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At least 19 recordsLinked to original sources
PubMed1998

Validation of transgenic mice carrying the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing.

Carcinogenicity testing is indispensable for identifying environmental carcinogens and for evaluating the safety of drugs in the process of development. Conventional 2-year rodent bioassays are one of the most resource-consuming tests in terms of animals, time, and costs. Development of rapid carcinogenicity testing systems that can assess carcinogenicity within a short period has become a social demand and is essential to improve efficacy in the identification of environmental carcinogens as well as in the development of new drugs. In this review we introduce the rapid carcinogenicity testing system using transgenic (Tg) mice carrying the human prototype c-Ha-ras gene, namely rasH2 mouse (CB6F1-TgHras2 mouse is the same mouse). The studies have been conducted to validate the rasH2 mouse as a model for the rapid carcinogenicity testing system. Our current validation studies revealed that rasH2 mice are able to detect various types of mutagenic carcinogens within 6 months. The rasH2 mice may also be able to detect various nonmutagenic carcinogens. The validation studies also revealed that rasH2 mice are generally much more susceptible to both mutagenic and nonmutagenic carcinogens than control non-Tg mice. No significant tumor induction has been observed in rasH2 mice with either mutagenic or nonmutagenic noncarcinogens. More rapid onset and higher incidence of more malignant tumors can be expected with a high probability after treatment with various carcinogens in the rasH2 mice than in control non-Tg mice. The rasH2 mouse appears to be a promising candidate as an animal model for development of a rapid carcinogenicity testing system.

Animals↗
PubMedDate not supplied

An evaluation of the hemizygous transgenic Tg.AC mouse for carcinogenicity testing of pharmaceuticals. I. Evidence for a confounding nonresponder phenotype.

We have completed 2 26-wk studies to evaluate the hemizygous transgenic Tg.AC mouse, which has been proposed as an alternative short term model for testing carcinogenicity. We attempted to evaluate the response to the known rodent carcinogens cyclophosphamide, phenolphthalein, and tamoxifen and to the noncarcinogen chlorpheniramine following topical application. In the first study, a weak response (2/17 animals) was observed to the positive control 12-O-tetradecanoylphorbol 13-acetate (TPA in ethanol, 1.25 micrograms), and no response was observed to cyclophosphamide, phenolphthalein, or chlorpheniramine, despite evidence for skin penetration. The second study compared 1.25 micrograms and 6.25 micrograms of TPA in ethanol and acetone solutions. Tamoxifen was also evaluated in both solvents and orally. No significant response was observed to tamoxifen by skin paint or oral routes. Over 60% of the high dose TPA-treated animals showed no (0 or 1) papilloma response, and 30% of the animals each developed more than 32 papillomas. The heterogenous response to high dose TPA may be related to variability in the responsiveness of hemizygous animals. In light of these findings, further Tg.AC studies should employ homozygous animals, and the underlying cause for heterogeneity in the tumorigenic response of Tg.AC mice should be identified and eliminated.

Administration, Topical↗
PubMed1995

A retrospective evaluation of COMPACT predictions of the outcome of NTP rodent carcinogenicity testing.

The carcinogenic potentials of 40 National Toxicology Program chemicals previously predicted by Computer Optimised Molecular Parametric Analysis for Chemical Toxicity (COMPACT), based on the identification of potential substrates of cytochromes P4501A and 2E (CYP1A and CYP2E), have been compared with new rodent carcinogenicity results. The COMPACT predictions have also been compared with published Ames mutagenicity data and with our own Hazardexpert predictions for carcinogenicity. Concordance evaluations between rodent carcinogenicity (1/4 segments positive) and predictions by COMPACT or Hazardexpert were 64% for COMPACT (CYP1A only), 72% for COMPACT (CYP1A plus CYP2E), 70% for Hazardexpert alone, and 86% for COMPACT (CYP1A plus CYP2E) plus Hazardexpert. Sensitivities of the predictions were for COMPACT, 75%; Hazardexpert, 60%; and Ames, 54%. Positive predictivities were for COMPACT, 75%; Hazardexpert, 78%; and Ames 81%. Negative predictivites were for COMPACT, 62%; Hazardexpert, 52%; and Ames, 42%.

Animals↗
PubMed1986

Strain A mouse pulmonary tumor test results for chemicals previously tested in the National Cancer Institute carcinogenicity tests.

Sixty-five chemicals were coded and examined for their ability to induce lung tumors in strain A/St (laboratory A) or strain A/J (laboratory B) mice. Thirty-five chemicals were tested in laboratory A only, 6 in laboratory B only, and 24 in both laboratories. Two-year carcinogenicity test results as well as genotoxicity test data are available for most of these chemicals. There was poor interlaboratory agreement in strain A test results for the 24 chemicals tested in both laboratories. In addition, there was poor agreement between strain A test results from either laboratory and 2-year carcinogenicity test results or genotoxicity results. Possible explanations for these findings include selection of a large number of aromatic amines in the group of chemicals submitted for strain A testing, differences in strain A testing protocols and in statistical analysis of results from the two laboratories, low sensitivity of the strain A/St mice used in this particular study, and general problems inherent in comparing any relatively short-term animal tumor model with 2-year carcinogenicity tests. Since there is no absolute reference for carcinogenicity, no one test system is better than another. Carcinogenicity test data are relevant only to the test model employed.

Animals↗
PubMed1984

The use of short-term tests and limited bioassays in carcinogenicity testing.

A brief discussion is given of the use of short-term in vivo and in vitro tests in carcinogenicity testing. Data are presented on the performance of nine such tests and five limited bioassays, as measured in terms of their sensitivity, specificity, accuracy, and predictive value. It is concluded that tests are available which, when used in combinations such as have been proposed by various authors, are capable of correctly identifying carcinogens and noncarcinogens with high confidence. A discussion of the statistics of batteries of tests is given. This is followed by a semiquantitative graphical representation and a discussion of how, on proceeding through a testing scheme such as that proposed by J. H. Weisburger and G. M. Williams (1981, Science 214, 401-407), the cumulative cost and the probability of correctly identifying a carcinogen or a noncarcinogen change as results become available from each of the stages of such a testing scheme.

Animals↗
PubMed1981

Carcinogen testing: current problems and new approaches.

The classic procedures for testing potential carcinogens in animals have basically not changed in the past 50 years. Considerable knowledge of the mechanisms of carcinogenesis has accrued in the last 20 years, particularly concepts on the metabolic activation of chemicals to reactive electrophilic compounds that can interact with nucleophilic including DNA. These developments, in turn, have yielded a framework for integrating into carcinogen testing the determination of genetic effects of chemicals. A systematic decision point approach to carcinogen testing has been developed which entails a sequential decision-making process as specific tests are performed and evaluated prior to initiation of higher order, more complex tests. Compared to conventional bioassays in rodents, this approach provides knowledge based on mechanisms of carcinogenesis, yields a substantial amount of data at minimal cost, and forms a solid base for eventual heath risk assessment.

Animals↗
PubMed1986

The peritoneal cell carcinogenicity test.

The peritoneal cell carcinogenicity test, which is a new short-term in vivo-in vitro transformation test invented by Nashed (1981), was evaluated in the present report. The experimental design and materials used were as close as possible to those used by Nashed (1981). Test compounds were the two carcinogenic/non-carcinogenic analog pairs benzo[a]pyrene/pyrene and 2-acetylamidofluorene/4-acetylamidofluorene. All 4 compounds were administered orally. Al(OH)3 was injected intraperitoneally to act as mitogen for peritoneal macrophages. The criterium for transformation was colony growth of macrophages in soft agar. Two transformed cell types formed colonies under the conditions used. Pulmonary and peritoneal macrophages formed colonies when colony-stimulating factor was added. No colony growth was observed on plates with macrophages from 256 animals tested (100 carcinogen treated, 80 treated with noncarcinogenic analogs and 76 untreated controls). Thus we were not able to confirm results published previously by the inventor of this test (Nashed, 1981).

Animals↗
PubMed1989

The interpretation of equivocal or marginal animal carcinogenicity tests.

The interpretation of animal carcinogenicity tests traditionally rely almost exclusively upon a comparison of specific tumor rates in treated vs. matched and, perhaps, historical control animals. Yet, carcinogenicity tests yield much more biological and pathological data than simply final tumor rates. This additional data should also be considered as part of the total weight of evidence, particularly when analyzing a marginal or equivocal test result. If there are no positive findings among the data discussed here and listed in Table 1, it is unlikely that a marginal or equivocal increase in tumor incidence is actually treatment-related, irrespective of statistical analysis.

Animals↗
PubMed1999

p53 induction as a genotoxic test for twenty-five chemicals undergoing in vivo carcinogenicity testing.

In vivo carcinogenicity testing is an expensive and time-consuming process, and as a result, only a relatively small fraction of new and existing chemicals has been tested in this manner. Therefore, the development and validation of alternative approaches is desirable. We previously developed a mammalian in vitro assay for genotoxicity based on the ability of cells to increase their level of the tumor-suppressor protein p53 in response to DNA damage. Cultured cells are treated with various amounts of the test substances, and at defined times following treatment, they are harvested and lysed. The lysates are analyzed for p53 by Western blot and/or enzyme-linked immunosorbent assay analysis. An increase in cellular p53 following treatment is interpreted as evidence for DNA damage. To determine the ability of this p53-induction assay to predict carcinogenicity in rodents and to compare such results with those obtained using alternate approaches, we subjected 25 chemicals from the predictive toxicology evaluation 2 list to analysis with this method. Five substances (citral, cobalt sulfate heptahydrate, D&C Yellow No. 11, oxymetholone, and t-butylhydroquinone) tested positive in this assay, and three substances (emodin, phenolphthalein, and sodium xylenesulfonate) tested as possibly positive. Comparisons between the results obtained with this assay and those obtained with the in vivo protocol, the Salmonella assay, and the Syrian hamster embryo (SHE) cell assay indicate that the p53-induction assay is an excellent predictor of the limited number of genotoxic carcinogens in this set, and that its accuracy is roughly equivalent to or better than the Salmonella and SHE assays for the complete set of chemicals.

Acyclic Monoterpenes↗
PubMed1985

Carcinogenicity testing of antitumor agents.

Carcinogenicity testing of antitumor agents in animal bioassays has been proposed because of the potential for carcinogenicity of this class of agents and the expectation that such testing may indicate prospectively the target organs of any related human oncogenesis. The literature reveals the anticipated confirmations in animals of the carcinogenicity of many antitumor agents. Furthermore, these agents have been associated with human tumors in numerous case reports. Review of the literature also indicates the inability of animal studies to predict the sites of carcinogen-induced tumors in man. The carcinogenic risk assessment of antitumor agents should begin with the determination of the ability of the agent to interact with DNA. Those agents which are capable of alkylating or binding DNA should be tested for mutagenic and teratogenic potential. The presumption of carcinogenicity should be made for DNA-reactive, mutagenic/teratogenic antitumor agents without requiring confirmation in long-term carcinogenicity bioassays in large numbers of animals. The inability of carcinogenicity studies in animals to accurately predict potential human tumor sites must also be recognized.

Abnormalities, Drug-Induced↗
PubMed2001

Mechanistic considerations in small fish carcinogenicity testing.

Historically, small fish species have proven useful both as environmental sentinels and as versatile test animals in toxicity and carcinogenicity bioassays. They can be bred in large numbers, have low maintenance and bioassay costs, and have a low background incidence of tumors. However, more mechanistic information is needed to help validate the information garnered from these models and to keep pace with other more fully developed animal models. This paper focuses on mechanistic considerations when using small fish models for carcinogenicity testing. Several small aquarium fish species have proven useful. The Japanese medaka is perhaps the best characterized small fish model for carcinogenicity testing; however, the zebrafish is emerging as an important model because it is well characterized genetically. Both route and methodology of exposure may affect the outcome of the study. Most studies have been conducted by introducing the test compound into the ambient water, but dietary exposures and embryo microinjection have also been used. Other considerations in study design include use of an initiating carcinogen, such as diethlynitrosamine, and differences in xenobiotic metabolism, such as the fact that fish CYP2B is refractory to phenobarbital induction. The small size of these models has perhaps limited some types of mechanistic studies, such as formation and repair of DNA adducts in response to carcinogen exposure. However, improved analytical methods are allowing greater resolution and should be applied to small fish species. Slide-based methods such as immunohistochemistry are an important adjunct to routine histopathology and should be included in study design. However, there is a need for development of more species-specific antibodies for fish research. There is also a need for more fish-specific data on cytokines, serum biochemistry, and oncogenes to strengthen the use of these important test models.

Animals↗
PubMed1998

Short- and intermediate-term carcinogenicity testing--a review. Part 1: the prototypes mouse skin tumour assay and rat liver focus assay.

Carcinogenicity testing is by far the most expensive and time-consuming study type of toxicology. For many years, the lifetime exposure with the maximum tolerated dose in two rodent species has been the gold standard of carcinogenicity testing of pharmaceuticals. Major change was introduced by the Fourth International Conference on Harmonization in July 1997; a chronic rodent bioassay in one species and a short-term carcinogenicity assay are regarded as sufficient for registration. Such requirements provide the opportunity to redirect the vast resources previously spent on the lifetime study in the second species. Numerous experimental protocols for short- and intermediate-term carcinogenicity testing in many target tissues have been available for years. The first part of this review describes the basic principles of short- and intermediate-term carcinogenicity testing using the examples of the widely used mouse skin tumour assay and the rat liver foci assay. In the context of these experimental models, the discrimination and quantification of initiating and promoting activity and the use of preneoplastic lesions as endpoints in carcinogenicity testing are described. The review includes the limitations of the models with regard to the extrapolation from effects observed in animal experiments to a potential exposure of humans.

Age Factors↗
PubMed1981

Carcinogenicity tests of certain environmental and industrial chemicals.

Fourteen chemicals of varied uses were tested for carcinogenicity by oral administration in male and female Charles River CD rats. Under the conditions of the tests, propane sultone, propylene imine, and ethylenethiourea, in addition to the positive control N-2-fluorenylacetamide, were carcinogenic. Avadex, bis(2-chloroethyl) ether, the potassium salt of bis(2-hydroxyethyl) dithiocarbamic acid, ethylene carbonate, and semicarbazide hydrochloride were not carcinogenic under the test conditions. Dithiooxamide, glycerol alpha-monochlorohydrin, and thiosemicarbazide gave somewhat ambiguous results, though administered at high enough dose levels to be toxic. An inadequate number of animals survived treatments with sodium azide, sodium bisulfide, and vinylene carbonate, or the animals may not have received sufficiently high doses of the test chemicals to provide maximum test sensitivity. However, there were no indications that these three chemicals were carcinogenic under the test conditions.

2-Acetylaminofluorene↗
PubMed1997

Rapid carcinogenicity testing system with transgenic mice harboring human prototype c-HRAS gene.

Rapid carcinogenicity tests were done with transgenic (Tg) mice human prototype c-HRAS gene, namely BALB/cByJ x C57BL/6JF1-TgN(HRAS)2 or CB6F1-HRAS2 mice. The studies were conducted as the first step in the evaluation of the CB6F1-HRAS2 mouse as a model for the rapid carcinogenicity testing system. Results of short-term tests of various genotoxic carcinogens indicated that CB6F1-HRAS2 mice are more susceptible to these carcinogens than control non-Tg mice. According to the first-step evaluation studies, more rapid onset and a higher incidence of more malignant tumors can be expected with a higher probability after treatment with various genotoxic carcinogens in the CB6F1-HRAS2 mice than in control non-Tg mice. The CB6F1-HRAS2 mouse seems to be a promising candidate as an animal model for the development of a rapid carcinogenicity testing system.

Animals↗
PubMed1998

Validation of transgenic mice harboring the human prototype c-Ha-ras gene as a bioassay model for rapid carcinogenicity testing.

Studies were conducted to validate the transgenic (Tg) mice harboring human prototype c-Ha-ras gene, namely the rasH2 mice (CB6F1), as a model for rapid carcinogenicity testing. Short-term (26 weeks) carcinogenicity testing of 18 mutagenic (Salmonella) trans-species carcinogens, two mutagenic single-species (mouse-only) carcinogens, six non-mutagenic trans-species carcinogens, one non-mutagenic single-species (mouse-only) carcinogen, four mutagenic non-carcinogens and four non-mutagenic non-carcinogens were completed. The studies revealed that the Tg mice are able to detect various types of mutagenic carcinogens and may also detect various non-mutagenic carcinogens within 26 weeks. Dose-dependent tumor responses were observed with various carcinogens except for a few equivocal cases. The validation studies also revealed that the Tg mice are generally much more susceptible to both mutagenic and non-mutagenic carcinogens than control non-Tg mice. Most of the malignant tumors were observed in the carcinogen-treated Tg mice and only very few or none in the corresponding non-Tg mice. Most of the carcinogens tested induced some of the target organ tumors observed in B6C3F1 mice in a 2-year bioassay as well as certain types of tumors specific to the Tg mice, i.e. lung alveolar epithelial tumors, spleen hemangiosarcomas, forestomach squamous cell tumors. No significant tumor induction has been observed in the Tg mice either with mutagenic or non-mutagenic non-carcinogens. Although further validation studies are still required, the rasH2 mouse seems to be a promising candidate as an animal model for the development of a rapid carcinogenicity testing system.

Animals↗
PubMed1989

Evaluation and grading of rat liver foci in carcinogenicity tests.

The significance of rat liver foci in carcinogenesis testing received major attention following their description in the National Cancer Institute workshop of 1974. However, the biological nature of foci remains uncertain despite numerous studies during the past 15 years. That is, in part, because criteria to define foci have been inconsistent, and studies of spontaneous foci in rats have been very few. This symposium has demonstrated that the induction or enhancement of rat liver foci, per se, may not provide sufficient evidence to classify a test compound as a carcinogen. Evidence presented suggests that some types of rat liver foci may not be related to carcinogenesis, and there is, consequently, a basis to further subclassify these lesions. In cases where foci are considered to be a part of the neoplastic process, semi-quantitative grading of these lesions, as well as of tumors, according to the extent of their development or progression, may assist in the interpretation of equivocal carcinogenicity test findings.

Animals↗