Relationship:887

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Key Event Relationship Overview

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Description of Relationship

Upstream Event Downstream Event/Outcome
Cytotoxicity, Increase Tissue Degeneration, Necrosis & Atrophy , Increase

AOPs Referencing Relationship

AOP Name Type of Relationship Weight of Evidence Quantitative Understanding
Intracellular Acidification Induced Olfactory Epithelial Injury Leading to Site of Contact Nasal Tumors Directly Leads to Moderate Moderate

Taxonomic Applicability

Name Scientific Name Evidence Links

How Does This Key Event Relationship Work

Cytotoxicity reaches sufficient levels to causes cellular necrosis, degeneration of the olfactory tissue, and tissue-level atrophy.

Weight of Evidence

Biological Plausibility

Biological plausibility for this relationship has been well established. Cytotoxicity is an obligate step leading to cellular necrosis. When reaching sufficient levels, necrosis of cells present in the olfactory epithelium results in degeneration and atrophy of the affected tissue.

Empirical Support for Linkage

Exposure-response data from subchronic and chronic inhalation studies establish the order of events and dependence on exposure level. Following inhalation exposure to the chemical initiator vinyl acetate, cytotoxicity is observed at lower concentrations and shorter exposure times than necrosis, tissue degeneration, and atrophy[1]. In the absence of cytotoxicity, necrosis, tissue degeneration and atrophy are not observed in these studies.

Uncertainties or Inconsistencies

We are not aware of any uncertainties or inconsistencies.

Quantitative Understanding of the Linkage

We are not aware of evidence supporting a specific level of cytotoxicity resulting in necrosis, degeneration and atrophy. This issue is subject to the criteria established by pathologists evaluating the tissue effects of a test compound. However, it is clear that low levels of cytotoxicity are by definition insufficient to lead to necrosis, degeneration and tissue atrophy.

Evidence Supporting Taxonomic Applicability

Cytotoxicity of olfactory epithelium preceding necrosis, tissue degeneration and atrophy have been observed in rats and mice[2].

References

  1. Bogdanffy, Dreef-van der Meulen, Beems, Feron, Cascieri, Tyler, Vinegar and Rickard (1994). Chronic toxicity and oncogenicity inhalation study with vinyl acetate in the rat and mouse. Fundam Appl Toxicol. 23: 215-229, Bogdanffy, Gladnick, Kegelman and Frame (1997). FOUR-WEEK INHALATION CELL PROLIFERATION STUDY OF THE EFFECTS OF VINYL ACETATE ON RAT NASAL EPITHELIUM. Inhalation Toxicology, Taylor & Francis. 9: 331-350, Hotchkiss, Krieger, Harkema and Mahoney (2013). Draft Report: VINYL ACETATE: EVALUATION OF VINYL ACETATE-SPECIFIC DNA ADDUCTS, HISTOPATHOLOGY AND EPITHELIAL CELL PROLIFERATION IN NASAL AIRWAYS OF Crl:CD(SD) RATS REPEATEDLY EXPOSED TO VINYL ACETATE VAPORS. Washington, DC, The Vinyl Acetate Council
  2. Bogdanffy, Dreef-van der Meulen, Beems, Feron, Cascieri, Tyler, Vinegar and Rickard (1994). Chronic toxicity and oncogenicity inhalation study with vinyl acetate in the rat and mouse. Fundam Appl Toxicol. 23: 215-229, Bogdanffy, Gladnick, Kegelman and Frame (1997). FOUR-WEEK INHALATION CELL PROLIFERATION STUDY OF THE EFFECTS OF VINYL ACETATE ON RAT NASAL EPITHELIUM. Inhalation Toxicology, Taylor & Francis. 9: 331-350, Hotchkiss, Krieger, Harkema and Mahoney (2013). Draft Report: VINYL ACETATE: EVALUATION OF VINYL ACETATE-SPECIFIC DNA ADDUCTS, HISTOPATHOLOGY AND EPITHELIAL CELL PROLIFERATION IN NASAL AIRWAYS OF Crl:CD(SD) RATS REPEATEDLY EXPOSED TO VINYL ACETATE VAPORS. Washington, DC, The Vinyl Acetate Council