Drosophila melanogaster exposed by feeding or injection. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples of male and female mice that received dermal applications of triethanolamine for 13 weeks. CONCLUSIONS: Under the conditions of these dermal studies, there was equivocal evidence of carcinogenic activity of triethanolamine in male F344/N rats based on a marginal increase in the incidence of renal tubule cell adenoma. There was no evidence of carcinogenic activity in female F344/N rats receiving 63, 125, or 250 mg triethanolamine per kilogram body weight. The study in male and female B6C3F1 mice was considered inadequate, because the presence of a Helicobacter hepaticus infection complicated inter pretation of the relationship between triethanolamine administration and liver neoplasms in these animals. Dosed rats and mice had varying degrees of acanthosis and inflammation, dosed rats had ulceration, and dosed female rats had epidermal erosion at the site of skin application. Synonyms: Nitrilo-2,2',2"-triethanol; 2,2',2"-nitrilotriethanol; 2,2',2"-nitrilotrisethanol; TEA; triaethanolamin-NG; triethanolamin; triethylolamine; tri(hydroxyethyl)amine; 2,2',2"-trihydroxytriethylamine; trihydroxytriethylamine; tris(hydroxyethyl)amine; tris(2-hydroxyethyl)amine; triethylolamine; trolamine Trade Names: Daltogen; Sterolamide; Thiofaco T-35
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PMID:NTP Toxicology and Carcinogenesis Studies of Triethanolamine (CAS No. 102-71-6) in F344 Rats and B6C3F1 Mice (Dermal Studies). 1259 26

Methyl carbamate is used as a chemical intermediate by the textile industry for the manufacture of dimethylol methyl carbamate-based resins that are applied on polyester/cotton blend fabrics as durable-press finishes. Experimental Design: Toxicology and carcinogenesis studies of methylyl carbamate (98% pure) were conducted by exposing groups of F344/N rats and B6C3F1 mice by gavage in water in a single dose and by repeated administration for 16 days, 13 weeks, 6 months, 12 months, 18 months, and 2 years. In addition, short-term mutagenicity studies in bacteria, mammalian cells, and Drosophila and of unscheduled DNA synthesis in rat liver cells were conducted. Single-Administration Studies: In the single-administration studies, 5/5 male and 5/5 female rats that received 8,000 mg/kg methyl carbamate and 2/5 male and 5/5 female that received 4,000 mg/kg died before the end of the 15-day observational period. Five of five male and 5/5 female mice that received 8,000 mg/kg and 1/5 females that received 4,000 mg/kg died before the end of the 15-day observational period. No compound-related morphologic effects were observed in rats or mice that received 2,000 mg/kg. Sixteen-Day Studies: In the 16-day studies, all rats dosed at 2,000 or 4,000 mg/kg died, and 3/5 male rats that received 1,000 mg/kg died. Male mice that received 2,000 or 4,000 mg/kg, female mice that received 4,000 mg/kg, and 1/5 female mice that received 2,000 mg/kg died. No compound-related gross pathologic or histopathologic effects were seen in male or female rats (groups of five each) that received 500 mg/kg or in mice that received 1,000 mg/kg. Thirteen-Week Studies: In the 13-week studies, groups of 10 male and 10 female rats and mice received up to 800 mg/kg (male rats), 1,000 mg/kg (female rats), 1,500 mg/kg (male mice), or 2,000 mg/kg (female mice). Four of 10 male rats that received 800 mg/kg and 1/10 female rats that received 1,000 mg/kg died of compound-related causes before the end of the studies. Toxic hepatitis, splenic pigmentation, bone marrow atrophy, and testicular atrophy were observed in the two highest dose groups of rats. One of the female mice that received 2,000 mg/kg died. The dosed female mice had significantly greater liver weights than did the vehicle controls. Experimental Design of Six-, Twelve-, and Eighteen-Month and Two-Year Studies: Based on the findings in the short-term studies, 2-year studies of methyl carbamate were conducted by administering 0, 100, or 200 mg/kg methyl carbamate in distilled water by gavage, 5 days per week for 103 weeks, to groups of 50 F344/N rats of each sex for 103 weeks. Groups of 50 B6C3F1 mice of each sex were administered 0, 500, or 1,000 mg/kg methyl carbamate on the same schedule. Additional groups of 30 rats of each sex were administered 0 or 400 mg/kg methyl carbamate, and additional groups of 30 mice of each sex were administered 0 or 1,000 mg/kg methyl carbamate in distilled water by gavage, 5 days per week. Ten animals from each group were killed at 6, 12, or 18 months so that the progression of lesions could be followed. Results of the Six-, Twelve-, and Eighteen-Month and Two-Year Studies: In the 6-month studies, all vehicle control and dosed (400 mg/kg) rats survived. Cytologic alterations and atypical proliferative changes were observed in the liver of all dosed male and female rats, and neoplastic nodules of the liver were observed in 6/10 dosed male and 5/10 dosed female rats. In the 12-month studies, all vehicle control male and female rats and dosed female rats survived. One of 10 dosed male rats died. Neoplastic nodules of the liver were observed in 7/10 dosed male and 9/10 dosed female rats, and hepatocellular carcinomas were observed in 8/10 dosed male and 6/10 dosed female rats. In the 18-month studies, 1/10 dosed male and 8/10 dosed female and all vehicle control rats survived. Hepatocellular carcinomas were observed in 9/10 dosed male and 8/10 dosed female rats. Compound-related neoplastic changes were not observed in mice in the 6-, 12-, or 18-month studies. In the 2-year studar studies, mean body weights of high dose (200 mg/kg) male rats were generally 5%-9% lower than those of the vehicle controls after week 20. Mean body weights of high dose female rats were 5%-8% lower than those of the vehicle controls after week 56. Survival of dosed and vehicle control rats was similar (male: vehicle control, 19/50; low dose, 26/50; high dose, 29/50; female: 29/50; 36/50; 35/50). The mean body weights of high dose (1,000 mg/kg) male mice were about 8%-18% lower than those of the vehicle controls after week 24. The mean body weights of high dose (1,000 mg/kg) female mice were about 16% lower than those of the vehicle controls after week 16 and 30% lower after week 64. Survival of dosed and vehicle control mice was similar (male: 28/50; 35/50; 28/50; female: 38/50; 36/50; 32/50). Chronic focal inflammation and cytologic alteration of the liver were observed at increased incidences in high dose rats of each sex. Hyperplasia of hepatocytes was observed atincreased incidences in dosed male and high dose female rats. Neoplastic nodules or hepatocellular carcinomas (combined) in female rats occurred with a significant positive trend (0/50; 0/50; 6/49; P<0.01); the incidence of neoplastic nodules or hepatocellular carcinomas (combined) in high dose female rats was greater (P<0.03) than that in the vehicle controls. Incidences of liver neoplasms in dosed male rats were not significantly increased (4/50; 0/50; 7/49). Inflammation of the harderian gland was observed at increased incidences in dosed rats (male: 4/50; 11/50; 16/50; female: 7/50; 16/50; 30/50). The lesions were considered to be chemically related. In the 2-year studies in rats, significant decreases in tumor incidences included the following: leukemia (both sexes), pituitary gland (male), adrenal gland (male), and mammary gland (female). In the 2-year mouse studies, multinucleate giant cells in the liver were observed at increased incidences in dosed male mice (14/50; 31/50; 31/49). Adenomatous hyperplasia and histiocytosis of the lung were observed at increased incidences in high dose mice (adenomatous hyperplasia--male: 13/50; 19/50; 24/49; female: 7/49; 10/50; 18/50; histiocytosis--male: 11/50; 7/50; 21/49; female: 9/49; 10/50; 21/50). Genetic Toxicology: Methyl carbamate was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535 when tested with or without metabolic activation in a preincubation protocol at doses up to 10 mg/plate. Methyl carbamate did not induce forward mutations in the mouse L5178Y/TK± lymphoma assay with or without metabolicactivation at doses up to 5 mg/ml. Unscheduled DNA synthesis was not detected in rat hepatocytes after in vitro treatment with methyl carbamate at concentrations of 1.0-1,000 ug/ml. When tested in Drosophila at doses of 25,000-50,000 ppm, methyl carbamate did not induce sex-linked recessive lethal mutations. Results of tests for induction of chromosomal aberrations and sister chromatid exchanges by methyl carbamate in cultured Chinese hamster ovary cells were also negative at doses up to 5 mg/ml. Data Audit: An audit of the experimental data was conducted for the 6-, 12-, and 18-month and 2-year studies of methyl carbamate. No data discrepancies were found that influenced the final interpretation. Conclusions: Under the conditions of these 6-, 12-, and 18-month and 2-year gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats given methyl carbamate as indicated by increased incidences of hepatocellular neoplastic nodules and hepatocellular carcinomas. There was no evidence of carcinogenic activity for male and female B6C3F1 mice given methyl carbamate at doses of 500 or 1,000 mg/kg. Methyl carbamate also induced inflammation of the harderian gland in male and female rats and adenomatous hyperplasia and histiocytosis of the lung in male and female mice. Synonyms: carbamic acid, methyl ester; methylurethan; methylurethane; urethylane
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PMID:NTP Toxicology and Carcinogenesis Studies of Methyl Carbamate (CAS No. 598-55-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1273 8