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AOP: 136

Title

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Intracellular Acidification Induced Olfactory Epithelial Injury Leading to Site of Contact Nasal Tumors

Short name
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pH Induced Nasal Tumors
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Handbook Version v1.0

Graphical Representation

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Authors

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Justin G. Teeguarden, PhD, DABT Pacific Northwest National Laboratory & Oregon State University

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Point of Contact

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Undefined   (email point of contact)

Contributors

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Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
2.7 Under Review
This AOP was last modified on April 29, 2023 16:02

Revision dates for related pages

Page Revision Date/Time
Decrease, Intracellular pH September 16, 2017 10:16
Increase, Tissue Degeneration, Necrosis & Atrophy September 16, 2017 10:16
Increase, Cell Proliferation December 10, 2024 15:01
Increase, Respiratory or Squamous Metaplasia September 29, 2017 14:47
Increase, Cytotoxicity September 16, 2017 10:16
Increase, Site of Contact Nasal Tumors September 16, 2017 10:16
Increase, Mutations in Critical Genes September 16, 2017 10:16
Decrease, Intracellular pH leads to Increase, Cytotoxicity November 29, 2016 20:42
Increase, Cytotoxicity leads to Increase, Tissue Degeneration, Necrosis & Atrophy November 29, 2016 20:42
Increase, Tissue Degeneration, Necrosis & Atrophy leads to Increase, Respiratory or Squamous Metaplasia December 01, 2016 14:22
Increase, Respiratory or Squamous Metaplasia leads to Increase, Cell Proliferation December 01, 2016 14:23
Increase, Cell Proliferation leads to Increase, Mutations in Critical Genes December 03, 2016 16:38
Increase, Mutations in Critical Genes leads to Increase, Site of Contact Nasal Tumors December 01, 2016 14:34
Increase, Cell Proliferation leads to Increase, Site of Contact Nasal Tumors December 01, 2016 14:35
Vinyl acetate November 29, 2016 18:42

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

The rodent olfactory epithelium is uniquely sensitive to cytotoxicity induced by exposure to inhaled compounds. Sustained cytotoxicity of the olfactory epithelium is a common precursor for the development of nasal tumors. This AOP describes intracellular pH reduction initiation of cytotoxicity leading to the development of olfactory tumors in rodents. Increased production or reduced buffering of protons in cells comprising the olfactory epithelium that exceed homeostatic control mechanisms and cause intracellular acidification is the MIE for this AOP. Reductions in cellular pH sufficient to denature or alter key cellular apparatus (enzymes, proteins) cause cytotoxicity. Sustained cytotoxicity of cell types comprising the olfactory epithelium, (e.g. olfactory sensory neurons, sustentacular cells, Bowmans glands) causes cell death and a reduction in cell numbers/volume of cells. Tissue necrosis, degeneration (deterioration and loss of function) and atrophy (reduction in tissue mass), are observed. Sustained atrophy/degeneration leads to adaptive tissue remodeling, where cell types unique to olfactory epithelium are replaced by cell types comprising respiratory epithelium or squamous epithelium. Tissue remodeling increases cell division rates. Mutations in critical genes accumulate under the combined influences of increased cell proliferation and cytotoxicity and cellular stress, which together increase the probability of mutation. Continued cell proliferation and accumulation of mutations in critical genes eventually leads to tumors arising from regions of the nasal epithelium that normally are composed of olfactory epithelium.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 867 Decrease, Intracellular pH Decrease, Intracellular pH
KE 868 Increase, Tissue Degeneration, Necrosis & Atrophy Increase, Tissue Degeneration, Necrosis & Atrophy
KE 870 Increase, Cell Proliferation Increase, Cell Proliferation
KE 869 Increase, Respiratory or Squamous Metaplasia Increase, Respiratory or Squamous Metaplasia
KE 768 Increase, Cytotoxicity Increase, Cytotoxicity
KE 876 Increase, Mutations in Critical Genes Increase, Mutations in Critical Genes
AO 872 Increase, Site of Contact Nasal Tumors Increase, Site of Contact Nasal Tumors

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help
Title Adjacency Evidence Quantitative Understanding
Decrease, Intracellular pH leads to Increase, Cytotoxicity adjacent Moderate High
Increase, Cytotoxicity leads to Increase, Tissue Degeneration, Necrosis & Atrophy adjacent Moderate Moderate
Increase, Tissue Degeneration, Necrosis & Atrophy leads to Increase, Respiratory or Squamous Metaplasia adjacent Moderate Moderate
Increase, Respiratory or Squamous Metaplasia leads to Increase, Cell Proliferation adjacent Moderate Moderate
Increase, Mutations in Critical Genes leads to Increase, Site of Contact Nasal Tumors adjacent High Moderate
Increase, Cell Proliferation leads to Increase, Mutations in Critical Genes non-adjacent High Low
Increase, Cell Proliferation leads to Increase, Site of Contact Nasal Tumors non-adjacent High High

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help
Name
Vinyl acetate

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Characterization of the AOP, MIE and AO

Overall, the AOP and the key events comprising the AOP are well characterized experimentally. Most key events have been consistently observed in subchronic and chronic in vivo studies with one or more chemical initiators (cytotoxicity, tissue degeneration/atrophy, metaplasia, cell proliferation). The role of metabolism in the production of protons and subsequent intracellular acidification (The MEI) was established experimentally in cells and nasal tissue extracts exposed the chemical initiator vinyl acetate. By analogy, similar esters subject to ester cleavage in vivo would have some capacity for reducing intracellular pH. These include other listed chemical initiators of several key events proposed in this AOP. The adverse outcome, site of contact nasal tumors, is well understood both qualitatively and quantitatively. Tumors of this kind, and pathology of the rodent nasal tissues in general, are commonly evaluated in almost all inhalation bioassays. There are standards for describing nasal lesions, and accepted practices for quantifying them (morphometry). The general pathobiology of nasal carcinogenesis, including tumors arising from areas of olfactory epithelium, is well understood. The adverse outcome, site of contact nasal tumors, has historically been of regulatory concern for inhalation-route toxicants.

Causal Linkages between Key Events and the Outcome

  • MEI: Intracellular acidification exceeding homeostatic controls is cytotoxic to cells, the first event leading to the proposed series of tissue changes, cell proliferation, mutation and tumor development. In the absence of sustained pH reduction induced cytotoxicity, the remaining events do not occur. The event is necessary, but not sufficient, until it reaches levels that induce cytotoxicity.
  • KE1: Cytotoxicity is directly linked to the remaining key events. All subsequent events are a direct response or consequence of cytotoxicity. The incidence of the AO is zero in the absence of cytotoxicity.
  • KE2: Tissue Necrosis, Degeneration and Atrophy is directly linked to the remaining key events. All subsequent events are a direct response or consequence of this event. The incidence of the AO is zero in the absence of this key event.
  • KE3: Increased respiratory or squamous metaplasia is directly linked to the remaining key events. All subsequent events are a direct response or consequence of this event. Metaplasia induces cell division, which increases the spontaneous mutation rate and influences tumor growth. The incidence of the AO is zero in the absence of this key event.
  • KE4: Increased cell proliferation is directly linked to the remaining key events and the AO. All subsequent events are a direct response or consequence of this event. Cell proliferation increases the spontaneous mutation rate and influences tumor growth. The incidence of the AO is zero in the absence of this key event.
  • KE5: Increased mutation is directly linked development of nasal tumors. Mutation is an obligate step in carcinogenesis, and is therefore causally linked to the adverse outcome.

Limitations in the evidence in support of the AOP

Limitations in the evidence in support of the AOP are sufficiently covered in other sections of the Wiki.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Tissue, Life-stage or Species Specificity

The AOP applies to all vertebrates with olfactory epithelium, without respect to life-stage or gender.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Support for Essentiality

Support for the essentiality of the key events was provided by in vitro metabolism studies, in vitro cytotoxicity studies in cells and nasal tissue explants, concepts of multistage carcinogenesis, and a series of rodent in vivo subchronic and chronic inhalation toxicity studies:

  1. Evidence for the essentiality of metabolic proton production for pH reduction[24], and the essentiality for proton production/pH reduction for induction of cytotoxicity was provided in several vitro studies exposing olfactory and respiratory nasal tissue explants to the chemical initiator vinyl acetate[25]. Reducing metabolic production of protons reduced cytotoxicity, but scavenging acetaldehyde did not. Acetic acid, but not the other predominant cytotoxic metabolite, acetaldehyde, was shown to be cytotoxic at the tested concentrations[26].
  2. The essentiality of increased mutations secondary to cell proliferation was inferred from fundamental concepts of multistage carcinogenesis[27] and broad evidence that increased cell proliferation increases replication error and mutation rates[28]In vitro studies demonstrated that acetaldehyde was not genotoxic at non cytotoxic cell concentrations[29], supporting the inference of mutation secondary to increased cell proliferation.
  3. Evidence for the essentiality of cytotoxicity, tissue degeneration, necrosis, and atrophy and subsequent respiratory and squamous cell metaplasia was provided by subchronic and chronic in vivo rodent studies consistently showing the absence of site of contact tumors in the absence of these events[30].
  4. Evidence for the essentiality of tissue degeneration, necrosis and atrophy in the development of respiratory and olfactory metaplasia was provided by fundamental understanding of the pathobiology of metaplastic change in these tissues derived from studies nasal toxicants [31] and from multiple subchronic and chronic inhalation studies of the chemical initiator vinyl acetate [32]

Rationale for essentiality calls:

  • Intracellular Acidification: Acetic acid shown to be cytotoxic, cytotoxicity dependent on metabolic production of protons, acetaldehyde shown to be less cytotoxic than acetic acid.
  • Increased Cytotoxicity: Obligate step in increased tissue degeneration, necrosis, and atrophy. Tumors absent at non-cytotoxic exposures.
  • Increased Tissue Degeneration, Necrosis and Atrophy: Obligate step in the induction of respiratory or squamous metaplasia, which is an adaptive response to chronic tissue injury.
  • Increased Respiratory or Squamous Metaplasia: Induces division of stem cells with the potential progress from early lesions to tumors. Induces chronic cell proliferation. Tumors absent at exposures where metaplasia does not occur.
  • Increased Cell Proliferation: Mechanistically linked to increased probability of mutational events in stem cells.
  • Increased Mutation: Acquisition of specific mutations is an obligate step in tumorigenesis.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Concordance of exposure-response relationships

Exposure-response relationships for nearly all of the key events have been established in vitro and/or in vitro, in some cases in two species. The most complete set of studies establishing the exposure-response relationships have been conducted using the chemical initiator vinyl acetate.

KE1(MEI): Concentration dependent intracellular acidification has been observed in hepatocytes and olfactory tissue explants exposed in vitro to vinyl acetate[1]. Acetic acid was shown to be toxic to olfactory tissue explants in vitro[2].

KE 2,3,4: Concentration dependent increases in cytotoxicity, respiratory and squamous metaplasia and cell proliferation were observed in SD rats exposed to vinyl acetate for 65 days[33]. Increases were observed almost exclusively at tumorigenic exposure concentrations (>50 ppm).

KE 2,3,4: Concentration dependent increases in cytotoxicity, respiratory and squamous metaplasia and cell proliferation were observed in SD rats exposed to vinyl acetate for 65 days[3]. Increases were observed almost exclusively at tumorigenic exposure concentrations (>50 ppm).

KE 2,3,4: Concentration dependent increases in cytotoxicity, respiratory and squamous metaplasia were observed in SD rats and ICR mice exposured for up to 104 weeks to vinyl acetate. Increases were observed exclusively at tumorigenic exposure concentrations (200 and 600 ppm).

KE5: Concentration dependent increases in olfactory tissue cell proliferation were observed after 1 day, but not 5 or 20 days inhalation exposure to vinyl acetate in rats[4]. Sustained cell proliferation occurs after longer term exposure, but only at exposures causing toxicity and metaplasia [5].

KE6: There are no studies measuring dose-dependent increases in mutation rates secondary to cell proliferation in vivo following exposure to chemical initiators of this AOP. Increased mutation secondary to increased cell proliferation would only occur at doses inducing cell proliferation. There is strong experimental and theoretical basis for a role of cell proliferation in enhancing rates of mutation that would otherwise be managed by protective cellular controls. Together, this provides moderate evidence for a dose dependency for this key event.

KE6: In vitro dose-response data for the site of contact nasal carcinogen vinyl acetate and its metabolite acetaldehyde show no increases in adducts or mutations up to ~200 µm, concentrations higher than those attainable at tumorigenic exposures to these compounds.

KE7 (AO): Concentration dependent increases in tumors derived from olfactory epithelium were observed in a rat two-year inhalation-route bioassay[6]. Tumors only occurred at exposures > than 200 ppm.

Temporal concordance among the key events and adverse effect

The temporal relationship between the MEI, key events and the AO has been thoroughly established through in vitro and in vivo studies. The most complete data set establishing the relationship between the key events is from metabolism and toxicity studies of the chemical initiator vinyl acetate. Supporting studies comprise short term in vitro metabolism studies, in vitro adduct and mutation studies, and short (1,5, 20, 65 day) and chronic (52 and 104 week ) rodent inhalation studies. Consistency with the fundamental concepts of multiage carcinogenesis was also considered.

KE1: Intracellular acidification following exposure to vinyl acetate has been shown to occur on a time scale of seconds in hepatocytes and no more than 5 minutes for olfactory explants exposed in vitro[7]

KE2,3: A single day of exposure 600 ppm or greater concentrations of vinyl acetate is sufficient to cause cytotoxicity, tissue degeneration of the olfactory epithelium[8] in rats exposed by inhalation.

KER3: Regenerative hyperplasia of the olfactory epithelium is observed after 5, or 20 days of exposure by inhalation to vinyl acetate, but not after a single day of exposure[9].

KE4:Loss of olfactory epithelium, evidenced by reductions in olfactory marker protein stained nerve bundles, reduced tissue thickness, and loss of olfactory marker protein stained epithelium, occurs as early as 5 days in rats after inhalation exposure to vinyl acetate and continues through the latest exposure period measured, 65 days (600 and 1000 ppm)[10]. By day 65, markers of olfactory tissue are absent at exposures equal to or greater than 600 ppm. This indicates metaplastic change from olfactory epithelium to a respiratory or squamous epithelial cell type.

KE5: Evidence of respiratory metaplasia in the form of appearance of AB/PAS positive mucoussubstances in areas of olfactory epithelium occurs as early as 5 days of exposure to greater than or equal to 200 ppm vinyl acetate[11].

KE5: Increases in cell proliferation in the olfactory epithelium following inhalation exposure to concentrations of vinyl acetate greater than 50 ppm occur after 1[12], 5, 20 and 65 exposures (90 day study)[13]. Cell proliferation is temporally related to tissue regeneration (resolving as hyperplasia or olfactory to respiratory epithelial transitioning) secondary to cytotoxicity.

KE7: Tumors arising from areas of the olfactory epithelium are observed after 104 weeks of exposure to vinyl acetate, but not after subchronic exposures of 28-90 days[14].

Strength, consistency, and specificity of association of final adverse outcome and MIE

The experimental evidence and pathophysiological basis for the association between the MIE (pH reduction) and the sequence of events leading to the AO is overall very strong. Each key event, with the exception of mutation, has been demonstrated using at least one chemical initiator in the target tissue (olfactory epithelium). Some or all of the key events have been observed in three in vivo studies, demonstrating consistency. Consistent dose-response data for almost all of the key events in vitro and in vivo in the selected target cells/tissues provide strong evidence in support of the postulated AOP and the linkages between the key events. Several reviews and other reports provide good summaries of the strength of the data[15]. While pH reduction is probable in any tissue where metabolic production of protons exceed homeostatic control, evidence supports this MIE in the olfactory epithelium, which appears more susceptible compared to other epithelial tissue types in the nose[16].

Biological plausibility, coherence, and consistency of the experimental evidence

In general, the biological plausibility and coherence of the linkages between pH reduction and site of contact tumors of the olfactory epithelium expressed in this AOP is very robust. More than two decades of research support the key events and key event relationships comprising the AOP. The AOP is consistent with our broad understanding of the pathobiology of the rodent nasal tissues following inhalation of toxicants[17], consistent with the concepts of multistage carcinogenesis[18], and consistent with the weak genotoxicity and cytotoxicity of acetaldehyde and high toxicity of acetic acid and pH reduction[19]. The coherence and consistency of the experimental data in support of the AOP was discussed in the section “Strength, consistency and specificity of the association of final adverse outcome and MIE”

Alternative mechanism(s)

Within the context of this AOP, the key events are well substantiated. The only additional or alternative mechanistic element that could be considered is a role for DNA alkylation in the key event “increased mutation.” For some chemical initiators, for example those that reduce pH and produce an alkylating agent, it is possible a direct mutational key event is also operative. DNA alkylation was not considered a key event in this AOP, which focuses on initiators that do not produce alkylating agents, or where there is evidence that DNA alkylation sufficient to cause mutation does not occur (e.g. vinyl acetate).

This AOP proposes pH reduction as one of many plausible MEI’s leading to the first of the five key events leading to site of contact olfactory epithelial tumors. Chemicals that cause site of contact tumor of the olfactory epithelium, but do not cause pH reduction, may have other MEI’s. For example, formaldehyde causes site of contact tumors in the olfactory epithelium, also involving cytotoxicity and metaplasia, but may trigger the initial cytotoxicity through alkylative damage. Acetaldehyde shows a similar set of key events and produces tumors of the olfactory epithelium, and produces both alkylative damage and has the potential to produce protons upon metabolism. In the latter case, both pH reduction and alkylative damage are plausible MEI’s. However, it was shown in olfactory and respiratory tissue explants that pH reduction was more cytotoxic than acetaldehyde exposure[20], suggesting that for the current AOP, pH reduction is the operative MEI.

In general, we expect that the key events of and the AO of this AOP will be linked to additional chemical initiators via different MEIs leading to cytotoxicity and the subsequent key events.

Uncertainties, inconsistencies and data gaps

There are two data gaps which impact the overall strength of the AOP. First, while there is a strong theoretical and broad experimental support for the influence of cell proliferation rates on spontaneous mutation, there are no specific data on this key event/key event relationship for the chemical initiators of the AOP (vinyl acetate, ethyl acetate, methyl methacrylate, etc. Second, there are no in vivo data demonstrating increases in mutations leading to tumors arising in the olfactory epithelium. This uncertainty should be viewed in the context of our understanding of carcinogenesis, in which the presence of tumors is a biomarker of cellular mutation.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

There is a rich data set providing substantial support for establishing quantitative relationships between exposure to the chemical initiator and each of the MIE and key events and the AO. These are detailed in the dose concordance table(s). Studies reported in the tables provide quantitative data for each of the key events[21].

Data establishing the quantitative relationship between any two key events, is incomplete, in part because of the semi-qualitative nature of pathology data for key events measured in whole animal studies. For example, while the linkage between cytotoxicity and necrosis, degeneration and atrophy is clear, the available data are not sufficient to determine a specific threshold for cytotoxicity that would trigger significant tissue degeneration. More qualitative relationships can be readily described as the extent of cytotoxicity and tissue degeneration observed. There is no quantitative data establishing the number or relative increase in indirect mutations leading to site of contact tumors of the nasal cavity. There are several quantitative relationships that have been described for key events that are critical to this AOP. For example, estimates of proton production and tissue pH change associated with cellular cytotoxicity have been described[22]. Thresholds for several key events, each related to a threshold for cytotoxicity, have been described for the chemical initiator vinyl acetate[23].

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help
  1. ↑ Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326, Lantz, Orozco and Bogdanffy (2003). Vinyl acetate decreases intracellular pH in rat nasal epithelial cells. Toxicol Sci. 75: 423-431
  2. ↑ 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
  3. ↑ Hotchkiss, Krieger, Harkema and Mahoney (2014). 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, The Dow Chemical Company
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326, Lantz, Orozco and Bogdanffy (2003). Vinyl acetate decreases intracellular pH in rat nasal epithelial cells. Toxicol Sci. 75: 423-431
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ Bogdanffy, Gladnick, Kegelman and Frame (1997). Cell proliferation responses in rat nasal eipithelium following repeated exposures to vinly acetate vapor. Inhalation Toxicology. 9: 331-350, 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
  15. ↑ Bogdanffy, Sarangapani, Plowchalk, Jarabek and Andersen (1999). A biologically based risk assessment for vinyl acetate-induced cancer and noncancer inhalation toxicity. Toxicol Sci. 51: 19-35, Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326, Bogdanffy and Valentine (2003). Differentiating between local cytotoxicity, mitogenesis, and genotoxicity in carcinogen risk assessments: the case of vinyl acetate. Toxicol Lett. 140-141: 83-98
  16. ↑ Hardisty, Garman, Harkema, Lomax and Morgan (1999). Histopathology of nasal olfactory mucosa from selected inhalation toxicity studies conducted with volatile chemicals. Toxicol Pathol. 27: 618-627
  17. ↑ Hardisty, Garman, Harkema, Lomax and Morgan (1999). Histopathology of nasal olfactory mucosa from selected inhalation toxicity studies conducted with volatile chemicals. Toxicol Pathol. 27: 618-627
  18. ↑ Weisburger (1978). Mechanisms of chemical carcinogenesis. Annu Rev Pharmacol Toxicol. 18: 395-415, Cohen and Ellwein (1991). Genetic errors, cell proliferation, and carcinogenesis. Cancer Res. 51: 6493-6505, Pitot (1993). Multistage carcinogenesis--genetic and epigenetic mechanisms in relation to cancer prevention. Cancer Detection & Prevention. 17: 567-573, Cohen (1995). Role of cell proliferation in regenerative and neoplastic disease. Toxicol Lett. 82-83: 15-21, Bertram (2000). The molecular biology of cancer. Mol Aspects Med. 21: 167-223
  19. ↑ Lantz, Orozco and Bogdanffy (2003). Vinyl acetate decreases intracellular pH in rat nasal epithelial cells. Toxicol Sci. 75: 423-431
  20. ↑ Lantz, Orozco and Bogdanffy (2003). Vinyl acetate decreases intracellular pH in rat nasal epithelial cells. Toxicol Sci. 75: 423-431
  21. ↑ 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, Albertini (2013). Vinyl acetate monomer (VAM) genotoxicity profile: relevance for carcinogenicity. Crit Rev Toxicol. 43: 671-706, Budinsky, Gollapudi, Albertini, Valentine, Stavanja, Teeguarden, Fensterheim, Rick, Lardie, McFadden, Green and Recio (2013). Nonlinear responses for chromosome and gene level effects induced by vinyl acetate monomer and its metabolite, acetaldehyde in TK6 cells. Environ Mol Mutagen. 54: 755-768, 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
  22. ↑ 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, Albertini (2013). Vinyl acetate monomer (VAM) genotoxicity profile: relevance for carcinogenicity. Crit Rev Toxicol. 43: 671-706, Budinsky, Gollapudi, Albertini, Valentine, Stavanja, Teeguarden, Fensterheim, Rick, Lardie, McFadden, Green and Recio (2013). Nonlinear responses for chromosome and gene level effects induced by vinyl acetate monomer and its metabolite, acetaldehyde in TK6 cells. Environ Mol Mutagen. 54: 755-768, 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
  23. ↑ Bogdanffy, Sarangapani, Plowchalk, Jarabek and Andersen (1999). A Biologically-Based Risk Assessment for Vinyl Acetate-Induced Cancer and Non-Cancer Inhalation Toxicity. Toxicological Sciences. 51: 19-35, Bogdanffy, Plowchalk, Sarangapani, Starr and Andersen (2001). Mode-of-action-based dosimeters for interspecies extrapolation of vinyl acetate inhalation risk. Inhal Toxicol. 13: 377-396
  24. ↑ Bogdanffy (2002). Vinyl acetate-induced intracellular acidification: implications for risk assessment. Toxicol Sci. 66: 320-326, Lantz, Orozco and Bogdanffy (2003). Vinyl acetate decreases intracellular pH in rat nasal epithelial cells. Toxicol Sci. 75: 423-431
  25. ↑ 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
  26. ↑ 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
  27. ↑ Bertram (2000). The molecular biology of cancer. Mol Aspects Med. 21: 167-223, Hanahan and Weinberg (2000). The hallmarks of cancer. Cell. 100: 57-70
  28. ↑ Preston-Martin, Pike, Ross, Jones and Henderson (1990). Increased cell division as a cause of human cancer. Cancer Res. 50: 7415-7421, Cohen, Purtilo and Ellwein (1991). Ideas in pathology. Pivotal role of increased cell proliferation in human carcinogenesis. Mod Pathol. 4: 371-382
  29. ↑ Albertini (2013). Vinyl acetate monomer (VAM) genotoxicity profile: relevance for carcinogenicity. Crit Rev Toxicol. 43: 671-706, Budinsky, Gollapudi, Albertini, Valentine, Stavanja, Teeguarden, Fensterheim, Rick, Lardie, McFadden, Green and Recio (2013). Nonlinear responses for chromosome and gene level effects induced by vinyl acetate monomer and its metabolite, acetaldehyde in TK6 cells. Environ Mol Mutagen. 54: 755-768
  30. ↑ 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
  31. ↑ Hardisty, Garman, Harkema, Lomax and Morgan (1999). Histopathology of nasal olfactory mucosa from selected inhalation toxicity studies conducted with volatile chemicals. Toxicol Pathol. 27: 618-627
  32. ↑ 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
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