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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A physico-chemical carcinogen-screening test was used to measure the rate constants of electron attachment, kes, of 105 chemicals that had been screened in long-term rodent bioassays and short-term in vitro tests by the NCI/NTP. In the ke test, a pulse-conductivity technique is used to generate and monitor the decay of excess electrons that serve as nucleophilic surrogates for the target tissue of rodents. Of the 61 chemicals that had been found to be rodent carcinogens as well as Salmonella mutagens, 36 yield kes that are equal to or greater than the diffusion-controlled ke of carbon tetrachloride and are considered to be positive ke test responses. In contrast, 29 of the remaining 44 chemicals that are putative non-carcinogens and non-mutagens yield kes that are negative ke test responses. These results are combined with the ke responses of 46 non-mutagenic carcinogens and 20 mutagenic non-carcinogens that were reported earlier and are evaluated to determine the degree to which the measure of electron-accepting capacity that ke provides complements or overlaps the electrophilicity or DNA reactivity of chemicals that is indicated by positive mutagenicity responses in the Ames Salmonella tester strains or by positive structural alerts, S/As, of the chemicals. The combined ke test results indicate that the overall predictivity of the ke test is comparable to and complements the Ames Salmonella test and S/As in identifying rodent carcinogens. Moreover, the electrons serve as non-discriminate nucleophilic targets for both genotoxic and non-genotoxic electron-accepting molecules and appear to attach with equal efficiency to carcinogens that are active in various tissues of rodents. This property of excess electrons suggests that the predictivity of the ke test could be enhanced by combining the measured ke with an appropriate lipophilicity or pharmacokinetic parameter. A pre-chemical electron-transfer step that had been proposed to precede chemical interactions between the carcinogen and target tissue is discussed in light of recent developments in electron-donor/-acceptor chemistry and in the application of structure--activity relationships to identify carcinogens.
Carcinogenesis 1992 Aug
PMID:Response of the ke test to NCI/NTP-screened chemicals. II. Genotoxic carcinogens and non-genotoxic non-carcinogens. 149 95

Classifications of carcinogenesis, mutagenesis and teratogenesis used by the National Toxicological Advisory Committee in Italy (CCTN), the Commission of the European Communities (CEC), the Environmental Protection Agency in the USA (EPA), the International Agency for Research on Cancer (IARC), and the National Toxicology Programme in the USA (NPT) are examined and commented on, with a synopsis of several allocations made by the above organizations. However, the authors consider it advisable to redefine the categories and create 5 groups of substances (designated C1 to C5), on the basis of given definitions, with the aim of rendering the allocations comparable. This procedure is used solely for carcinogenesis and excludes the NTP. From such comparison, good agreement was found between CCTN and EPA and between CCTN and CEC, whereas agreement between IARC and other organizations was poor.
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PMID:[The definitions and classifications of carcinogenesis, mutagenesis and teratogenesis used by national and international agencies and institutions]. 825 65

Bioassay dose-level data for 226 chemicals unequivocally defined as carcinogens or non-carcinogens in mice and/or rats by the U.S. NTP have been standardized to gavage equivalent dose-levels according to a modification of the methods of Gold et al. Correlations by bioassay dose-level with chemical structure, mutagenicity to Salmonella, sites of carcinogenesis and extent of trans-species activity have been studied. The data obtained add further weight to the proposition that two classes of rodent carcinogen are present in the NTP database--genotoxic carcinogens that occur predominantly in the dose range 20-800 mg/kg and putative non-genotoxic carcinogens that are equally distributed over the dose range less than 20- greater than 3000 mg/kg. The latter carcinogens are characterized by the lack of structural alerts to DNA reactivity, the absence of mutagenicity to Salmonella, an inability to induce tumours in 8 reference tissues and a strong tendency to be tissue and species-specific in their activity. Where comparisons can be made, the present findings for the NTP carcinogens and non-carcinogens are consistent with the recent observations by Gold et al. for a larger group of carcinogens.
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PMID:Correlations between bioassay dose-level, mutagenicity to Salmonella, chemical structure and sites of carcinogenesis among 226 chemicals evaluated for carcinogenicity by the U.S. NTP. 233 72

Data on 49 randomly selected studies from the NCI/NTP Carcinogenesis Bioassay Program were reanalyzed using four statistical decision rules to classify substances as either being negative or falling into one of three categories indicating increasing evidence of oncogenicity. The data available for analysis were the crude marginal counts of numbers of animals with specified lesions, as well as the number of animals surviving at the time the studies were terminated. Statistical analysis was based primarily on the Cochran-Armitage test for linear trend in proportions, with and without the use of historical control information. If only concurrent controls were used, classifications of carcinogenicity obtained in between 34 and 57% of the studies, depending on the decision rule used. The incorporation of historical control information into the Cochran-Armitage test statistic led to almost universal findings of carcinogenicity. The data base assembled here was used to estimate false negative and false positive rates for each of the four decision rules.
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PMID:Statistical issues in the analysis of the long-term carcinogenicity bioassay in small rodents: an empirical evaluation of statistical decision rules. 265 37

Identification of potentially cancer-causing chemicals is a priority in our society. Short-term assays for mutation or chromosomal damage, which are rapid, inexpensive, and reproducible, have found widespread use; however, concern has arisen recently because such assays do not coincide completely with the standard rodent bioassay for carcinogenesis. Lack of perfect correlation is not surprising, given the complex, multicausal nature of the carcinogenic process. We have developed methodologies for interpreting short-term tests to predict carcinogenicity, which allow consideration of the influence of the proportion of carcinogens expected in the tested chemicals, the complexities of the rodent carcinogenesis bioassay, and factors affecting the worth of information. These methodologies are applied to a set of data on genotoxicity and carcinogenicity of 73 chemicals (NTP-73) recently published by the National Toxicology Program; they illustrate that with this approach, batteries of short-term tests can indeed be predictive of rodent carcinogenicity or noncarcinogenicity and that batteries are more predictive than the Salmonella assay alone. The analysis is validated using an additional group of chemicals with results in the same short-term tests as NTP-73.
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PMID:Application of the carcinogenicity prediction and battery selection method to recent National Toxicology Program short-term test data. 273 84

Male F-344 rats were fed a diet containing 2% di-(2-ethylhexyl)phthalate (DEHP) for 95 weeks. Liver nodules and/or hepatocellular carcinomas (HCC) developed in 6/10 rats fed DEHP and none were found in controls (P less than 0.005 by chi 2 test). All the nodules and HCC were negative for gamma-glutamyl transpeptidase. In the non-tumorous portions of liver, the hepatocytes contained an increased number of peroxisomes and extensive accumulation of lipofuscin. By immunocytochemical analysis, the liver peroxisomes in rats treated chronically with DEHP had visually detectable decrease in the H2O2-degrading catalase and increase in H2O2-producing fatty acyl-CoA oxidase. These results show that higher dietary level of DEHP, which causes substantially greater degree of peroxisome proliferation than the 1.2% dietary level used in the National Toxicology Program bioassay (1982, Publication no. NTP-80-37, Tech. Report Series No. 217), can induce liver tumors in male rats.
Carcinogenesis 1987 Sep
PMID:Absence of gamma-glutamyl transpeptidase activity in neoplastic lesions induced in the liver of male F-344 rats by di-(2-ethylhexyl)phthalate, a peroxisome proliferator. 288 2

Consulting toxicologists began in 1982 to question the use and potential involvement of oil gavage test-compound administration in unexpected NTP carcinogenesis responses. Investigations have focused on corn oil gavage alternatives, vehicle type and volume, alteration of MTD, teratogenic effects, disposition of test compounds, and target tissues. Micoencapsulation will require considerable development research to make it a suitable alternative. Vehicle type and volume appear to have different effects on the apparent MTD, teratogenicity and disposition of very similar compounds. Only two tissue effects have been observed in the NTP oil gavage bioassay data. First, there is a sporadic and weak association with exocrine pancreatic acinar cell proliferative lesions; these lesions are highly correlated with overweight male Fischer 344/N rats. Second, leukemia is reduced about 50 percent in the male Fischer 344/N rats; this is a strong association which results in an 8-10 percent increase in survival. The protective effect of corn oil gavage is remarkable and there is no significant enhancement of tumor development. Corn oil gavage under the conditions of the NTP carcinogenesis bioassay does contribute to overnutrition and undesirable increased body weight, especially in male Fischer 344/N rats. The NTP and NCTR research programs include research plans to address critical oil gavage, diet composition feeding regimen, exercise and hormonal status questions. Results of these studies will point the way to improving long-term carcinogenesis and toxicity testing.
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PMID:Oil gavage test-compound administration effects in NTP carcinogenesis-toxicity testing. 309 53

The inhibitory effect of oral administration of garlic on experimental carcinogenesis in buccal pouches induced by painting 9,10-dimethyl-1,2-benz(a)anthracene (DMBA) was studied on 40 golden Syrian hamsters. The animals were grouped at random into four experimental groups (oral administration of garlic, NTP, BP or mineral oil followed by DMBA painting on buccal pouches), three chemical control groups (oral administration of garlic, NTP or BP without DMBA painting) and a DMBA control group (only painted DMBA on buccal pouches). Starting from the fourth week after DMBA painting, the pouch mucosae were examined biweekly for its tumor formation and blood vessel architecture. Animals were sacrificed 25 weeks after DMBA application. Tumors and pouch mucosae were dissected to examine tumor nature and biochemical reactions of DNA synthesis and GGTase activity. The inhibitory efficacy of garlic, BP and NTP were evaluated according to the results of these examinations. Garlic was found to have a higher inhibitory efficacy than BP and NTP through the probable mechanism of competitive binding with nuclear DNA and diminishing the opportunity of DMBA to initiate carcinogenesis. Other factors related to cancer inhibition included insufficient local blood flow, low GGTase activity and lesser DNA synthesis. The inhibitory effect of fractions of garlic on experimental carcinogenesis should be a reasonable and necessary continuation in future studies of the series of cancer prevention by garlic.
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PMID:The inhibitory effect of oral administration of garlic on experimental carcinogenesis in hamster buccal pouches by DMBA painting. 311 23

A survey has been conducted of 222 chemicals evaluated for carcinogenicity in mice and rats by the United States NCI/NTP. The structure of each chemical has been assessed for potential electrophilic (DNA-reactive) sites, its mutagenicity to Salmonella recorded, and the level of its carcinogenicity to rodents tabulated. Correlations among these 3 parameters were then sought. A strong association exists among chemical structure (S/A), mutagenicity to Salmonella (Salm.) and the extent and sites of rodent tumorigenicity among the 222 compounds. Thus, a approximately 90% correlation exists between S/A and Salm. across the 115 carcinogens, the 24 equivocal carcinogens and the 83 non-carcinogens. This indicates the Salmonella assay to be a sensitive method of detecting intrinsic genotoxicity in a chemical. Concordance between S/A and Salm. have therefore been employed as an index of genotoxicity, and use of this index reveals two groups of carcinogens within the database, genotoxic and putatively non-genotoxic. These two broad groups are characterized by different overall carcinogenicity profiles. Thus, 16 tissues were subject to carcinogenesis only by genotoxins, chief among which were the stomach, Zymbal's glands, lung, subcutaneous tissue and circulatory system. Conclusions of carcinogenicity in these 16 tissues comprised 31% of the individual chemical/tissue reports of carcinogenicity. In contrast, both genotoxins and non-genotoxins were active in the remaining 13 tissues, chief among which was the mouse liver which accounted for 24% of all chemical/tissue reports of carcinogenicity. Further, the group of 70 carcinogens reported to be active in both species and/or in 2 or more tissues contained a higher proportion of Salmonella mutagens (70%) than observed for the group of 45 single-species/single-tissue carcinogens (39%). 30% of the 83 non-carcinogens were mutagenic to Salmonella. This confirms earlier observations that a significant proportion of in vitro genotoxins are non-carcinogenic, probably due to their non-absorption or preferential detoxification in vivo. Also, only 30% of the mouse liver-specific carcinogens were mutagenic to Salmonella. This is consistent with tumors being induced in this tissue (and to a lesser extent in other tissues of the mouse and rat) by mechanisms not dependent upon direct interaction of the test chemical with DNA. Detection of 103 of the 115 carcinogens could be achieved by use of only male rats and female mice.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the U.S. NCI/NTP. 327 47

A quantitative framework for the analysis of results of the Salmonella (Ames) test is presented, and the relationship between mutagenesis and carcinogenesis is examined. Color graphics are used for the Salmonella data to describe variability, and trends across multiple chemicals and test conditions. Positivity in the Salmonella test, using statistical criteria to classify results, is compared to positivity in carcinogenesis bioassays for 48 chemicals tested in NCI/NTP-sponsored programs. Sensitivity of the Salmonella test across 5 tester strains was 91% (21/23), while specificity was only 36% (9/25). Results were most concordant for TA100 Aroclor-induced rat S9: sensitivity was 87%, specificity 64%. The correlation of mutagenic potency and carcinogenic potency was 0.41 (p less than 0.001) for 80 chemicals, using results from both the general published literature and the NCI/NTP-sponsored programs. After removal of 3 extreme values, the correlation was 0.24 (p = 0.04).
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PMID:Statistical analysis of Salmonella test data and comparison to results of animal cancer tests. 328 86


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