Carcinogenicity study of outdoor airborne particulate matter in newborn male NMRI mice.

An organic extract of airborne particulate matter (APM) was tested for carcinogenicity at two dose levels in the newborn mouse bioassay. The samples used were taken under specific polluted conditions. The doses tested corresponded with 0.75 and 1.5 times the amount of air man inhales during lifetime. Benzo(a)pyrene, which was used as a positive control, significantly increased the lung tumor incidence. No evidence was found for a carcinogenic activity of the organic extract of APM. Considering the high dose of APM applied in this animal model and the much lower actual cumulative dose to which man is exposed to in many areas, the conclusion can be drawn that exposure to APM alone probably does not represent an important cancer risk for man.

Chronic toxicity and oncogenicity inhalation study with vinyl acetate in the rat and mouse.

Vinyl acetate was evaluated for chronic toxicity and oncogenicity in male and female rats and mice in a 104-week study. Target concentrations were 0, 50, 200, and 600 ppm. The study included interim terminations at approximately 53 and 83 weeks and a group whose exposure was terminated at 70 weeks and allowed a 15-week recovery period. Over the course of the exposures, body weight gain was consistently depressed in all 600 ppm groups and in the 200 ppm mice. Except for female rats of the 600 ppm exposure group, recovery animals showed significant improvements in weight gain relative to controls. There were no changes in hematological parameters of either species that could be unequivocally related to treatment. The only effect noted on clinical chemical parameters during the study were decreases in blood glucose in the 600 ppm females. There were no adverse effects on survival in either species. Increases in lung weight were noted in rats and mice primarily in the 600 ppm groups. These changes were associated with bronchial exfoliation, macrophage accumulation, and fibrous plaques and buds extending into the airway lumen, and bronchial/bronchiolar epithelial disorganization. The most significant histopathological changes were noted in the nasal cavity. In the olfactory epithelium of both rats and mice, the main nonneoplastic changes included epithelial atrophy, regenerative effects (squamous metaplasia and respiratory metaplasia of olfactory epithelium), basal cell hyperplasia, and epithelial nest-like infolds. No nonneoplastic changes were observed in the respiratory epithelium of rats, while squamous metaplasia at the naso/maxilloturbinate region was prevalent in mice. Nonneoplastic changes were similar in the recovery groups. Oncogenic responses to vinyl acetate exposure were mainly confined to the nasal cavity in rats and included endo- and exophytic papillomas, squamous cell carcinoma, carcinoma in situ in olfactory regions, and endophytic papilloma in respiratory regions. Squamous cell carcinomas were also found either in areas normally covered by cuboidal epithelium or areas of unknown origin. One squamous cell carcinoma was found in the larynx of a rat of the 600 ppm groups. One squamous cell carcinoma was found in the lung of a mouse of the 600 ppm group.(ABSTRACT TRUNCATED AT 400 WORDS)

EO9: a novel bioreductive alkylating indoloquinone with preferential solid tumour activity and lack of bone marrow toxicity in preclinical models.

EO9 is a novel and fully synthetic bioreductive alkylating indoloquinone. Although structurally-related to mitomycin C, EO9 exhibits a distinct preclinical antitumour profile and there are also differences in its biochemical activation. In this study, EO9 was found to demonstrate preferential cytotoxicity against solid tumours in vitro as compared to leukaemia cell lines both in the Corbett two-tumour assay and in the disease-oriented human tumour cell line panel of the U.S. National Cancer Institute. In the latter system activity was particularly apparent in colon, melanoma and central nervous system lines, together with some renal and non-small cell lung lines. Preferential cytotoxicity towards hypoxic versus aerobic EMT6 mouse mammary tumour cells was observed. In vivo, EO9 was inactive against the P388 murine leukaemia, while exerting significant antiproliferative effects against several murine and human solid tumours, including the generally resistant MAC mouse colon tumours and gastric, ovarian and breast xenografts. These results confirmed in vitro observations of preferential solid tumour activity. In animal toxicology studies, EO9 induced vascular congestion in the gastrointestinal tract, but no significant bone marrow toxicity. The LD10 value of EO9 after a single intravenous injection into mice was 9 mg/kg (27 mg/m2). A dose of one-tenth of the mouse equivalent LD10 (2.7 mg/m2), the recommended starting dose for clinical phase I studies, was found to be safe in rats. Considering its distinct mechanism of bioactivation as compared to mitomycin C, its preferential solid tumour activity, its excellent activity against hypoxic cells, and lack of significant bone marrow toxicity in animals studies, EO9 has been selected for clinical evaluation within the framework of the EORTC.

Preclinical antitumour activity and animal toxicology studies of rhizoxin, a novel tubulin-interacting agent.

Rhizoxin is a 16-membered antifungal macrocyclic lactone isolated from the plant pathogenic fungus Rhizopus chinensis. The compound binds to tubulin, preventing microtubule formation, and inhibiting mitosis. It possesses antitumour activity in vivo against various preclinical murine models, both leukaemias and solid tumours model, as well as in vincristine- and doxorubicin-resistant leukaemia lines. In the present study, cytotoxic activity was observed in human tumour cell lines in vitro at very low concentrations (+/- 10(-10) M) particularly against melanoma, colon, renal, non-small cell and small cell lung cancer. In vivo antitumour activity was demonstrated in murine P388 and L1210 murine leukaemias, solid tumour models B16 melanoma and M5076 sarcoma, and in 5 out of 9 human solid tumour xenografts: LOX melanoma, MX-1 breast cancer, non-small cell lung cancer A549, and small cell lung cancers LXFS 605 and LXFS 650. The absence of cross-resistance to vinca alkaloids was confirmed in vivo against the vincristine-resistant P388 leukaemia subline and the vincristine-resistant human small cell lung cancer LXFS 650. In addition, the antitumour activity of rhizoxin was improved by prolonged or repeated drug administration indicating a schedule dependency. In animal toxicology studies, transient changes in erythrocyte and leukocyte numbers, local phlebitis, diarrhea, and spermatogenic arrest were observed. The LD10 value of rhizoxin after a single intravenous injection was 2.8 mg/kg (8.4 mg/m2). One-tenth of the mouse equivalent LD10 (0.84 mg/m2), the starting dose for clinical phase I studies, was considered to be safe in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Multistage prostate carcinogenesis: the role of hormones.

Prostate cancer is the most frequently occurring non-skin cancer in men in the U.S.A. and other Western countries, but its etiology is poorly understood. Human prostate carcinogenesis has been viewed as a multi-step process involving progression from low histologic grade, small latent carcinoma, to large, higher grade, metastasizing carcinoma. However, recent data suggest that a variety of pathogenetic pathways exist. The precise role of hormones in the genesis of human prostate cancer remains largely undefined. It is difficult to investigate stages in the development of human prostate cancer, but some animal models provide opportunities in this regard. Short-term treatment of rats with chemical carcinogens will produce a low incidence (5-15%) of prostate cancer, provided that prostatic cell proliferation is enhanced during carcinogen exposure. A high carcinoma incidence can only be produced by chronic treatment with testosterone following administration of carcinogens such as N-methyl-N-nitrosourea (MNU). Testosterone markedly enhances prostate carcinogenesis even at doses that do not measurably increase circulating testosterone. Thus, testosterone is a strong tumor promoter for the rat prostate. All such MNU-initiated, testosterone-promoted tumors are adenocarcinomas mostly originating from the dorsolateral and anterior, but not ventral, prostate lobes. A high frequency (70%) of activation of the K-ras gene by a G35 to A mutation occurs in these carcinomas. A variable frequency of activation of H-ras and K-ras genes occurs in human prostate carcinomas. Another rat model, representing a different pathogenetic pathway, involves chronic administration of estradiol-17 beta in combination with low-dose testosterone. The resulting carcinomas are low-grade and originate exclusively from periurethral ducts of the dorsolateral and anterior prostate. We recently found a major adduct by 32P postlabeling analysis in the tissue region that includes these ducts, but not in, e.g., the ventral prostate, of rats treated for 16-24 weeks. While it is unknown whether testosterone is a tumor promoter in this system, the presence of a DNA adduct suggests that estradiol-17 beta acts as a tumor-initiating agent in this system.

Chronic inhalation toxicity and carcinogenicity study of methyl bromide in Wistar rats.

The toxicity and carcinogenicity of methyl bromide (MeBr) were studied in male and female Wistar rats exposed by inhalation to 0, 3, 30 or 90 ppm MeBr 6hr/day, 5 days/wk for 29 months. After 13, 52 and 104 wk ten rats/sex/group were killed to provide interim information. Body weights, clinical signs, haematology, biochemistry and gross and microscopic pathology were studied. Mortality was increased by wk 114 in the 90-ppm group. Body weights in males and females of the 90-ppm group were lower than those of the controls throughout the study. Increased incidences of degenerative and hyperplastic changes of the nasal olfactory epithelium were observed in all exposed groups, the incidences being positively correlated with the MeBr concentration; the nasal lesions did not progress appreciably with time. Exposure to 90 ppm MeBr was associated with an increased incidence of lesions in the heart (thrombi, myocardial degeneration), and with hyperkeratosis in the oesophagus and forestomach. Data on site, type and incidence of tumours in the various groups did not indicate carcinogenic activity of MeBr.

Subchronic (13-week) oral toxicity of neohesperidin dihydrochalcone in rats.

Neohesperidin dihydrochalcone was administered to groups of 20 male and 20 female Wistar rats at dietary levels of 0, 0.2, 1.0 and 5.0% for 91 days. No treatment-related ophthalmoscopical, haematological or histopathological effects were observed. In the high-dose group, a marked caecal enlargement occurred in both sexes, accompanied by soft stools in the early stages of the study, somewhat lower plasma urea concentrations and increased plasma alkaline phosphatase activity and a decreased urinary pH. This group also showed slight growth depression accompanied by transient reduction in food intake; in males the body weights remained relatively low throughout the experimental period. Furthermore, bilirubin level was increased in females and total protein level was decreased in males of the high-dose group. The above changes were considered adaptive responses or chance effects rather than manifestations of clear toxicity. The low-and intermediate- dose groups did not show any compound-related untoward effect. It was concluded that the intermediate dose, providing an overall intake of about 750 mg neohesperidin dihydrochalcone per kg body weight per day, was the no-effect level.

Upper respiratory tract tumors in Cpb:WU (Wistar random) rats.

A survey is given of upper respiratory tract tumors in Cpb:WU (Wistar random) rats. Data were collected from ten 24- to 30-month toxicity/carcinogenicity studies and from one 12-month study. Nasal tumors may lead to dyspnea, mouth breathing, and nasal discharge. These clinical signs mainly occurred in rats bearing squamous cell carcinomas. The large nasal tumors were often osteolytic, they invaded the subcutis over the premaxilla, resulting in swellings on the back of the nose, and extended into the brain. The incidence of nasal tumors in untreated male controls was 1.1% (7/661), the tumors invariably being squamous cell carcinomas. There were no nasal tumors found in untreated female controls. The type of compound-induced nasal tumor most frequently observed was adenocarcinoma (of the olfactory epithelium) followed, in order of decreasing incidence, by squamous cell carcinoma, carcinoma in situ, polypoid adenoma, Schwannoma, and carcinosarcoma. It was proposed that adenocarcinomas of the olfactory epithelium should be classified as neuroepitheliomas. It was also suggested that squamous cell carcinomas, seen in association with necrotizing inflammation of an incisor tooth, should be considered as part of the malocclusion syndrome. No spontaneous tracheal tumors were observed, and only one out of 422 untreated female controls (0.2%) was seen to have a laryngeal tumor, an adenoma. Induced laryngeal tumors included carcinoma in situ, squamous cell carcinoma, and adenocarcinoma. Squamous cell carcinoma was the only type of treatment-related tracheal tumor found. The incidences of induced laryngeal and tracheal tumors were very low, and in no case were these tumors statistically significantly different from the respective incidences in controls.

Chronic toxicity and carcinogenicity study of isomalt in rats and mice.

The chronic toxicity and possible carcinogenicity of the sugar replacer isomalt was studied in Wistar rats and Swiss mice. Groups of 50 animals of each sex were fed 0, 2.5, 5 or 10% isomalt in the diet for nearly 2.5 yr (rats) or 2 yr (mice). Control groups received either basal diet with 10% maize starch or basal diet with 10% sucrose. Additional groups of ten rats/sex were fed the same diets and were killed after 1 yr. Isomalt and sucrose were included in the diet at the expense of maize starch. Administration of isomalt was started, in rats, in utero, and in mice, at weaning age. Feeding isomalt did not affect the appearance or behaviour of rats or mice, nor did it cause diarrhoea. Mortality rate was unaffected. Body weights of rats and mice fed 10% isomalt were generally slightly lower than those of controls. Periodic examinations of rats for haematological criteria, clinical chemistry of the blood, urine composition and kidney function did not reveal any changes of toxicological significance. Periodic haematological examinations of mice were likewise negative. Caecal enlargement was observed in rats and mice of the high-dose group, but the microscopic structure of the caecal wall was unaffected. An increased number of treated male and female rats showed hyperplasia of the urothelium in the renal pelvis accompanied by mineralization, whereas the number of females showing corticomedullary mineralization was decreased in the treated groups. The incidence, type or location of neoplasia provided no evidence of a carcinogenic potential of isomalt. Feeding 10% sucrose did not induce significant differences compared with the controls fed 10% maize starch, whereas isomalt at levels of up to 10% produced some of the changes that are common to rats fed high levels of poorly digestible carbohydrates.

Spontaneous hyperplastic and metaplastic duct epithelium in the sublingual salivary glands of Wistar rats.

Focal epithelial hyperplasia and metaplasia were observed in the intralobular ducts of the sublingual salivary glands of 302 out of 1142 Wistar rats. These rats (aged 16-145 weeks) served as controls in toxicological experiments. The ductal changes varied from small groups of irregular cylindrical cells with basophilic cytoplasm and vesicular nuclei, with often prominent nucleoli, to large areas of non-keratinized stratified squamous epithelium with marked mitotic activity and necrotic superficial cells being released in the lumen. Mononuclear inflammatory cells were often present in fibrous tissue surrounding altered ducts. Within certain limits the degree and incidence of the changes increased with increasing age; their aetiology is unknown.