Interlaboratory comparison of the CB6F1-Tg rasH2 rapid carcinogenicity testing model

Maronpot, Robert R.; Mitsumori, Kunitoshi; Mann, Peter C.; Takaoka, Masaya; Yamamoto, Satoshi; Usui, Tomohiro; Okamiya, Hideaki; Nishikawa, Shingo; Nomura, Tatsuji

doi:10.1016/s0300-483x(00)00168-2

Cited by 23 publications

(22 citation statements)

References 7 publications

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“…The rasH2 mouse is hemizygous for the human c-Ha-ras transgene under control of its endogenous promoter and enhancer sequences. It was developed by Saitoh et al (1990) in CB6F1 mice to evaluate the association of chemically induced transgene expression and tumor induction (Katsuki et al 1991;Yamamoto et al 1996Yamamoto et al , 1998a +d; +g (Blanchard et al 1998;+g (Yamamoto et al 1998b (Storer et al 2001) ±d; +g (Eastin et al 2001) ±g; +g; (Weisburger 1977) +g (Usui et al 2001;Yamamoto et al 1998b) Melphalan 148-82-3 1 Known +; +; +; +ip +; + +ip (Eastin et al 1998;+g (Eastin et al 1998;±ip (Yamamoto et al 1998b) (Weisburger 1977) Storer et al 2001) 2001) Cyclosporin A 79217-60-0 1 Known NT -; --g; +f; +f (Eastin et al 1998;±f (Eastin et al 1998; ±g (Maronpot et al 2000;Storer et al 2001) 2001) Usui et al 2001;Yamamoto et al 1998a) Diethylstilbestrol 56-53-1 1 Known NT -; NT -sc; +f (Eastin et al 1998;-g (Eastin et al 1998 (Yamamoto et al 1998b) (NCI/NTP 1978a) Abbreviations: -, negative; +, positive; ±, equivocal; d, dermal; f, food; g, gavage; I, inhalation; ip, intraperitoneal; LET, linear energy transfer; NT, not tested or no published record; sc, subcutaneous; wb, whole body. Individual results were found in the cited references or in the IARC (2002) or the NTP databases (NTP 2002).…”

Section: Review Of Research Progressmentioning

confidence: 99%

The role of transgenic mouse models in carcinogen identification.

Pritchard

French

Davis

et al. 2003

Environ Health Perspect

127

100

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In this article, we examine existing data on the use of transgenic mouse models for identification of human carcinogens. We focus on the three most extensively studied of these mice, Trp53+/-, Tg/AC, and RasH2, and compare their performance with the traditional 2-year rodent bioassay. Data on 99 chemicals were evaluated. Using the International Agency for Research on Cancer/Report on Carcinogens determinations for the carcinogenicity of these chemicals to humans as the standard for comparison, we evaluated a variety of potential testing strategies ranging from individual transgenic models to combinations of these three models with each other and with traditional rodent assays. The individual transgenic models made the "correct" determinations (positive for carcinogens; negative for noncarcinogens) for 74-81% of the chemicals, with an increase to as much as 83% using combined strategies (e.g., Trp53+/- for genotoxic chemicals and RasH2 for all chemicals). For comparison, identical analysis of chemicals in this data set that were tested in the 2-year, two-species rodent bioassay yielded correct determinations for 69% of the chemicals. However, although the transgenic models had a high percentage of correct determinations, they did miss a number of known or probable human carcinogens, whereas the bioassay missed none of these chemicals. Therefore, we also evaluated mixed strategies using transgenic models and the rat bioassay. These strategies yielded approximately 85% correct determinations, missed no carcinogens, and cut the number of positive determinations for human noncarcinogens in half. Overall, the transgenic models performed well, but important issues of validation and standardization need further attention to permit their regulatory acceptance and use in human risk assessment.

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Section: Review Of Research Progressmentioning

confidence: 99%

The role of transgenic mouse models in carcinogen identification.

Pritchard

French

Davis

et al. 2003

Environ Health Perspect

127

100

View full text Add to dashboard Cite

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“…Hisada S, 1 Tanifuji H, 1 Shibata S, 1 Nagashima M, 1 Sato A, 1 Isobe M, 1 Morimoto H, 1 Iizuka K, 1 Masuda S, 1 Iida N, 1 Usui T. 2 Takaoka M, 1 Imai T, 2 Torii M, 3 Sato H, 4 Tyosawa K, 5 Tanakamaru Z, 6 Aclachi T, 7 Hisada S, 8 Ueda M, 9 Ogasawara H, 10 Matsumoto M, 11 Kobayashi K, 12 Mutai M, 12 Usui T. 13 …”

Section: Cyclophosphamidementioning

confidence: 99%

CB6F1-rasH2 Mouse: Overview of Available Data

Usui

Mutai²,

Hisada³

et al. 2001

Toxicol Pathol

104

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This article presents data from short-term carcinogenicity studies of compounds tested in the CB6F1-rasH2 transgenic mouse as part of the International Life Sciences Institutes' (ILSI) Health and Environmental Sciences' (HESI) Alternative to Carcinogenicity Testing (ACT) project. Additionally, data from other studies that were not conducted as part of the ILSI program, but used comparable or slightly modi ed protocols, are included here. A signi cant number (3 of 4) of the genotoxic carcinogens tested were positive in the rasH2 mouse; the other compound was equivocally positive. The positive control, N-Methyl-N-nitrosurea (MNU), gave reproducible responses across all participating laboratories with tumors noted at multiple sites in the animal. The immunosuppressive human carcinogen, Cyclosporin A, was equivocal. Two hormones that are human tumorigens, Diethylstilbestrol and 17b -Estradiol, gave positive and negative results, respectively. Of the twelve additional compounds tested that are classi ed as non-genotoxic rodent carcinogens and putative human non-carcinogens, only the two peroxisome proliferators (clo brate and diethylhexylphthalate(DEHP)) produced a positive response (liver effects). The three non-genotoxic non-carcinogens that were tested also gave negative responses in the rasH2 model. This result provides con dence that the model is likely to have a low false-positive rate.

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“…However, it should be noted that in almost all cases, the decision made by the researchers, matches the expectation based upon the NTP bioassay results and suggests that prior knowledge may have influenced the interpretation of the data. As an example where prior knowledge clearly influenced the evaluation process, Maronpot and associates (2000) stated in the report of their collaborative study using the ras H2 mouse that “ p -Cresidine was also considered positive, primarily because of the preneoplastic changes noted and its known carcinogenicity for urinary bladder (NCI, 1978) rather than the number of actual tumors diagnosed in the present study.”…”

Section: Evaluation/validation Of Genetically Modified Mouse Modelsmentioning

confidence: 94%

The use of genetically modified mice in cancer risk assessment: Challenges and limitations

Eastmond¹,

Vulimiri

French

et al. 2013

Critical Reviews in Toxicology

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The use of genetically modified (GM) mice to assess carcinogenicity is playing an increasingly important role in the safety evaluation of chemicals. While progress has been made in developing and evaluating mouse models such as the Trp53+/−, Tg.AC and the rasH2, the suitability of these models as replacements for the conventional rodent cancer bioassay and for assessing human health risks remains uncertain. The objective of this research was to evaluate the use of accelerated cancer bioassays with GM mice for assessing the potential health risks associated with exposure to carcinogenic agents. We compared the published results from the GM bioassays to those obtained in the National Toxicology Program’s conventional chronic mouse bioassay for their potential use in risk assessment. Our analysis indicates that the GM models are less efficient in detecting carcinogenic agents but more consistent in identifying non-carcinogenic agents. We identified several issues of concern related to the design of the accelerated bioassays (e.g., sample size, study duration, genetic stability and reproducibility) as well as pathway-dependency of effects, and different carcinogenic mechanisms operable in GM and non-GM mice. The use of the GM models for dose-response assessment is particularly problematic as these models are, at times, much more or less sensitive than the conventional rodent cancer bioassays. Thus, the existing GM mouse models may be useful for hazard identification, but will be of limited use for dose-response assessment. Hence, caution should be exercised when using GM mouse models to assess the carcinogenic risks of chemicals.

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Interlaboratory comparison of the CB6F1-Tg rasH2 rapid carcinogenicity testing model

Cited by 23 publications

References 7 publications

The role of transgenic mouse models in carcinogen identification.

The role of transgenic mouse models in carcinogen identification.

CB6F1-rasH2 Mouse: Overview of Available Data

The use of genetically modified mice in cancer risk assessment: Challenges and limitations

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