Event:768

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Event Title

Cytotoxicity, Increase
Cytotoxicity, Increase

Key Event Overview

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AOPs Including This Key Event

AOP Name Event Type Essentiality
Inhibition of pyruvate dehydrogenase kinase leading to hepatocellular adenomas and carcinomas (in mouse and rat) KE
Intracellular Acidification Induced Olfactory Epithelial Injury Leading to Site of Contact Nasal Tumors KE Strong

Taxonomic Applicability

Name Scientific Name Evidence Links
Rattus sp. ABTC 42503 Rattus sp. ABTC 42503 Strong NCBI
mouse Mus musculus Strong NCBI
human Homo sapiens Moderate NCBI

Level of Biological Organization

Biological Organization
Cellular

How this Key Event works

Reductions in cellular pH that exceed homeostatic controls leads to denatured/dysfunctional cellular apparatus (enzymes)[1] and cell death[2].

How it is Measured or Detected

Cytotoxicity is measured in vitro using one of many available standardized methods, including the release of the intracellular enzyme lactate dehydrogenase[3], alkaline phosphatase[4] cell counts [5], mitochondrial function[6] and dye exclusion assays[7]. Cytotoxicity is measured in vivo by histopathological evaluation of tissue. The presence of dead cells and/or cellular debris is direct evidence of cytotoxicity at the time of tissue sampling. Histological evidence of previous cytotoxicity is reported as tissue degeneration and/or atrophy.

Evidence Supporting Taxonomic Applicability

Cell death is the inevitable outcome of sufficient cellular disruption in any living cell. Cytotoxicity has been observed in the olfactory epithelium of rats and mice exposed by inhalation to one or more of the listed chemical initiators. Cytotoxicity is expected in humans based conserved properties of the of the olfactory epithelium across species.

References

  1. Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326
  2. Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326, Izumi, Torigoe, Ishiguchi, Uramoto, Yoshida, Tanabe, Ise, Murakami, Yoshida, Nomoto and Kohno (2003). Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy. Cancer Treat Rev. 29: 541-549, Fais (2010). Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism. J Intern Med. 267: 515-525
  3. (2008). Principles and Methods of Toxicology. Boca Raton, FL, Taylor and Francis: 2193
  4. Kuykendall, Taylor and Bogdanffy (1993). Cytotoxicity and DNA-protein crosslink formation in rat nasal tissues exposed to vinyl acetate are carboxylesterase-mediated. Toxicol Appl Pharmacol. 123: 283-292
  5. Theiszova, Jantova, Dragunova, Grznarova and Palou (2005). Comparison the cytotoxicity of hydroxyapatite measured by direct cell counting and MTT test in murine fibroblast NIH-3T3 cells. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 149: 393-396, (2008). Principles and Methods of Toxicology. Boca Raton, FL, Taylor and Francis: 2193
  6. Theiszova, Jantova, Dragunova, Grznarova and Palou (2005). Comparison the cytotoxicity of hydroxyapatite measured by direct cell counting and MTT test in murine fibroblast NIH-3T3 cells. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 149: 393-396, (2008). Principles and Methods of Toxicology. Boca Raton, FL, Taylor and Francis: 2193
  7. Weisenthal, Dill, Kurnick and Lippman (1983). Comparison of dye exclusion assays with a clonogenic assay in the determination of drug-induced cytotoxicity. Cancer Res. 43: 258-264, Elia, Storer, Harmon, Kraynak, McKelvey, Hertzog, Keenan, DeLuca and Nichols (1993). Cytotoxicity as measured by trypan blue as a potentially confounding variable in the in vitro alkaline elution/rat hepatocyte assay. Mutat Res. 291: 193-205