Sodium tungstate dihydrate (ST) is present naturally in the environment and can enter waterways through the weathering of rocks and soils. ST also is a high-production volume compound that is used in a variety of commercial applications including fire- and waterproofing fabrics, in the preparation of complex compounds (e.g., phosphotungstate and silicotungstate), as a reagent for biological products, and as a precipitant for alkaloids. Tungsten was nominated to the National Toxicology Program (NTP) by the Centers for Disease Control and Prevention to evaluate its potential to cause chronic toxicity and carcinogenicity because of concern about potential human exposure via contaminated drinking water (e.g., in the form of salts like tungstate) and inadequate data to assess human health implications of elevated exposures. ST was selected for study because it is the most prevalent water-soluble form of tungsten. In these studies, Sprague Dawley (Hsd:Sprague Dawley SD) rat dams were exposed to ST in drinking water from gestation day (GD) 6 through lactation day (LD) 20. Their pups were exposed to the same exposure concentrations in drinking water from postnatal day (PND) 12 through 3 months or 2 years. Adult male and female B6C3F1/N mice were exposed to ST in drinking water for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, rat and mouse peripheral blood erythrocytes, and cells from liver, kidney, and ileum; peripheral blood leukocytes from rats and mice also were assessed for DNA damage. (Abstract Abridged).

Dried concentrated extracts from Camellia sinensis contain high amounts of catechins and are a popular source for green tea extract nutraceutical supplements and medicinal uses. Supplements containing green tea extract are commonly consumed for weight loss and green tea extracts are popular ingredients in sunblocks, cream rinses, and other cosmetics. Numerous studies in both experimental animals and clinical settings have examined the possible anticancer, anti-inflammatory, antimicrobial, and cardio- and neuroprotective properties of green tea extract. The presumed active ingredient of green tea extract, epigallocatechin gallate (EGCG), was originally nominated by the National Cancer Institute for toxicity and carcinogenicity studies because it is the most abundant catechin in green tea extract, it was being investigated as a potential chemotherapeutic agent, and there was a lack of adequate information with regard to its toxicity. However, the NTP selected green tea extract [containing EGCG (48.4% by weight) and other green tea catechins] for study because human exposure is to green tea extract products that contain concentrated mixtures of various green tea catechins. The NTP analyzed four lots of green tea extract and selected a source based on quantities of EGCG, consistency with other products on the market, and availability in bulk quantity. Oral gavage was chosen as the route of administration because it was considered most relevant to human exposure. Male and female F344/NTac rats and B6C3F1/N mice were administered green tea extract in water 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 green tea extract in water by gavage for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. (Abstract Abridged).

Topical retinoids, compounds that are metabolites, analogues, or derivatives of retinol and possess biological vitamin A activity, are among the most used adjunctive agents for the mitigation of fine wrinkles, mottled hyperpigmentation, and tactile roughness of photodamaged and chronically aged skin. Retinoic acid (RA) is the most active biological form of vitamin A and remains the medical treatment of choice for photoaged skin. Retinyl palmitate (RP) is the major storage form of vitamin A in the skin and, because RP is also the most stable of available vitamin A esters, it is readily incorporated into the oil phase of cosmetic creams or lotions. Therefore, the topical application of RP is a practical strategy for increasing the levels of vitamin A in the skin. Usual cosmetic product concentrations of RA range from 0.025% to 0.1% and those of RP range from 0.1% to 5%. With a maximum absorbance around 325 nm, RA and RP absorb both ultraviolet A and B radiation (UVA and UVB) in incident sunlight. A 1-year study was conducted in mice to determine whether RA and RP would alter the photocarcinogenicity of broad-UV spectrum light generated by xenon arc lamps, termed simulated solar light (SSL), or narrow spectrum UV light generated by UVA and UVB lamps.

CHEMICAL AND PHYSICAL PROPERTIES: Ginseng is a perennial aromatic herb widely used in herbal remedies, dietary supplements, cosmetics, and as a food additive. Ginseng was nominated for study by the National Cancer Institute based on significant human exposure through the uses described above and the lack of information on its toxicity. Male and female F344/N rats and B6C3F1 mice were administered extracts of ginseng root by gavage 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 administered ginseng in 0.5% aqueous methylcellulose by gavage at doses of 0, 125, 250, 500, 1,000, or 2,000 mg/kg, 5 days per week for 16 days. All rats survived to the end of the study. Mean body weight gain of 2,000 mg/kg males was significantly greater than that of the vehicle controls. There were no chemical-related gross or microscopic findings attributed to the administration of ginseng. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were administered ginseng in 0.5% aqueous methylcellulose by gavage at doses of 0, 125, 250, 500, 1,000, or 2,000 mg/kg, 5 days per week for 17 days. All mice survived to the end of the study. The final mean body weight of 1,000 mg/kg males was significantly less than that of the vehicle controls. There were no significant chemical-related gross or histopathologic changes in dosed mice. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered ginseng in sterile water by gavage at doses of 0, 1,000, 2,000, 3,000, 4,000, or 5,000 mg/kg, 5 days per week for 14 weeks. 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. No lesions that were observed by gross or histopathologic examination were attributed to the administration of ginseng. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered ginseng in sterile water by gavage at doses of 0, 1,000, 2,000, 3,000, 4,000, or 5,000 mg/kg, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of all dosed groups were similar to those of the vehicle control groups. Although sporadic incidences of lesions were observed in the vehicle control and 5,000 mg/kg groups, there were no chemical-related gross or microscopic findings in dosed mice. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered ginseng in sterile water by gavage at doses of 0, 1,250, 2,500, or 5,000 mg/kg, 5 days per week for 104 to 105 weeks. Survival of 5,000 mg/kg females was significantly less than that of the vehicle controls; however, the deaths were not attributed to the administration of ginseng because no histopathologic findings attributable to ginseng were found. Mean body weights of 5,000 mg/kg females were less than those of the vehicle controls after week 61 of the study, and mean body weights of other dosed groups of rats were similar to those of the vehicle controls throughout the study. No increases in the incidences of neoplasms or nonneoplastic lesions were attributed to the administration of ginseng. The incidence of mammary gland fibroadenoma was significantly decreased in 5,000 mg/kg females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered ginseng in sterile water by gavage at doses of 0, 1,250, 2,500, or 5,000 mg/kg, 5 days per week for 105 weeks. Survival of dosed groups was similar to that of the vehicle control groups. Mean body weights of dosed mice were similar to those of the vehicle controls. No neoplasms or nonneoplastic lesions were attributed to the administration of ginseng. Ginseng was not mutagenic in either of two independent bacterial mutagenicity assays, each conducted with or without exogenous metabolic activation enzymes. Bacterial strains tested included S. typhimurium strains TA97, TA98, TA100, TA102, TA104, and TA1535, as well as E. coli strain WP2 uvrA/pKM101. No significant increases were seen in the frequencies of micronucleated erythrocytes in the peripheral blood of male or female B6C3F1 mice exposed for 3 months to 1,000 to 5,000 mg/kg ginseng via gavage. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of ginseng in male or female F344/N rats or B6C3F1 mice administered 1,250, 2,500, or 5,000 mg/kg. The incidence of mammary gland fibroadenoma was significantly decreased in 5,000 mg/kg female rats.

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. 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. 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. 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.