National Toxicology Program technical report series最新文献

Unlabelled: Goldenseal root powder is used in folk medicine for the treatment of gastrointestinal disturbances, urinary disorders, hemorrhage, skin, mouth, and eye infections, and inflammation. The major alkaloids in goldenseal are berberine, hydrastine, and canadine. Goldenseal root powder was nominated for study by the National Institute of Environmental Health Sciences based on the potential for human exposure and the lack of carcinogenicity data, and because it is one of the most widely used herbs in the United States. Male and female F344/N rats and B6C3F1 mice were exposed to ground goldenseal root powder in feed for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, mouse bone marrow cells, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were fed diets containing 0, 1,560, 3,121, 6,250, 12,500, 25,000, or 50,000 ppm goldenseal root powder (equivalent to average daily doses of approximately 155, 315, 630, 1,190, 2,465, and 4,815 mg goldenseal root powder/kg body weight for males and 150, 290, 640, 1,240, 2,370, and 4,870 mg/kg for females) for 15 days. All rats survived to the end of the study. Mean body weights and feed consumption of all exposed groups of males and females were similar to those of the control groups throughout the study. Liver weights of males exposed to 6,250 ppm or greater and females exposed to 12,500 ppm or greater were significantly greater than those of the controls. Minimal to moderate hepatocellular hypertrophy occurred in three males and all females exposed to 25,000 ppm and in all 50,000 ppm males and females. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were fed diets containing 0, 1,560, 3,121, 6,250, 12,500, 25,000, or 50,000 ppm goldenseal root powder (equivalent to average daily doses of approximately 380, 840, 1,760, 3,435, 6,700, and 15,170 mg/kg body weight for males and 330, 670, 1,240, 2,375, 4,760, and 8,475 mg/kg for females) for 15 days. All mice survived to the end of the study. Mean body weights and feed consumption of all exposed groups of males and females were similar to those of the control groups throughout the study. Significant increases in liver weights occurred in males exposed to 25,000 and 50,000 ppm and in females exposed to 50,000 ppm. Absolute and relative thymus weights of 12,500 and 50,000 ppm males were significantly decreased. Minimal hypertrophy of centrilobular hepatocytes occurred in all males and females exposed to 50,000 ppm. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 3,121, 6,250, 12,500, 25,000, or 50,000 ppm goldenseal root powder (equivalent to average daily doses of approximately 255, 500, 1,000, 2,020, and 4,060 mg/kg for males and 260, 500, 1,030, 2,070, and 4,100 mg/kg for females) for 14 weeks. Additional groups of 10 male and 10 female clinical pathology study r

Background: Ethinyl estradiol is a potent synthetic estrogen that is widely prescribed in oral contraceptives and is also used in the treatment of breast and prostate cancer. Ethinyl estradiol is one of a class of chemicals known as“environmental estrogens” which can affect the hormone activities and possibly reproductive function of wildlife and humans through exposure. The NTP conducted a series of studies on three such chemicals to detect if exposure over the course of multiple generations could have any cumulative effect on animals' reproductive systems or development of cancers. This report describes the results of a set of studies in which rats and their offspring were exposed to ethinyl estradiol over the course of four generations.

Methods: The continuous-breeding study began with groups of 35 Sprague-Dawley rats of each sex exposed to ethinylestradiol in their feed at concentrations of 2, 10, or 50 parts per billion (ppb). Control animals received the same feed with no ethinyl estradiol added. Animals from the same dose treatment groups were paired and mated, and 25 litters of pups at each exposure concentration (culled to four males and four females each) were continued on study and given feed containing the same concentration of ethinyl estradiol. The process was repeated through a second and third generation, after which the pups were given control feed only, and two more generations were bred in the same manner and given control feed without ethinyl estradiol. Measures of fertility and reproduction were taken for each generation and tissues from the study animals were examined histopathologically.

Results: In all three offspring generations the time to vaginal opening (a measure of onset of puberty) was accelerated in females fed 50 ppb ethinyl estradiol. In the first two offspring generations the estrous cycles of the exposed females were prolonged or aberrant prior to mating. Male rats exposed to ethinyl estradiol had increased rates of mammary gland hyperplasia and mineralization of the kidney tubules.

Conclusions: We conclude that exposure to trace amounts of ethinyl estradiol in the feed showed clear biological activity in male and female rats, including reduced body weights in both sexes, perturbed estrous cycles in females, and induction of mammary gland hyperplasia and kidney tubule mineralization in males.

Background: Ethinyl estradiol is a potent synthetic estrogen that is widely prescribed in oral contraceptives and is also used in the treatment of breast and prostate cancer. Ethinyl estradiol is one of a class of chemicals known as"environmental estrogens" that can affect the hormone activities and possibly reproductive function of wildlife and humans through exposure. The NTP conducted a series of studies on three such chemicals to detect if exposure over the course of multiple generations could have any cumulative effect on animals' reproductive systems or development of cancers. This report describes the results of a set of studies in which rats were exposed to ethinylestradiol for part or all of the study period and examined at the end of two years.

Methods: The study consisted of three separate study components; in each, animals were exposed to ethinyl estradiol from the time of conception and through weaning through their mothers, who were given ethinyl estradiol in their feed.In one study we gave feed containing 2, 10, or 50 parts per billion (ppb) of ethinyl estradiol to groups of 50 male and female rats from conception through two years. In the second study, groups of 50 male and female rats were given the same feed concentrations up to 20 weeks following birth, followed by untreated feed for the remainder of the two years. In the third study groups of 50 male and female rats were exposed from conception through weaning, and then given untreated feed for the duration of the study. Control animals received the same feed with no ethinyl estradiol added. Enthinyl estradiol is known to cause cancer at higher dose levels; the concentrations given in this study were below the levels of detection by chemical analysis, to determine the possible effects of trace amounts in the environment. At the end of the study tissues from more than 40 sites were examined for every animal.

Results: In all three study sets effects were seen in the uterus of female rats. The rates of squamous metaplasia increased in females exposed for two years and in females exposed from conception through weaning; endometrial hyperplasia and atypical focal hyperplasia of the uterus also were increased in females exposed for two years. Uterine stromal polyps were increased in female rats exposed from conception through 20 weeks after birth or from conception through weaning. Male rats exposed from conception through weaning had small increases in the rates of preputial gland tumors and three male rats in that study had rare mammary gland adenomas or carcinomas.

Conclusions: We conclude that exposure to trace amounts of ethinyl estradiol during the period from conception through weaning may have been related to development of uterine stromal polyps in female rats and to preputial gland tumors and mammary gland tumors in male rats.

Unlabelled: 5-(Hydroxymethyl)-2-furfural is formed when reducing sugars such as fructose and sucrose are heated in the presence of amino acids. 5-(Hydroxymethyl)-2-furfural is ubiquitous in the human diet and occurs at concentrations greater than 1 g/kg in dried fruits, caramel products, certain types of fruit juices, and up to 6.2 g/kg in instant coffee. 5-(Hydroxymethyl)-2-furfural also occurs naturally and has been identified in honey, apple juice, citrus juices, beer, brandy, milk, breakfast cereal, baked foods, tomato products, and home cooking of sugar and carbohydrates. Industrially, 5-(hydroxymethyl)-2-furfural is used in the synthesis of dialdehydes, glycols, ethers, aminoalcohols, acetals, and phenol/furfural novolak-type resins. 5-(Hydroxymethyl)-2-furfural was nominated by the National Institute of Environmental Health Sciences for study because of extensive human exposure and the lack of adequate data characterizing its toxicity and carcinogenicity. Male and female F344/N rats and B6C3F1 mice were administered 5-(hydroxymethyl)-2-furfural (at least 99% pure) by gavage in deionized water for 3 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli and mouse peripheral blood erythrocytes. 3-WEEK STUDY IN RATS: core study groups of five male and five female rats were administered 0, 94, 188, 375, 750, or 1,500 mg 5-(hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for a total of 13 doses over a 22-day period. Special study groups of five male and five female rats designated for neuropathology were administered 0 or 1,500 mg/kg on the same schedule. Except for one 1,500 mg/kg core study male rat, all rats survived to the end of the study. The final mean body weight of 1,500 mg/kg males was significantly less than that of the vehicle control group. No chemical-related histopathologic lesions were observed in core or special study animals. 3-WEEK STUDY IN MICE: groups of five male and five female mice were administered 0, 94, 188, 375, 750, or 1,500 mg 5-(hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for a total of 13 doses over a 22-day period. Three male and three female mice administered 1,500 mg/kg died before the end of the study. Mean body weights of 1,500 mg/kg males were significantly less than those of the vehicle control group. Heart weights of 1,500 mg/kg females were significantly greater than those of the vehicle controls. No chemical-related lesions were observed. 3-MONTH STUDY IN RATS: core groups and special study groups (for clinical pathology and neuropathological evaluation) of 10 male and 10 female rats were administered 0, 94, 188, 375, 750, or 1,500 mg 5-(hydroxymethyl)-2-furfural/kg body weight in deionized water by gavage for 3 months. One male and three female rats administered 1,500 mg/kg died before the end of the study; the male died as a result of gavage trauma. Mean body weights of 75

Unlabelled: 1,2-Dibromo-2,4-dicyanobutane is used in cosmetics and other household products. 1,2-Dibromo-2,4-dicyanobutane was nominated for study by the National Institute of Environmental Health Sciences because of its widespread use as a component of numerous over-the-counter health care products. Male and female F344/N rats and B6C3F1 mice received 1,2-dibromo-2,4-dicyanobutane (greater than 99% pure) in acetone (2-week and 3-month studies) or 95% ethanol (2-year studies) by dermal administration for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were dermally administered 0, 37.5, 75, 150, 300, or 600 mg 1,2-dibromo-2,4-dicyanobutane/kg body weight in acetone, 5 days per week for 16 days. All male and female rats survived to the end of the study. Mean body weights of dosed male and female rats were similar to those of the vehicle controls. Irritation, thickened skin, and ulcers were observed at the site of application in most dosed males and females. The thyroid gland weights of males administered 600 mg/kg were significantly less than those of the vehicle controls. The liver and kidney weights of 300 and 600 mg/kg females were significantly increased. A spectrum of nonneoplastic lesions including epidermal hyperplasia and hyperkeratosis, sebaceous gland hyperplasia, and dermal chronic active inflammation occurred at the site of application in all dosed groups of rats. Necrosis, ulcer, and parakeratosis of the epidermis occurred in most dosed groups of rats. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were dermally administered 0, 75, 150, 300, 600, or 1,200 mg/kg 1,2-dibromo-2,4-dicyanobutane in acetone, 5 days per week for 16 days. All male and female mice survived to the end of the study. The final mean body weight of 300 mg/kg males was significantly less than that of the vehicle controls. Hyperactivity was observed in all dosed groups of mice. Irritation, thickened skin, and ulcers were observed at the site of application in dosed mice. The liver weights of 600 and 1,200 mg/kg males and 1,200 mg/kg females were significantly increased relative to those of the vehicle control groups. The heart weights of 600 and 1,200 mg/kg males and the kidney weights of 150 and 600 mg/kg males were significantly increased. The thymus weights of males administered 300 mg/kg or greater and those of all dosed groups of females were significantly decreased. Skin lesions at the site of application including epidermal hyperplasia, hyperkeratosis, parakeratosis, necrosis, and ulcers; dermal chronic active inflammation; and sebaceous gland hyperplasia occurred in all dosed groups of mice. Necrosis of the dermis occurred in most dosed groups of mice. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were dermally administered 0, 0.2, 0.6, 2,

Unlabelled: Chromium picolinate monohydrate is the commercially available form of chromium picolinate. Chromium picolinate is one of a number of compounds that contain chromium in the trivalent state (Cr III), which is the predominant form of chromium in nature. Humans ingest Cr III in food and dietary supplements. The major uses of Cr III in the chemical and manufacturing industries include production of chromium pigments and leather tanning. Chromium picolinate was nominated by the National Cancer Institute and a private individual for testing based on the potential for widespread consumer exposure from use as a dietary supplement. Male and female F344/N rats and B6C3F1 mice were exposed to chromium picolinate monohydrate (95% to 96% pure) in feed for 3 months or 2 years. Genetic toxicology studies with chromium picolinate monohydrate were conducted in Salmonella typhimurium and mouse peripheral blood erythrocytes. Genetic toxicology studies with chromium picolinate were conducted in S. typhimurium and rat bone marrow cells. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 80, 240, 2,000, 10,000, or 50,000 ppm chromium picolinate monohydrate (equivalent to average daily doses of approximately 7, 20, 160, 800, and 4,240 mg chromium picolinate monohydrate/kg body weight to males and 6, 20, 160, 780, and 4,250 mg/kg to females) for 14 weeks. All rats survived to the end of the study. Mean body weights and feed consumption of all exposed groups of males and females were similar to those of the control groups throughout the study. No exposure-related lesions occurred in males or females. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 80, 240, 2,000, 10,000, or 50,000 ppm chromium picolinate monohydrate (equivalent to average daily doses of approximately 17, 50, 450, 2,300, and 11,900 mg chromium picolinate monohydrate/kg body weight to males and 14, 40, 370, 1,775, and 9,140 mg/kg to females) for 14 weeks. All mice survived to the end of the study. Mean body weights and feed consumption of all exposed groups were similar to those of the control groups throughout the study. No exposure-related lesions occurred in male or female mice. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 2,000, 10,000, or 50,000 ppm chromium picolinate monohydrate (equivalent to average daily doses of approximately 90, 460, and 2,400 mg/kg to males and 100, 510, and 2,630 mg/kg to females) for 105 weeks. Survival of all exposed groups of males and females was similar to that of the control groups. Mean body weights and feed consumption of exposed groups of males and females were generally similar to those of the controls throughout the study. The incidence of preputial gland adenoma was significantly increased in males exposed to 10,000 ppm and exceeded the historical control ranges. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 fema

Background: Dibromoacetonitrile occurs in chlorinated drinking water that contains bromine and interacts with organic matter.We studied the effects of dibromoacetonitrile in drinking water on male and female rats and mice to identify potential toxic or cancer-related hazards.

Methods: We gave drinking water containing 50, 100, or 200 milligrams of dibromoacetonitrile per liter of water to groups of 50 male and female rats and mice for two years. Control animals received the same tap water with no chemical added. At the end of the study, tissues from more than 40 sites were examined for every animal.

Results: Survival was similar for animals receiving dibromoacetonitrile and the controls. Male and female rats receiving dibromoacetonitrile had increased rates of squamous cell adenomas or carcinomas of the mouth (oral mucosa or tongue). Two male rats receiving 200 mg/L had rare adenomas of the glandular stomach. There were a few instances of skin tumors in female rats receiving 100 or 200 mg/L. Male and female mice exposed to dibromoacetonitrile had increased rates of squamous cell papillomas of the forestomach. There were also slight increases in the occurrence of liver tumors in male mice.

Conclusions: We conclude that dibromoacetonitrile in the drinking water caused cancer of the oral cavity in male and female rats and of the glandular stomach in male rats. We conclude that dibromoacetonitrile caused cancer of the forestomach in male and female mice. Tumors of the skin in female rats and of the liver in male mice may also have been related to exposure to dibromoacetonitrile.

Background: Bromochloroacetic acid occurs as a by-product of water disinfection. We studied the effects of bromochloroacetic acid in drinking water on male and female rats and mice to identify potential toxic or cancer-related hazards.

Methods: We gave drinking water containing 250, 500, or 1,000 mg of bromochloroacetic acid per liter of water to groups of 50 male and female rats and mice for 2 years. Control animals received the same tap water with no chemical added. At the end of the study tissues from more than 40 sites were examined for every animal.

Results: Survival was similar for rats and female mice receiving bromochloroacetic acid and the controls; survival of 1,000 mg/L male mice was less. Male rats receiving bromochloroacetic acid had increased rates of malignant mesotheliomas. Adenomas of the large intestine were seen in both male and female rats receiving the highest concentration of bromochloroacetic acid. Exposed female rats also had increased incidences of multiple fibroadenomas of the mammary gland. Slightly increased incidences of liver hepatocellular adenomas in male and female rats and pancreatic islet adenomas in male rats were also observed in exposed animals. Male and female mice exposed to bromochloroacetic acid had increased rates of a variety of liver cancers.

Conclusions: We conclude that bromochloroacetic acid in the drinking water caused mesothelioma in male rats, multiple fibroadenomas of the mammary gland in female rats, and adenomas of the large intestine in both male and female rats. Adenomas of the liver in male and female rats and of the pancreatic islets in male rats may also have been related to bromochloroacetic acid exposure. We conclude that bromochloroacetic acid caused liver cancer in male and female mice.

Background: Cumene occurs naturally in petroleum and is used as a solvent, in gasoline and diesel fuels, and as the principal chemical in the production of phenol and acetone. We studied cumene to determine if it caused cancer in rats or mice.

Methods: We exposed groups of 50 male and female rats and mice to air containing cumene 6 hours per day for 2 years. Rats and male mice were exposed to concentrations of 250, 500, or 1,000 parts per million (ppm) of cumene in air, and female mice were exposed to concentrations of 125, 250, or 500 ppm. Similar groups of 50 animals were exposed to clean air in the same inhalation chambers 6 hours per day as the untreated control groups. Tissues from more than 40 sites were examined for every animal.

Results: All groups of animals exposed to cumene exhibited hyperplasia of the epithelial tissues of the nose, and exposed male and female mice experienced metaplasia and hyperplasia of the lung. Male mice also had nonneoplastic lesions in the forestomach and liver. Adenomas of the respiratory epithelium of the nose were observed in male and female rats, and male rats had increased incidences of renal tubule adenoma or carcinoma (combined) and interstitial cell adenoma of the testis. Adenomas and carcinomas of the lung were markedly increased in male and female mice exposed to cumene. The rate of liver neoplasms was also increased in exposed female mice, and a few hemangiosarcomas of the spleen and follicular cell adenomas of the thyroid gland were seen in male mice exposed to the highest concentration of cumene.

Conclusions: We conclude that the increased occurrences of adenomas of the epithelium of the nose in male and female rats, of renal tubule adenoma or carcinoma (combined), of adenomas and carcinomas of the lung in male and female mice, and of liver neoplasms in female mice were caused by exposure to cumene. The occurrence of interstitial cell adenoma of the testis in male rats and hemangiosarcomas of the spleen and follicular cell adenomas of the thyroid gland in male mice may also have been associated with exposure to cumene.

Background: Cresols are petroleum byproducts that are used to make resins, solvents, disinfectants, fragrances, and wood preservatives. We performed tests to determine if cresols caused cancer in rats or mice.

Methods: We fed groups of 50 male rats and female mice cresols mixed into their feed. Male rats were given concentrations of 1,500, 5,000, or 15,000 parts per million (ppm) of cresols in their feed, and female mice were given concentrations of 1,000, 3,000, or 10,000 ppm. Similar groups of 50 animals were given undosed feed as the control groups. Tissues from more than 40 sites were examined for every animal.

Results: The groups fed the highest concentration of cresols weighed less than their control groups. A few rare tumors of the kidney were seen in exposed male rats, and the rate of tumors of the forestomach was increased in exposed female mice. Male rats and female mice given cresols had hyperplasia of the epithelium of the nose. Exposed male rats also had hyperplasia of the kidney, and female mice had hyperplasia of the lung and degeneration of the thyroid gland.

Conclusions: We conclude that the occurrence of forestomach papillomas in female mice was caused by exposure to cresols. The occurrence of a few kidney tumors in male rats may have been related to exposure to cresols.