摘要:

Five categories of evidence of carcinogenicity in rats and mice were used to group interpretative results on 86 chemicals studied in recent carcinogenicity tests carried out by the National Toxicology Program (NTP). Of these studies, 50% (43/86) were regarded as showing carcinogenic effects, 42% (36/86) gave no evidence of carcinogenicity, 6% (5/86) showed equivocal evidence of carcinogenicity, and 2% (2/86) were regarded as inadequate experiments. The liver was the most frequent site of cancer in male and female Fischer‐344 rats and in male and female B6C3F1mice. Male rats appeared more sensitive than female rats to the induction of neoplasia, while for mice the females seemed more responsive. The routes of administration yielding the highest percentage (80–83%) of positive studies were gavage and inhalation; approximately one‐third of the feed, drinking water, and dermal studies showed carcinogenic effects. In feeding studies, overall survival in dosed and control groups were similar, while the majority of gavage studies showed significantly reduced survival in one or more dosed groups relative to the corresponding controls. The overall percentage of studies showing carcinogenic effects (50%) agrees closely with the rate reported by other investigators for nearly 200 earlier carcinogenicity experiments conducted by the National Cancer Institute.

ISSN:0098-4108    

DOI:10.1080/15287398409530613

出版商:Taylor & Francis Group    

年代:1984

数据来源: Taylor

摘要:

Dry sedimented volcanic ash samples from each of three widely separated volcanoes of the “Circum Pacific” region have been subjected to mineralogic analysis and in vitro tests for cytotoxicity. The ash samples from the three different volcanoes varied in particle size, surface area, and concentration of silica. Total crystalline silica in the respirable fraction of ashes was 1.5% (Mount St. Helens, Moses Lake); 1.36% (Galunggung, Bandung‐1); 1.95% (Gallunggung, Bandung‐2); and 1.72% (El Chichon, Tuxtia). Hemolysis as an index of cytotoxicity was measured by in vitro tests on sheep blood erythrocytes and indicated wide differences in hemolytic activity among ash samples. Alveolar macrophage cytosolic (lactate dehydrogenase) and lysosomal (β‐glucuronidase and β‐N‐acetyl glucosaminidase) enzymes were measured as an index of cellular integrity following dust exposure. Hemolysis and release of enzymes from alveolar macrophages were greater with volcanic ash from Galunggung (Bandung‐1) and El Chichon (Tuxtia) than the other ashes. Although crystalline silica induced an effect similar to volcanic ash from Galunggung (Bandung‐1) on the release of enzymes from alveolar macrophages, the hemolytic potency of silica was much greater. Light and electron microscopic observations of dust‐exposed alveolar macrophages indicated that the ash particles were readily phagocytized. These results indicate that volcanic ash is moderately cytotoxic and that exposure may lead to overt reactions and the exacerbation of preexisitng chronic inflammatory processes.

ISSN:0098-4108    

DOI:10.1080/15287398409530614

出版商:Taylor & Francis Group    

年代:1984

数据来源: Taylor

摘要:

Male Fisher‐344 rats were exposed by inhaltion to low levels of diesel exhaust and coal dust, alone or in combination, or to filtered air, 7 h/d, 5 d/wk for 24 mo. Cyto‐chrome P‐450‐associated benzo[a]pyrene hydroxylase and 7‐ethoxycoumarin deethylase activities were assayed in lung and liver microsomes after 3, 6, and 24 mo. Age‐related changes in enzyme activities were observed, but they were not altered by the exposures. When the data were adjusted for age, only one difference was observed. Lung benzo[a]pyrene hydroxylase activity in rats exposed to diesel exhaust and coal dust in combination was lower than that in animals exposed to coal dust alone (2.8 versus 4.4 pmol/min·mg protein). Neither value, however, differed significantly from the filtered‐air controls, and no differences were observed in the other lung and liver activities. The data suggest exposure of the rats to diesel exhaust and/or coal dust had little or no effect on the selected lung and liver cytochrome P‐450 activities under the conditions of the experiment.

ISSN:0098-4108    

DOI:10.1080/15287398409530615

出版商:Taylor & Francis Group    

年代:1984

数据来源: Taylor

摘要:

Amsacrine is a DNA intercalating agent with antineoplastic properties in lymphopro‐liferative disorders. This report describes a group of short‐term tests with multiple endpoints to characterize the mutagenic and carcinogenic properties of this drug. In vitro studies included bacterial and mammalian cell mutagenesis, and slster‐chromatid exchange and chromosome aberrations in mammalian cells. In vivo, mice were given amsacrine for 7 wk at 2, 5, and 10 mg/kg and were observed for an additional 17 wk. The standard bacterial assay revealed cytotoxicity at 2000 and 5000 μg/plate in the pre‐incubation assay. No significant increase in revertants occurred in Salmonella strains, except for TA1537 in the activation phase. Amsacrine at 4.0 μg/ml was cytotoxic to V‐79 cells in the cell mutation assay, and at lower dose levels was a direct‐acting mutagen for the HGPRT locus. Sister‐chromatid exchange rate of Chinese hamster ovary cells was increased more than twofold at 2 μg/ml without metabolic activation. Cell anomalies included changes in metaphase cell kinetics and chromosome damage. Mice in the lung adenoma bioassay failed to show increased numbers of tumors, while indicating lack of tolerance and survival beyond 5 mg/kg. The results indicate clear genotoxicity to mammalian cell systems with a spectrum of changes from point mutation and SCE induction to cell‐cycle alterations, irrespective of exogenous metabolic activation. These results corroborate previous findings in animal and human cell systems in vitro. The reduction of genotoxicity in bacterial assays after exogenous metabolic activation may suggest some detoxification, and the magnitude of effects observed in mammalian cells indicates that exogenous metabolic activation is not required to manifest amsacrine's activity. The lack of tumor‐inducing potential in mice may be attributed to strong cytotoxic effects in this species, or to an insensitivity of the target organ, or to assay systems that may mask the carcinogenic potential.

ISSN:0098-4108    

DOI:10.1080/15287398409530616

出版商:Taylor & Francis Group    

年代:1984

数据来源: Taylor

摘要:

The influences of in vivo pretreatment with phenobarbitone (PB), 3‐methylcholanthrene (3‐MC), 2,2’,4,4’,5,5'‐hexachlorobiphenyl (HCBP), and 3,3’,4,4'‐tetrachlorobiphenyl (TCBP) on cytocidal hepatotoxicity of two pyrrolizidine alkaloids, lasiocarpine (LC) and senecionine (SC), were compared in short‐term primary cultures of rat hepatocytes. Toxicity was measured by release of lactate dehydrogenase (LDH) into culture medium at 24 h. LC was slightly more toxic to control hepatocytes than SC in the graded response range of 10–160 μM. PB and HCBP (a PB‐type polychlorobiphenyl inducer) similarly potentiated toxicity of SC, and each diminished the degree to which cell killing by LC and SC was inhibited by SKF‐525‐A. By comparison, 3‐MC and TCBP (a 3‐MC‐type PCB inducer) each diminished toxicity of SC but had little effect on toxicity of LC. Alpha‐naphthoflavone (ANF) potentiated toxicity of both LC and SC in hepatocytes induced by 3‐MC or TCBP but had little effect on responses of hepatocytes induced by either PB or HDBP. These results indicate that xenobiotics that induce similar patterns of cytochrome P‐450 isozymes have qualitatively similar modulating influences on cytocidal hepatotoxicity of pyrrolizidine alkaloids in primary cultures. However, the observed modulating effects could not be explained solely on the basis of altered activation rates by the cytochrome P‐450 species known to be induced by the various xenobiotics.

ISSN:0098-4108    

DOI:10.1080/15287398409530617

出版商:Taylor & Francis Group    

年代:1984

数据来源: Taylor

摘要:

Firemaster FF‐1, a polybrominated biphenyl (PBB) mixture, was dissolved in corn oil and given as a dose of 200 mg/kg body weight to Sherman rats on d 7 and 14 of pregnancy. Control rats received equivalent doses of corn oil alone. Selected pups and all dams were killed 1 mo after pups were weaned. A total of 50 male and 50 female offspring per group were followed until they were 2 yr old. The livers of offspring killed at the ages of 2 mo and 2 yr had PBB levels of 2.4 (SD 1.2) and 0.8 (SD 0.65) mg/kg for females and 3.0 (SD 1.6) and 0.6 (SD 0.37) mg/kg for males, respectively. The incidence of hepatocellular carcinomas was 3/51 (5.9%) and 4/41 (9.6%) after 2 yr in females and males, respectively. Hepatocellular carcinomas were not observed among the controls.

ISSN:0098-4108    

DOI:10.1080/15287398409530618

出版商:Taylor & Francis Group    

年代:1984

数据来源: Taylor

摘要:

A one‐generation, two‐litter rat reproduction study was done in a kennel in Allegan County, Michigan, as part of an investigation of reproductive problems in Shetland sheepdogs (shelties). Since 1970, at least 115 sheltie litters at this kennel have been grossly deformed and/or have died, generally within 3 d of birth. The causative factor(s) appears to be associated with the environment, as the shelties have had successful pregnancies elsewhere. There was some concern that a potential threat to human reproduction also might exist in this area. After it was discovered that fluoride in the dog food had apparently caused mottled teeth and bony exostoses in dogs at this and at least two other kennels, dog‐food fluoride content and local well water were investigated as possible causes of the reproductive problems. A two‐way factorial statistical design allowed assessment of dietary fluoride content and water source and interaction between the two. UPj: TUC(SD)spf rats, 9 males and 18 females in each group, were assigned to treatment with high‐fluoride dog food (460 ppm) and well water; high‐fluoride dog food and distilled water; low‐fluoride dog food (56 ppm) and well water; and low‐fluoride dog food and distilled water. After 60 d in the kennel, the rats were mated. Even after two litters, the only adverse effect was dental fluorosis in the high‐fluoride groups. The results indicated that rats cannot be used in the search for the cause(s) of reproductive problems in dogs in this kennel.

ISSN:0098-4108    

DOI:10.1080/15287398409530619

出版商:Taylor & Francis Group    

年代:1984

数据来源: Taylor

摘要:

Male rats were orally administered an inhibitor of angiotensin‐converting enzyme (ACE), N‐[(S)‐1 ‐(ethoxycarbonyl)‐3‐phenylpropyl] ‐1 ‐ala‐1 ‐pro maleate (enalapril, MK‐0421) at dosage levels of 10, 30, and 90 mg/kg·d. After 2–6 wk of dosing, the rats receiving 30 and 90 mg/kg·d produced large numbers of seminal plugs and had lacerated penises due to licking in an attempt to recover urine. Providing 0.9% saline as the source of drinking water prevented this behavior and subsequent lesions. There were no adverse effects on reproductive performance. A subsequent study showed that enalapril at 5 mg/kg·d po and captopril (another ACE inhibitor) at 25 mg/kg·d po increased NaCI intake in rats. Our results with captopril confirm those of Fregly (1980) and Evered and Robinson (1983) and show that both converting‐enzyme inhibitors (enalapril and captopril) increase salt appetite in rats.

ISSN:0098-4108    

DOI:10.1080/15287398409530620

出版商:Taylor & Francis Group    

年代:1984

数据来源: Taylor

摘要:

2,4‐Dichlorophenol (DCP) is a drinking and waste‐water contaminant formed by the spontaneous reaction of chlorine with phenols following chlorination of water for disinfection and deodorization. Rats were exposed to 0, 3, 30, or 300 ppm DCP in drinking water either in utero or for 12 wk postnatally following in utero exposure. Toxicity to DCP was assessed by organ and body weight changes, histopathology, and effects on reproduction and immunocompetence. Reproductive parameters measured included conception, litter size, pup birth weight, number stillborn, survival to weaning, and weaning weight. Immune parameters assessed were humoral immunity (antibody production) by an indirect enzyme‐linked immunosorbent assay (ELISA), cell‐mediated immunity by a delayed‐type hypersensitivity response, and macrophage function by phagocytosis of radiolabeled blood cells. Rats that received the combined in utero and postnatal treatment with 300 ppm DCP had significantly increased liver and spleen weights, enhanced humoral immune responsiveness, and depressed cell‐mediated immunity. Histopathologic changes were unremarkable in DCP‐exposed rats, even in the presence of increased liver and spleen weights. The 6‐wk‐old progeny of DCP‐treated dams had normal immune functions and showed no signs of DCP toxicity, other than increased spleen weights in the 300‐ppm exposure group. The results indicate that (1) the immune system may be a sensitive target for chlorinated phenolic compounds, (2) DCP may exert different effects on separate major immune responses, and (3) unlike some other chlorinated phenols, DCP does not appear to alter reproductive performance in rats.

ISSN:0098-4108    

DOI:10.1080/15287398409530621

出版商:Taylor & Francis Group    

年代:1984

数据来源: Taylor

摘要:

The bioconcentratlon and metabolism of picric acid and picramic acid were determined for rainbow trout. The bloconcentration factor (BCF) in the epaxlal muscle at 42 d for both of these compounds was less than 1; the skin had a BCF value of 1 and 9, respectively. The half‐life (t½> elimination for the high and low dose of picric acid was 12.0 and 12.5 d, respectively; and for picramic acid was 9.0 and 9.5 d, respectively. In separate experiments, approximately 34% of the injected [14C]plcric acid was metabolized to picramic acid, glucuronide conjugates, and an unidentified group of compounds, and 42% of the [14C]plcric acid was metabolized to picric acid, giucuronide conjugates, and an unidentified group of compounds. The low bioconcentration in the trout muscle may be due to the trout's ability to excrete the parent compound and metabolites. The higher radioactivity observed on the skin may be due to the water route of exposure and the binding of the parent compounds to protein.

ISSN:0098-4108    

DOI:10.1080/15287398409530622

出版商:Taylor & Francis Group    

年代:1984

数据来源: Taylor