National Toxicology Program technical report series最新文献

Unlabelled: Bromodichloromethane is a by-product of the chlorination of drinking water. It is formed by the halogen substitution and oxidation reactions of chlorine with naturally occurring organic matter (e.g., humic or fulvic acids) in water containing bromide. Bromodichloromethane has been shown to be carcinogenic at multiple sites in rats (large intestine and kidney) and in mice (liver and kidney) after administration by gavage in corn oil. To further characterize its dose-response relationships for evaluations of human risk, bromodichloromethane was nominated to the NTP by the United States Environmental Protection Agency for toxicity and carcinogenicity studies in rats and mice by drinking water exposure. Male F344/N rats and female B6C3F1 mice were exposed to bromodichloromethane (greater than 98% pure) in drinking water for 3 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, mouse bone marrow cells, and mouse peripheral blood erythrocytes. 3-WEEK STUDY IN RATS: Groups of 10 male F344/N rats were exposed to target concentrations of 0, 43.7, 87.5, 175, 350, or 700 mg/L bromodichloromethane (equivalent to average daily doses of approximately 0, 6, 12, 20, 38, or 71 mg bromodichloromethane/kg body weight) in drinking water for 3 weeks. All rats survived to the end of the study. The mean body weight gains of 350 and 700 mg/L rats were significantly less than that of the controls. Concentration-related decreases in water consumption were evident during the first week on study. Relative kidney weights of rats in the 175, 350, and 700 mg/L groups were significantly greater than that of the controls. There were no significant chemical-related histopathological changes. 3-WEEK STUDY IN MICE: Groups of 10 female B6C3F1 mice were exposed to target concentrations of 0, 43.7, 87.5, 175, 350, or 700 mg/L bromodichloromethane (equivalent to average daily doses of approximately 0, 6, 10, 16, 29 or 51 mg/kg) in drinking water for 3 weeks. All mice survived to the end of the study. Final mean body weights of the 175, 350, and 700 mg/L mice and mean body weight gains of 350 and 700 mg/L mice were significantly less than those of the controls. These decreases were attributed to decreased water consumption. There were significant concentration-related decreases in water consumption by groups exposed to 87.5 mg/L or greater throughout the study; these decreases were attributed to poor palatability of the dosed water. Relative liver, kidney, and thymus weights of mice in the 350 and 700 mg/L groups were significantly greater than those of the controls. Absolute lung weights of mice in the 350 and 750 mg/L groups were significantly less than that of the controls. There were no significant chemical-related histopathological changes. 2-YEAR STUDY IN RATS: Groups of 50 male F344/N rats were exposed to target concentrations of 0, 175, 350, or 70

DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized they accumulate in adipose tissue resulting in chronic lifetime human exposure. Since human exposure to DLCs always occurs as a complex mixture, the Toxic Equivalency Factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD that is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation, because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally-related polychlorinated biphenyls (PCBs) and mixtures of these compounds. 3,3',4,4',5-Pentachlorobiphenyl (PCB 126) was produced commercially before 1977 for the electric industry as a dielectric insulating fluid for transformers and capacitors. Manufacture and use of the chemical was stopped because of increased PCB residues in the environment, but it continues to be released into the environment through the use and disposal of products containing PCBs, as by-products during the manufacture of certain organic chemicals, and during combustion of some waste materials. Bioaccumulation of PCB 126 results in persistent levels in animal and human tissues and the biological responses to PCB 126 are similar to those of TCDD, a known human carcinogen. PCB 126 was selected for study by the National Toxicology Program as a part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCBs. The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. PCB 126 was included since this is the most potent coplanar PCB that has dioxin-like activities. Wh

Background: Sodium chlorate occurs when drinking water is disinfected by chlorine dioxide. We studied the effects of sodium chlorate in rats and mice to identify potential toxic or carcinogenic hazards to humans.

Methods: We gave groups of male and female rats drinking water containing 125, 1,000, or 2,000 milligrams (mg) of sodium chlorate per liter (L) of water for two years. Male and female mice received 500, 1,000, or 2,000 mg/L. Other groups of animals received plain tap 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: Male and female rats receiving sodium chlorate had higher rates of follicular cell hypertrophy of the thyroid gland, and the groups receiving 2,000 mg/L had higher rates of thyroid gland cancer, compared with the control groups. Female mice exposed to sodium chlorate had a few pancreatic islet cell tumors.

Conclusions: We conclude that sodium chlorate caused some thyroid gland neoplasms in male and female rats. The pancreatic islet cell tumors in female mice may have been related to sodium chlorate exposure.

The NTP chose to initiate studies in fish as an exploration of alternate or additional models for examining chemical toxicity and carcinogenicity. The use of small fish species in carcinogenicity testing offered potential advantages as a bioassay test system, including significant savings in cost and time over rodent studies. Large numbers of small fish could be easily maintained in a limited area. The two species chosen for study were guppy (Poecilia reticulata) and medaka (Oryzias latipes), both of which are hardy, easily maintained, and have a low occurrence of background lesions. The three chemicals chosen for study in fish had already been studied by the NTP in rodents, permitting a comparison of results between the two models. Two of the chemicals used (2,2-bis(bromomethyl)-1,3-propanediol and 1,2,3-trichloropropane) were mutagenic and multisite carcinogens in rats and mice. The third chemical, nitromethane, was nonmutagenic with a more modest carcinogenic response in rodents. Male and female guppies and medaka were exposed to 2,2-bis(bromomethyl)- 1,3-propanediol (greater than 99% pure), nitromethane, (greater than 99% pure), or 1,2,3-trichloropropane (99% pure) in aquaria water for up to 16 months. OVERALL STUDY DESIGN: Groups of approximately 220 guppies (two replicates of 110) were maintained in aquaria water containing nominal concentrations of 0, 24, 60, or 150 mg/L 2,2-bis(bromomethyl)-1,3-propanediol; 0, 10, 30, or 70 mg/L nitromethane; or 0, 4.5, 9.0, or 18.0 mg/L 1,2,3-trichloropropane. Groups of approximately 340 medaka (two replicates of 170) were maintained in aquaria water containing 0, 24, 60, or 150 mg/L 2,2-bis(bromomethyl)-1,3-propanediol; 0, 10, 20, or 40 mg/L nitromethane; or 0, 4.5, 9.0, or 18.0 mg/L 1,2,3-trichloropropane. The overall study durations were 16 months for all guppy studies, 14 months for 2,2-bis(bromomethyl)-1,3-propanediol-exposed medaka, and 13 months for nitromethane- and 1,2,3-trichloropropane-exposed medaka. Ten guppies and 10 medaka from each group replicate were sacrificed at 9 months for histopathologic analysis. Approximately one third of the remaining fish from each group were placed in chemical-free water at 9 months and constituted a stop-exposure study component. The remainder of the fish were exposed for the duration of the study and constituted the core study component. A stop-exposure component was added to determine if stopping the exposure at 9 months and transferring to chemical-free aquaria might allow for better survival and tumor development. The sex of guppies and medaka was determined at histopathologic analysis. 2,2-BIS(BROMOMETHYL)-1,3-PROPANEDIOL - 16-MONTH STUDY IN GUPPIES: 2,2-Bis(bromomethyl)-1,3-propanediol was chronically toxic to guppies in the 60 and 150 mg/L core and stop-exposure groups. Due to mortality, exposure of core study animals in the 150 mg/L group was terminated on day 443, after approximately 64 weeks on study, and fish were maintained in 2,2-bis(bromom

Background: Anthraquinone is used to make dyes and paper and as a bird repellant. We studied anthraquinone to determine if it caused cancer in rats or mice.

Methods: We fed groups of 50 male and female rats feed containing 469, 938, 1,875, or 3,750 parts per million (ppm) anthraquinone for 2 years. Similar groups of male and female mice received feed containing 833, 2,500, or 7,500 ppm anthraquinone. Groups of 50 male and female rats and mice receiving undosed feed served as the control groups. Tissues from more than 40 sites were examined for every animal.

Results: In each group, the group receiving the highest dose of anthraquinone weighed less than its control group. Male and female rats given anthraquinone had higher rates of tumors of the kidney and urinary bladder. Liver tumors also were increased in female rats and slightly increased in male rats. In male and female mice given anthraquinone, the rates of liver tumors were greatly increased, and a few of these animals developed thyroid gland tumors.

Conclusions: We conclude that anthraquinone caused cancer of the kidney and urinary bladder in male and female rats and of the liver in female rats. The occurrence of some liver tumors in male rats may have been related to anthraquinone exposure. We conclude that anthraquinone caused liver cancer in male and female mice, and thyroid gland tumors in mice may have been related to anthraquinone.

Background: Malachite green chloride is a dye used to prevent fungus infections in commercial fisheries. Leucomalachite green is formed from malachite green and remains in the tissues of exposed fish. We studied the effects of malachite green on female rats and female mice, and the effects of leucomalachite green on male and female rats and female mice, to identify potential toxic or cancer-related hazards to humans.

Methods: For each study we mixed the dye into the feed of rats and mice. The doses of malachite green chloride given were 100, 300, or 600 parts per million (ppm) for female rats and 100, 225, or 450 ppm for female mice. Doses of leucomalachite green were 91, 272, or 543 ppm for male and female rats and 91, 204, or 408 ppm for female mice. There were 48 animals in each dose group. Control animals received the same feed with no chemical added. The study lasted for two years. Tissues from more than 40 sites were examined for every animal.

Results: Rats, but not mice, exposed to malachite green chloride or leucomalachite green weighed less on average than the control animals. In rats exposed to the dyes, there were very slight increases in a few types of tumors: cancers of the thyroid gland, liver, and mammary gland in females exposed to malachite green chloride; of the thyroid gland and testes in males exposed to leucomalachite green; and of the thyroid gland and liver of females exposed to leucomalachite green. We saw no increase in cancers in female mice given malachite green chloride, but there was an increase in liver tumors in female mice given to leucomalachite green.

Conclusions: We conclude that tumors of the thyroid gland, liver, or mammary gland in female rats might have been caused by malachite green chloride, but the malachite green chloride did not cause cancer in female mice. We conclude that leucomalachite green might have caused cancers of the thyroid gland in male and female rats, and of the testes in male rats and liver in female rats. Leucomalachite green caused an increase in cancer of the liver in female mice.

Decalin is used as an industrial solvent for naphthalene, fats, resins, oils, and waxes. It is also used as a substitute for turpentine in lacquers, paints, and varnishes; as a solvent and stabilizer for shoe polishes and floor waxes; and as a constituent of motor fuels and lubricants. Other applications include use as a paint thinner and remover, a patent fuel in stoves, a high-density fuel in submarine-launched cruise missile systems, and in stain removal and cleaning machinery. Decalin was nominated for study by the National Cancer Institute because of its chemical structure, its potential for consumer exposure, and a lack of adequate testing of the chemical. Male and female F344/N rats and B6C3F(1) mice were exposed to decalin (greater than 99% pure) by inhalation for 2 weeks, 3 months, or 2 years. Groups of male NBR rats were exposed to decalin for 2 weeks. Male NBR rats do not produce alpha2u-globulin; the NBR rats were included to study the relationship of alpha2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. 2-WEEK STUDIES IN RATS: Groups of five male and five female F344/N rats and five male NBR rats were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 16 days. All rats survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber controls. Renal toxicity studies were performed in male F344/N and NBR rats. The numbers of labeled cells and the labeling indices in the left kidney of 200 and 400 ppm F344/N male rats were significantly greater than those in the chamber controls. The alpha2u-globulin/soluble protein ratios were significantly increased in all exposed groups of F344/N rats. Liver weights of male F344/N and NBR rats exposed to 100 ppm or greater were significantly increased, as were those of all exposed groups of females. Kidney weights of male F344/N rats exposed to 50 ppm or greater were significantly increased. Exposure-related hyaline droplet accumulation, degeneration and regeneration of renal cortical tubules, and granular casts occurred in the kidney of exposed F344/N male rats. 2-WEEK STUDIES IN MICE: Groups of five male and five female B6C3F(1) mice were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 17 days. All mice survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber control groups. Liver weights of 200 and 400 ppm males and females and 100 ppm females were significantly increased. 3-MONTH STUDY IN RATS: Groups of 25 male and 20 female F344/N rats were exposed to 0, 25, 50, 100, 200, or 400 ppm decalin vapor 6 hours per day, 5 days per week for 2 (five male renal toxicity rats), 6 (10 male and 10 female clinical pathology rats), or 14 (10 core study rats) weeks. All rats survived to the end of the study, and mean bod

Background: 2-methylimidazole is used to make many other chemicals for drugs, photography, dyes, rubber, and agriculture. We studied the effects of 2-methylimidazole on male and female rats and mice to identify potential toxic or cancer-related hazards to humans.

Methods: We studied the effects of 2-methylimidazole by mixing it in the feed of rats and mice for 2 years. The doses given were 300, 1,000, or 3,000 parts per million (ppm) 2-methylimidazole (equivalent to 0.03%, 0.1%, or 0.3%) for male rats; 1,000, 2,500, or 5,000 ppm for female rats; and 625, 1,250, or 2,500 ppm for male and female mice. There were 50 animals in each exposure group. Control animals received the same feed with no chemical added. Tissues from more than 40 sites were examined for every animal.

Results: For both male and female rats and mice, the groups receiving the highest amounts of 2-methylimidazole weighed less on average than the control animals. Male and female rats and male mice receiving 2-methylimidazole had higher rates of thyroid gland cancers than did the untreated control animals. The rates of liver tumors were greater in male and female mice receiving 2-methylimidazole and also slightly increased in male and female rats receiving 2-methylimidazole.

Conclusions: We concluded that 2-methylimidazole caused increased rates of cancer of the thyroid gland and liver in rats and mice.

Unlabelled: Stoddard solvent (white spirit/mineral spirit) is the most widely used solvent in the paint industry. It is used as a dry cleaning agent; as an extraction, cleaning, and degreasing solvent; and as a solvent in aerosols, paints, wood preservatives, asphalt products, lacquers, and varnishes. Stoddard solvent IIC was nominated by the International Union, United Auto Workers, for carcinogenicity testing because of the large volume used in industrial and other settings. Male and female F344/N rats and B6C3F1 mice were exposed to Stoddard solvent IIC (greater than 99% pure) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138, 275, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 16 days. All rats survived to the end of the study, and mean body weights of all exposed groups were similar to those of the chamber controls. Liver weights of males exposed to 550 mg/m3 or greater and of females exposed to 275 mg/m3 or greater were increased. Minimal diffuse cytoplasmic vacuolization of hepatocytes of the liver occurred in all females exposed to 2,200 mg/m3. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138, 275, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 17 days. All mice survived to the end of the study, and mean body weights of all exposed groups were similar to those of the chamber controls. Liver weights of males and females exposed to 275 mg/m3 or greater were significantly increased. Cytomegaly of the liver occurred in all males and females exposed to 2,200 mg/m3. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to Stoddard solvent IIC by inhalation at concentrations of 0, 138, 275, 550, 1,100, or 2,200 mg/m3, 6 hours per day, 5 days per week for 14 weeks. All rats survived to the end of the study, and the final mean body weight of females exposed to 275 mg/m3 was greater than that of the chamber controls. The relative kidney, liver, and testis weights of all exposed groups of males and the absolute kidney weights of males exposed to 550 mg/m3 or greater were increased. The sperm motility of 550 mg/m3 or greater males was significantly decreased. The incidences of renal tubule granular casts were significantly increased in males exposed to 550 mg/m3 or greater, and the severities of renal tubule hyaline droplet accumulation, granular casts, and regeneration increased with increasing exposure concentration in males. The incidences of goblet cell hypertrophy of the nasal respiratory epithelium in males and females exposed to 2,200 mg/m3 were significantly increased. Sperm motility was decreased in males exposed to 550 mg/m3 or gr

Background: Urethane occurs naturally as a by-product of fermentation. The main exposure of humans to urethane is from drinking alcoholic beverages. The International Agency for Research on Cancer has determined that consumption of alcoholic beverages is clearly linked to certain cancers in humans. We studied mixtures of urethane and ethanol (alcohol) to determine if urethane, alone or in combination with ethanol, caused cancer in mice.

Methods: We gave groups of 48 male and female mice drinking water containing combinations of urethane (0, 10, 30, or 90) and other ethanol (0%, 2.5%, or 5%) for two years. Tissues from more than 40 sites were examined for every animal.

Results: Ther were more deaths and lower body weights in groups of animals exposed to higher concentrations of urethane. Higher concentrations of urethane increased the rates of cancer of the liver, lung, harderian gland, and of hemangiosarcomas in both male and female mice. Urethane also increased the rates of cancer of the skin and forestomach in male mice and of the mammary gland and ovary in female mice. There were also small increases in the occurrence of hemangiosarcoma in the spleen in male mice and in the uterus and skin of female mice.

Conclusion: We conclude that urethane caused cancer at several sites in male and female mice. It was not possible to determine from this study whether ethanol alone caused cancer in mice, and there was weak evidence that ethanol may have affected the carcinogenicity of urethane, slightly lowering the incidence of lung and harderian gland tumors in male mice and increasing the incidence of heart and lung tumors in female mice.