High incidences of pheochromocytomas after long-term administration of retinol acetate to F344/DuCrj rats

The carcinogenicity of retinol acetate [(RAC) CAS: 127-47-9], a synthetic derivative of retinol, was tested by continuous oral administration in the drinking water of F344/DuCrj rats for 104 weeks. Groups of 50 male and 50 female rats were given solutions of 0.25 or 0.125% RAC in the form of gelatinized beadlets suspended in distilled water. Control groups consisting of the same numbers of rats were given 0.25% of placebo beadlets. All of the surviving animals were killed at 108 weeks, 4 weeks after the cessation of the RAC treatments. The survival rates were 72-84% and were sufficiently high for statistical comparison of all groups. Inhibition of body weight gain was marked in females of the high-dose group. Higher incidences of malignant pheochromocytomas, benign pheochromocytomas, and hyperplasias of the adrenal medulla were observed in the RAC-treated groups. The combined incidences of tumors of the adrenal medulla in males and females of the high-dose groups and the incidence in females of the low-dose group were significantly higher than the incidence in the controls. Conversely, statistically significant decreases were found in the incidences of the mammary gland tumors in males of the high-dose group, of thyroid tumors in females of the high-dose group, and of clitoral gland tumors in females of both high- and low-dose groups. It was concluded that RAC given orally possesses potential for increasing the incidence of pheochromocytomas in male and female F344 rats in a dose-related manner under the conditions of this bioassay.     

Tumor induction by a single subcutaneous injection of sterigmatocystin in newborn mice.

Sterigmatocystin, a mycotoxin produced by Aspergillus versicolor, Aspergillus sydowi, Aspergillus nidulans, and a species of Bipolaris, was given to newborn BALB/c X DBA/2F1 (hereafter referred to as CD2F1) mice by a single s.c. administration in 1% gelatin suspension. In an acute toxicity study, the maximum tolerated dose of sterigmatocystin was 5 mug/g body weight. In a chronic study, a single s.c. injection of 5, 1, or 0.5 mug/g body weight gave rise to high incidences of lung and liver adenomas when the animals were killed at the end of 1 year. The incidence of both tumors in mice at the dose of 5 mug/g body weight was statistically significant, and the incidences of lung tumor in female mice and of liver tumor in male mice at the dose of 1 mug/g body weight were also statistically significant, compared with tumors in control mice. Other tumors also were induced in treated mice (two malignant lymphomas and one adenoma of the submaxillary gland), in contrast to a zero incidence in vehicle control mice. These results confirm that a small quantity of sterigmatocystin induces tumors of lung and liver and that the dose of sterigmatocystin is related to the incidence of tumors in mice.     

Clinical analysis of salivary gland tumor cases in West China in past 50 years

In our study, 3461 cases of salivary gland tumor treated between 1955 and 2002 at West China Stomatology Hospital of Sichuan University were retrospectively analyzed, and compared with the previous reports. Measures such as age, tumor location, tumor histological type, and the nature of the growth (benign or malignant) were recorded at the same time. The findings are as follows: the average ages of salivary gland tumor patients were 41.38 years for the benign cases and 45.20 for the malignant ones; the male:female ratio was 0. 99:1 in the benign cases and 1.34:1 in the malignant ones; primary tumors were mostly in the parotid gland, palate and submandibular gland in sequence. Pleomorphic adenoma was the most frequent benign tumor followed by Warthin's tumor and basal cell adenoma, whereas mucoepidermoid carcinoma, adenoid cystic carcinoma and adenocarcinoma not otherwise specified were the most frequent malignant tumors. The incidence of salivary gland tumors increased with age. The male:female ratio of malignant tumors was higher than that of benign ones. The parotid gland and palate were the most common locations of salivary gland tumors. Pleomorphic adenoma and mucoepidermoid carcinoma were the most frequent benign and malignant tumors, respectively.     

Carcinogenicity Testing of the Cosmetic Dye: D&C Red No. 36

D&C Red No. 36, a drug and cosmetic dye commonly used for coloring lipsticks, was evaluated for its carcinogenicpotential in male and female Wistar rats. This dye has been shown to exhibit mutagenic activity towards Salmonellatyphimurium TA 98 in the presence of S9 mix. In the present study, 50 male and 50 female rats in each group weregiven diets containing D&C Red No. 36 at 2 different concentrations, 1,000 ppm and 2,000 ppm, for 78 weeks andsacrificed at week 98.It was found that dye treatment had no significant effect on the survival of either male or female animals as wellas the body weight gain in males. However, body weight gain of treated females was slightly lower than that of thecontrol group. Histopathological assessment demonstrated a number of benign and malignant tumors to havedeveloped in various organs of both dye treated and control groups. In male rats, benign liver tumors were found atincidences of 16.7% and 18.8% of the low (1,000 ppm) and high (2,000 ppm) dose groups, respectively, similar to the20% for the control group. Malignant tumors of the thyroid gland were observed only in the low dose and controlgroups, at 4.2% and 2%, respectively. In the high dose group, the incidences of lung, liver, urinary bladder and softtissue cancers were 4.2%, 2.1%, 2.1% and 2.1%, respectively, only one soft tissue cancer being observed in a controlgroup animal. In females, benign tumors were observed in the liver and mammary glands. The incidences of livertumors in the low and high dose groups were 12.8% and 16%, respectively, and 6% in the control group. Values formammary gland tumors were 10.6%, 10%, and 18% respectively. Malignant tumors were also observed in variousother organs, including the uterus, lung, kidney, thyroid, thymus and salivary gland, but the incidences were verylow (about 2-4%) and in dye treated male and female rats were not statistically different from those in the controlanimals.The results of the present study thus demonstrated that D&C Red No. 36 at the concentrations of 1,000 ppm and2,000 ppm in the diet is not carcinogenic either to male or female Wistar rats. While the occurrence of benign livertumors in female rats may be related to dye treatment, the lack of any apparent dose-dependence or any statisticallysignificant difference from the control group (P = 0.06) suggests that this is unlikely.     

Mammary tumor induction in ACI rats exposed to low levels of 17beta-estradiol

Animal models play a major role in understanding the etiology, molecular mechanisms, strategizing intervention and treatment of human diseases. ACI, an inbred line derived from August and Copenhagen strains, is unique for its susceptibility to estrogen-induced mammary tumors. Histologically and in many molecular aspects, the tumors formed in these rats are similar to human breast cancers. Previous studies have shown high mortality and significant weight loss in this model associated with pituitary gland abnormality. We hypothesized that this could be due to overwhelming the biological system with estrogen. Three groups of female ACI rats (7-8 weeks) received either 3-cm sham silastic implants, or the conventional 3-cm silastic implants containing 27 mg of 17beta-estradiol, or 1.2-cm silastic implants containing 9 mg 17beta-estradiol. The sham and 3-cm implant rats were euthanized at 180 days while the 1.2-cm implant rats were euthanized at 240 days. The 1.2-cm implants resulted in significantly reduced serum estrogen levels and pituitary gland size. Animals with 1.2-cm implants had 100% tumor incidence, while not all rats developed tumors with 3-cm implants. Both the tumor burden (from 1,011+/-402 to 2,324+/-454 mm(3); p=0.01) and tumor multiplicity (from 5.78+/-1.4 to 7.6+/-1.04) increased by lowering the estrogen dose, and the inter-animal variability in the tumor indices decreased. Finally, the weight of the pituitary gland was also significantly (p=0.0004) reduced (from 178+/-23.5 mg to 80+/-8.9 mg) and the mortality rate decreased from 42% to 0% (p=0.01). Our data indicate that the improvised model will provide valuable insights into the molecular alterations in the estrogen-induced mammary tumorigenesis and will be ideal for inhibition studies.     

Comparative tumorigenicity of 1-nitropyrene, 1-nitrosopyrene, and 1-aminopyrene administered by gavage to Sprague-Dawley rats

The carcinogenic activities of 1-nitropyrene, a mutagenic component of diesel exhaust, and its reduced derivatives 1-nitrosopyrene and 1-aminopyrene were evaluated in male and female Sprague-Dawley rats. Within 24 h of birth, groups of 22-36 rats were treated by gavage with trioctanoin or the appropriate compound in trioctanoin once weekly for 16 weeks. The approximate total doses per rat were as follows: 1-nitropyrene, high dose (800 mumol); 1-nitropyrene, low dose (320 mumol); 1-nitrosopyrene (320 mumol); 1-aminopyrene (320 mumol). The experiment was terminated after 94 weeks. The main site of tumor induction was the mammary glands of female rats. Percentages of incidences of mammary adenocarcinomas in female rats were as follows: 1-nitropyrene, high dose (63%); 1-nitropyrene, low dose (42%); 1-nitrosopyrene (19%); 1-aminopyrene (4%) trioctanoin (3%). These incidences were significantly greater than those of controls for the female rats treated with either 1-nitropyrene or 1-nitrosopyrene. Low and generally insignificant incidences of tumors of a variety of other sites were also observed in rats treated with 1-nitropyrene. The induction of mammary tumors by 1-nitropyrene confirms the results of a previous study (Hirose et al., Cancer Res., 44: 1158-1162, 1984). The present results also demonstrate that, under the conditions of this bioassay, 1-nitropyrene was significantly more carcinogenic than either 1-nitrosopyrene or 1-aminopyrene.     

Dose- and Sex-related Carcinogenesis by N-Bis(2-hydroxypropyl)nitrosamine in Wistar Rats

An initiation-promotion medium-term bioassay for detection of chemical carcinogens, developed in the male F344 rat, uses 0.1% N-bis(2-hydroxypropyl)nitrosamine (DHPN) among five genotoxic chemicals for the initiation of carcinogenesis in multiple organs. To establish this bioassay in the Wistar strain, the effects of two dose levels of DHPN were evaluated on the main DHPN rat target organs: lung, thyroid gland, kidneys and liver. Four groups of male and female animals were studied: Control—untreated group; Multi-organ initiated group (also referred to as DMBDD, based on the initials of the five initiators)—treated sequentially with N-diethylnitrosamine (DEN, i.p.), N-methyl-N-nitrosourea (MNU, i.p.), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, drinking water), N, ďN'-dimethylhydrazine (DMH, s.c.) and DHPN (drinking water) for 4 weeks; a third group treated with 0.1% DHPN in drinking water for 2 weeks and the last group treated with 0.2% DHPN in drinking water for 4 weeks. The animals were sacrificed after 30 weeks. DHPN at 0.2% induced preneoplasia in the liver and kidneys of rats of both sexes, the number and area of the putative preneoplastic liver glutathione S-transferase-positive hepatocyte foci being significantly increased in these animals. It also induced benign and malignant tumors in female and in male rats. However, there was no relationship between the increased incidence of preneoplastic lesions and tumor development in the 0.2% DHPN-exposed groups of both sexes. DHPN at 0.1% induced only a few preneoplastic lesions in the liver and kidney and no tumors in both male and female rats. A clear dose and sex-related carcinogenic activity of DHPN was registered, although Wistar rats of both sexes showed a relative resistance to the carcinogenic activity of this compound.     

Dose- and sex-related carcinogenesis by N-bis(2-hydroxypropyl)nitrosamine in Wistar rats.

An initiation-promotion medium-term bioassay for detection of chemical carcinogens, developed in the male F344 rat, uses 0.1% N-bis(2-hydroxypropyl)nitrosamine (DHPN) among five genotoxic chemicals for the initiation of carcinogenesis in multiple organs. To establish this bioassay in the Wistar strain, the effects of two dose levels of DHPN were evaluated on the main DHPN rat target organs: lung, thyroid gland, kidneys and liver. Four groups of male and female animals were studied: Control -- untreated group; Multi-organ initiated group (also referred to as DMBDD, based on the initials of the five initiators) -- treated sequentially with N-diethylnitrosamine (DEN, i.p.), N-methyl-N-nitrosourea (MNU, i.p.), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, drinking water), N, N'-dimethylhydrazine (DMH, s.c.) and DHPN (drinking water) for 4 weeks; a third group treated with 0.1% DHPN in drinking water for 2 weeks and the last group treated with 0.2% DHPN in drinking water for 4 weeks. The animals were sacrificed after 30 weeks. DHPN at 0. 2% induced preneoplasia in the liver and kidneys of rats of both sexes, the number and area of the putative preneoplastic liver glutathione S-transferase-positive hepatocyte foci being significantly increased in these animals. It also induced benign and malignant tumors in female and in male rats. However, there was no relationship between the increased incidence of preneoplastic lesions and tumor development in the 0.2% DHPN-exposed groups of both sexes. DHPN at 0.1% induced only a few preneoplastic lesions in the liver and kidney and no tumors in both male and female rats. A clear dose and sex-related carcinogenic activity of DHPN was registered, although Wistar rats of both sexes showed a relative resistance to the carcinogenic activity of this compound.     

Effects of X-irradiation, ovariohysterectomy and estradiol-17 beta on incidence, benign/malignant ratio and multiplicity of rat mammary neoplasms--a preliminary report

An overview is given of the effects of X-irradiation, ovariohysterectomy and estradiol-17 beta administration on mammary tumorigenesis in females of 3 rat strains, viz. the WAG/Rij, BN/BiRij and SD. The 3 rat strains differed significantly in their spontaneous mammary tumor incidence. Female SD rats had the highest incidence (47%) and female BN/BiRij rats the lowest (17%). Female WAG/Rij rats had an intermediate incidence of 29%. The benign/malignant ratio in female WAG/Rij, BN/BiRij and SD rats was 1.0, 2.0 and 7.3, respectively. The average number of mammary gland neoplasms per untreated tumor-bearing female was 1.2 in the WAG/Rij, 1.0 in the BN/BiRij and 1.6 in the SD, whereas the respective maximum numbers were 2, 1 and 5. Ovariohysterectomy almost entirely prevented mammary tumor formation in all 3 rat strains, whereas estrogen treatment enhanced it. In addition, estrogen treatment resulted in an increased number of mammary tumors per tumor-bearing female and changed the benign/malignant ratio into the direction of malignant. X-irradiation increased the mammary tumor incidence in all 3 rat strains, especially of the benign tumors. Estrogen potentiated the effect of irradiation. An effect of irradiation on mammary tumorigenesis was not observed in ovariohysterectomized females of all 3 rat strains.     

Androgen-mediated development of irradiation-induced thyroid tumors in rats: dependence on animal age during interval of androgen replacement in castrated males

When male Long-Evans rats at age 8 weeks were radiation treated (40 microCi Na131I), thyroid follicular adenomas and carcinomas were observed at age 24 months with a high incidence of 94%. Castration of males prior to irradiation significantly reduced this tumor incidence to 60%. When testosterone (T) was replaced in castrated, irradiated male rats, differentially increased incidences of thyroid tumors occurred, depending on the time interval for hormone replacement. Immediate (age 2-6 mo) or early (age 6-12 mo) T replacement at approximate physiologic levels led to thyroid follicular tumor incidences of 100 and 82%, respectively, whereas intermediate (12-18 mo) or late (18-24 mo) T treatment led to only 70 and 73% incidences, respectively. Continuous T replacement (2-24 mo) in castrated irradiated male rats raised thyroid tumor incidence to 100%. Since elevated thyroid-stimulating hormone (TSH) is a reported requisite for development of radiation-associated thyroid tumors, the effects of T on serum TSH levels were examined. Mean serum TSH values in all irradiated animal groups were significantly elevated above age-matched nonirradiated animals at 6, 12, 18, and 24 months. Serum TSH levels were higher in continuous T-replaced irradiated castrates than in intact, irradiated males, whereas such intact male TSH levels were greater than those for irradiated castrates without T treatment. Interval T replacement in castrated male rats was generally associated with increased serum TSH levels during the treatment interval and with lowered TSH levels after discontinuation of T treatment, particularly in irradiated rats. However, when irradiated, castrated males received late T replacement (age 18-24 mo), there was no elevation of TSH at the end of the treatment interval. Thus an indirect effect of T via early stimulation of TSH may be at least partly responsible for the high incidence of irradiation-induced thyroid tumors in rats.     

5-Bromodeoxyuridine-induced carcinogenesis and its modification by persistent estrus syndrome, unilateral nephrectomy, and X-irradiation in rats

We showed earlier that 5-bromodeoxyuridine (BrdUrd), which can substitute for thymidine during DNA synthesis, inducing transition mutations, is incorporated into DNA of various tissues when administered to newborn rats and is not subjected to repair processes. The main purpose of the present experiment is to verify if a direct perturbation of DNA would be sufficient to initiate carcinogenesis. Rats aged 1, 3, 7, and 21 days were given BrdUrd s.c. at a dose of 3.2 mg/animal. At 2 months some of the females were subjected to treatment known to induce persistent estrus; at 1 month a group of males underwent removal of one kidney, and groups of males and females were exposed to a single total-body X-irradiation at a dose of 1.5 Gy (150 rads) per rat. In females, treatment with BrdUrd induced tumors of the ovaries, polyps in the uterus, and tumors of the soft tissues, nervous system, forestomach, glandular stomach, and salivary gland; no such tumor occurred in control females. Induction of persistent estrus increased the incidences of ovarian tumors and of malignant tumors of the uterus. Treatment with BrdUrd also increased the carcinogenic effect of X-rays on the mammary gland. In males, BrdUrd induced tumors of the testis (seminomas) and adenomas of the thyroid gland; solitary tumors of the kidney, nervous system, soft tissues, and bladder were also found. Unilateral nephrectomy reduced the incidences of tumors in the testis and pituitary gland, whereas subsequent treatment with X-rays did not alter the incidences of tumors induced by BrdUrd. These studies demonstrated for the first time that a nucleoside analogue, BrdUrd, has carcinogenic potential. Possible molecular mechanisms for its carcinogenicity and for the effects of the promoting factors are discussed.     

Strain variation in renal carcinogenesis by N-ethyl-N-hydroxyethylnitrosamine in F1 (Wistar–Fischer) rats

The present study was conducted to compare the incidences of renal tumors in Wistar (W), Fischer (F) and F1 rats (WF: female Wistar rats×male Fischer rats; FW: female Fischer rats×male Wistar rats) induced by N-ethyl-N-hydroxyethylnitrosamine (EHEN). Levels of 8-OHdG in renal DNA were also investigated in Wistar and Fischer rats. After 2000 ppm of EHEN was administered orally for 2 weeks, the animals were fed basal diet until week 32. Wistar males and females demonstrated significantly higher sensitivity regarding induction of renal lesions, while both WF and FW rats had similar incidences, generally intermediate between those for the two parent strains. The formation of 8-OHdG was maximal 60–180 min after an intraperitoneal dose of 750 mg/kg to Wistar and Fischer rats, which correlates with the increase tending to the incidence of renal tumors in male and female Wistar and Fischer rats. The results suggest that EHEN induction of renal tumors is related to oxygen radical damage and that the genes in the Wistar strain responsible for the sensitivity are not inherited in a sex-dependent fashion, despite the male being more susceptible.     

Dose-responsive induction of mammary gland carcinomas by the intraperitoneal injection of 1-methyl-1-nitrosourea

Dose-response relationships for the induction of mammary tumors by a single i.p. injection of 1-methyl-1-nitrosourea (MNU) were studied. Groups of 30 female Sprague-Dawley rats were given i.p. injections of 50, 37.5, 25, 12.5, or 0 mg MNU/kg body weight at 50 days of age. Animals were palpated for tumor detection twice weekly throughout a 28-week observation period. Administration of MNU i.p. caused no acute toxicity. Both benign and malignant mammary tumors were induced by MNU, but malignant tumors appeared earlier and at a faster rate than benign tumors. The incidence and numbers of mammary carcinomas increased whereas median cancer-free time decreased with increasing dose of MNU. Approximately twice as many mammary cancers were observed in the cervical-thoracic as in the abdominal-inguinal mammary gland chains irrespective of carcinogen dose, while the frequency of tumor occurrence in the left versus right chains was similar. Tumor latency decreased with increasing dose of MNU, but the quartiles for time to detection of all tumors within each carcinogen dose group were similar irrespective of anatomical region in which the tumors occurred. The mammary tumor response attained via i.p. injection was similar but the coefficient of variation for tumor multiplicity within a carcinogen dose group was lower in comparison to that observed when MNU was administered i.v. or s.c. Among these techniques for carcinogen injection, the i.p. route is the most rapid method and offers an added advantage of ease of administration with quantitative, reproducible delivery of the desired amount of carcinogen and a decrease in variability of tumor response among animals within a treatment group. This method is well suited for the technically less experienced investigator and for those in need for a rapid method of injecting MNU to large numbers of animals.     

NTP technical report on the toxicity studies of 2- and 4-Methylimidazole (CAS No. 693-98-1 and 822-36-6) administered in feed to F344/N rats and B6C3F1 mice

[Structure-see text] 2-Methylimidazole and 4-methylimidazole are intermediate/starting materials or components in the manufacture of pharmaceuticals, photographic and photothermographic chemicals, dyes and pigments, agricultural chemicals, and rubber; these chemicals have been identified as undesirable by-products in several foods and have been detected in mainstream and sidestream tobacco smoke. The National Cancer Institute nominated 2- and 4-methylimidazole as candidates for toxicity and carcinogenicity studies. Toxicity studies were carried out in male and female F344/N rats and B6C3F1 mice. Animals were exposed to 2- or 4-methylimidazole in feed for 15 days or 14 weeks; clinical pathology studies were conducted in the 14-week studies on days 8, 29, and 86 and at week 14. Genetic toxicity studies were conducted in Salmonella typhimurium, rat and mouse bone marrow, and mouse peripheral blood. Groups of five male and five female rats and mice were fed diets containing 0, 1,200, 3,300, or 10,000 ppm 2-methylimidazole (equivalent to average daily doses of approximately 115, 290, or 770 mg 2-methylimidazole/ kg body weight to rats; 220, 640, or 2,100 mg/kg to male mice; 300, 800, or 2,400 to female mice) for 15 days. Groups of five male and five female rats and mice were fed diets containing 0, 300, 800, or 2,500 ppm 4-methylimidazole (equivalent to average daily doses of approximately 30, 80, or 220 mg/kg for rats and 65, 170, or 500 mg/kg for mice) for 15 days. In the 15-day 2-methylimidazole studies, all animals survived to the end of the studies. The mean body weights of 10,000 ppm male rats and female mice were significantly less than those of the controls. Feed consumption by 10,000 ppm male and female rats was reduced. Enlarged thyroid glands were observed in 3,300 and 10,000 ppm male and female rats. The incidences of diffuse hyperplasia of follicular cells of the thyroid gland in 3,300 and 10,000 ppm male and female rats and pars distalis hypertrophy of the pituitary gland in 3,300 and 10,000 ppm males and 10,000 ppm females were increased compared to the controls. In all exposed groups of male and female mice, the incidences and severities of follicular cell hypertrophy of the thyroid gland and the severities of hematopoietic cell proliferation of the spleen generally increased with increasing exposure concentration. In the 4-methylimidazole studies, all animals survived to the end of the studies, and there were no significant differences in mean body weights, clinical findings, organ weights, or gross or microscopic lesions between exposed and control groups. Groups of 10 male and 10 female rats and mice were fed diets containing 0, 625, 1,250, 2,500, 5,000, or 10,000 ppm 2- or 4-methylimidazole (equivalent to average daily doses of approximately 40, 80, 160, 300, or 560 mg/kg 2- or 4-methylimidazole to rats; and 100, 165, 360, 780, or 1,740 mg/kg 2-methylimidazole or 100, 240, 440, 915, or 1,840 mg/kg 4-methylimidazole to male mice; and 90, 190, 400, 800, or 1,860 mg/kg 2-methylimidazole or 110, 240, 540, 1,130, or 3,180 mg/kg 4-methylimidazole to females) for 14 weeks. All animals survived to the end of the 14-week 2-methylimidazole studies. Compared to the controls, the mean body weights were significantly decreased in groups of male rats and mice exposed to 2,500 ppm or greater and in 5,000 and 10,000 ppm female rats and mice. In rats, 2-methylimidazole induced a transient erythrocytosis in females and a minimal, exposure concentration-related, microcytic, normochromic, nonresponsive anemia. 2-Methylimidazole increased thyroid-stimulating hormone concentrations and decreased thyroxine and triiodothyronine concentrations of male and female rats in an exposure concentration-related manner. 2-Methylimidazole induced a mild to moderate, exposure concentration-related, macrocytic, hyperchromic, responsive anemia in mice. Triiodothyronine concentrations were increased in exposed male and female mice, and thyroxine concentrations were decreased in exposed females. Relative to the control groups, clinical chemistry evaluations on day 29 and at week 14 identified decreases in alanine aminotransferase concentrations and total protein and albumin concentrations of rats. In the 2-methylimidazole studies, absolute spleen weights were significantly increased in all exposed groups of male rats. The heart and liver weights were increased in all exposed groups of male mice, as were the spleen weights of female mice exposed to 2,500 ppm or greater. Spermatid heads per testis and mean spermatid count were significantly decreased in 10,000 ppm male rats. The estrous cycle of 10,000 ppm female rats was significantly increased. Gross pathology observations included enlarged thyroid glands, small uteri, and mottled spleen in 5,000 and 10,000 ppm mice. The incidences of diffuse follicular cell hyperplasia of the thyroid gland were significantly increased in male rats exposed to 1,250 ppm or greater and female rats exposed to 2,500 ppm or greater. The incidence of testicular degeneration was significantly increased in 10,000 ppm male rats, and two males in the 10,000 ppm group had follicular cell adenoma of the thyroid gland. In mice, there were generally significant increases in the incidences of follicular cell hypertrophy of the thyroid gland, hematopoietic cell proliferation of the spleen, and hemosiderin pigmentation of the renal tubule in males exposed to 1,250 ppm or greater and females exposed to 2,500 ppm or greater. In the 14-week 4-methylimidazole studies, one 10,000 ppm male mouse was found dead during week 4, and seven 10,000 ppm female mice were found dead during weeks 1 and 2. Mean body weights were significantly less than those of the controls for male rats exposed to 2,500 ppm or greater, 5,000 and 10,000 ppm female rats, male mice exposed to 1,250 ppm or greater, and all exposed groups of female mice. Reduced feed consumption was observed in 5,000 and 10,000 ppm male and female rats. Clinical findings included nasal/eye discharge, ruffled fur, thinness, ataxia, and abnormal breathing in rats, and ruffled fur and dull coats in female mice. On days 29 and 82, functional observations in 5,000 and 10,000 ppm rats included labored or increased respiration, mild tremors, walking on tiptoes, hunched posture, piloerection, crouching over, impaired coordination of movement, ataxia, and pupillary constriction. 4-Methylimidazole induced a transient erythrocytosis and a minimal, exposure concentration-related, microcytic, normochromic, nonresponsive anemia in male and female rats. Clinical chemistry evaluations generally showed a cholestatic effect in exposed male and female rats. At week 14, there was a significant decrease in total protein and albumin concentrations of female rats exposed to 5,000 or 10,000 ppm. In mice, 4-methylimidazole induced a macrocytic, hyperchromic, responsive anemia and, particularly in males, increases in triiododthyronine concentrations and transient decreases in thyroxine concentrations. In the 4-methylimidazole studies, the liver weights of male rats exposed to 2,500 ppm or greater were significantly increased; spleen weights of female rats exposed to 2,500 ppm or greater were decreased. The absolute liver weight was decreased in 10,000 ppm male mice, and relative weights were significantly increased in all exposed groups of mice. In female mice, there was a significant decrease in the absolute weights and increase in the relative weights of the heart, right kidney, and liver in groups exposed to 2,500 ppm or greater. The epididymal spermatozoal concentration was significantly increased in 5,000 ppm male rats. Gross pathology observations included pale livers in male rats exposed to 2,500 ppm or greater and small testes and uteri in 10,000 ppm male and female rats. Microscopic analysis identified significantly increased incidences of cytoplasmic hepatocyte vacuolization of the liver of male rats exposed to 2,500 ppm or greater and 10,000 ppm female rats, hypospermia of the epididymis in 10,000 ppm male rats, atrophy and inflammation of the prostate gland in 10,000 ppm male rats, and degeneration of the testes in 5,000 and 10,000 ppm male rats. 2-Methylimidazole and 4-methylimidazole were negative in the S. typhimurium mutation assay when tested in strains TA97, TA98, TA100, and TA1535, with and without S9 activation enzymes. Testing of 2-methylimidazole in vivo for induction of chromosomal damage, as measured by micronucleated erythrocyte frequency, produced mixed results. When administered by intraperitoneal injection three times at 24-hour intervals, 2-methylimidazole produced negative results in bone marrow micronucleus tests in rats and mice. However, in the 14-week study of 2-methylimidazole, a significant exposure-related increase in the frequency of micronucleated normochromatic erythrocytes was noted in peripheral blood of male and female mice. In vivo, 4-methylimidazole produced uniformly negative results in three-injection bone marrow micronucleus tests in rats and mice and in 14-week peripheral blood micronucleus tests in male and female mice.     

Promotion of estrogen-induced mammary gland carcinogenesis by androgen in the male Noble rat: probable mediation by steroid receptors

Both endogenous and exogenous estrogen exposure is associated with an increased breast cancer risk. In some studies, elevated serum testosterone levels have also been linked to an increased breast cancer risk. Estrogen alone or combined with progesterone induces high mammary tumor incidences in various strains of both male and female rats. Mammary gland ductal adenocarcinomas were induced after 17beta- estradiol (E2) and testosterone propionate (TP) treatment in male Noble rats. Tumor incidence was 100% after 8-9 months of treatment. Such neoplasms were not detected after either estrogen or androgen exposure alone within this time period. TP alone caused disruption of mammary gland ducts and proliferation of stromal tissue, while E2 treatment alone induced both ductal epithelial growth and nodular atypical hyperplasia. To study the interaction of these hormones in mammary tumorigenesis, sex hormone receptors were characterized in mammary glands of Noble rats. Estrogen receptor-alpha (ER) was detected in age- matched, untreated mammary gland epithelium; in most early atypical hyperplastic lesions appearing after E2 and E2 + TP treatment and in E2 + TP-induced mammary tumors. Two major ER putative isoforms, 116 and 120 kDa, were detected in E2- and E2 + TP-treated mammary glands, and in the induced tumors. A 54 kDa ER protein was found in untreated and TP-treated mammary glands, and in the induced tumors. Both progesterone receptor-B (PR-B) and PR-A2, as well as androgen receptor-B (AR-B) and AR-A isoforms were markedly elevated in all E2 + TP-induced mammary tumors. However, the levels of both PR and AR were very low in mammary glands of E2- and E2 + TP-treated male rats. Low and moderate levels of AR and PR, respectively, were detected in most atypical hyperplastic lesions induced by E2- and E2 + TP-treated mammary glands. These results suggest that androgens may interact with either AR or PR, and perhaps both receptors, in E2 + TP-induced mammary glands and the induced tumors to effect the reduction in latency period, enhance tumor size, and increase incidence to 100%.      

头颈部肿瘤7878例分析

7878 patients with tumors in the head and neck confirmed by pathology from Jan. 1961 to Dec. 1981 are analysed. In this series, there were 5485 malignant tumors and 2393 benign. In malignant tumors, the ratio of male to female was 2.84:1 while the mean age incidence was 53.38 years. Nearly half of malignant tumors were in the nasopharynx (49.32%). Of the 2716 nasopharyngeal malignant tumors, 2698 were carcinoma and only 18 sarcoma. Male was 3.5 times higher than female. The mean age of NPC was 53.64 years in male and 52.33 years in female. Nine of them were under 10 years of age and the youngest was 3 years old. There was 87.06% of squamous cell carcinoma in NPC. Adenocarcinoma was predominant in the minor salivary gland carcinomas. The malignant tumors in the eyeball were glioma retinae of which 96.15% was under 10 years of age. The common metastatic tumor in the neck was squamous cell carcinoma. The incidence of head and neck tumors was 37.66% and that of the head and neck malignancies was 26.22% of tumors in the whole body. This study indicates that the incidence of malignant tumor in the head and neck is rather high.     

Occurrence and relevance of chemically induced benign neoplasms in long-term carcinogenicity studies

Recent carcinogenicity studies conducted and evaluated by the National Toxicology Program/National Institute of Environmental Health Sciences were examined to determine the frequency of chemically increased incidences of neoplasia. Many of the chemicals originally selected for study were chosen because of an a priori suggestion that they might be carcinogens. Of the 143 chemical studies evaluated, usually involving male and female rats and mice, 42 (29%) did not induce any neoplasms, 20 (14%) gave marginal or equivocal neoplastic responses, and 81 (57%) showed positive neoplastic responses in one or more of the 524 species-gender experiments. Of these 81 positive studies, 60 (74%) were considered positive based on malignant neoplasia, 16 (20%) were positive due primarily to benign neoplasia, but hd supporting evidence of malignant neoplasia in the same organ/tissue, and 5 (6%) were positive based only on benign neoplasia. These five chemicals are a) allyl isothiocyanate (transitional cell papillomas of the urinary bladder in male rats), b) 2-amino-4-nitrophenol (tubular cell adenomas of the kidney in male rats), c) asbestos intermediate range chrysotile (adenomatous polyps of the large intestine in male rats), d) decabromodiphenyl oxide (neoplastic nodules of the liver in male and female rats), and e) nitrofurazone (fibroadenomas of the mammary gland in female rats and benign mixed tumors and granulosa cell tumors of the ovary in female mice). For all but one of these lesions (mammary gland), the occurrence in historic controls is low. Thus, only 5 of the 143 chemicals studied (3.5%) induced benign neoplasia alone, and those observed benign neoplasms are known to progress to malignancy. Accordingly, we consider chemically induced benign neoplasia to be an important indicator of a chemical's carcinogenic potential in rodents, and believe it should continue to be made an integral part of the overall weight-of-the evidence evaluation process for identifying potential human health hazards.     

Effects of the prostaglandin synthetase inhibitor indomethacin on tumorigenesis, tumor proliferation, cell kinetics, and receptor contents of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in Sprague-Dawley rats fed a high- or low-fat diet

The effects of indomethacin on tumorigenesis, tumor proliferation, cell kinetics, and receptor content of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma have been examined in female Sprague-Dawley rats. The rats were fed either a high-fat (20% corn oil) or low-fat (0.5% corn oil) diet with or without 0.005% indomethacin starting 7 days after intragastric administration of a single dose of 5 mg 7,12-dimethylbenz(a)anthracene. The results demonstrated that indomethacin completely blocked the stimulatory effect of fat on tumorigenesis, as demonstrated by a decreased tumor incidence, a decreased number of tumors per group, and an increased latency. Contrary to what had been expected, however, indomethacin promoted tumor proliferation in both the high- and low-fat diet groups, as evidenced by an increased tumor size, an increased bromodeoxyuridine-labeling index, and a decreased potential tumor-doubling time. No significant difference in either the estrogen receptor or progesterone receptor content of the tumor was noted. It can be concluded, therefore, that indomethacin significantly reduced tumorigenesis in the high-fat diet group but significantly promoted tumor proliferation in both the high- and low-fat diet groups.     

Long-term administration of ddt or phenobarbital-na in wistar rats

In lifespan studies, outbred male and female Wistar rats were given either technical DDT mixed into the diet at a dose of 500 parts per million (ppm) or phenobarbital-sodium dissolved in drinking water at a dose of 500 ppm. Liver-cell tumors developed in treated animals but not in controls. The incidence of liver tumors was 45% in the DDT-treated group and 44% in the phenobarbital-sodium-group. When evaluated by sex, DDT-treated females and males had incidences of 56% and 35%, respectively, while in the phenobarbital-sodium group, the respective incidences were 32% and 59% in females and males. These data show a varying susceptibility between the sexes, with regard to induction of liver-cell tumors by the two compounds. In both treated groups, the number of nodular tumors per rat and the average size increased with age and were greater in females. None of these tumors had metastasized. Histologically, the liver tumors were nodular growths, which compressed surrounding parenchyma but did not infiltrate it. The total incidence of extrahepatic tumors was higher in controls than in treated animals. In this connection, we must mention the apparent, but not significant, reduction of adrenal tumors in treated rats compared to the controls.     

Post-initiation treatment of rats with indole-3-carbinol or beta-naphthoflavone does not suppress 7, 12-dimethylbenz[a]anthracene-induced mammary gland carcinogenesis

Indole-3-carbinol (I3C) and β-naphthoflavone (β-NF), blocking agents of 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mammary gland carcinogenesis, were examined as potential post-initiation suppressing agents. Treatment of female Sprague–Dawley rats with I3C (250 mg/kg body weight (b.w.)), β-NF (20 mg/kg b.w.) or the vehicle ethanol:corn oil (2:3) (2.5 ml/kg b.w.), three times weekly by gavage, started 3 weeks after the initiation with one oral dose of DMBA (20 mg/rat at 7 weeks of age) and continued for up to 12 weeks. I3C- or β-NF- or vehicle-treated groups did not differ significantly in the overall outcome of mammary tumorigenesis including cumulative mammary tumor incidences and multiplicities, latent periods and number and weight of mammary tumors per tumor-bearing rat for malignant, benign and/or malignant + benign tumors. A tendency of the I3C-treated rats to develop fewer mammary adenocarcinomas with a greater average weight per tumor per rat (2.32±1.50 g) than in the β-NF- (1.52±1.58 g) or vehicle- (1.55±1.53 g) treated groups suggests an effect, yet to be confirmed, of I3C on tumor development and growth. A 12-week treatment with I3C or β-NF significantly increased the P450-dependent activities of ethoxy-, methoxy-, benzyloxy- and pentoxy-(with I3C only) resorufin O-dealkylase in hepatic microsomes indicating induction of several P450s. The alterations in the P450 complement may affect endogenous estrogen metabolism and mammary gland and tumor characteristics at the molecular level, e.g. estrogen receptor status and/or proliferative activity, which require further studies.