PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “data auditing”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 793 records · Page 44Linked to original sources
PubMed1985

NTP Toxicology and Carcinogenesis Studies of Dimethyl Hydrogen Phosphite (CAS No. 868-85-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Dimethyl hydrogen phosphite (DMHP) is used as an intermediate in the production of insecticides and herbicides, as an additive to lubricants, and as a stabilizer in oil and plaster and was considered for use as a chemical to simulate the physical (but not the biologic) properties of anticholinesterase agents. Results of 13-week gavage studies in F344/N rats (0-400 mg DMHP/kg body weight) and in B6C3F1 mice (0-1,500 mg DMHP/kg body weight) were used to identify short-term toxicity and to establish doses for the 2-year toxicology and carcinogenesis studies. In these studies, dimethyl hydrogen phosphite (greater than 97% pure) was administered for 103 weeks in corn oil by gavage to groups of 50 male F344/N rats and to groups of 50 male and female B6C3F1 mice at doses of 0, 100, or 200 mg/kg and to groups of 50 female F344/N rats at doses of 0, 50, or 100 mg/kg. In the 2-year studies, survival of high dose male rats and high dose male mice was lower (P<0.05) than that of the vehicle controls (male rats: vehicle control, 39/50; low dose, 29/50; high dose, 23/50; male mice: 42/50; 34/50; 32/50). At the end of the studies, mean body weights were lower than those of the corresponding vehicle controls for high dose male rats (-15%), for high dose female rats (-5%), and for high dose male mice (-5%). Dimethyl hydrogen phosphite caused dose-related increases in nonneoplastic and neoplastic lesions of the lung in male and female rats. In high dose male rats, there were increased incidences of lung neoplasms, including squamous cell carcinomas (0/50; 0/50; 5/50), alveolar/bronchiolar adenomas (0/50; 0/50; 5/50), and alveolar/bronchiolar carcinomas (0/50; 1/50; 20/50). In high dose female rats, there was a marginal increase in the incidence of alveolar/bronchiolar carcinomas of the lung (0/50; 1/49; 3/50). Hyperplasia of the lung and chronic interstitial pneumonia were increased in dosed male rats and in high dose female rats. Dimethyl hydrogen phosphite caused increases in forestomach lesions in male and female rats. In male rats, there was an increased incidence of forestomach neoplasms, including squamous cell papillomas (0/50; 1/50; 3/50) and squamous cell carcinomas (0/50; 0/50; 3/50). High dose male rats had increased incidences of hyperkeratosis and hyperplasia of the forestomach. In high dose female rats, the incidence of forestomach hyperplasia was increased. Neoplastic lesions of the forestomach (a squamous cell papilloma and a squamous cell carcinoma) were found in two high dose female rats. Mineralization of the cerebellum was seen in high dose male rats (12/49) and in no other group. Focal calcification of the testis occurred at increased incidence in dosed male mice in the 2-year studies (2/50; 9/47; 24/50). Compound-related testicular atrophy was seen in male mice in the 13-week study. Dimethyl hydrogen phosphite did not induce any neoplasms in male or female mice. Dimethyl hydrogen phosphite was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver S9. This chemical did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. An audit of the experimental data was conducted for these carcinogenic studies on dimethyl hydrogen phosphite. No data discrepancies were found that influenced the final interpretations. Under the conditions of these gavage studies, there was clear evidence of carcinogenicity in male rats receiving dimethyl hydrogen phosphite, as shown by increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and squamous cell carcinomas of the lung and of neoplasms of the forestomach. There was equivocal evidence of carcinogenicity in female F344/N rats receiving dimethyl hydrogen phosphite, as shown by marginally increased incidences of alveolar/bronchiolar carcinomas of the lung and of neoplasms of the stomach. There was no evidence of carcinogenicity in male or female B6C3F1 mice receiving dimethyl hydrogen phosphite at doses of 100 ogen phosphite at doses of 100 or 200 mg/kg for 103 weeks. Synonyms: phosphonic acid, dimethyl ester (9CI); dimethyl phosphite; dimethyl phosphorus acid; methyl phosphonate; dimethyl phosphonate; dimethoxyphosphine oxide; TL 585; DMHP; phosphorous acid, dimethyl ester; dimethylphosphite; dimethyl phosphonate; dimethylphosphorous acid; bis(hydroxymethyl) phosphine oxide

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of n-Butyl Chloride (CAS No. 109-69-3) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of n-butyl chloride (greater than 99.5% pure), a solvent as well as an alkylating agent, were conducted by exposing groups of F344/N rats and B6C3F1 mice to n-butyl chloride in corn oil by gavage for 14 days, 13 weeks, and 2 years. In the 14-day studies, no compound-related gross pathologic effects were observed in groups of five male or female rats or mice administered doses of up to 3,000 mg/kg body weight. However, deaths occurred in the groups administered 750, 1,500, or 3,000 mg/kg. Tremors and convulsions following gavage administration were observed. In the 13-week studies, groups of 10 male and 10 female rats were administered up to 500 mg/kg n-butyl chloride, and similar groups of mice received up to 1,000 mg/kg, Three of 10 male rats in the 500 mg/kg dose group and one female mouse in the 120 mg/kg dose group died before the end of the studies. Mild to moderate extramedullary hematopoiesis was observed in 3/10 male rats receiving 500 mg/kg. Mean body weights of male and female rats receiving 250 or 500 mg/kg were lower than those of the vehicle controls. Convulsions were observed in male and female rats receiving 250 mg/kg or higher and in 2/10 female mice receiving 1,000 mg/kg. Based on these results, 2-year toxicology and carcinogenesis studies of n-butyl chloride were conducted by administering doses of 0, 60, or 120 mg/kg in corn oil by gavage to groups of 50 male and 50 female rats and doses of 0, 500, or 1,000 mg/kg to groups of 50 male and 50 female mice. In the 2-year studies, survival relative to that of vehicle controls was significantly lower in high dose male rats (40/50 vs 17/50) and high dose female rats (35/50 vs 11/50) and in male mice receiving 1,000 mg/kg (33/50 vs 10/50). Due to excessive mortality in the 1,000 mg/kg female mice, the group was terminated in the 45th week and a second series of 2-year studies in mice of each sex was started at concentrations of 0 and 250 mg/kg. Male mice in the 1,000 mg/kg group had 10% lower mean body weights than the vehicle control group. No adverse effects on survival or body weights in other dosed groups of rats and mice were observed. Convulsions were observed before or after gavage administration on several occasions during the rat studies. These observations were noted primarily in the high dose groups (male: vehicle control, 1/50; low dose, 3/50; high dose, 27/50; female: vehicle control, 0/50; low dose, 7/50; high dose, 45/50). Hemorrhage of the brain and alveoli were observed primarily in high dose male and female rats dying from convulsions. Lymphoid depletion of the spleen and splenic hemosiderosis were also observed inthese animals. In mice, convulsions were observed only in the first studies (in the high dose female mice that were terminated early and in 6/50 high dose male mice). Pheochromocytomas of the adrenal gland occurred at marginally increased incidence in low dose female rats (1/50; 6/50; 1/49). Hyperplasia was observed in 3/50 vehicle controls, 7/50 low dose females, and 4/49 high dose females. The incidence of pheochromocytomas was low, not dose related, and not seen in males, and thus it was not considered to be compound related. Cytoplasmic vacuolization of the adrenal cortex occurred at increased incidences in males (5/50; 10/50; 20/50) but not in female rats. Nephropathy of the kidney occurred at increased incidences in female rats (13/50; 25/50; 20/50) but not in male rats. Additional nonneoplastic lesions such as congestion, inflammation, or nephrosis were not present to any degree in either vehicle control or dosed female rats. An increased incidence of alveolar/bronchiolar adenomas or carcinomas (combined) was observed in the 500 mg/kg group of female mice (3/50 vs 9/50), but little effect was seen in the 250 mg/kg group (6/50 vs 8/50). The incidences of adenomas or carcinomas (combined) in dosed female mice were not significantly different from that in the pooled vehicle control group from the first and second studies (pooled controls, 9/100; 250 mg/kg, 8/50; 500 mg/kg, 9/50). The lack o0). The lack of hyperplasia in female mice and the negative trend in male mice suggest that these marginal effects were probably not related to the administration of n-butyl chloride. An increased incidence of hepatocellular adenomas or carcinomas (combined) was observed in the 500 mg/kg dose group of female mice (3/50 vs 8/50) but not in the 250 mg/kg dose group (9/50 vs 7/50). An increased incidence of hemangiosarcomas was observed in male mice in the first study (1/50; 3/50; 4/50) but not in the second study (4/50 vs 2/50). Neither of these marginal effects was regarded as compound related. n-Butyl chloride was not mutagenic in Salmonella typhimurium strains TA98, TA1535, or TA1537 in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat liver S9 or in the presence of male Syrian hamster liver S9. n-Butyl chloride was mutagenic in the mouse lymphoma L5178Y/TK&plusmn; assay in the absence of Aroclor-induced male rat liver S9 and was not tested in the presence of S9. n-Butyl chloride did not induce sister-chromatid exchanges or chromosomal aberrations in Chinesehamster ovary cells in the presence or absence of Aroclor-induced male rat liver S9. An audit of the experimental data was conducted for the 2-year studies of n-butyl chloride. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity of n-butyl chloride for male and female F344/N rats at daily doses of 60 or 120mg/kg, for male B6C3F1 mice at doses of 250, 500, or 1,000 mg/kg, or for female B6C3F1 mice at doses of 250 or 500 mg/kg. Chemical-induced toxicity in high dose rats (primarily females) reduced the sensitivity of the study for determining carcinogenicity. Synonyms: 1-chlorobutane; butyl chloride; n-propylcarbinyl chloride

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Tetrachloroethylene (Perchloroethylene) (CAS No. 127-18-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Tetrachloroethylene is used primarily as a dry cleaning agent, an industrial solvent for fats, oils, tars, rubber, and gums, and a metal degreasing agent. Tetrachloroethylene had antihelminthic uses, particularly for hookworms (1.6-8 g/60 kg), and was formerly used in combination with some grain protectants and fumigants. Toxicology and carcinogenesis studies of tetrachloroethylene (99.9% pure) were conducted by inhalation exposure of groups of 50 male and 50 female F344/N rats and B6C3F1 mice 6 hours per day, 5 days per week, for 103 weeks. The exposure concentrations used (0, 200, or 400 ppm for rats and 0, 100, or 200 ppm for mice) were selected on the basis of results from 13-week inhalation studies in which groups of 10 rats and 10 mice of each sex were exposed to tetrachloroethylene at 100-1,600 ppm for 6 hours per day, 5 days per week. During the 13-week studies, 1,600 ppm tetrachloroethylene was lethal to 20%-70% of the rats and mice and reduced the final body weights of survivors. In rats, tetrachloroethylene at 200-800 ppm caused minimal to mild hepatic congestion. In dosed male and female mice, minimal to mild hepatic leukocytic infiltration, centrilobular necrosis, bile stasis (400-1,600 ppm), and mitotic alteration (200-1,600 ppm) were produced. Tetrachloroethylene exposure also caused minimal renal tubular cell karyomegaly in mice at concentrations as low as 200 ppm. During the 2-year studies, exposure to tetrachloroethylene did not consistently affect body weight gains in either rats or mice. Exposure at 400 ppm tetrachloroethylene reduced the survival of male rats (control, 23/50; low dose, 20/50; high dose, 12/50). This reduced survival may have been related to an increased incidence of mononuclear cell leukemia. Tetrachloroethylene at both exposure concentrations reduced the survival of male mice (46/50; 25/50; 32/50), whereas exposure at 200 ppm reduced female mouse survival (36/50; 31/50; 19/50). Early deaths in mice may have been related to the development of hepatocellular carcinomas. Both concentrations of tetrachloroethylene were associated with increased incidences of mononuclear cell leukemia in male rats (28/50; 37/50; 37/50). In female rats, tetrachloroethylene increased the incidence of leukemia (18/50; 30/50; 29/50) and decreased the time to occurrence of the disease. Tetrachloroethylene produced renal tubular cell karyomegaly in male and female rats, renal tubular cell hyperplasia in male rats, and renal tubular cell adenomas or adenocarcinomas (combined) in male rats (1/49; 3/49; 4/50). The incidence of the renal tubular cell tumors was not statistically significant; these uncommon tumors have been consistently found at low incidences in male rats in other 2-year studies of chlorinated ethanes and ethylenes. One low dose male rat had a kidney lipoma, and another had a nephroblastoma. Four high dose male and two high dose female rats had gliomas of the brain, whereas one control male and one control female had this tumor. In male and female mice, tetrachloroethylene caused dose-related increases in the incidences of hepatocellular neoplasms. In males, tetrachloroethylene at 200 ppm increased the incidence of hepatocellular adenomas (11/49; 8/49; 18/50) and at both concentrations increased the incidence of hepatocellular carcinomas (7/49; 25/49; 26/50). In female mice, tetrachloroethylene at both concentrations increased the incidences of hepatocellular carcinomas (1/48; 13/50; 36/50). Tetrachloroethylene also produced renal tubular cell karyomegaly in both sexes of mice, and one low dose male mouse had a tubular cell adenocarcinoma. In these inhalation studies, there were no neoplastic changes in the respiratory tracts of either species, but there was an increase in the incidence of squamous metaplasia in the nasal cavities in dosed male rats (0/50; 5/50; 5/50). Tetrachloroethylene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of male Syrian hamster or male Sprague-Dawley rat liver S9. Tetrachloroethylene was not mutagenic in was not mutagenic in L5178Y/TK&plusmn; mouse lymphoma cells with or without metabolic activation and did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. Tetrachloroethylene did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of metabolic activation. An audit of the experimental data was conducted for these 2-year studies on tetrachloroethylene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenicity of tetrachloroethylene for male F344/N rats as shown by an increased incidence of mononuclear cell leukemia and uncommon renal tubular cell neoplasms. There was some evidence of carcinogenicity of tetrachloroethylene for female F344/N rats as shown by increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenicity for B6C3F1 mice as shown by increased incidences of both hepatocellular adenomas and carcinomas in males and of hepatocellular carcinomas in females. Synonyms: carbon bichloride; carbon dichloride; ethylene tetrachloride; per; perc; perchlor; perchlorethylene; perchloroethylene; perk; tetrachlorethylene; 1,1,2,2-tetrachloroethylene Trade names: Ankilostin; Antisal 1; Dee-Solv; Didakene; Dow-Per; ENT 1860; Fedel-Un; Nema; Perclene; Percosolv; Perklone; PerSec; Tetlen; Tetracap; Tetraleno; Tetravec; Tetroguer; Tetropil

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Chlorinated Paraffins (C12, 60% Chlorine) (CAS No. 108171-26-2*) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis assessments of chlorinated paraffins (C12, 60% chlorine), a material widely used as a flame retardant and extreme-pressure lubricant, were conducted in male and female F344/N rats and male and female B6C3F1 mice in single-administration, 16-day, 13-week, and 2-year studies. Doses used in the 2-year studies were 0, 312, or 625 mg/kg body weight per day administered by gavage in corn oil five times per week to groups of 70 male and female rats and 0, 125, or 250 mg/kg administered to groups of 50 male and female mice. Ten male and 10 female rats were killed after 6 and 12 months of dosing and examined for toxicity. No chemically related toxicity was observed in single-administration studies in which male and female rats received doses of chlorinated paraffins (C12, 60% chlorine) up to 13,600 mg/kg body weight and male and female up to 27,200 mg/kg. In 16-day studies, deaths did occur in groups of male and female rats given 7,500 mg/kg and in groups of male and female mice given doses of 1,875 mg/kg or higher. In 13-week studies, no chemically related deaths occurred among male and female rats given up to 5,000 mg/kg or mice given up to 2,000 mg/kg. Increased liver weights were noted in dosed rats and mice of each sex in the short-term studies, and dosed male rats showed more severe nephropathy than did vehicle controls. Doses selected for the 2-year studies were those that caused a minimal increase in liver weight in the short-term studies. Liver and kidney weights were increased in dosed rats killed at 6 and 12 months. Morphometric measurements demonstrated hepatocyte hypertrophy in the livers of dosed rats. Lesions of the kidney tubules and interstitial inflammation increased with dose in male and female rats. During the 2-year studies, body weights of high dose male rats were 8%-12% lower than those of vehicle controls after week 20, and body weights of dosed female mice were about 10% lower than those of vehicle controls during the second year. Survival of dosed male rats was lower than that of vehicle controls after about week 85, perhaps due to toxicity to the kidney (final survival: vehicle control, 27/50; low dose, 6/50; high dose, 3/50). Survival of low dose female rats was lower than that of vehicle controls (34/50; 24/50; 29/50). Survival of dosed male mice was not significantly different from that of vehicle controls (34/50; 31/50; 31/50). Survival of high dose female mice was lower than that of vehicle controls after about week 75 (final survival: 36/50; 31/50; 25/50). Chemically related nonneoplastic lesions consisted of hypertrophy and minimal focal necrosis of the liver in rats; erosion, inflammation, and ulceration of the glandular stomach and forestomach a in male rats; and formation ofmultiple cysts in the kidney tubules of male rats. The incidence of nephropathy was also increased in dosed female rats and mice. The maximum tolerated dose may have been exceeded in male and female rats. Neoplastic lesions associated with chlorinated paraffins (C12, 60% chlorine) administration were found in the liver of rats and mice of each sex (see table p. 12 of Technical Report) Dosed male rats showed increased incidences of kidney tubular cell hyperplasia (1/50; 9/50; 12/49) and of tubular cell adenomas (0/50; 7/50; 3/49); two low dose males had tubular cell adenocarcinomas. The incidences of mononuclear cell leukemia were increased in dosed male rats (7/50; 12/50; 14/50) and in low dose female rats (11/50; 22/50; 16/50). Pancreatic acinar cell tumors occurred at increased incidences in low dose male rats (11/50; 22/50; 17/50). Follicular cell adenomas or carcinomas (combined) of the thyroid gland were found at increased incidences in both female rats (0/50; 6/50; 6/50) and female mice (8/50; 12/49; 15/49). Chlorinated paraffins (C12, 60% chlorine) was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535 in the presence or absence of Aroclor 1254-induced male Sprague-Dawley or male Syrian hamster liver S9 when tested according to the preincubational protocol. An ed according to the preincubational protocol. An audit of the experimental data was conducted for these 2-year studies on chlorinated paraffins (C12, 60&percnt; chlorine). No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of chlorinated paraffins (C12, 60&percnt; chlorine) for F344/N rats based on increased incidences of hepatocellular neoplasms (primarily neoplastic nodules) in male and female rats, of adenomas or adenocarcinomas (combined) of the kidney tubular cells in male rats, and of follicular cell adenomas or carcinomas (combined) of the thyroid gland in female rats. Mononuclear cell leukemia in dosed male rats may have been related to administration of chlorinated paraffins (C12, 60&percnt; chlorine). There was clear evidence of carcinogenicity of chlorinated paraffins (C12, 60&percnt; chlorine) for B6C3F1 mice as shown by increased incidences of hepatocellular adenomas and of adenomas or carcinomas (combined) in dosed male and female mice and increased incidences of adenomas and of adenomas or carcinomas (combined) of thyroid gland follicular cells in dosed female mice.

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Ephedrine Sulfate (CAS No. 134-72-5) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Ephedrine sulfate is a sympathomimetic amine that affects both the central and peripheral nervous systems. An effective bronchiodilator and weak vasoconstrictor, ephedrine sulfate is used extensively in nonprescription pharmaceutical preparations such as nose drops, cold tablets, cough syrups, and, in particular, asthma relief medicines. Ephedrine sulfate was nominated for carcinogenesis studies by the National Cancer Institute because of its widespread and long-term use for the relief of symptoms associated with asthma. In 14-day repeated-exposure studies, F344/N rats of each sex received diets containing 0-1,500 ppm ephedrine sulfate or drinking water containing 0-1,200 ephedrine sulfate; B6C3F1 mice received diets or drinking water containing 0-5,000 ppm ephedrine sulfate. In the feed studies, the average feed consumption by dosed rats and mice was comparable to that of their respective controls. The average water consumption by rats and mice decreased with increasing concentration of ephedrine sulfate in the drinking water. Thus, subsequent studies used the feed route of administration. Doses for the 2-year studies were selected on the basis of results from 13-week studies in which F344/N rats of each sex were given diets containing 0, 125, 250, 500, 1,000, or 2,000 ppm ephedrine sulfate and B6C3F1 mice of each sex were given diets containing 0, 310, 630, 1,250, 2,500, or 5,000 ppm ephedrine sulfate. The major response that occurred during the 13-week studies was compound-associated reduction in weight gain. Toxicology and carcinogenesis studies of ephedrine sulfate were conducted by administering diets containing 0, 125, or 250 ppm ephedrine sulfate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. The estimated average amount of ephedrine sulfate consumed per day during the 2-year study was 4 mg/kg and 9 mg/kg for low dose and high dose male rats, 5 mg/kg and 11 mg/kg for female rats, 14 mg/kg and 29 mg/kg for male mice, and 12 mg/kg and 25 mg/kg for female mice. Survival of chemically exposed female rats during the 2-year study was greater than that of the controls (control, 27/50; low dose, 39/50; high dose, 39/50); survival of exposed male rats and male and female mice was comparable to that of controls. Throughout most of the 2-year studies, mean body weights of rats and mice of each sex receiving diets containing ephedrine sulfate were lower than those of controls. Neoplasms that occurred in these studies were not considered to be related to administration of ephedrine sulfate. Two high dose female mice had ovarian granulosa cell tumors, and luteomas were found in one low dose and one high dose female mouse. Because of the low incidence, these uncommon, benign tumors could not be clearly related to ephedrine sulfate administration. Ephedrine sulfate was not mutagenic in four strains of Salmonella typhimurium (TA100, TA1535, TA97, or TA98) with or without Aroclor 1254-induced male Sprague-Dawley rat or Syrian hamster liver S9 activation. Ephedrine sulfate did not induce sister-chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. An audit of the experimental data was conducted for these 2-year studies of ephedrine sulfate. No data discrepancies were found that influenced the final interpretations. Under the conditions of these studies, there was no evidence of carcinogenicity for F344/N rats or B6C3F1 mice of either sex receiving 125 or 250 ppm ephedrine sulfate in the diet for 2 years.

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Dichloromethane (Methylene Chloride) (CAS No. 75-09-2) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Dichloromethane is widely used in industrial processes, food preparation, and agriculture. In industry, dichloromethane is used as a solvent in paint removers, degreasing agents, aerosol propellants, and triacetate solutions; as a blowing agent in flexible urethane foams; and as a process solvent in the manufacture of steroids, antibiotics, vitamins, and tablet coatings. The use of dichloromethane as an extraction solvent for spice oleoresins, hops, and caffeine from coffee has been approved by the U.S. Food and Drug Administration. Dichloromethane has been used as an inhalation anesthetic and as a fumigant for grain and strawberries. Toxicology and carcinogenesis studies of dichloromethane (99% pure) were conducted by inhalation exposure of groups of 50 male and 50 female F344/N rats and B6C3F1 mice 6 hours per day, 5 days per week, for 102 weeks. The exposure concentrations used (0, 1,000, 2,000, or 4,000 ppm for rats and 0, 2,000, or 4,000 ppm for mice) were selected on the basis of results from 13-week inhalation studies in which groups of 10 rats and 10 mice of each sex were exposed to dichloromethane at concentrations of 525-8,400 ppm 6 hours per day, 5 days per week. During the 2-year studies in rats, body weight gains for exposed males and females were comparable to those of the chamber controls. The survival of exposed male rats was comparable to that of the chamber controls; however, the survival of all groups of males at the termination of the study was low (control, 16/50; low dose, 16/50; mid dose, 17/50; high dose, 9/50). Most of the early deaths among male rats occurred during the final weeks of the study; the survival of male rats through week 86 of the study was 36/50, 39/50, 37/50, and 33/50. This decreased survival is believed to be related to the high incidence of leukemia (34/50; 26/50; 32/50; 35/50). Survival of female rats exposed at 4,000 ppm was reduced relative to that of the chamber controls (30/50; 22/50; 22/50; 15/50); leukemia occurred frequently in all female rat groups. Final mean body weights of high dose male mice and low and high dose female mice were 10%-17% lower than those of the chamber controls; these reductions occurred during the last 16 weeks of the study. The survival of dosed male mice and high dose female mice was reduced relative to that of the chamber controls (male: control, 39/50; low dose, 24/50; high dose, 11/50; female: 25/50; 25/50; 8/50). This reduced survival may have been due to the chemically induced development of liver and lung neoplasia in male and female mice. Increased incidences of benign mammary gland lesions (adenomas and fibroadenomas) occurred in male and female rats exposed to dichloromethane (male: 0/50; 0/50; 2/50; 5/50; female: 5/50; 11/50; 13/50; 23/50). The incidence of malignant mammary gland neoplasms was not increased in female rats (2/50; 2/50; 2/50; 0/50); none was observed in male rats. In addition, integumentary system tumors in the area of the mammary chain occurred with a positive trend in male rats (subcutaneous tissue fibroma or sarcoma: 1/50; 1/50; 2/50; 5/50); the combined incidence of all tumors in the mammary area in male rats was 1/50, 1/50, 4/50, and 9/50. Exposure to dichloromethane was associated with increased incidences of hepatic hemosiderosis, cytomegaly, cytoplasmic vacuolization, necrosis, granulomatous inflammation, and bile duct fibrosis in both male and female rats. There was a positive but marginal trend in the incidence of hepatocellular neoplastic nodules or hepatocellular carcinomas (combined) in female rats (2/50; 1/50; 4/50; 5/50). The incidence of squamous metaplasia of the nasal cavity was increased in female rats exposed at 4,000 ppm (1/50; 2/50; 3/50; 9/50) but not in males (4/50; 5/50; 3/50; 3/50). No nasal cavity tumors were observed in rats. The increased incidences of mononuclear cell leukemia in mid dose and high dose female rats (17/50; 17/50; 23/50; 23/50) were statistically significant by age-adjusted analyses. In male rats, mesotheliomas (arising primarily from the tunica vaginalis) occurred at increas) occurred at increased incidences (0/50; 2/50; 5/50; 4/50). Lung tumors occurred at increased incidences in male and female mice exposed to dichloromethane (alveolar/bronchiolar adenomas: male - 3/50; 19/50; 24/50; female - 2/50; 23/48; 28/48; alveolar/bronchiolar carcinomas: male - 2/50; 10/50; 28/50; female - 1/50; 13/48; 29/48). Cytologic degeneration of the liver was observed at increased incidences in high dose male and dosed female mice (male: 0/50; 0/49; 22/49; female: 0/50; 23/48; 21/48). Incidences of hepatocellular adenomas or hepatocellular carcinomas (combined) were increased in high dose male and dosed female mice (male: 22/50; 24/49; 33/49; female: 3/50; 16/48; 40/48). There were also dose-related increases in the numbers of mice bearing multiple lung or liver neoplasms. Dose-related increases were observed in the incidences of testicular atrophy in male mice and uterine and ovarian atrophy in female mice; these effects are considered to be secondary responses to neoplasia. An audit of the experimental data was conducted for the 2-year studies of dichloromethane. No data discrepancies were found that influenced the final interpretations. Under the conditions of these inhalation studies, there was some evidence of carcinogenicity of dichloromethane for male F344/N rats as shown by an increased incidence of benign neoplasms of the mammary gland. There was clear evidence of carcinogenicity of dichloromethane for female F344/N rats as shown by increased incidences of benign neoplasms of the mammary gland. There was clear evidence of carcinogenicity of dichloromethane for male and female B6C3F1 mice, as shown by increased incidences of alveolar/bronchiolar neoplasms and of hepatocellular neoplasms. Synonyms: DCM; methylene chloride

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Chlorinated Paraffins (C23, 43% Chlorine) (CAS No. 108171-27-3) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of chlorinated paraffins (C23, 43% chlorine), an extreme-pressure lubricant and flame retardant, were conducted by administering the chemical in corn oil by gavage to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week for 103 weeks. Additional groups of 10 rats per sex and dose were examined at 6 and at 12 months. Male rats received doses of 0, 1,875, or 3,750 mg/kg body weight; female rats were given 0, 100, 300, or 900 mg/kg. Male and female mice received 0, 2,500, or 5,000 mg/kg. Doses selected for the 2-year studies were based on the results from 13-week studies in which rats of each sex received 0 to 3,750 mg/kg, and mice of each sex, 0 to 7,500 mg/kg. No toxicity of chlorinated paraffins (C23, 43% chlorine) was observed in male rats or in male or female mice in the 13-week studies. A dose-related inflammation of the liver was observed in female rats in the 13-week studies and in male and female rats in the 13-week studies and in male and female rats at 6 and 12 months in the 2-year studies. Chlorinated paraffins (C23, 43% chlorine) administration did not influence mean body weights of rats during the 2-year studies, but both male and female low dose mice gained less weight than did vehicle controls or the high dose groups. Survival of dosed and vehicle control groups was similar for each sex and species (male rats: vehicle control, 30/50; low dose, 32/50; high dose, 27/50; female rats: 34/50; 30/50; 33/50; 31/50; male mice: 29/50; 36/50; 28/50; female mice: 21/50; 22/50; 20/50). For female mice, 60%-70% of the early deaths in each group were attributed to utero-ovarian infection. The lower survival for female mice may have decreased the sensitivity of this study to detect a carcinogenic effect. Pheochromocytomas of the adrenal gland medulla occurred with an increased incidence in female rats exposed to chlorinated paraffins (C23, 43% chlorine) (vehicle control, 1/50; low dose, 4/50; mid dose, 6/50; high dose, 7/50). However, adrenal gland medullary hyperplasia was not increased (6/50; 3/50; 1/50; 6/50). Malignant lymphomas were increased in dosed male mice (6/50; 12/50; 16/50). High dose female mice showed a marginal increase in the incidence of hepatocellular carcinomas (1/50; 1/49; 6/50) and in the incidence of adenomas or carcinomas (combined) (4/50; 3/49; 10/50). The primary nonneoplastic lesion associated with chlorinated paraffins (C23, 43% chlorine) administration was a diffuse lymphohistiocytic inflammation in the liver and in the pancreatic and mesenteric lymph nodes of male and female rats. Splenic congestion was a secondary effect. These lesions occurred earlier and at lower doses in female rats than in male rats. No significant nonneoplastic lesions were considered compound related in mice. Chlorinated paraffins (C23, 43% chlorine) was not mutagenic in strains TA100, TA1535, TA97, or TA98 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when assayed according to the preincubation protocol. An audit of the experimental data was conducted for these 2-year studies of chlorinated paraffins (C23, 43% chlorine). No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for male F344/N rats given 1,875 or 3,750 mg/kg per day. There was equivocal evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for female F344/N rats as shown by an increased incidence of adrenal gland medullary pheochromocytomas. There was clear evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for male B6C3F1 mice as shown by an increase in the incidence of malignant lymphomas. There was equivocal evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for female B6C3F1 mice as shown by a marginal increase in the incidence of hepatocellular neoplasms. *The Chemical Abstract Service Seal increase in the incidence of hepatocellular neoplasms. *The Chemical Abstract Service Service (CAS) number that appeared on this technical report at the time of publication (63449-39-8) reflects the generic CAS number for chlorinated paraffins. This number has been replaced in the NTP Chemtrack chemical tracking system with the more appropriate number.

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of 4-Vinylcyclohexene (CAS No. 100-40-3) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of 4-vinylcyclohexene (greater than 98% pure), a dimer of 1,3-butadiene present in the off-gasses from tire curing, were conducted by administering the chemical in corn oil by gavage 5 days per week at doses of 0, 200, or 400 mg/kg body weight to groups of 50 F344/N rats and B6C3F1 mice of each sex for 103 weeks. Doses selected for the 2-year studies were based on survival, body weight gains, and histopathologic effects observed during the 14-day and 13 week studies. All rats and most mice in the 14-day studies died when administered doses greater than or equal to 1,250 mg/kg, although no compound-related gross or histopathologic effects were observed. Final body weights were reduced in the 13-week studies in male rats receiving doses greater than or equal to 400 mg/kg of 4-vinylcyclohexene, in female rats receiving 800 mg/kg, and in female mice receiving 600 mg/kg. Extensive mortality was observed only in mice dosed at 1,200 mg/kg. Compound-related histopathologic effects in the 13-week studies included hyaline droplet degeneration of the proximal convoluted tubules of the kidney in dosed male rats, the severity of which was dose related, and a reduction in the number of primary follicles and mature graafian follicles in the ovaries of female mice receiving 1,200 mg/kg of 4-vinylcyclohexene. No compound-related gross or histopathologic effects were evident in dosed female rats or male mice in the 13-week studies. Many dosed rats died early in the 2-year studies (male: vehicle control, 17/50; low dose, 37/50; high dose, 45/50; female: vehicle control, 10/50; low dose, 22/50; high dose, 36/50; P<0.001 for all groups except low dose female rats, for which P=0.022). The poor survival of dosed male and female rats reduced the sensitivity of the studies for detecting the possible carcinogenic effects of 4-vinylcyclohexene. Mean body weights of dosed rats were comparable to those of their respective vehicle controls, except for high dose males late in the study. Survival of high dose mice of each sex was lower (P<0.001) than that of the vehicle controls, whereas survival of low dose mice of each sex was comparable to that of the vehicle controls. Mean body weights of high dose mice of each sex were generally lower than those of the vehicle controls throughout most of the 2-year studies. Administration of 4-vinylcyclohexene to F344/N rats by gavage for 2 years was associated with a slightly increased incidence of epithelial hyperplasia of the forestomach (1/50; 3/50; 5/47) and squamous cell papillomas or carcinomas (combined) of the skin in high dose males (0/50; 1/50; 4/50). Low dose female rats, whose survival was more similar to that of the vehicle controls, had a marginally increased incidence of adenomas or squamous cell carcinomas (combined) of the clitoral gland (1/50; 5/50; 0/49). In B6C3F1 mice, administration of 4-vinylcyclohexene for two years by gavage was associated with mild, acute inflammatory lesions and epithelial hyperplasia of theforestomach, especially in males (0/47; 7/50; 7/46), and with an increased incidence of a number of other nonneoplastic lesions, including lung congestion in high dose males and females, splenic red pulp atrophy in high dose males, congestion of the adrenal gland in high dose females, and cytologic alteration of the adrenal cortex in low dose and high dose females. The incidences of uncommon ovarian neoplasms were markedly increased (P<0.01) in both groups of dosed female mice (mixed tumor, benign: 0/49; 25/48, 52%; 11/47, 23%; granulosa cell tumor or carcinoma [combined]: 1/49, 2%; 10/48, 21%; 13/47, 28%). In addition, a slight increase in the incidence of adrenal gland adenomas in high dose females was observed (0/50; 3/49, 6%; 4/48, 8%). The extensive mortality seen in the high dose male mice confounded interpretation of the increased incidences of malignant lymphomas and alveolar/bronchiolar adenomas or carcinomas (combined) of the lung seen in these animals surviving to the end of the study (malignant lymphomas: 3/37, 8%; 5/39, 13%; 4/7, 57d of the study (malignant lymphomas: 3/37, 8&percnt;; 5/39, 13&percnt;; 4/7, 57&percnt;; alveolar/bronchiolar adenomas or carcinomas [combined]: 3/37, 8&percnt;; 9/39, 23&percnt;; 3/7, 43&percnt;). 4-Vinylcyclohexene was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when tested according to the preincubational protocol. However, several of its metabolites, including 4-vinylcyclohexene diepoxide, have been shown to be mutagenic in Salmonella and/or induce chromosomal damage in vitro. An audit of the experimental data was conducted for these 2-year carcinogenesis studies on 4-vinylcyclohexene. No data discrepancies were found that influenced the final interpretations. 4-Vinylcyclohexene was administered by gavage in corn oil to F344/N rats and B6C3F1 mice of each sex at doses of 200 or 400 mg/kg for 103 weeks. Under these conditions, the 2-year gavage studies of 4-vinylcyclohexene in male and female rats and male mice were considered inadequate studies of carcinogenicity because of extensive and early mortality at the high dose or at both doses and the lack of conclusive evidence of a carcinogenic effect. There was clear evidence of carcinogenicity of 4-vinylcyclohexene for female mice, as shown by markedly increased incidences of uncommon ovarian neoplasms at both doses. In addition, the increased incidence of adrenal gland adenomas in high dose female mice may have been related to the administration of 4-vinylcyclohexene. Synonym: 4-ethenylcyclohexene

Journal Article↗
PubMed1987

NTP Toxicology and Carcinogenesis Studies of Pentachloronitrobenzene (CAS No. 82-68-8) in B6C3F1 Mice (Feed Studies).

Toxicology and carcinogenesis studies of pentachloronitrobenzene (99% pure), a fungicide, were conducted by administering diets containing 0, 2,500, or 5,000 ppm pentachloronitrobenzene to groups of 50 B6C3F1 mice of each sex for 103 weeks. These doses were selected because, in 13-week studies in which the chemical was administered in feed at doses up to 20,000 ppm in male mice and up to 40,000 ppm in female mice, body weight gain depression was observed at 10,000 ppm and above in males and female and deaths occurred at 40,000 ppm in females. The National Cancer Institute had conducted 2-year (diet) studies in B6C3F1 mice and Osborne-Mendel rats (See TR-61 reported in 1978). Survival among male mice was low, not all livers were examined from dosed female mice, and the size of the control group was considered to be small. For these reasons, the NCI decided to conduct additional 13-week and 2-year studies in B6C3F1 mice. Under the conditions of the NCI studies, pentachloronitrobenzene was not carcinogenic in either Osborne-Mendel rats or B6C3F1 mice. In the studies reported in this Technical Report, the survival of male mice was comparable among control and dosed groups (control, 35/50; low dose, 31/50; high dose, 32/50). Final mean body weights of low dose and high dose male mice were 96% and 90% that of the controls. All groups of female mice showed evidence of bacterial infection. At week 84, survival in dosed and control female mice was 38/50; 34/50; 30/50; after week 84, survival in dosed groups decreased, with the final survival being 30/50; 20/50; 15/50. The mean body weight of high dose female mice was more than 10% lower than that of the control group after week 20 and was 21% lower than controls at week 104. The mean body weight of low dose female mice was within 10% that of the control group until week 88 and was 18% lower than controls at week 104. No compound-related neoplastic lesions were seen in either male or female mice. The nonneoplastic lesions observed in female mice were considered to be secondary to bacterial infection (primarily Klebsiella) and included hematopoiesis of the liver (9/50; 21/50; 23/50) and spleen (14/50; 23/48; 27/50), plasma cell hyperplasia of the mediastinal lymph nodes (1/44; 4/47; 9/45), and ovarian abscesses (12/49; 22/50; 29/50). Pentachloronitrobenzene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor 1254-induced male Syrian hamster or male Sprague-Dawley rat liver S9 when tested according to the preincubational protocol. Pentachloronitrobenzene was not mutagenic at the TK+/- locus of L5178Y mouse lymphoma cells in the presence or absence of Aroclor 1254-induced F344/N rat liver S9. In cultured Chinese hamster ovary cells, pentachloronitrobenzene did not induce sister-chromatid exchanges but did induce chromosomal aberrations both with and without Aroclor 1254-induced male Sprague-Dawley rat liver S9. An audit of the experimental data was conducted for the 2-year studies of pentachloronitrobenzene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year feed studies, there was no evidence of carcinogenicity for either male or female B6C3F1 mice receiving 2,500 or 5,000 ppm of pentachloronitrobenzene. Infection is considered to have decreased survival of the female mice and thus reduced the sensitivity for determining the presence or absence of a carcinogenic response. Synonyms or Trade Names: Avicolreg.; PCNB; quintozene; Botrilexreg.; Brassicolreg.;Folosanreg.; PKhNB; Tilcarexreg.; Terraclorreg.; Tritosanreg.

Journal Article↗
PubMed1987

NTP Toxicology and Carcinogenesis Studies of Phenylephrine Hydrochloride (CAS No. 61-76-7) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Phenylephrine hydrochloride is a sympathomimetic amine recommended for use as a nasal decongestant and as a mydriatic in ophthalmic applications. In 1977, total U.S. human exposure was estimated at 1.9 x 107 g per year. Phenylephrine hydrochloride was nominated for toxicology and carcinogenesis studies because of a lack of previous long-term studies and because two other sympathomimetic agents (soterenol hydrochloride and mesuprine hydrochloride) produced mesovarial leiomyomas in Sprague-Dawley rats. Toxicology and carcinogenesis studies of USP-grade phenylephrine hydrochloride were conducted by administering diets containing the chemical (99% pure) to F344/N rats and B6C3F1 mice of each sex in studies of 14 days, 12 weeks, and 2 years. In the 14-day studies, no toxic effects were seen in rats or mice fed diets containing up to 2,000 ppm phenylephrine hydrochloride. Doses were increased in the 12-week studies, and deaths of male rats and male mice were observed in groups fed diets containing 10,000 or 20,000 ppm; 1/10 male rats in the 5,000-ppm group died. Other than inflammatory eye lesions (considered secondary to the pharmacologic drying action of the chemical), no specific organ toxicity was noted. Body weights decreased as concentrations of phenylephrine hydrochloride in the diet were increased, and feed consumption was lower in dosed rats. Doses of 0, 620, and 1,250 ppm for rats and 0, 1,250, and 2,500 ppm for mice were selected for the 2-year studies because of the decreased body weight gains in animals given higher doses in the 12-week studies. In the 2-year studies, the approximate amount of phenylephrine hydrochloride consumed per day was 24 mg/kg for low dose rats, 50 mg/kg for high dose rats, 133 mg/kg for low dose mice, and 270 mg/kg for high dose mice. Body weight differences in rats appeared to be dose related, and dosed animals were 3%-15% lighter than controls. Body weights of dosed mice averaged 3%-14% lower than those of controls throughout the 2-year studies. Survival of high dose male rats was greater than that of the controls (control, 30/50; low dose, 33/50; high dose, 42/50); differences in survival were not significant for female rats (42/50; 34/50; 36/50), male mice (35/50; 38/50; 43/50), or female mice (37/50; 34/50; 34/50). Few nonneoplastic lesions were related to phenylephrine hydrochloride dosing in rats or mice. Chronic focal inflammation of the liver was observed at increased incidences in dosed rats (male: 2/50; 13/50; 17/50; female:17/50; 28/50; 35/50). Inflammation of the prostate was seen more frequently in dosed than in control males (10/50; 24/50; 24/50). The incidence of focal cellular change in the liver was increased slightly in high dose male mice (0/50; 2/50; 7/50). In male rats, mononuclear cell leukemia (24/50; 9/50; 5/50) and pheochromocytomas of the adrenal gland (14/49; 11/50; 2/50) occurred with negative trends, and the incidences in the high dose group were lower than those in the controls. No increases in neoplasia were seen in dosed male or female rats or mice. Phenylephrine hydrochloride was not mutagenic in four strains of Salmonella typhimurium (TA100, TA1535, TA1537, and TA98) with or without Aroclor 1254-induced liver S9 from male Sprague-Dawley rats or male Syrian hamsters. The results of mutagenicity studies of phenylephrine hydrochloride were equivocal in the mouse lymphoma L5178Y/TK+/- assay in the absence of S9; it was not tested in the presence of S9. Phenylephrine hydrochloride induced sister-chromatid exchanges (SCEs) but not chromosomal aberrations in Chinese hamster ovary cells. The increase in SCEs was seen only in the absence of metabolic activation with S9. An audit of the experimental data was conducted for the 2-year studies of phenylephrine hydrochloride. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year studies, there was no evidence of carcinogenicity of phenylephrine hydrochloride for male B6C3F1 mice given 1,250 or 2,500 ppm in feed. Survival of high dose male rats was greater than of high dose male rats was greater than that of controls, and the incidences of mononuclear cell leukemia and pheochromocytomas were lower in dosed than in control male rats. Inflammation was observed more frequently in the liver and prostate gland of dosed male rats than in controls. Synonyms: benzene methanol,3-hydroxy-a[(methylamino)methyl]hydrochloride (R)-; (-)-meta-hydroxy-a-[(methylamino)methyl]benzyl alcohol hydrochloride; meta-Synephrine hydrochloride; Neo-synephrinereg.

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Dimethylvinyl Chloride (1-Chloro-2-Methylpropene) (CAS No. 513-37-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Dimethylvinyl chloride is a clear colorless liquid, which, because of its volatility and flammability at room temperature, is a significant fire hazard. It has a boiling point of 68.1 degrees C (155 degrees F) and a density at 20 degrees C of 0.919 g/ml. Dimethylvinyl chloride is a byproduct in the production of 3-chloro-2-methylpropene by the chlorination of isobutene. It is not known to be produced in the United States for other than laboratory purposes. This chemical was nominated for toxicologic studies because of its reported presence in ambient air in the Baltimore area and was selected for toxicologic characterization because of its structural similarity to the known animal and human carcinogen, vinyl chloride monomer. Toxicology and carcinogenesis studies of dimethylvinyl chloride (96%-98% pure), a structural analog of vinyl chloride monomer, a known human carcinogen, by administered dimethylvinyl chloride in corn oil by gavage to groups of 50 male and 50 female F344/N rats and B6C3F1 mice at doses of 0, 100, or 200 mg/kg body weight 5 days per week for 102 or 103 weeks. The selection of these doses was based on results of 13-week studies, which included depression of body weight at doses of 500 mg/kg or above in rats as well as histopathologic changes intestinal epithelium, bone marrow, hepatocytes, and the testes at doses of 250 mg/kg and above; doses in mice were selected on the basis of histopathologic changes in lymphopoietic cells, liver, pancreatic islets, ovary, testis, and spleen, with changes being most prominent at doses of 500 mg/kg and above. In the 2-year studies, body weights of rats and mice given 100 mg/kg were comparable to those of the vehicle controls except for the last few weeks in mice when body weights were markedly lower than those for the vehicle controls. At 200 mg/kg, the mean body weights of rats and mice were progressively decreased relative to those of vehicle controls, with the significant departure from vehicle controls occurring somewhat earlier in males than in females. Survival of vehicle control rats and mice was comparable to historical values; however, survival of dosed male and female rats was significantly lower than that of vehicle controls, with the incidence of mortality being more severe at the high dose than at the low dose. There were no survivors in the high dose group of male rats after week 85 or in the high dose group of female rats after week 97. Survival was significantly lower among dosed male and female mice compared with vehicle controls. In the absence of toxicological findings that would explain the early deaths, it is assumed that the high incidence of tumors and chemical-related toxicity contributed to the decreased survival of dosed rats and mice. In rats, the severity and incidence of nonneoplastic lesions were minimal; these lesions included necrosis of the duodenum and epithelial hyperplasia at the sites of tumor formation--the nasal cavity, esophagus, and forestomach. In mice, the severity of nonneoplastic lesions was also minimal; the lesions included necrosis of the liver, bone marrow granulocytic hyperplasia, and inflammation of the nasal cavity (small number, females only.) Several types of neoplastic lesions occurred with significantly increased incidences in dosed animals as shown in the following table (see page 11 of Technical Report). Among rats, these lesions included malignant epithelial tumors of the nasal cavity and squamous cell tumors of the oral cavity, esophagus, and forestomach in males and females. The increased number of fibroadenomas of the mammary gland in female rats may have been related to dimethylvinyl chloride administration. The lack of a clear dose-response relationship for certain tumors in rats is considered to be related to the increased number of early deaths observed in the high dose groups. Among dosed mice, there were significantly increased incidences of squamous cell carcinomas of the forestomach (both sexes), squamous cell papillomas of the forestomach (males), and squamous cell carcinomas of the preputial gla preputial gland (males). The increased incidence of papillary adenomas of the harderian gland and alveolar/bronchiolar adenomas or carcinomas in female mice may have been related to administration of dimethylvinyl chloride. Limited metabolism studies of 14C-labeled dimethylvinyl chloride were conducted in male F344/N rats and B6C3F1 mice. Single doses of 150 mg/kg were administered to rats for 1, 2, or 4 consecutive days. About 25&percnt; of the administered doses was exhaled as carbon dioxide; this amount was independent of the number of doses administered. Another 25&percnt;-35&percnt; of the administered dose was exhaled; 96&percnt; of this parent was material. Approximately 35&percnt; and 6&percnt; were excreted in the urine and feces, respectively. The elimination half-life of radioactive label was 3-4 days for the liver and kidney, the two organs containing the greatest amounts of the administered dose. In mice, a much smaller fraction of the dose was exhaled and a larger proportion was excreted in urine compared with rats. Dimethylvinyl chloride was not mutagenic in four strains ofSalmonella typhimurium with or without metabolic activation, but it was mutagenic in the mouse lymphoma L5178Y/TK&plusmn; assay in the absence of metabolic activation. Sister-chromatid exchanges were induced in Chinese hamster ovary cells with and without metabolic activation, but there was no increase in chromosomal aberrations. When fed to Drosophila, dimethylvinyl chloride induced significant increases in the frequencies of both sex-linked recessive lethal mutations and reciprocal translocations. Studies of the immunotoxicity of dimethylvinyl chloride were conducted in which female B6C3F1 mice received daily oral doses of 0, 50, 100, 200, or 400 mg dimethylvinyl chloride per kilogram body weight. Compound-related increases in susceptibility to bacterial infection and decreases in macrophage cytostasis were observed at all doses. At the highest dose, the decreased resistance to bacterial and viral challenge could be related to alterations in specific immune function. However, the increased mortality in rats and mice in the 2-year studies was not relatable to infectious processes. An audit of the experimental data was conducted for these2-year toxicology and carcinogenesis studies on dimethylvinyl chloride. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of dimethylvinyl chloride for both sexes of F344/N rats and B6C3F1 mice. This was based on increased incidences of neoplasms of the nasal cavity, oral cavity, esophagus, and forestomach of male and female F344/N rats. B6C3F1 mice showed increased incidences of squamous cell neoplasms of the forestomach in males and females and squamous cell carcinomas of the preputial gland in males. Synonym: 1-chloro-2-methylpropene

Journal Article↗
PubMed1987

NTP Toxicology and Carcinogenesis Studies of Oxytetracycline Hydrochloride (CAS No. 2058-46-0) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Toxicology and carcinogenesis studies were conducted on oxytetracycline hydrochloride (greater than 98.8% pure), a broad-spectrum antibiotic. Groups of F344/N rats and B6C3F1 mice were fed diets containing oxytetracycline hydrochloride for a series of 14-day, 13-week, and 2-year studies. In the 14-day studies, no compound-related gross pathologic effects were seen in rats or mice (groups of five animals per sex per species) given up to 100,000 ppm in their feed. The final mean body weight of male rats receiving in feed was 27% lower than that of the controls. Final mean body weights of mice that received 25,000, 50,000, or 100,000 ppm were lower (male: 11%; 16%; 17%; female: 6%; 5%; 17%) than those of the controls. In the 13-week studies, groups of 10 male and 10 female rats and mice were fed diets containing up to 50,000 ppm in feed, and no chemically related gross or histopathologic effects were observed in mice of either sex or in female rats. In male rats, fatty metamorphosis of minimal severity was diagnosed in the liver of 5/10 animals at 6,300, 12,500, and 50,000 ppm and in 2/10 animals at 3,100 and 25,000 ppm. None was seen in the controls. Oxytetracycline levels in bones of rats and mice (as determined fluorometrically) at the end of the 13-week studies increased with dose, the highest levels (3-10 times background levels) being observed at 50,000 ppm. The 2-year toxicology and carcinogenesis studies were conducted by administering diets containing 0, 25,000, or 50,000 ppm oxytetracycline hydrochloride to groups of 50 male and 50 female rats and diets containing 0, 6,300, or 12,500 ppm oxytetracycline hydrochloride to groups of 50 male and 50 female mice for 103 weeks. The highest dose selected for rats was considered to be the maximum level that would not affect the nutritional value of dosed feed. The dietary concentrations correspond to the following approximate doses: rats-- 0, 1,000, or 2,000 mg/kg body weight per day; mice-- 0, 650, or 1,400 mg/kg per day. Mean body weights were approximately 5%-8% lower than those of controls in high dose male rats during weeks 4-47, in high dose male mice after week 31, and in high dose female mice after week 26. The mean body weights of dosed female rats and low dose male and female mice were comparable to those of controls. The survival of control male rats was lower than that of the high dose group (22/50 vs 38/50). No significant differences in survival were observed between the remaining groups of rats or between any groups of mice. Pheochromocytomas of the adrenal gland occurred with positive trends in male rats (control, 10/50; low dose, 18/50; high dose, 24/50), and the incidence in the high dose group was greater than that in the controls. Two additional control males and one additional low dose male had malignant pheochromocytomas. The incidence of adrenalgland medullary hyperplasia was elevated slightly but not significantly in dosed male rats (7/50; 14/50; 9/50). Adenomas and adenomas and adenocarcinomas (combined) of the pituitary gland in female rats occurred with positive trends, and the incidences in the high dose group were greater than that in the controls (adenomas: 19/50; 17/50; 30/50; adenomas or adenocarcinomas [combined]: 20/50; 24/50; 32/50). The incidence of pituitary gland hyperplasia was slightly decreased in dosed female rats (16/50; 10/50; 11/50). No compound-related increases in nonneoplastic or neoplastic lesions were observed in male or female mice. Oxytetracycline hydrochloride was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when assayed according to the preincubational protocol. Oxytetracycline hydrochloride was mutagenic in L5178Y/TK+/- mouse lymphoma cells in the presence but not in the absence of Aroclor 1254-induced male rat liver S9. In cultured Chinese hamster ovary cells, oxytetracycline was weakly positive in inducing sister-chromatid exchanges both with and without Aroclor 1254-induced mang sister-chromatid exchanges both with and without Aroclor 1254-induced male Sprague-Dawley rat liver S9 but did not induce chromosomal aberrations. An audit of the experimental data was conducted for these 2-year carcinogenesis studies of oxytetracycline hydrochloride. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year feed studies of oxytetracycline hydrochloride, there was equivocal evidence of carcinogenicity for male F344/N rats, as indicated by increased incidences of pheochromocytomas of the adrenal gland. There was equivocal evidence of carcinogenicity for female F344/N rats fed diets containing oxytetracycline hydrochloride, as indicated by increased incidences of adenomas of the pituitary gland. There was no evidence of carcinogenicity for male or female B6C3F1 mice fed diets containing 6,300 or 12,500 ppm oxytetracycline hydrochloride for 2 years. Synonyms: 2-naphthacenecarboxamide,4(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6-10,2,12a-pentahydroxy-6-methyl-1,11-dioxo-monohydrochloride; Biosolvmycin; Hydrocyclin; Liquamycin; Otetryn; Oxlopar; 5-hydroxytetracycline hydrochloride; Terramycin Hydrochloride; Tetramine; Tetran Hydrochloride

Journal Article↗
PubMed1986

NTP Toxicology and Carcinogenesis Studies of Methyl Methacrylate (CAS No. 80-62-6) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Toxicology and carcinogenesis studies of methyl methacrylate, a liquid chemical intermediate used in the plastics industry in the manufacture of plexiglass and other acrylic products, were conducted by exposing groups of F344/N rats and B6C3F1 mice by inhalation for 14 weeks and 2 years. In the 14-week studies, groups of 10 male and 10 female rats and mice were exposed to methyl methacrylate at concentrations of up to 5,000 ppm. All male and female rats and eight male and eight female mice exposed at 5,000 ppm died, one male and nine female rats and four male and no female mice exposed at 3,000 ppm died, and one male and three female rats and two male and one female mouse exposed at 2,000 ppm died; all rats and mice exposed at 500 or 1,000 ppm survived. Compared with the controls, the body weights of the exposed male and female rats and mice were lower. Compound-related lesions included inflammation associated with necrosis and loss of olfactory epithelium in the nasal turbinates in both male and female rats; malacia and gliosis in female rats; inflammation of the nasal turbinates and nasal epithelium metaplasia in both male and female mice; and renal cortical necrosis, renal cortical tubular degeneration, renal focal mineralization, and liver necrosis in male mice. Based on these results, 2-year inhalation toxicology and carcinogenesis studies were conducted in which groups of 50 male rats were exposed to methyl methacrylate at 0, 500, or 1,000 ppm; female rats at 0, 250, or 500 ppm; and male and female mice at 0, 500, or 1,000 ppm. In the 2-year studies, the body weights of the low dose and high dose male and female rats were within 10% of those of the controls. There was no difference in survival between the dosed male and female rats and the controls. Incidences of inflammation of the nasal cavity and degeneration of the olfactory sensory epithelium were greater in the dosed male and female rats than in the controls, with lesions seen in virtually all high dose animals. An increased incidence of mononuclear cell leukemia was observed in female rats exposed to methyl methacrylate at 500 ppm compared with the controls (control, 11/50; 250 ppm, 13/50; 500 ppm, 20/50). This increase was not significant by life table tests, the method of analysis most appropriate for this fatal neoplasm. The mean body weights of dosed male and female mice were 5%-8% lower than those of the controls at the end of the 2-year studies. However, during most of the second year of the studies, body weights of dosed male mice and high dose female mice were 10%-18% lower than those of the controls. Survival rates of the dosed and control mice were similar. Incidences of inflammation and epithelial hyperplasia of the nasal cavity and degeneration of the olfactory sensory epithelium were significantly greater in all dosed groups of male and female mice compared with those of the controls. Compound-related neoplastic lesions were not found in the dosed mice. Significant dose-related decreases were observed in the incidences of pituitary gland and preputial gland tumors in male rats, alveolar/bronchiolar adenomas or carcinomas (combined) in male mice, hepatocellular adenomas in both male and female mice, and pituitary gland adenomas or adenocarcinomas (combined) and uterine adenocarcinomas in female mice. Methyl methacrylate was not mutagenic in strains TA100, TA1535, TA97, or TA98 of Salmonella typhimurium in the presence or absence of male rat or hamster liver S9 when assayed by a preincubational protocol but gave a positive response in L5178Y/TK+/- mouse lymphoma cells in the presence or absence of male rat liver S9. In cultured Chinese hamster ovary cells, methyl methacrylate produced a reproducible, dose-related increase in the frequency of sister-chromatid exchanges, both with and without rat liver S9. A slight, dose-related increase in chromosomal aberrations was also induced in cultured Chinese hamster ovary cells in the absence of S9; in the presence of S9, an increase in the frequency of aberrations was seen only at the highest, near-lethalas seen only at the highest, near-lethal dose of 5 mg/ml. An audit of the experimental data was conducted for the 2-year carcinogenesis studies on methyl methacrylate. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenicity of methyl methacrylate for male F344/N rats exposed at 500 or 1,000 ppm, for female F344/N rats exposed at 250 or 500 ppm, or for male and female B6C3F1 mice exposed at 500 or 1,000 ppm. Inhalation of methyl methacrylate was associated with inflammation of the nasal cavity and degeneration of the olfactory sensory epithelium in male and female rats and mice; epithelial hyperplasia of the nasal cavity was also observed in exposed mice. Synonyms: acrylic acid, 2-methyl, methyl ester; methacrylic acid, methyl ester; methyl a-methylacrylate; methyl methylacrylate; methyl-2-methylpropenoate; methyl-2-methyl-2-propenoate; 2-methyl-2-propenoic acid methyl ester; MME

Journal Article↗
PubMed2000

Care management in three practices--scope for improvement?

OBJECTIVE: The process of assessment of older people for residential/nursing home care may take place by hospital based social workers, or by care managers working in the community. We sought to compare the assessment process in each setting. The standards for the audit were that the data collection for both groups was equivalent, that both groups had a multi-disciplinary assessment, and that outcomes in both settings were appropriate. DESIGN: Identification of all older people assessed as requiring residential/nursing home care from 1/7/97-31/12/97, who were registered with the three general practices in Aberdeen participating in this study. Social Work case files and care plans were reviewed. All individuals were visited and dependency scores obtained--Abbreviated Mental Test, Barthel Index, and CAPE (Clifton Assessment Procedures for the elderly--Behaviour Rating Scale component) score. SETTING: Review of hospital social work case files, and community based case files. Interviewing of the older person in their own home, hospital, residential or nursing home to obtain dependency scores. SUBJECTS: Thirty three people were referred-17 from the community, and 16 from hospital. RESULTS: Case files in both groups were well maintained. There were differences in procedures between the assessment processes, but outcomes appeared to be similar. There was no statistical difference in mean dependency scores between each group. However, information on levels of support in the files was limited, particularly for the community group. Dependency scores correlated with residential/nursing home care being appropriate for the 33 individuals, but only 50% of people were identified as wanting such arrangements. Evidence of a recorded medical assessment was absent in 47% of the community referred population. CONCLUSION: Evidence of a multi-disciplinary assessment was not always available, especially for the community referred individuals. A greater emphasis on a multi-disciplinary assessment could highlight a need for rehabilitation, which might allow for the improvement and maintenance of some frail older people in the community, this often being in accordance with their wishes.

Activities of Daily Living↗
PubMed2003

Clinical and management factors related to outcome in neonatal tetanus.

Although tetanus is a well-recognised, well-described, preventable and eradicable infection, it continues to ravage the lives of children in developing countries, especially among neonates. A cross-sectional review of cases of neonatal tetanus seen in LUTH was carried out retrospectively. Thirty-nine (39) cases were studied, comprising 26 (63.4%) males and 15 (36.6%) females, giving a male: female ratio of 1.6:1. Case fatality rate was 10.3%, thirty-five (89.7%) cases survived, of which nine (23.8%) survived with complications. Clinical factors that influence outcome were: a short interval between onset and presentation (p = 0.03), low tetanus score below 6.0 (p = 0.002), hyperpyrexia (p = 0.0001), heart failure (p = 0.035), cyanosis (p = 0.008) and crepitations (p = 0.003). Although several management factors were associated with mortality, these failed to meet statistical significance (p > 0.05). In this study, clinical factors, including presentation interval, were the principal determinants of outcome. The need for intensification and sustenance of preventive measures, early recognition and presentation, prompt treatment as well as improved care are emphasised. We recommend periodic audit of patient clinical data towards improving quality of care.

Cross-Sectional Studies↗
PubMed1992

Setting district stroke standards and objectives. A Report of the West Lambeth Health Authority Stroke Steering Group.

Although stroke is a common disease consuming considerable NHS resources little is known about how effectively these resources are distributed. A local district stroke register has revealed the burden and pattern of care for stroke patients locally which has prompted the setting up of a stroke steering group whose aim is to promote the effective local use and provision of services for stroke patients. The multidisciplinary group has adopted the Royal College of Physicians' recommendations on stroke care for local use and incorporated them into a document which has been distributed to all health care professionals managing stroke patients. The group has also devised a standardised clerking proforma to collect data with which to audit stroke care. Based on these recommendations, standards have been set in the main domains of care for stroke patients with the aim of improving stroke services locally. Having identified local problems in the provision of care, set standards and devised a mechanism for the audit of stroke care, the district is now hopefully in a position to effect change and close the audit loop.

Age Factors↗
PubMedDate not supplied

Key issues in diagnosing and treating hepatitis C infection.

A strategy and action plan is in place for the management of hepatitis C. However, recent evidence suggests that this is not being implemented and hepatitis C remains a significant public health concern. This article summarises the condition and potential problems, highlights data from the recent audit of practice and outlines the latest recommendations for managing hepatitis C.

Benchmarking↗
PubMedDate not supplied

Clinical databases in nephrology: research and clinical practice goals and challenges.

In clinical practice we formulate direct questions related to patient management that should be answered on the basis of results of valid studies. Bias problems are dealt with using different approaches in observational studies and in clinical trials. The clinical trial is the standard for assessing the efficacy of treatments while the efficiency of treatments at community level is better captured by observational studies. Electronic medical records have now emerged as a precious, matchless data source for clinical audits. The value of an audit cannot be taken for granted and should be tested in the specific health care setting where it is applied. Electronic medical records and high quality clinical databases offer a great opportunity for performing observational studies and for reducing the cost of clinical trials. Research on audit and feedback functionality is a new, useful and stimulating research area which may be of great interest to nephrologists.

Clinical Audit↗