In vitro mammalian cell mutation assays based on transgenic reporters: A report of the International Workshop on Genotoxicity Testing (IWGT)

White, Paul A.; Luijten, Mirjam; Mishima, Masayuki; Cox, Julie A.; Hanna, Joleen; Maertens, Rebecca M.; Zwart, Edwin

doi:10.1016/j.mrgentox.2019.04.002

Cited by 24 publications

(28 citation statements)

References 140 publications

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“…In these cases, the addition of S9 provides enzymatic activity, such as that of sulfotransferases, which are required to metabolize PhIP into DNA reactive metabolites. (White et al ., 2019). Toxicity was evaluated using relative increases in cell counts (RICC); for this test, an RICC of <20% was considered toxic.…”

Section: Methodsmentioning

confidence: 99%

“…At least 50,000 plaque forming units were required for a concentration to be evaluated. For this in vitro assay, the spontaneous rate of mutation for the FE1 cells (43.9 × 10 −5 cells) is much higher than the rate of spontaneous MutaMouse lung rate of mutation (White et al ., 2019). Our experience with this assay is limited, and thus we did not have a robust historical vehicle/solvent control dataset to utilize in data analysis.…”

Section: Methodsmentioning

confidence: 99%

“…neous MutaMouse lung rate of mutation(White et al, 2019). Our experience with this assay is limited, and thus we did not have a robust historical vehicle/solvent control dataset to utilize in data analysis.2.5 | Big Blue ® in vivo mutation test 2.5.1 | Dose range finding study Prior to the Big Blue ® in vivo mutation study, a 21-day, non-GLP dose range finding study was conducted in C57BL/6 female mice (Charles River Laboratories, Portage, MI).…”

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confidence: 99%

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In vitro and in vivo mammalian mutation assays support a nonmutagenic mechanism of carcinogenicity for hydrazine

Nicolette

Murray

Sonders

et al. 2020

Environ and Mol Mutagen

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Hydrazine has been described as a mutagenic, probable human carcinogen. It is mutagenic in in vitro systems such as bacterial reverse mutation (Ames) tests and some yeast systems, as well as in in vivo systems with drosophila. It was shown to cause chromosome damage both in vitro and in vivo but was negative in some wellvalidated mammalian mutation systems such as CHO HPRT assays. Importantly, there is only one in vivo gene mutation test reported, which was negative. Our objective was to determine if hydrazine is mutagenic in mammalian test systems. Thus, we conducted an in vitro gene mutation test in Muta™Mouse lung epithelial cells (FE1 cell assay) and a regulatory-compliant in vivo Big Blue ® mouse test. Consistent with previous reports, an additional six-well Ames assay showed that hydrazine was mutagenic to bacteria. The FE1 cell assay was negative in conditions with and without metabolic activation when tested to cytotoxicity limits. In the Big Blue ® mouse study, female mice received dosages of hydrazine up to 10.9 mg/kg via drinking water for 28 days. This dose is comparable to a dose used in a carcinogenicity study where female mice had significant increases in hepatocellular adenoma at 11.5 mg/kg. There were no increases in mutant frequency in liver and lung, two tissues sensitive to the carcinogenic effects of hydrazine in mice. Our research shows that hydrazine is not mutagenic in mammalian cells either in vitro or in vivo, indicating mutagenicity may not play a role in the carcinogenicity of hydrazine.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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In vitro and in vivo mammalian mutation assays support a nonmutagenic mechanism of carcinogenicity for hydrazine

Nicolette

Murray

Sonders

et al. 2020

Environ and Mol Mutagen

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“…476 (OECD 2016c), Transgenic Rodent Somatic and Germ Cell Gene Mutation Assays Test No. 488 (OECD 2013;White et al 2019), and Thymidine kinase Test No. 490 (OECD 2016g)) and other assays such as the RaDR-GFP transgenic mouse that detects mutational errors in homologous recombination (Kiraly et al 2015;Sukup-Jackson et al 2014).…”

Section: Dna Damage Gi and Mutationmentioning

confidence: 99%

“…490 (OECD 2016g)) and other assays such as the RaDR-GFP transgenic mouse that detects mutational errors in homologous recombination (Kiraly et al 2015;Sukup-Jackson et al 2014). One of the approved TG 488 transgenic mouse lines (Jakubczak et al 1996) has been used to measure mutations in mammary gland in vivo, and the RaDR-GFP mouse and several TG 488 approved lines have been used for primary or established mammary cell lines (Sukup- Jackson et al 2014;White et al 2019). The other tests are limited to specific non-mammary tissues, and should be validated for relevance to mammary gland.…”

Section: Dna Damage Gi and Mutationmentioning

confidence: 99%

Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast

Helm

Rudel

2020

Arch Toxicol

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Knowledge about established breast carcinogens can support improved and modernized toxicological testing methods by identifying key mechanistic events. Ionizing radiation (IR) increases the risk of breast cancer, especially for women and for exposure at younger ages, and evidence overall supports a linear dose-response relationship. We used the Adverse Outcome Pathway (AOP) framework to outline and evaluate the evidence linking ionizing radiation with breast cancer from molecular initiating events to the adverse outcome through intermediate key events, creating a qualitative AOP. We identified key events based on review articles, searched PubMed for recent literature on key events and IR, and identified additional papers using references. We manually curated publications and evaluated data quality. Ionizing radiation directly and indirectly causes DNA damage and increases production of reactive oxygen and nitrogen species (RONS). RONS lead to DNA damage and epigenetic changes leading to mutations and genomic instability (GI). Proliferation amplifies the effects of DNA damage and mutations leading to the AO of breast cancer. Separately, RONS and DNA damage also increase inflammation. Inflammation contributes to direct and indirect effects (effects in cells not directly reached by IR) via positive feedback to RONS and DNA damage, and separately increases proliferation and breast cancer through pro-carcinogenic effects on cells and tissue. For example, gene expression changes alter inflammatory mediators, resulting in improved survival and growth of cancer cells and a more hospitable tissue environment. All of these events overlap at multiple points with events characteristic of "background" induction of breast carcinogenesis, including hormone-responsive proliferation, oxidative activity, and DNA damage. These overlaps make the breast particularly susceptible to ionizing radiation and reinforce that these biological activities are important characteristics of carcinogens. Agents that increase these biological processes should be considered potential breast carcinogens, and predictive methods are needed to identify chemicals that increase these processes. Techniques are available to measure RONS, DNA damage and mutation, cell proliferation, and some inflammatory proteins or processes. Improved assays are needed to measure GI and chronic inflammation, as well as the interaction with hormonally driven development and proliferation. Several methods measure diverse epigenetic changes, but it is not clear which changes are relevant to breast cancer. In addition, most toxicological assays are not conducted in mammary tissue, and so it is a priority to evaluate if results from other tissues are generalizable to breast, or to conduct assays in breast tissue. Developing and applying these assays to identify exposures of concern will facilitate efforts to reduce subsequent breast cancer risk.Biological systems studied This review article summarizes and synthesizes data from cell-culture, experimental animals, and human epidem...

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Genetic Toxicology: Basics and Practical Insights into Its Appropriate Application

Pottenger¹,

Gollapudi²,

Moore³

2023

Patty's Toxicology

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Genetic toxicology data play an important role in a variety of regulatory applications. Thus, industrial hygienists and toxicologists need a basic understanding of the principles and testing approaches for the evaluation of genotoxicity. Genetox tests are used for hazard assessment, to support the classification of chemicals as carcinogens or mutagens, and to support the evaluation of modes of action for tumor induction. Genetic toxicology has primarily been used in the evaluation of potential carcinogens, and for predicting potential germ cell and heritable risk. More recent considerations include using genetic damage as a standalone adverse outcome. Many genetox tests are recommended for regulatory use, with OECD test guidelines that describe conduct and data interpretation. Since these recommendations have evolved over the years, data from older studies must be carefully evaluated before accepting study conclusions. In silico models now contribute by complementing the biological tests. This chapter includes our insights into strategies for selecting appropriate tests and generating optimal data sets to address specific questions and advice for conducting weight of the evidence evaluations on information from multiple endpoints and tests. Genetic toxicology data provide not only qualitative results, but with careful study design, can also provide information useful to address dose–response issues.

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In vitro mammalian cell mutation assays based on transgenic reporters: A report of the International Workshop on Genotoxicity Testing (IWGT)

Cited by 24 publications

References 140 publications

In vitro and in vivo mammalian mutation assays support a nonmutagenic mechanism of carcinogenicity for hydrazine

In vitro and in vivo mammalian mutation assays support a nonmutagenic mechanism of carcinogenicity for hydrazine

Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast

Genetic Toxicology: Basics and Practical Insights into Its Appropriate Application

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