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The increase in cancer incidence with increasing age is becoming more obvious and more important as the average age of the population increases. The close link between old age and cancer development is the result of three main factors: the substantial length of time required for carcinogenesis; the occurrence of age-related molecular changes that mimic carcinogenesis; and, changes in bodily environment that favour cancer progression, which is a consequence of increasing age. The clinical behaviour of common malignant diseases, eg, breast, ovarian, and lung cancers, lymphomas, and acute leukaemias, may change with age because of intrinsic variation of the neoplastic cells and the ability of the tumour host to support neoplastic growth. Therapeutic decisions should be based on an estimation of the patient's life expectancy, and risks and benefits should be weighted up accordingly. A comprehensive geriatric assessment of function, comorbidity, cognition, depression, social support, nutrition, and polypharmacy, would allow interventions to be tailored to individual needs. In developed countries, the numbers of older people who develop cancer are increasing and many questions remain unanswered. These issues include: the causes of the association of cancer and ageing; the age-related differences in cancer biology; the goals of cancer treatment in the aged; and the effectiveness of cancer prevention. We review the biological and clinical interactions of cancer and ageing and discuss the skills and knowledge necessary for caring for older patients.
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PMID:A case for geriatric oncology. 1206 6

Reactions to oral contraceptive therapy tend to be maximal during the first few months of use. They include nausea or epigastric discomfort, malaise, dizziness, nervousness, fatigue, weakness, leg cramps, headache, and depression. The estrogenic component is thought to be the cause. There may also be a psychogenic basis reflecting apprehension. Breast tenderness is an occasional complaint and intermenstrual spotting or breakthrough bleeding is often reported. Increasing dosage has reduced this symptom. Dysmenorrhea prior to treatment may be improved but occasionally it is aggravated. Drug-induced amenorrhea presents a double problem in that failure to resume medication 7 days after completion of a cycle results in a risk of conception. Episodes of severe uterine bleeding in patients discontinuing use after several months or years have been reported. Other side effects include a skin reaction resembling acne, pruritus, hirsutism, thinning of scalp hair, increased skin pigmentation, and weight gain or loss. Serious vascular complications and hepatic dysfunction have been shown and deviation of thyroid function may be shown by increase of serum protein-bound iodine (PBI). Clinical signs of hyperthyroidism have not been described. Oral contraception is associated with elevated plasma cortisol (hydrocortisone) levels and decreased urinary levels of 17-hydroxycorticosteroids (17-OCHS). Suppression of ovarian activity by oral contraceptives is rapidly reversible. Fear of carcinogenesis has caused much alarm but no proof as of the present time. Safety of long term use will require additional years of experience.
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PMID:Side-effects and possible complications of oral contraceptive drugs. 1225 41

Repression of telomerase in the somatic tissues of humans, and probably other long-lived mammals, appears to have evolved as a powerful protective barrier against cancer. Immortalization in vitro of normal human cells that lack telomerase involves the reactivation of telomerase or, rarely, an alternative (ALT) mechanism for maintaining telomeres. Inactivation of the effectors of replicative senescence, i.e. genes encoding one or more elements of the p16/pRB and/or ARF/p53/p21 anti-proliferative pathways, is required for telomerase depression leading to immortalization. Regulation of telomerase in normal human cells is mediated primarily by transcriptional repression of hTERT, the gene encoding the catalytic subunit of telomerase. Rodent cells do not possess stringent controls on telomerase activity in the soma and this explains why they are so readily immortalized and transformed in culture compared with their human counterparts. Because active telomerase has been found to exist in the proliferative compartments of self-renewing tissues, it is not yet clear whether the telomerase present in 90% of human cancers exists as a consequence of selection of pre-existing telomerase-positive cells during carcinogenesis or through induction of hTERT expression in cells in which it is normally tightly repressed. In support of the latter, chromosome transfer techniques have revealed the presence of genes on normal human chromosomes that are able to extinguish hTERT transcription in cancer cells and induce them to undergo senescence. It is clear that telomerase is obligatory for continuous tumour cell proliferation, clonal evolution and malignant progression. Telomerase therefore represents an attractive target at which to aim new anti-cancer drugs. Results with a variety of telomerase inhibitory strategies in human cancer cells have confirmed that its functional inactivation results in progressive telomere shortening, leading to growth arrest and/or cell death through apoptosis. Promising candidate small molecule inhibitors are beginning to emerge that will form the basis for anti-telomerase drug development.
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PMID:The significance of telomerase activation and cellular immortalization in human cancer. 1243 51

Manganese is the 12th most abundant element in the earth's crust. The base metal does not occur naturally, but is a component of more than 100 minerals, including sulfides, oxides, carbonates, silicates, phosphates, and borates. In addition to occurring in foods and drinking water, manganese occurs in the atmosphere from dust, volcanic activity, forest fires, and industrial emissions. Manganese (II) sulfate monohydrate was chosen for study because of its stability, solubility, and availability. Toxicology and carcinogenesis studies were conducted by administering manganese (II) sulfate monohydrate (97% pure) in feed to groups of male and female F344/N rats and B6C3F1 mice for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, germ cells of Drosophila melanogaster, and cultured Chinese hamster ovary cells. 14-DAY STUDY IN RATS: Groups of five male and five female rats received diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II) sulfate monohydrate. All rats survived to the end of the study. Male rats exposed to 50,000 ppm had a mean body weight gain 57% lower and a final mean body weight 13% lower than those of the controls. The mean body weight gain of 50,000 ppm females was 20% lower and the final mean body weight was 7% lower than those of the controls. During the second week, 50,000 ppm males and females exhibited diarrhea. 14-DAY STUDY IN MICE: Groups of five male and five female mice received diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II) sulfate monohydrate. One female mouse in the 25,000 ppm group died on day 1 of unknown causes; all other mice survived to the end of the study. Differences in body weights between exposed and control mice could not be attributed to chemical administration. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received diets containing 0, 1,600, 3,130, 6,250, 12,500, or 25,000 ppm manganese (II) sulfate monohydrate. Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 110 to 1,700 mg/kg body weight in males and 115 to 2,000 mg/kg in females. All rats survived to the end of the study. Mean body weight gains were marginally lower than that of controls in males exposed to 3,130 ppm or more; mean body weight gains were significantly lower than that of the controls in females exposed to 6,250,12,500, or 25,000 ppm. At the end of the study, absolute and relative liver weights of all exposed male rats and of 25,000 ppm female rats were significantly lower than those of controls. The total leukocyte count in males was similar between exposed and control rats; however, neutrophil counts of all exposed groups were greater than those of the controls, whereas lymphocyte counts of the 6,250, 12,500, and 25,000 ppm groups were significantly lower than those of the controls. Total leukocyte counts in 6,250,12,500, and 25,000 ppm females were significantly decreased because of a decrease in lymphocytes. Male rats also demonstrated marginal but significant increases in percent hematocrit and erythrocyte count in the 6,250,12,500, and 25,000 ppm groups. No clinical or histopathologic findings in rats were chemical related. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm manganese (II) sulfate monohydrate. Mean daily ingestion of manganese (II) sulfate monohydrate ranged from 330 to 7,400 mg/kg body weight in males and 390 to 6,900 mg/kg body weight in females. No deaths were chemical related. The mean body weight gains of exposed male mice and of 50,000 ppm female mice were significantly lower than those of controls. The absolute and relative liver weights of 50,000 ppm males were significantly lower than those of controls. The percent hematocrit and hemoglobin concentration of males and females exposed to 50,000 ppm were lower than those of the controls, and the mean erythrocyte volumes were significantly lower than those of the controls. The total leukocyte counts of males in the 25,eukocyte counts of males in the 25,000 and 50,000 ppm groups were significantly lower than that of the controls. No clinical findings were attributed to manganese (II) sulfate monohydrate ingestion. Epithelial hyperplasia and hyperkeratosis of the forestomach occurred in three 50,000 ppm males. 2-YEAR STUDY IN RATS: Groups of 70 male and 70 female rats were fed diets containing 0, 1,500, 5,000, or 15,000 ppm manganese (II) sulfate monohydrate. Based on average daily feed consumption, these doses resulted in the daily ingestion of 60, 200, or 615 mg/kg body weight (males) or 70, 230, or 715 mg/kg (females). Eight to 10 rats from each group were evaluated at 9 and 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of 15,000 ppm male rats in the 2-year study was significantly lower than that of the control group. The deaths of males in the control and exposure groups were attributed to a variety of spontaneous neoplastic and nonneoplastic lesions; however, the greater number of deaths in the 15,000 ppm group resulted from increased incidences of advanced renal disease related to ingestion of manganese (II) sulfate monohydrate. The decreased survival of the 15,000 ppm males did not occur until approximately week 93 of the study; before week 93, survival was similar in all groups. Survival of exposed females was similar to that of the controls. The mean body weight of 15,000 ppm male rats was within 5&percnt; of the control group until week 89, by week 104, the mean body weight of 15,000 ppm males was 10&percnt; lower than that of the control group. The mean body weights of 1,500 and 5,000 ppm male rats and all exposed female groups were similar to those of the controls throughout the study. Feed consumption by all exposure groups was similar to that by the control groups. No clinical findings were attributed to manganese (II) sulfate monohydrate ingestion. Hematology, Clinical Chemistry, and Tissue Metal Concentration Analyses No differences in hematology and clinical chemistry parameters attributable to the ingestion of manganese (II) sulfate monohydrate occurred between exposed and control groups. At both the 9- and 15-month interim evaluations, tissue concentrations of manganese were significantly elevated in the livers of 5,000 and 15,000 ppm male and female rats, with an accompanying depression of hepatic iron. Pathology Findings: The ingestion of diets containing 15,000 ppm manganese (II) sulfate monohydrate was associated with a marginal increase in the average severity of nephropathy in male rats (0 ppm, 2.9; 1,500 ppm, 3.0; 5,000 ppm, 3.0; 15,000 ppm, 3.2). The increased severity of nephropathy in the 15,000 ppm male rats was accompanied by significantly increased incidences of mineralization of the blood vessels (4/52, 10/51, 6/51,17/52) and glandular stomach (8/52,13/51, 9/51, 23/52), parathyroid gland hyperplasia (14/51, 14/46, 12/49, 23/50), and fibrous osteodystrophy of the femur (12/52,14/51,12/51, 24/52). These lesions are manifestations of renal failure, uremia, and secondary hyperparathyroidism. The increased incidence of advanced renal disease caused reduced survival of the high-dose male rats. No increase in the incidence of neoplasms in male or female rats was attributed to the ingestion of diets containing manganese (II) sulfate monohydrate. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice received diets containing 0, 1,500, 5,000, or 15,000 ppm manganese (II) sulfate monohydrate. These levels resulted in an average daily ingestion of 160, 540, or 1,800 mg/kg body weight (males) or 200, 700, or 2,250 mg/kg (females). Nine or 10 mice from each group were evaluated at the 9-month and 15-month interim evaluations. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival rates of exposed male and female mice in the 2-year study were similar to those of the control groups. The mean body weights of exposed male mice were similar to that of the control group. Compared to controls, female mice had exposure related lower mean body weights after week 37, and the final mean body weights for the 1,500, 5,000, and 15,000 ppm groups were 6&percnt;, 9&percnt;, and 13&percnt; lower than that of the control group. Feed consumption by all exposure groups was similar to that by the control groups. No clinical findings were attributed to the administration of manganese (II) sulfate monohydrate. Hematology, Clinical Chemistry, and Tissue Metal Concentration Analyses No chemical-related differences between exposed and control groups occurred in hematology or clinical chemistry parameters. At the 9- and 15-month interim evaluations, tissue concentrations of manganese were significantly elevated in the livers of the 5,000 and 15,000 ppm groups. Hepatic iron levels were significantly lower in exposed females at the 9-month interim evaluation and in 5,000 and 15,000 males and all exposed females at the 15-month interim evaluation. Pathology Findings: Incidences of thyroid follicular dilatation and hyperplasia were significantly greater in 15,000 ppm male and female mice than in controls. Follicular cell adenomas occurred in one 15,000 ppm male at the 15-month interim evaluation and in three 15,000 ppm males at the end of the study but not in the lower exposure groups or the control group. Follicular cell adenomas also occurred in two control, one 1,500, and five 15,000 ppm female mice at the end of the study. It is uncertain if the slightly increased incidence of follicular cell adenoma is related to the ingestion of manganese (II) sulfate monohydrate. The incidences of focal hyperplasia of the forestomach epithelium were significantly greater in the 15,000 ppm male and exposed female groups. The hyperplasia was associated with ulcers and inflammation in some mice, particularly males. GENETIC TOXICOLOGY: Manganese (II) sulfate monohydrate was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9), and did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster. Tests for induction of sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells treated without S9 were positive; with S9, only the sister chromatid exchange test with manganese (11) sulfate monohydrate was positive. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of manganese (II) sulfate monohydrate in male or female F344/N rats receiving 1,500, 5,000, or 15,000 ppm. There was equivocal evidence of carcinogenic activity of manganese (II) sulfate monohydrate in male and female B6C3F1 mice, based on the marginally increased incidences of thyroid gland follicular cell adenoma and the significantly increased incidences of follicular cell hyperplasia. The ingestion of diets containing manganese (II) sulfate monohydrate was associated with an increased severity of nephropathy in male rats, focal squamous hyperplasia of the forestomach in male and female mice, and ulcers and inflammation of the forestomach in male mice. These studies were not designed to assess any neurotoxicity that might have been expected with chronic exposure to sufficiently high doses of manganese. Synonyms: Manganese sulfate; manganous sulfate; sulfuric acid. manganese2+ salt (1:1), monohydrate
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PMID:NTP Toxicology and Carcinogenesis Studies of Manganese (II) Sulfate Monohydrate (CAS No. 10034-96-5) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1261 3

3,3'-Dimethylbenzidine dihydrochloride is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. 3,3'-Dimethylbenzidine dihydrochloride was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Toxicology and carcinogenesis studies were conducted by administering 3,3'-dimethylbenzidine dihydrochloride (approximately 99% pure) in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, or 9 or 14 months. The 14-month exposures were planned as 24-month exposures but were terminated early because of rapidly declining animal survival, due primarily to neoplasia. These studies were performed only in rats because similar studies were being performed in mice at the National Center for Toxicological Research (NCTR). Hematologic and serum chemical analyses and thyroid hormone determinations were conducted in conjunction with the 13-week and 9-month studies. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. 14-Day Studies: Rats were exposed to 3,3'-dimethylbenzidine dihydrochloride in drinking water at doses ranging from 600 to 7,500 ppm. All five males and one female in the 7,500 ppm group and 1/5 males in the 5,000 ppm group died. Final mean body weights were decreased in males receiving 1,250 ppm or more and in all exposed females, and final mean body weights of animals receiving 2,500 ppm or more were lower than initial weights. Water consumption decreased with increasing chemical concentration. Compound-related effects observed in rats receiving 5,000 ppm or more included minimal to slight hepatocellular necrosis, accumulation of brown pigment (presumably bile) in individual hepatocytes, increased severity of nephropathy relative to controls, and severe lymphocytic atrophy of the thymus. Treated animals also showed an increased severity of atrophy of the bone marrow relative to controls, varying degrees of lymphocytic atrophy of the mandibular and mesenteric lymph nodes and spleen, increased vacuolization and necrosis of cells of the adrenal cortex, focal acinar cell degeneration in the pancreas, and, in males, increased immature sperm forms in the testis and epididymis. 13-Week Studies: 3,3'-Dimethylbenzidine dihydrochloride was administered in drinking water at doses of 300, 500, 1,000, 2,000, and 4,000 ppm. All rats receiving 4,000 ppm and 4/10 males and 1/10 females receiving 2,000 ppm died before the end of the studies. Depressions in final mean body weight relative to controls ranged from 12% to 48% for males and from 9% to 42% for females. Water consumption decreased with increasing dose. At compound concentrations of 300 to 2,000 ppm, mean water consumption was 29% to 83% of control values. Compound-related effects included an increase in the severity of nephropathy relative to controls; hepatocellular necrosis and accumulation of brown pigment (presumably bile) in sinusoidal lining cells; lymphocytic atrophy of the thymus, spleen, and mandibular and mesenteric lymph nodes; atrophy of the bone marrow in the higher-dose groups; degeneration of pancreatic acinar cells; and, in males, immature sperm forms in the testis and epididymis. Decreases in serum triiodothyronine (T3) values were observed in exposed females, and decreases in mean thyroxin (T4) concentrations in exposed males and females; no significant changes were observed in thyroid stimulating hormone (TSH) levels in exposed rats. Based on the decreased survival, reductions in water consumption and body weight gain, and chemical-induced hepatocellular and renal lesions observed in the 13-week studies, the doses selected for the 9- and 14-month drinking water studies of 3,3'-dimethylbenzidine dihydrochloride were 0, 3 3,3'-dimethylbenzidine dihydrochloride were 0, 30, 70, and 150 ppm. Seventy rats of each sex were used in the control group, 45 in the low-dose group, 75 in the mid-dose group, and 70 in the high-dose group. 9-Month Studies: Ten rats of each sex in the control and 150 ppm dose groups were evaluated after 9 months. Chemical-related effects observed in exposed animals included alveolar/bronchiolar carcinoma in one male, basal cell carcinoma of the skin in one male, a squamous cell carcinoma of the oral cavity in one female, preputial gland carcinoma in two males, clitoral gland carcinoma in three females, adenocarcinoma of the small intestine in two males, Zymbal's gland carcinoma in two males and three females, hepatocellular carcinoma in two males, and adenomatous polyps of the large intestine in three males. Other effects seen in dosed rats included focal cellular alteration in the liver, lymphoid atrophy in the spleen, and increased severity of nephropathy relative to controls. An increase in serum T3 values was observed in exposed males, and a decrease in mean T4 concentrations in exposed males and females. TSH concentrations were increased in exposed male and female rats. Body Weights and Survival in the 14-Month Studies: The average amount of 3,3'-dimethylbenzidine dihydrochloride consumed per day was approximately 1.8, 4.0, or 11.2, mg/kg for low-, mid-, or high-dose male rats and 3.0, 6.9, or 12.9 mg/kg for low-, mid-, or high-dose female rats. The mean body weight of high-dose males was about 85&percnt; of the control value by week 28. By the end of the study, mean body weights of low-, mid-, and high-dose males were 97&percnt;, 92&percnt;, and 70&percnt; of the control values, respectively. Mean body weights of high- and mid-dose females were about 85&percnt; of the control values at week 32 and week 44, respectively. At the end of the study, mean body weights of exposed females were about 94&percnt;, 81&percnt;, and 74&percnt; of the control values for low-, mid-, and high-dose groups, respectively. Because of extensive neoplasia, many exposed males and females were dying or were sacrificed moribund in the first year, and all high-dose males died by week 55. The studies were terminated at weeks 60 to 61, at which time the group survivals were male: control, 60/60, low dose, 41/45; mid dose, 50/75; high dose, 0/60; female: 59/60; 39/45; 32/75; 10/60. Nonneoplastic Effects in the 14-Month Studies: Increases in nonneoplastic lesions in dosed rats included cystic degeneration and foci of cellular alteration in the liver; exacerbation of nephropathy; and focal or multifocal hyperplasia of the Zymbal's gland, preputial and clitoral glands, and alveolar epithelium. Neoplastic Effects in the 14-Month Studies: Neoplasms were observed in exposed rats at many sites: skin, Zymbal's gland, preputial and clitoral glands, liver, oral cavity, small and large intestine, mammary gland, lung, brain, and mesothelium. The incidence of these neoplastic effects in male and female rats is summarized in the table at the end of this section (see page 8 of the Technical Report). Genetic Toxicology: 3,3'-Dimethylbenzidine dihydrochloride was mutagenic in Salmonella typhimurium strain TA98 with exogenous metabolic activation; it was not mutagenic in strains TA100, TA1535, or TA97 with or without activation. 3,3'-Dimethylbenzidine dihydrochloride induced sister-chromatid exchanges (CHO) and chromosomal aberrations in CHO cells in the absence of exogenous metabolic activation; these effects were not evident in test with S9 activation. Sex-linked recessive lethal mutations were induced in germ cells of adult male Drosophila melanogaster administered 3,3'-dimethylbenzidine dihydrochloride in feed or by injection. No reciprocal translocations occurred in D. melanogaster germ cells following exposure to 3,3'-dimethylbenzidine dihydrochloride. Conclusions: Under the conditions of these 14-month drinking water studies, there was clear evidence of carcinogenic activity of 3,3'-dimethylbenzidine dihydrochloride for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, preputial gland, liver, oral cavity, small and large intestine, lung, and mesothelium. Increased incidences of neoplasms of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity, small and large intestine, mammary gland, and lung. Increased incidences of neoplasms of the brain and mononuclear cell leukemia may have been related to chemical administration. Synonyms: o-tolidine dihydrochloride; 3,3'-dimethylbiphenyl-4,4'-diamine dihydrochloride; 3,3'-dimethylbiphenyl-4,4'-biphenyldiamine dihydrochloride; 4,4'-diamino-3,3'-dimethylbiphenyl dihydrochloride
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PMID:NTP Toxicology and Carcinogenesis Studies of 3,3'-Dimethylbenzidine Dihydrochloride (CAS No. 612-82-8) in F344/N Rats (Drinking Water Studies). 1263 69

Toxicology and carcinogenesis studies of d-limonene, a naturally occurring monoterpene found in many volatile oils, especially in citrus oils, were conducted because of its widespread use as a flavor and fragrance additive for food and household cleaning products and its increasing use as an industrial solvent. The d-limonene used in these studies was more than 99% pure and was administered in corn oil by gavage. Short-term studies were conducted in F344/N rats and B6C3F1 mice to identify toxic effects and affected sites and to help establish doses for the 2-year studies. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. The doses selected for the 16-day studies ranged from 413 to 6,600 mg/kg for both rats and mice; deaths and reduction in body weight gain occurred at the two highest doses. No compound-related clinical signs or histopathologic lesions were observed in any of the surviving dose groups. In the 13-week studies, doses of d-limonene ranged from 150 to 2,400 mg/kg for rats and from 125 to 2,000 mg/kg for mice. Deaths occurred in the high dose group of each species and sex. Greater than 10% reductions in body weight gain were observed in the two highest dose groups of male rats and male mice and the high dose female rats. Rough hair coats and decreased activity were observed at the two highest doses in both rats and mice. There were no chemical-related histopathologic lesions in female rats or in mice of either sex. A compound-related increased severity of nephropathy was observed in the kidney of male rats. This lesion was characterized by degeneration of epithelial cells in the convoluted tubules, granular casts in the outer stripe of the outer medulla, and epithelial regeneration. These lesions have been described as reasonably characteristic of the hyaline droplet nephropathy that is associated with an accumulation of liver-generated a2u-globulin in the cytoplasm of tubular epithelial cells. Two-year studies of d-limonene were conducted by administering 0, 75, or 150 mg/kg d-limonene in corn oil by gavage to groups of 50 F344/N male rats, 5 days per week for 103 weeks; groups of 50 female F344/N rats were administered 0, 300, or 600 mg/kg. These doses were selected based on compound-related, potentially life-threatening kidney lesions observed in males at 300 mg/kg and higher and on the large number of deaths of female rats at 2,400 mg/kg. Groups of 50 male B6C3F1 mice were administered 0, 250, or 500 mg/kg according to the same schedule; groups of 50 female B6C3F1 mice were administered 0, 500, or 1,000 mg/kg. These doses were selected based on the deaths observed for both male and female mice at 2,000 mg/kg during the 13-week studies and the body weight depression in male mice at 1,000 mg/kg and higher. Mean body weights of rats dosed with d-limonene were similar to those of vehicle controls throughout the studies. Survival of the high dose female rats after week 39 and of the vehicle control male rats after week 81 was significantly reduced (survival at week 104-- male: vehicle control, 29/50; low dose, 33/50; high dose, 40/50; female: 42/50; 40/50; 26/50). Mean body weights of dosed and vehicle control male mice were similar throughout the studies. Mean body weights of high dose female mice were notably lower than those of the vehicle controls after week 28. Survival of the low dose group of male mice was significantly lower than that of vehicle controls at the end of the study (33/50; 24/50; 39/50). No difference in survival was observed between vehicle control and dosed female mice (43/50; 44/50; 43/50). In the 2-year studies, the kidney was confirmed as the primary target organ for chemically related lesions. No lesions were observed in female rats. For males, the nonneoplastic lesions included exacerbation of the age-related nephropathy, linear deposits of mineral in the renal medulla and papilla, and focal hyperplasia of the transitional epithelium overlying the renal papilla. Uncommon tubular cell adenomas and adenocarc and adenocarcinomas of the kidney also occurred in dosed male rats, and this effect was supported by a dose-related increased incidence of tubular cell hyperplasia, as shown in the table below. INCIDENCES OF MALE RATS WITH RENAL LESIONS IN THE TWO-YEAR GAVAGE STUDY OF d-LIMONENE Site/Lesion Vehicle Control 75 mg/kg 150 mg/kg Renal papilla Mineralization 7/50 43/50 48/50 Epithelial hyperplasia 0/50 35/50 43/50 Kidney Tubular cell hyperplasia 0/50 4/50 7/50 Tubular cell adenoma 0/50 4/50 8/50 Tubular cell adenocarcinoma 0/50 4/50 3/50 In subsequent 21-day studies, male and female F344/N rats were administered d-limonene at doses ranging from 75 to 1,200 mg/kg. Microscopic examination of the kidney sections from these rats indicated a compound-related increase in intracytoplasmic granules in the proximal convoluted tubules of dosed male rats but not of female rats. The granules were shown to contain a2u-globulin by an immunohistochemical strain. a2u-Globulin was shown to be increased in kidney homogenates from dosed male rats by an ELISA test. In mice, no chemically related increases in neoplasms were observed. The incidence of neoplasms of the anterior pituitary gland in high dose female mice was lower than that in vehicle controls (adenomas or carcinomas, combined:vehicle control, 12/49; high dose, 2/48). Cells with an abnormal number of nuclei (8/49; 32/50) and cytomegaly (23/49; 38/50) were observed in the liver of high dose male mice. Genetic Toxicology: d-Limonene was not mutagenic in four strains of S. typhimurium (TA98, TA100, TA1535, or TA1537), did not significantly increase the number of trifluorothymidine (Tft)-resistant cells in the mouse L5178Y/TK± assay, and did not induce chromosomal aberrations or sister chromatid exchanges (SCEs) in cultured CHO cells. All assays were conducted in the presence and absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of d-limonene for male F344/N rats, as shown by increased incidences of tubular cell hyperplasia, adenomas, and adenocarcinomas of the kidney. There was no evidence of carcinogenic activity of d-limonene for female F344/N rats that received 300 or 600 mg/kg. There was no evidence of carcinogenic activity of d-limonene for male B6C3F1 mice that received 250 or 500 mg/kg. There was no evidence of carcinogenic activity of d-limonene for female B6C3F1 mice that received 500 or 1,000 mg/kg. An increased severity of spontaneous nephropathy, increased incidences of linear mineralization of the renal medulla and papilla, and hyperplasia of the transitional epithelium of the renal papilla were present in dosed male rats. Synonyms: cyclohexene; 4-isopropenyl-1-methyl; 1-methyl-4-(1-methylethenyl)cyclohexene; p-mentha-1,8-diene; carvene; cinene; cajeputene
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PMID:NTP Toxicology and Carcinogenesis Studies of d-Limonene (CAS No. 5989-27-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1270 37

The anticarcinogenic effect of tomato juice, a natural source of antioxidants and other chemopreventive / antimutagenic agents, was studied in a skin carcinogenesis model in mice. The possible mode of action was also investigated. Oral administration of tomato juice afforded protection from development of skin tumour and increased life expectancy which may be attributed to the combined action of a number of chemical compounds with cancer chemopreventive properties present in tomato. The protective role may be associated with a decreased level of lipid peroxides noted in the tomato treated group and modulation of host detoxification enzymes. Exposure to the carcinogen resulted in a depression of the liver enzymes- glutathione-S-transferase (GST), glutathione peroxidase (GPx) and superoxide dismutase (SOD). Oral administration of tomato juice resulted in significant activation of all these enzymes (p<0.001). These results suggest a preventive role of tomato juice during carcinogenesis which is mediated possibly by their modulatory effects on biotransformation enzymes and the detoxification system of the host.
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PMID:Protective Effects of Tomato Juice on Mouse Skin Carcinogenesis. 1271 53

Toxicology and carcinogenesis studies of technical-grade benzyl alcohol (99% pure), a textile dye additive, solvent, and food flavoring agent, were conducted by administering the chemical by gavage in corn oil vehicle to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Short-Term Studies: In 16-day studies, all five male and five female rats and mice dosed with 2,000 mg/kg benzyl alcohol died. Two of five male and 3/5 female rats and 1/5 male and 2/5 female mice dosed with 1,000 mg/kg died. Rats and mice of each sex in the two highest dose groups were lethargic after dosing. Other toxic responses to benzyl alcohol in these dose groups included blood around the mouth and nose, subcutaneous hemorrhages, and blood in the urinary and gastrointestinal tracts of rats and blood in the urinary bladder of mice. Animals administered lower doses of benzyl alcohol (125, 250, or 500 mg/kg) had no compound-related histologic lesions. Doses selected for the 13-week studies were 0, 50, 100, 200, 400, and 800 mg/kg for rats and mice. Eight of 10 male rats dosed with 800 mg/kg died during weeks 7 and 8; four of these deaths were described as gavage related. Rats dosed with 800 mg/kg exhibited clinical signs indicative of neurotoxicity including staggering, respiratory difficulty, and lethargy. Hemorrhages occurred around the mouth and nose, and there were histologic lesions in the brain, thymus, skeletal muscle, and kidney. In mice, deaths were scattered among all dose levels, but none occurred in vehicle controls. Four male and six female mice died after being dosed; all deaths but one were described as gavage related. Staggering after dosing also occurred during the first 2 weeks of the studies in mice dosed with 800 mg/kg. Some of the deaths in the rats and mice may have been caused by a combination of the gavage procedure and chemical toxicity, since there was evidence that benzyl alcohol induced neurotoxic effects. There were reductions in relative weight gain in male rats dosed with 800 mg/kg benzyl alcohol, in female rats dosed with 200 mg/kg or more, in male mice dosed with 400 or 800 mg/kg, and in female mice dosed with 200 mg/kg or more. No notable changes in body weight gain or compound-related histopathologic lesions were observed in rats or mice from the lower dose groups. Based on mortality, reduction in relative body weight gain, and the histopathologic lesions, doses selected for 2-year studies in rats were 0, 200, and 400 mg/kg. Doses selected for 2-year studies in mice were 0, 100, and 200 mg/kg, based on mortality and depression in relative body weight gain. Body Weight and Survival in the Two-Year Studies: Fifty animals of each species and sex were administered benzyl alcohol in corn oil by gavage 5 days per week for 103 weeks. Administration of benzyl alcohol did not affect survival in male rats (final survival rates: vehicle control, 28/50; low dose, 27/50; high dose, 24/50) but reduced survival of dosed female rats by half (36/50; 18/50; 17/50). Many of the early deaths were considered related to the gavage procedure. Survival in mice was not affected by benzyl alcohol administration (male: 34/50; 33/50; 35/50; female: 26/50; 32/50; 36/50). No effect of benzyl alcohol on body weight gain in rats or mice was observed. In the third month of the studies, clinical signs of sialodacryoadenitis virus infection were observed in rats. A positive serologic reaction for rat coronavirus was observed in sentinel animals at 6 months and again at 18 months. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: No apparent compound-related nonneoplastic responses were observed. Dose-related negative trends in the incidences of anterior pituitary gland neoplasms were seen in female rats (vehicle control, 29/50; low dose, 17/47; high dose, 9/49) and of harderian gland adenomas in male mice (8/50; 3/50; 2/50). Adenomas of the adrenal cortex occurred at an increased incidence in high dose male mice (0/48; 0/44; 3/48), but this slight increase was not considered to be related to chemical expcal exposure. Genetic Toxicology: Benzyl alcohol was not mutagenic when tested by the preincubational protocol in the presence or absence of exogenous metabolic activation in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537. In the mouse L5178Y/TK± lymphoma assay, benzyl alcohol induced an increase in trifluorothymidine (Tft)-resistant cells in the absence, but not in the presence, of S9; the effect was associated with toxicity. In cytogenetic assays with Chinese hamster ovary (CHO) cells, treatment with benzyl alcohol produced an increase in sister chromatid exchanges (SCEs) which was judged to be equivocal both with and without S9; a significant increase in chromosomal aberrations was observed after exposure to benzyl alcohol in the presence, but not the absence, of S9. Audit: The data, documents, and pathology materials from the 2-year studies of benzyl alcohol have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of benzyl alcohol for male or female F344/N rats dosed with 200 or 400 mg/kg. Survival in both dose groups of female rats was 50&percnt; that of vehicle controls, primarily due to an increased number of gavage-related deaths. There was no evidence of carcinogenic activity of benzyl alcohol for male or female B6C3F1 mice dosed with 100 or 200 mg/kg for 2 years. Synonyms: benzenemethanol; phenylcarbinol; phenylmethanol; a-hydroxytoluene; benzenecarbinol; phenolcarbinol; a-toluenol
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PMID:NTP Toxicology and Carcinogenesis Studies of Benzyl Alcohol (CAS No. 100-51-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1272 82

Benzyl acetate, a water-white liquid with a pear-like odor, is a natural constituent of several essential oils and flower absolutes extracted from jasmine, hyacinth, gardenia, tuberose, ylang-ylang, cananga, and neroli. Commercial benzyl acetate, a liquid prepared synthetically from benzyl chloride, acetic acid, and triethylamine is used primarily as a component of perfumes for soaps and as a flavoring ingredient. This compound is practically insoluble in water but is miscible in alcohol and ether and soluble in benzene and chloroform. Toxicology and carcinogenesis studies of benzyl acetate (>99% pure) were conducted by administering benzyl acetate in corn oil gavage to groups of 50 male and 50 female F344/N rats at doses of 0, 250, or 500 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 0, 500, or 1,000 mg/kg once daily five days per week for 103 weeks. Dose selection for the 2-year study was based on mean body weight gain depression and decreased survival observed at higher doses in 13 week studies. The absence of any observable adverse effect of benzyl acetate on the survival or mean body weight gains of the rats or mice in the 2-year studies suggests that both the rats and the mice of each sex could have tolerated higher doses. An infection in the genital tract was probably responsible for the deaths of 26/35 control, 14/32 low-dose, and 8/20 high-dose female mice before the end of the study. Acinar-cell adenomas in the pancreas of male rats occurred with a positive trend (P<0.01), and the incidence in the high-dose group (37/49, 76%) was significantly (P<0.01) higher than in the vehicle controls (22/50, 40%). The incidence of these tumors in the low-dose group (27/50, 54%) was comparable to that in the gavage controls. Acinar-cell hyperplasia of the pancreas was observed in 37/50 control, 34/50 low-dose, and 36/49 high-dose male rats. No acinar-cell hyperplasia or adenoma of the pancreas was observed in female rats. The incidence of retinopathy and cataracts in the high-dose male rats was increased compared with the controls (retinopathy: 1/50; 0/50; 20/50; cataracts: 0/50; 0/50; 13/50). Low-dose female rats had an increased incidence of retinopathy (18/50). Retinopathy and cataracts in rats have been associated with proximity to fluorescent light in this and previous studies. Preputial gland neoplasms occurred with a positive trend (P<0.05) in male rats (cystadenocarcinoma: 0/50; 0/50; 3/50; all adenocarcinoma: 0/50; 1/50; 4/50; adenocarcinoma or carcinoma combined: 1/50; 1/50; 6/50). However, the incidence of all preputial gland tumors was not significantly elevated (2/50; 1/50; 6/50). For female rats the incidence of clitoral gland neoplasms was marginally increased (2/50; 0/50; 5/50). Hepatocellular adenomas occurred in mice of each sex with statistically positive trends (males: 0/50; 5/49; 13/50; females: 0/50; 0/50; 6/50), and the incidences in the high-dose groups were greater than those in the controls (males: P<0.001; females: P<0.05). Hepatocellular carcinomas were marginally elevated in dosed male and high-dose female mice (males: 10/50; 14/49; 12/50; females: 1/50; 0/50; 4/50). Squamous cell papillomas or carcinomas of the forestomach (uncommon neoplasms) occurred with a positive trend (P<0.05) in male mice (4/49; 4/48; 11/49). The incidence of these tumors was also marginally (P=0.054) increased in the high-dose female mice (0/50; 0/50; 4/48). The incidences of these tumors in both the high-dose male and the high-dose female mice were considerably higher than the historical corn oil gavage control rates at this laboratory (males, 2/296, 0.7%; females, 2/297, 0.7%) and throughout the program (males, 14/1,070, 1.3%; females, 3/1,073, 0.3%). Forestomach hyperplasia occurred at increased incidences in dosed mice of either sex (males: 1/49, 7/48, 22/49; females: 1/50, 6/50, 17/48). The neoplasms and hyperplasia of the forestomach were probably related to administration of benzyl acetate. In a separate metabolism study, benzyl acetate was absorbed from the gastrointestinal traolism study, benzyl acetate was absorbed from the gastrointestinal tract of rats and mice, with approximately 90&percnt; of the administered dose recovered as various metabolites in the urine within 24 hr. The primary metabolite was hippuric acid, with minor amounts of a mercapturic acid, and one or more unidentified metabolites. This capacity for absorption, metabolism, and disposition was unaffected by the amount or number of doses administered. Benzyl acetate was not mutagenic in strains TA100, TA98, TA135, or TA137 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced Sprague-Dawley rat or Syrian hamster S9 when tested according to the preincubation protocol. Benzyl acetate did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of Aroclor 1254-induced Sprague-Dawley rat liver S9. Benzyl acetate was mutagenic in the mouse lymphoma L5178Y/TK± assay in the presence, but not in the absence, of Aroclor 1254-induced Fisher 344 rat liver S9. An audit was conducted on the experimental data and the draft technical report for these 2-year studies on benzyl acetate. Based on the results of this audit additional pathology examinations were conducted on all target organs in male rats and male and female mice. The Technical Report reflects these final pathology evaluations. The overall conclusions regarding the toxicology and carcinogenicity of benzyl acetate did not change as a result of this evaluation. Under the conditions of these gavage studies, benzyl acetate increased the incidence of acinar-cell adenomas of the exocrine pancreas in male F344/N rats; the gavage vehicle may have been a contributing factor. There was no evidence of carcinogenicity for female F344/N rats. For male and female B6C3F1 mice there was some evidence of carcinogenicity in that benzyl acetate caused increased incidences of hepatocellular adenomas and squamous cell neoplasms of the forestomach. Synonyms: alpha-acetoxytoluene; benzyl ethanoate; acetic acid, benzyl ester
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PMID:NTP Toxicology and Carcinogenesis Studies of Benzyl Acetate (CAS No. 140-11-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1274 78

Tris(2-ethylhexyl)phosphate is one of a family of triakyl phosphates that have been widely used as fire retardants and plasticizers. Another triakyl phosphate, tris(2,3-dibromopropyl)phosphate (Tris-BP), once used as a flame retardant in children's sleepwear, has been shown to be carcinogenic, but tris(2-ethylhexyl)phosphate has not been previously studied. Tris(2-ethylhexyl)phosphate, a clear, viscous liquid, is used as a component of vinyl stabilizers, grease additives, and flame-proofing compositions; however, it is used primarily as a plasticizer for vinyl plastic and synthetic rubber compounds. In 1974, approximately 3 million pounds of tris(2-ethylhexyl)phosphate was produced in the United States; imports during that year were negligible. Substantial human exposure probably occurs during production of tris(2-ethylhexyl)phosphate and during the manufacture and use of products containing it, but data on the magnitude of exposure are not available. Two-year toxicology and carcinogenesis studies of tris(2-ethylhexyl)phosphate were conducted by administering the test chemical in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 male and 50 female F344/N rats and B6C3F1 mice. Male rats received doses of 2,000 or 4,000 mg/kg body weight, female rats received 1,000 or 2,000 mg/kg, and male and female mice received 500 or 1,000 mg/kg. Fifty vehicle control animals of each sex and species received 10 ml/kg body weight (rats) or 3.3 ml/kg (mice) corn oil by gavage on the same schedule. Inflammation of the gastric mucosa in mice and mild weight depression in rats and mice were the only dose-related effects observed in the preliminary studies. In the 2-year studies, survival rates and mean body weight gains of dosed female rats and dosed mice were comparable to those of their perspective controls. Survival rates of dosed male rats were comparable to that of the vehicle controls, but body weight gains were depressed. One nonneoplastic lesion, follicular cell hyperplasia of the thyroid, was observed at increased incidences in dosed male and female mice. Two compound-related increased incidences of neoplasms could not be discounted. In male rats, the incidence of pheochromocytoma of adrenal glands increased with dose (2/50, 4%; 9/50, 18%; 12/50, 24%). There were also two additional malignant pheochromocytomas in the high dose group. However, the incidence of adrenal pheochromocytoma in vehicle controls of this study (2/50, 4%) was low compared with the 25% incidence observed in two previous studies in this laboratory or the overall historical incidence of 18% observed throughout the Program, and thus the evidence of carcinogenicity was considered to be equivocal. In female mice, the incidence of hepatocellular carcinoma (0/48; 4/50; 7/50) in high dose animals (1,000 mg/kg) was significantly increased relative to that of the vehicle controls. Decreased incidences were observed for acinar cell adenomas of the pancreas in dosed male rats (14/50, 28%; 5/48, 10%; 2/49, 4%) and for fibroadenomas of the mammary glands in low dose female rats (11/50, 22%; 2/50, 4%; 7/50, 14%). Hemangiosarcomas of the circulatory system in male mice (7/50, 14%; 0/50; 1/49, 2%) and lymphomas of the hematopoietic system in female mice (14/49, 29%; 10/50, 20%; 6/50, 12%) were decreased compared with vehicle controls. A decrease in the incidence of lymphomas and an increased incidence of carcinomas of the liver in female mice (both seen in this study) were observed in studies of di(2-ethylhexyl)adipate. Increased incidences of liver carcinomas and decreased incidences of mammary fibroadenomas were observed also in female rats in the di(2-ethylhexyl)phthalate studies. A possible link among these three chemicals may be metabolic conversion to 2-ethylhexanol. Tris(2-ethylhexyl)phosphate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of 9000 x g (S9) fractions from Aroclor 1254-induced Sprague-Dawley rat or Syrian hamster liver. An audit of the experimental data from these carcinogeneoclor 1254-induced Sprague-Dawley rat or Syrian hamster liver. An audit of the experimental data from these carcinogenesis studies was conducted by the National Toxicology Program. No data discrepancies were found that significantly influenced the final interpretations of these experiments. Under the conditions of these studies, a comparison of concurrent and historical controls indicated that there was equivocal evidence of carcinogenicity in male F344/N rats receiving 2,000 and 4,000 mg/kg tris(2-ethylhexyl)phosphate, as evidenced by increased incidences of pheochromocytomas of the adrenal glands. There was no evidence of carcinogenicity in female F344/N rats or in male B6C3F1 mice receiving tris(2-ethylhexyl)phosphate. There was some evidence of carcinogenicity in female B6C3F1 mice that received 1,000 mg/kg tris(2-ethylhexyl)phosphate, as shown by an increased incidence of hepatocellular carcinoma. Tris(2-ethylhexyl)phosphate was associated with increased incidences of follicular cell hyperplasia of the thyroid gland in male and female B6C3F1 mice. Synonyms and Trade Names: TOF; trioctyl phosphate; phosphoric acid tri(2-ethylhexyl) ester; Flexolreg. TOF; Kronitexreg.
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PMID:NTP Toxicology and Carcinogenesis Studies of Tris(2-ethylhexyl)phosphate (CAS No. 78-42-2) In F344/N Rats and B6C3F1 Mice (Gavage Studies). 1274 80

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