API

Relationship: 887

Title

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Increase, Cytotoxicity leads to Increase, Tissue Degeneration, Necrosis & Atrophy

Upstream event

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Increase, Cytotoxicity

Downstream event

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Increase, Tissue Degeneration, Necrosis & Atrophy

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Intracellular Acidification Induced Olfactory Epithelial Injury Leading to Site of Contact Nasal Tumors adjacent Moderate Moderate

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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

Evidence Supporting this KER

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Biological Plausibility

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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 Evidence

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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 and Inconsistencies

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We are not aware of any uncertainties or inconsistencies.

Quantitative Understanding of the Linkage

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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.

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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

References

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  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