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Wiley Interdisciplinary Reviews.... 2010Nanomaterials are commonly defined as particles or fibers of less than 1 microm in diameter. For these reasons, they may be respirable in humans and have the potential,... (Review)
Review
Nanomaterials are commonly defined as particles or fibers of less than 1 microm in diameter. For these reasons, they may be respirable in humans and have the potential, based upon their geometry, composition, size, and transport or durability in the body, to cause adverse effects on human health, especially if they are inhaled at high concentrations. Rodent inhalation models to predict the toxicity and pathogenicity of nanomaterials are prohibitive in terms of time and expense. For these reasons, a panel of in vitro assays is described below. These include cell culture assays for cytotoxicity (altered metabolism, decreased growth, lytic or apoptotic cell death), proliferation, genotoxicity, and altered gene expression. The choice of cell type for these assays may be dictated by the procedure or endpoint selected. Most of these assays have been standardized in our laboratory using pathogenic minerals (asbestos and silica) and non-pathogenic particles (fine titanium dioxide or glass beads) as negative controls. The results of these in vitro assays should predict whether testing of selected nanomaterials should be pursued in animal inhalation models that simulate physiologic exposure to inhaled nanomaterials. Conversely, intrathoracic or intrapleural injection of nanomaterials into rodents can be misleading because they bypass normal clearance mechanisms, and non-pathogenic fibers and particles can test positively in these assays.
Topics: Animals; Cell Proliferation; Cells, Cultured; Gene Expression; Humans; Mutagenicity Tests; Nanostructures; Toxicity Tests
PubMed: 20063369
DOI: 10.1002/wnan.54 -
Mutation Research. Genetic Toxicology... Apr 2018Trimethylolpropane triacrylate (TMPTA) is a trifunctional acrylate monomer which polymerizes rapidly when exposed to sources of free radicals. It is widely used as a... (Review)
Review
Trimethylolpropane triacrylate (TMPTA) is a trifunctional acrylate monomer which polymerizes rapidly when exposed to sources of free radicals. It is widely used as a reactive diluent and polymer building block in the formulation of overprint varnishes, inks and a variety of wood, plastic and metal coatings. TMPTA has been tested in a range of in vitro and in vivo genotoxicity tests. There is no clear evidence of induction of gene mutations by TMPTA in bacteria or mammalian cells in vitro, but there is evidence of clastogenicity from induction of small colony tk mutants in the mouse lymphoma assay, and also induction of micronuclei and chromosomal aberrations. However, TMPTA was negative in bone marrow or blood micronucleus tests in vivo following oral or repeated dermal application, and did not induce comets in bone marrow or liver of mice following intravenous administration, which would have achieved plasma (and therefore tissue) concentrations estimated to exceed those inducing clastogenic effects in vitro. It is concluded that TMPTA is not genotoxic in vivo.
Topics: Acrylates; Animals; Bacteria; Bone Marrow; Comet Assay; Mammals; Mice; Micronucleus Tests; Mutagenicity Tests; Mutagens; Mutation
PubMed: 29555063
DOI: 10.1016/j.mrgentox.2018.02.006 -
Genes & Genetic Systems Apr 2023Chromosomal damage occurs both endogenously and exogenously and is a crucial factor in the induction of carcinogenesis. Chemically induced chromosomal damage is mainly... (Review)
Review
Chromosomal damage occurs both endogenously and exogenously and is a crucial factor in the induction of carcinogenesis. Chemically induced chromosomal damage is mainly exogenous. The OECD has developed methods to detect chemicals that induce chromosomal damage so as to identify hazardous substances and limit their exposure to humans. The development and improvement of in vitro mammalian cell methods have been the focus of recent research, as these techniques have higher throughput than in vivo animal methods and are cruelty-free. In vitro mammalian cell methods are highly sensitive and widely used. Nevertheless, they have a high frequency of misleading positive test results, causing the wastage of vital raw materials and pharmaceutical agents, and necessitating additional in vivo animal tests. Therefore, the improvement of in vitro mammalian cell methods is required. Novel methodologies have been proposed and developed for robust animal-free evaluation. As they include omics and AI approaches that use big data, they may enable objective, multidirectional interpretation when applied in combination with current in vitro experimental techniques. We review the existing approaches toward improving chromosome damage detection and introduce innovative techniques that facilitate animal-free testing. The current and latest evaluation methods can support the protection of public health as well as the development of promising chemicals that enrich our lives.
Topics: Animals; Humans; Mutagenicity Tests; Public Health; Carcinogenesis; DNA Damage; Chromosomes; Mammals
PubMed: 36754383
DOI: 10.1266/ggs.22-00058 -
Toxicology Letters Sep 2018Skin tumors have been observed in C3H/HeJ mice following treatment with high and strongly irritating concentrations of 2-ethylhexyl acrylate (2-EHA). Dermal... (Review)
Review
Skin tumors have been observed in C3H/HeJ mice following treatment with high and strongly irritating concentrations of 2-ethylhexyl acrylate (2-EHA). Dermal carcinogenicity studies performed with 2-EHA are reviewed, contrasting the results in two mouse strains (C3H/HeJ and NMRI) under different dosing regimens. Application of contemporary evaluation criteria to the existing dermal carcinogenicity dataset demonstrates that 2-EHA induces skin tumors only at concentrations exceeding an maximum tolerated dose (MTD) and in the immune-dysregulated C3H/HeJ mouse model. Overall, the available chronic toxicity and genotoxicity data on 2-EHA support a non-genotoxic chemical irritant mechanism, whereby chronic irritation leads to inflammation, tissue injury, and wound repair, the latter of which is disrupted in C3H/HeJ mice and leads to tumor formation. Tumor response information in excess of an MTD should not be considered in a human hazard or risk assessment paradigm. For the purposes of an appropriate hazard assessment, 2-EHA did not cause or initiate dermal carcinogenesis in an immune competent (NMRI) mouse model, and, even in the immune compromised C3H/HeJ model, did not induce skin tumors at doses which did not exceed the MTD.
Topics: Acrylates; Air Pollutants, Occupational; Animals; Carcinogenesis; Dose-Response Relationship, Drug; Guidelines as Topic; Humans; Immunocompromised Host; Maximum Tolerated Dose; Mutagenicity Tests; Reproducibility of Results; Risk Assessment; Skin; Skin Neoplasms; Species Specificity; Toxicity Tests, Acute; Toxicity Tests, Chronic
PubMed: 29775721
DOI: 10.1016/j.toxlet.2018.05.016 -
Prioritization of Mycotoxins Based on Their Genotoxic Potential with an In Silico-In Vitro Strategy.Toxins Oct 2021Humans are widely exposed to a great variety of mycotoxins and their mixtures. Therefore, it is important to design strategies that allow prioritizing mycotoxins based...
Humans are widely exposed to a great variety of mycotoxins and their mixtures. Therefore, it is important to design strategies that allow prioritizing mycotoxins based on their toxic potential in a time and cost-effective manner. A strategy combining in silico tools (Phase 1), including an expert knowledge-based (DEREK Nexus Lhasa Limited, Leeds, UK) and a statistical-based platform (VEGA QSAR©, Mario Negri Institute, Milan, Italy), followed by the in vitro SOS/umu test (Phase 2), was applied to a set of 12 mycotoxins clustered according to their structure into three groups. Phase 1 allowed us to clearly classify group 1 (aflatoxin and sterigmatocystin) as mutagenic and group 3 (ochratoxin A, zearalenone and fumonisin B1) as non-mutagenic. For group 2 (trichothecenes), contradictory conclusions were obtained between the two in silico tools, being out of the applicability domain of many models. Phase 2 confirmed the results obtained in the previous phase for groups 1 and 3. It also provided extra information regarding the role of metabolic activation in aflatoxin B1 and sterigmatocystin mutagenicity. Regarding group 2, equivocal results were obtained in few experiments; however, the group was finally classified as non-mutagenic. The strategy used correlated with the published Ames tests, which detect point mutations. Few alerts for chromosome aberrations could be detected. The SOS/umu test appeared as a good screening test for mutagenicity that can be used in the absence and presence of metabolic activation and independently of Phase 1, although the in silico-in vitro combination gave more information for decision making.
Topics: Activation, Metabolic; Animals; DNA Damage; Expert Systems; Male; Mutagenicity Tests; Mycotoxins; Quantitative Structure-Activity Relationship; Rats, Sprague-Dawley; Salmonella typhimurium; Rats
PubMed: 34679027
DOI: 10.3390/toxins13100734 -
The Journal of Toxicological Sciences Aug 2010We investigated the genotoxicities or mutagenicities of 2 chemicals (octane and tetrasodium pyrophosphate) with limited toxicological data in spite of their common usage...
We investigated the genotoxicities or mutagenicities of 2 chemicals (octane and tetrasodium pyrophosphate) with limited toxicological data in spite of their common usage based on Ames reverse mutation test. In this test, treatment of 2 chemicals at each five dose did not induce mutagenicity in Salmonella typhimurium TA98, TA100, TA1535, TA1537, and in Escherichia coli WP2uvrA with and without metabolic activation. These results indicate that 2 chemicals do not have mutagenic potentials under the conditions examined in each study. Despite these results, it can affect by inducing inhalation, skin or eye contact, ingestion, and have affected central nervous system as a target organ. It is thus necessary to prepare the local exhaust system and personal protective equipments. Based on this study, we suggest that future studies should be directed toward chronic inhalation, carcinogenic test and so on.
Topics: Diphosphates; Escherichia coli; Mutagenicity Tests; Mutagens; Octanes; Salmonella typhimurium
PubMed: 20686342
DOI: 10.2131/jts.35.555 -
Toxicology Apr 2013The nephrotoxicity and nephrocarcinogenicity of trichloroethylene (TCE) and tetrachloroethylene (PCE) are believed to be mediated primarily through the cysteine... (Comparative Study)
Comparative Study
The nephrotoxicity and nephrocarcinogenicity of trichloroethylene (TCE) and tetrachloroethylene (PCE) are believed to be mediated primarily through the cysteine S-conjugate β-lyase-dependent bioactivation of the corresponding cysteine S-conjugate metabolites S-(1,2-dichlorovinyl)-l-cysteine (DCVC) and S-(1,2,2-trichlorovinyl)-l-cysteine (TCVC), respectively. DCVC and TCVC have previously been demonstrated to be mutagenic by the Ames Salmonella mutagenicity assay, and reduction in mutagenicity was observed upon treatment with the β-lyase inhibitor aminooxyacetic acid (AOAA). Because DCVC and TCVC can also be bioactivated through sulfoxidation to yield the potent nephrotoxicants S-(1,2-dichlorovinyl)-l-cysteine sulfoxide (DCVCS) and S-(1,2,2-trichlorovinyl)-l-cysteine sulfoxide (TCVCS), respectively, the mutagenic potential of these two sulfoxides was investigated using the Ames Salmonella typhimurium TA100 mutagenicity assay. The results show both DCVCS and TCVCS were mutagenic, and TCVCS exhibited 3-fold higher mutagenicity than DCVCS. However, DCVCS and TCVCS mutagenic activity was approximately 700-fold and 30-fold lower than DCVC and TCVC, respectively. DCVC and DCVCS appeared to induce toxicity in TA100, as evidenced by increased microcolony formation and decreased mutant frequency above threshold concentrations. TCVC and TCVCS were not toxic in TA100. The toxic effects of DCVC limited the sensitivity of TA100 to DCVC mutagenic effects and rendered it difficult to investigate the effects of AOAA on DCVC mutagenic activity. Collectively, these results suggest that DCVCS and TCVCS exerted a definite but weak mutagenicity in the TA100 strain. Therefore, despite their potent nephrotoxicity, DCVCS and TCVCS are not likely to play a major role in DCVC or TCVC mutagenicity in this strain.
Topics: Carbon-Sulfur Lyases; Cysteine; Mutagenicity Tests; Oxamic Acid; Tetrachloroethylene; Trichloroethylene
PubMed: 23416178
DOI: 10.1016/j.tox.2013.02.003 -
PloS One 2017An increasing number of industrial, agricultural and commercial chemicals in the aquatic environment lead to various deleterious effects on organisms, which is becoming...
An increasing number of industrial, agricultural and commercial chemicals in the aquatic environment lead to various deleterious effects on organisms, which is becoming a serious global health concern. In this study, the Ames test and SOS/umu test were conducted to investigate the potential genotoxicity and mutagenicity caused by organic extracts from drinking water sources. Organic content of source water was extracted with XAD-2 resin column and organic solvents. Four doses of the extract equivalent to 0.25, 0.5, 1 and 2L of source water were tested for toxicity. All the water samples were collected from six different locations in Guangdong province. The results of the Ames test and SOS/umu test showed that all the organic extracts from the water samples could induce different levels of DNA damage and mutagenic potentials at the dose of 2 L in the absence of S9 mix, which demonstrated the existence of genotoxicity and mutagenicity. Additionally, we found that Salmonella typhimurium strain TA98 was more sensitive for the mutagen. Correlation analysis between genotoxicity, Organochlorine Pesticides (OCPs) and Polycyclic Aromatic Hydrocarbons (PAHs) showed that most individual OCPs were frame shift toxicants in drinking water sources, and there was no correlation with total OCPs and PAHs.
Topics: China; Drinking Water; Mutagenesis; Mutagenicity Tests; Mutagens; Pesticides; Salmonella typhimurium; Water Pollutants, Chemical
PubMed: 28125725
DOI: 10.1371/journal.pone.0170454 -
Mutation Research. Genetic Toxicology... May 2015This workshop reviewed the current science to inform and recommend the best evidence-based approaches on the use of germ cell genotoxicity tests. The workshop questions... (Review)
Review
This workshop reviewed the current science to inform and recommend the best evidence-based approaches on the use of germ cell genotoxicity tests. The workshop questions and key outcomes were as follows. (1) Do genotoxicity and mutagenicity assays in somatic cells predict germ cell effects? Limited data suggest that somatic cell tests detect most germ cell mutagens, but there are strong concerns that dictate caution in drawing conclusions. (2) Should germ cell tests be done, and when? If there is evidence that a chemical or its metabolite(s) will not reach target germ cells or gonadal tissue, it is not necessary to conduct germ cell tests, notwithstanding somatic outcomes. However, it was recommended that negative somatic cell mutagens with clear evidence for gonadal exposure and evidence of toxicity in germ cells could be considered for germ cell mutagenicity testing. For somatic mutagens that are known to reach the gonadal compartments and expose germ cells, the chemical could be assumed to be a germ cell mutagen without further testing. Nevertheless, germ cell mutagenicity testing would be needed for quantitative risk assessment. (3) What new assays should be implemented and how? There is an immediate need for research on the application of whole genome sequencing in heritable mutation analysis in humans and animals, and integration of germ cell assays with somatic cell genotoxicity tests. Focus should be on environmental exposures that can cause de novo mutations, particularly newly recognized types of genomic changes. Mutational events, which may occur by exposure of germ cells during embryonic development, should also be investigated. Finally, where there are indications of germ cell toxicity in repeat dose or reproductive toxicology tests, consideration should be given to leveraging those studies to inform of possible germ cell genotoxicity.
Topics: Animals; DNA Mutational Analysis; Education; Genome-Wide Association Study; Germ Cells; Germ-Line Mutation; High-Throughput Nucleotide Sequencing; Humans; Mutagenicity Tests; Mutagens; Risk Assessment
PubMed: 25953399
DOI: 10.1016/j.mrgentox.2015.01.008 -
Toxins Jun 2018Griseb. has a long history of collection from the wild as a traditional remedy for respiratory and gastrointestinal complaints. It has also been investigated for its...
Griseb. has a long history of collection from the wild as a traditional remedy for respiratory and gastrointestinal complaints. It has also been investigated for its promising pharmacological activities in the central nervous system. However, its toxicological data is entirely missing. This study investigated the acute and repeated-dose oral toxicity of a 20% (/) ethanol extract in Sprague Dawley rats, and mutagenicity using the Ames test. No gross pathological abnormalities and no toxicity signs or mortality were detected in animals treated with the dose of 2000 mg/kg bw during 14 days of observation. The tested extract was assigned to category 5 of the GHS. To evaluate a repeated-dose toxicity, an extract has been tested over a 28-day period followed by a 14-day recovery period. No mortality and no changes in body/organ weight or food consumption have been observed. The no-observed-adverse-effect-level of the extract was determined at 1000 mg/kg bw. The results of Ames tests conducted on extracts of different polarity (water; 20% (/) ethanol; 50% (/) ethanol; n-heptane), were unequivocally negative. The study reveals no toxicity of and no concerns for its mutagenic effects, supports its positive safety profile, and confirms the acknowledged traditional medicinal use in human.
Topics: Administration, Oral; Animals; Female; Male; Mutagenicity Tests; No-Observed-Adverse-Effect Level; Phytochemicals; Plant Extracts; Rats, Sprague-Dawley; Sideritis; Toxicity Tests, Acute; Toxicity Tests, Subchronic
PubMed: 29937516
DOI: 10.3390/toxins10070258