Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: Confirmation of earlier results with 41 additional chemicals

Zeiger, Errol; Haseman, Joseph K.; Shelby, Michael D.; Margolin, Barry H.; Tennant, Raymond W.; Holden, Henry E.

doi:10.1002/em.2850160502

Cited by 211 publications

(79 citation statements)

References 28 publications

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“…assay, 67% for SCE induction and 66% for the mouse lymphoma assay. Similar results, which confirmed that Salmonella is the most predictive for carcinogenicity, were obtained by Zeiger et al [32]. In a comparison of results from in vitro clastogenicity assays and evaluation of carcinogenicity, Ishidate et al [11] found that among 165 clastogens, 91 (55%) were carcinogens and 56 (34%) were chemicals which had shown some indications of carcinogenicity.…”

Section: Discussionsupporting

confidence: 74%

Genotoxicity and Carcinogenicity Studies of Bronchodilators and AntiAsthma Drugs

Brambilla

Mattioli

Robbiano

et al. 2013

Basic Clin Pharma Tox

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This survey is a compendium of genotoxicity and carcinogenicity information of bronchodilators and antiasthma drugs. Data from 46 marketed drugs were collected. Of these 46 drugs, 25 (54.3%) did not have retrievable genotoxicity or carcinogenicity data. The remaining 21 (45.7%) had at least one genotoxicity or carcinogenicity test result. Of these 21 drugs, 10 had at least one positive finding: three tested positive in at least one genotoxicity assay, eight in at least one carcinogenicity assay, and one of them gave positive results in both genotoxicity assay and carcinogenicity assay. Concerning the predictivity of genetic toxicology findings for the result(s) of long-term carcinogenesis assays, 15 drugs had both genotoxicity and carcinogenicity data: seven of them (46.6%) were neither genotoxic nor carcinogenic, 6 (40.0%) were carcinogenic in at least one sex of mice or rats but tested negative in genotoxicity assays, 1 (6.7%) tested positive in genotoxicity assay but was non-carcinogenic, and 1 (6.7%) gave positive responses in both genotoxicity and carcinogenicity assay. Only 11 (23.9%) of the 46 drugs considered had all data required by current guidelines for testing of pharmaceuticals, but a large fraction of them were developed and marketed prior to the present regulatory climate.Bronchodilators and antiasthma drugs are continuously or frequently used in the treatment for chronic airways diseases. Among the various adverse reactions of concern that these pharmaceuticals might cause, genotoxic and carcinogenic effects cannot be excluded. Therefore, we deemed useful to verify to what extent the drugs of this family have been tested for their potential genotoxic and carcinogenic risk to human beings.The regulatory authorities of USA, Europe and Japan recommend th at genotoxicity and carcinogenicity assays are performed before application for marketing approval of pharmaceuticals. Present guidelines for genotoxicity testing of pharmaceuticals [1-3] indicate a standard test battery that consists of (i) a test for gene mutation in bacteria; (ii) an in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mammalian cells gene mutation assay and (iii) an in vivo test for chromosomal damage performed with rodent hematopoietic cells. Guidelines for carcinogenicity testing of pharmaceuticals [4,5] indicate that long-term carcinogenicity studies in rodents should be performed for all pharmaceuticals whose expected clinical use is continuous for at least 6 months as well as for pharmaceuticals used frequently in an intermittent manner in the treatment for chronic recurrent conditions. In long-term carcinogenicity assays, the highest dose should be at least 25 times higher, on a mg/m 2 basis, than the maximum recommended human daily dose or represent a 25-fold ratio of rodent to human AUC. In the chapter bronchodilators and antiasthma drugs of the 2007 edition of Martindale: The Complete Drug Reference [6] are included 46 drugs still on the market, the majority of wh...

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Section: Discussionsupporting

confidence: 74%

Genotoxicity and Carcinogenicity Studies of Bronchodilators and AntiAsthma Drugs

Brambilla

Mattioli

Robbiano

et al. 2013

Basic Clin Pharma Tox

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“…The results obtained for the 41 chemicals were similar to those reported for the 73 chemicals (12). No significant differences between the two datasets were detected and hence the two datasets were combined into a single dataset of 114.…”

Section: Introductionsupporting

confidence: 77%

Predicting carcinogenicity by using batteries of dependent short-term tests.

Kim

Margolin

1994

Environ Health Perspect

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Amnag the various nmehods for predictingcarcinogencity from a battery ofshort-term tests (STlb), thecarciDgenity prediction and battery selection (CPBS) procedure is the most prominent. A major ass pn of CPBS is that the STIs used in the prediction are conditionally independent. Resultsof recent Nationa Tlblcology Program studies offour commonly used in vuvSlb ona t thistsrpebon, ofCPBSto cies. This is accomplished via log-linear ing, which then also yields an important dividend: standard errors for the predicted probabilities of carcinogenicity.

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“…Approximately one-third of nonmutagenic chemicals are carcinogenic, and approximately one-third of the mutagenic chemicals are noncarcinogenic in the 2-year rodent bioassay (14,15). It has been proposed that chemicals that induce tumors in two rodent species are less influenced by the genetic variability among different species than chemicals that induce tumors in only one species (16).…”

Section: Introductionmentioning

confidence: 99%

Validation of Transgenic Mice Carrying the Human Prototype c-Ha-ras Gene as a Bioassay Model for Rapid Carcinogenicity Testing

Yamamoto¹,

Urano²,

Koizumi³

et al. 1998

Environmental Health Perspectives

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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. Environ Health Perspect 1 06(Suppl 1 ):57-69 (1998). http.//ehpnetl.niehs.nih.gov/ docs/1998/Suppl-1/57-69yamamoto/abstract.html

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Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: Confirmation of earlier results with 41 additional chemicals

Cited by 211 publications

References 28 publications

Genotoxicity and Carcinogenicity Studies of Bronchodilators and AntiAsthma Drugs

Genotoxicity and Carcinogenicity Studies of Bronchodilators and AntiAsthma Drugs

Predicting carcinogenicity by using batteries of dependent short-term tests.

Validation of Transgenic Mice Carrying the Human Prototype c-Ha-ras Gene as a Bioassay Model for Rapid Carcinogenicity Testing

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