National Toxicology Program technical report series最新文献

Vinylidene chloride is used as an intermediate in organic synthesis reactions and is widely used in the production of a variety of polymers. Most of the vinylidene chloride in the plastics industry is used in the production of copolymers with polyvinylidene polymers that have a broad spectrum of application, including in films for household and industrial food packaging, as coatings on a variety of products, in flame-resistant fiber and carpet backing, as binders in paints, and to fabricate filaments, pipes, pipe liners, and gaskets. The highest potential for human exposure to vinylidene chloride is at its point of production and formulation, and occupational exposure may occur via inhalation or dermal contact. The general population is exposed via inhalation and ingestion of contaminated drinking water. Vinylidene chloride was nominated for study by the Agency for Toxic Substances and Disease Registry because of the potential for human exposure, and because there was insufficient critical information concerning its health effects and a need to fill critical data gaps. Male and female F344/N rats and B6C3F1/N mice were exposed to vinylidene chloride (greater than 99.9% pure) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, L5178Y mouse lymphoma cells, Drosophila melanogaster, and mouse peripheral blood erythrocytes. (Abstract Abridged).

Widespread exposure to cobalt metal dust occurs occupationally through the production of alloys, in the manufacture of cobalt salts, and in nuclear technology. It is an effective catalyst for many organic reactions, particularly in hydrotreating catalysts, which have molybdenum and cobalt sulfides as active components. Concerns have been raised about the occurrence of occupational disease, i.e. hard metal disease, associated with exposure to cobalt and its compounds, including cobalt metal-tungsten carbide. Cobalt metal is also widely dispersed in low concentrations in the environment and the general population may be exposed by breathing air, drinking water, or skin contact with soil, water, cobalt alloys, or other substances that contain cobalt. In addition, cobalt metal is an essential trace element as a component of cyanocobalamin (vitamin B12). Cobalt metal dust was nominated for toxicology and carcinogenesis studies by the United Auto Workers and the Cobalt Development Institute based on the widespread occupational exposure and limited availability of data on chronic toxicity and carcinogenic potential of inhaled insoluble cobalt compounds, particularly cobalt metal dust. Inhalation was selected as the route of exposure because this is the most common route of exposure to cobalt metal dust in occupational settings in humans. Male and female F344/N or F344/NTac rats and B6C3F1/N mice were exposed to cobalt metal by inhalation for 2 weeks, 3 months, or 2 years (F344/NTac rats). In addition, genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. (Abstract Abridged).

Glycidamide is a reactive electrophile that occurs primarily as a metabolite of acrylamide. Because acrylamide can be formed as a by-product during the cooking of starchy foods (including French fries, potato chips, and bread) and the roasting of coffee, the National Toxicology Program performed simultaneous studies to determine and compare the long-term effects of acrylamide and glycidamide in male and female F344/N Nctr rats and B6C3F1/Nctr mice. The data from the animals exposed to acrylamide formed the basis for NTP Technical Report 575. The results from the studies with glycidamide form the basis for the current report. (Abstract Abridged).

Tetrabromobisphenol A is a flame retardant used in epoxy resin circuit boards, in electronic enclosures (of polycarbonate-acrylonitrile-butadiene-styrene plastics), in paper, and in textiles. It may also be used as a chemical intermediate for the synthesis of other flame retardants. Tetrabromobisphenol A was nominated by the NIEHS for toxicity and carcinogenicity studies based on its high production volume, the potential for widespread human exposures, and the absence of standard toxicity and carcinogenicity studies reported in the scientific literature. Male and female F344/NTac rats and B6C3F1/N mice were administered tetrabromobisphenol A (purity of greater than 99%) in corn oil by gavage for 3 months, and male and female Wistar Han [Crl:WI(Han)] rats (referred to as Wistar Han rats) and B6C3F1/N mice were administered tetrabromobisphenol A (purity of approximately 99%) in corn oil by gavage for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. (Abstract Abridged).

β-Picoline is used as a solvent in the synthesis of pharmaceuticals, resins, dyes, rubber accelerators, and insecticides. β-Picoline was nominated by the National Institute of Environmental Health Sciences for toxicological evaluation and carcinogenicity studies based on its high production volume and potential for human exposure. Male and female F344/N rats and B6C3F1/N mice were exposed to β-picoline (greater than 96% pure) in drinking water for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. (Abstract Abridged).

Background: Extracts from the leaves of the Aloe vera plant (Aloe barbadensis Miller) have long been used as herbal remedies and are also now promoted as a dietary supplement, in liquid tonics, powders or tablets, as a laxative and to prevent a variety of illnesses. We studied the effects of Aloe vera extract on rats and mice to identify potential toxic or cancer-related hazards.

Methods: We gave solutions of nondecolorized extracts of Aloe vera leaves in the drinking water to groups of rats and mice for 2 years. Groups of 48 rats received solutions containing 0.5%, 1% or 1.5% of Aloe vera extract in the drinking water, and groups of mice received solutions containing 1%, 2%, or 3% of Aloe vera extract. Similar groups of animals were given plain drinking water and served as the control groups. At the end of the study tissues from more than 40 sites were examined for every animal.

Results: In all groups of rats and mice receiving the Aloe vera extract, the rates of hyperplasia in the large intestine were markedly increased compared to the control animals. There were also increases in hyperplasia in the small intestine in rats receiving the Aloe vera extract, increases in hyperplasia of the stomach in male and female rats and female mice receiving the Aloe vera extract, and increases in hyperplasia of the mesenteric lymph nodes in male and female rats and male mice receiving the Aloe vera extract. In addition, cancers of the large intestine occurred in male and female rats given the Aloe vera extract, though none had been seen in the control groups of rats for this and other studies at this laboratory.

Conclusions: We conclude that nondecolorized Aloe vera caused cancers of the large intestine in male and female rats and also caused hyperplasia of the large intestine, small intestine, stomach, and lymph nodes in male and female rats. Aloe vera extract also caused hyperplasia of the large intestine in male and female mice and hyperplasia of the mesenteric lymph node in male mice and hyperplasia of the stomach in female mice.

Ginkgo biloba extract has been used primarily as a medicinal agent in the treatment or prevention of cardiovascular and cerebrovascular dysfunction. Ginkgo biloba extract was nominated for study by the National Cancer Institute because of its widespread use as an herbal supplement to promote mental function and the limited availability of toxicity and carcinogenicity data. Furthermore, one of the major ingredients in Ginkgo biloba extract, quercetin, is a known mutagen. The Ginkgo biloba extract used in the current studies was procured from a supplier known to provide material to United States companies and contained 31.2% flavonol glycosides, 15.4% terpene lactones (6.94% bilo-balide, 3.74% ginkgolide A, 1.62% ginkgolide B, 3.06% ginkgolide C), and 10.45 ppm ginkgolic acid. Male and female F344/N rats and B6C3F1/N mice were administered Ginkgo biloba extract in corn oil by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 62.5, 125, 250, 500, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses, 5 days per week for 23 days. All rats survived to the end of the study. Mean body weights of all dosed groups were similar to those of the vehicle control groups. Liver weights of all dosed groups of males and females were significantly greater than those of the vehicle control groups. The incidences of hepatocyte hypertrophy in all dosed groups of males and in 500 and 1,000 mg/kg females were significantly greater than those in the vehicle control groups; there was a dose-related increase in severity of this lesion in males. Hepatocyte fatty change occurred in all dosed males. The incidences of thyroid gland follicular cell hypertrophy were significantly increased in 500 and 1,000 mg/kg males and in 1,000 mg/kg females. The incidences of pigmentation in the olfactory epithelium of the nose were significantly increased in 500 and 1,000 mg/kg males and in females administered 125 mg/kg or greater. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 125, 250, 500, 1,000, or 2,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. One female mouse in the 1,000 mg/kg group died of a dosing accident during week 11. Mean body weights of 2,000 mg/kg females were significantly less than those of the vehicle control group. Ruffled fur was observed in two 1,000 mg/kg males between weeks 7 and 8 and all 2,000 mg/kg males between weeks 5 and 9. Liver weights of 250 mg/kg or greater males and all dosed groups of females were significantly greater than those of the vehicle control groups. Kidney weights of 2,000 mg/kg males were significantly less tha

Unlabelled: The current main commercial use of pyrogallol is the production of pharmaceuticals and pesticides. In analytical chemistry, pyrogallol is used as a complexing agent, reducing agent, and, in alkaline solution, as an indicator of gaseous oxygen. Pyrogallol was nominated for testing by private individuals based on its frequent occurrence in natural and manufactured products, including hair dyes, and the apparent lack of carcinogenicity data. Male and female F344/N rats and B6C3F1/N mice were administered pyrogallol (99% pure) dermally for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, mouse bone marrow cells, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats received dermal applications of pyrogallol in 95% ethanol at doses of 0, 9.5, 18.75, 37.5, 75, or 150 mg pyrogallol/kg body weight, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female special study rats were administered the same doses, 5 days per week for 23 days. All rats survived until the end of the study except for one vehicle control female. Mean body weights of dosed groups of males and females were generally similar to those of the vehicle controls. Chemical-related clinical findings included brown staining and irritation of the skin at the site of application. There were no changes in the hematology, serum clinical chemistry, thyroid hormone values, or organ weights attributable to the dermal administration of pyrogallol. The incidences of squamous hyperplasia, hyperkeratosis, and chronic active inflammation of the skin at the site of application were significantly increased in all dosed groups of males and females. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice received dermal applications of pyrogallol in 95% ethanol at doses of 0, 38, 75, 150, 300, or 600 mg pyrogallol/kg body weight, 5 days per week for 14 weeks. All mice survived until the end of the study. Mean body weights of dosed groups of males and females were similar to those of the vehicle controls. Chemical-related clinical findings included brown staining and irritation at the site of application. There were no changes in the hematology values or organ weights attributable to the dermal administration of pyrogallol. The incidences of squamous hyperplasia, hyperkeratosis, and chronic active inflammation of the skin at the site of application were significantly increased in all dosed groups of males and females. The incidence of hematopoietic cell proliferation of the spleen in 600 mg/kg males was significantly greater than that in the vehicle control group. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats received dermal applications of pyrogallol in 95% ethanol at doses of 0, 5, 20, or 75 mg pyrogallol/kg body weight, 5 days per week for up to 104 weeks. Survival of dosed groups of male and female rats was similar to that of the vehicle

Background: Antiretroviral drugs are used to treat patients positive for the human immunovirus HIV-1, and increasingly treatments include a combination of such drugs. The noninfected children of women who are pregnant and receiving such treatment may also be exposed to the drugs by transplacental exposure. We studied the long-term effects of such transplacental exposure in mice by exposing pregnant mice to combinations of four such antiretroviral drugs for seven days and then observing their pups for two years following birth. The four drugs studied were 3′-azido-3′-deoxythymidine (AZT), lamivudine (3TC), nevirapine (NVP), and nelfinavir mesylate (NFV).

Methods: Four different sets of exposure studies were performed: exposure to AZT; to AZT plus 3TC; to AZT, 3TC, and NVP; or to AZT, 3TC, and NFV. In each of these studies, groups of pregnant females were given one of three concentrations of the drug combinations seven times though a tube directly into their stomachs, and after birth their pups were maintained with no further exposure for two years. The offspring of another group of pregnant females not treated with the drugs served as controls. At the end of the study, tissues from more than 40 sites were examined for every animal.

Results: Survival of pups whose mothers were exposed to AZT or AZT plus 3TC was similar to their controls, while the survival rates for offspring of mice exposed to AZT, 3TC, and NVP or AZT, 3TC, and NFP were lower than for controls. In most cases the body weights of pups from mothers exposed were slightly less than those of the controls. There were slight increases in the incidences of thyroid gland tumors and skin tumors in the female pups of mothers exposed to AZT alone and of lung tumors in female pups of mothers exposed to AZT plus 3TC. For offspring of mothers exposed to AZT, 3TC, and NVP there were increased incidences of skin tumors in both male and female pups, and more so in the males.

Conclusions: We conclude that exposure to the combination of AZT, 3TC, and NVP during pregnancy caused an increase in skin tumors in the male offspring and possibly also to the female offspring. Exposure to AZT alone during pregnancy may have been related to thyroid gland or skin tumors in female offspring, and exposure to AZT plus 3TC may have been related to lung tumors in female offspring.

Background: Trimethylolpropane triacrylate (TMPTA) is used as an ingredient in a wide variety of coatings, resins, photosensitive materials, and superabsorbent baby diapers. We studied the effects of TMPTA on male and female rats and mice to identify potential toxic or cancer-related hazards.

Methods: We applied solutions containing TMPTA in acetone on the backs of male and female rats and mice. Groups of 50 male and female rats and mice received 0.3, 1, or 3 milligrams of TMPTA per kilogram of body weight five days per week for two years. Groups of animals receiving acetone alone served as the control groups. At the end of the study, tissues from more than 40 sites were examined for every animal.

Results: Survival and body weights of all groups of exposed animals were similar to the control groups. Epidermal hyperplasia was observed in the skin at the site where the chemical was applied in all groups of animals receiving 1 mg/kg or more. Hyperkeratosis at the site of application was also increased in rats receiving TMPTA, and chronic inflammation was also seen in the skin of male and female mice receiving TMPTA. Malignant mesotheliomas were seen in a few male rats exposed to TMPTA. Two different rare forms of liver cancer (hepatoblastoma and hepatocholangiocarcinoma) were observed in some of the female mice exposed to TMPTA, and tumors of the uterus (stromal polyp or stromal sarcoma) also occurred in some exposed female mice.

Conclusions: We conclude that exposure to TMPTA caused rare cancers of the liver and tumors of the uterus in female mice and may have been related to the occurrence of malignant mesothelioma in male rats. No occurrences of cancer were associated with exposure to TMPTA in female rats or male mice. Skin lesions at the site of application, including hyperplasia in rats and mice, hyperkeratosis in rats, and inflammation in mice occurred in all animal groups exposed to higher concentrations of TMPTA.