This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 3504

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase, Cell death leads to Increased, nasal lesions

Upstream event

The causing Key Event (KE) in a Key Event Relationship (KER). More help

Increase, Cell death

Downstream event

The responding Key Event (KE) in a Key Event Relationship (KER). More help

Increased, nasal lesions

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name	Adjacency	Weight of Evidence	Quantitative Understanding	Point of Contact	Author Status	OECD Status
Cytochrome oxidase inhibition leading to increased nasal lesions	adjacent	High		Katy Goyak (send email)	Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. More help

Term	Scientific Term	Evidence	Link
rodents	rodents	High	NCBI
human	Homo sapiens	High	NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help

Sex	Evidence
Unspecific	High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER. More help

Term	Evidence
All life stages	High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Increases in cell death, when localized in the nasal tissue (or olfactory rosettes if specific to olfaction), lead to an increased number of nasal lesions, or injury at the organ level. Among the nasal lesions that are frequently observed are hyperplasia, metaplasia, degeneration, and inflammation (Hardisty et al. 1999; Harkema et al. 2006). Preference is given to document location and tissue layer of the injury (Hardisty et al. 1999; Harkema et al. 2006).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings. Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

This Key Event Relationship was developed as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. Goyak and Lewis (2021) focused on identifying Adverse Outcome Pathways that linked hydrogen sulfide exposure to adverse outcomes by using a comparative weight of evidence assessment from selected advisory agency reviews, and provided initial network analysis.

Cited empirical studies are focused on increased cell death and resulting increased nasal lesions in mammals, in support of development of AOP 368 for Goyak and Lewis (2021) content.

Authors of KER 3504 did a further evaluation of published peer-reviewed literature to provide additional evidence in support of the key event relationship.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Biological Plausibility

Addresses the biological rationale for a connection between KEupstream and KEdownstream. This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured. More help

Increased cell death and resulting increased nasal lesions have been investigated by addition of toxicants to induce trauma in laboratory mammals, with a marked preference for inhaled toxicants in order to focus injury on nasal tissues. Evidence from histological studies show a consistent response in increased cell death leading to increased nasal lesions.

Empirical Evidence

Provides specific (citable) evidence that supports the idea of a change in the upstream KE (KEupstream) leading to, or being associated with, a subsequent change in the downstream KE (KEdownstream), assuming the perturbation of KEupstream is sufficient. More help

Species	Duration	Dose	Increase cell death?	Increase nasal lesions?	Summary	Citation
Laboratory rats (Rattus norvegicus) and mice (Mus musculus)	13 weeks	1, 5, 25 ppm 1,2-dibromo-3-chloropropane; 3, 15, 75 ppm 1,2-Dibromoethane each 6 hours per day, 5 days per week.	yes	yes	Rats and mice had increased nasal cell death at the highest concentration (25 ppm 1,2-dibromo-3-chloropropane; 75 ppm 1,2-Dibromoethane) leading to increased nasal lesions; severity of response was dose related with increased frequency of nasal lesions (cytomegaly, focal hyperplasia, squamous metaplasia, loss of cilia) as concentration increased.	Reznik et al. (1980)
Laboratory rats (Rattus norvegicus)	14 days	148 umol/L 3-methylfuran for 1 hour.	yes	yes	CD/CR rats exposed to 3-methylfuran had increased nasal cell death starting at 1 day, leading to increased nasal lesions (stratified squamous epithelial metaplasia, swollen and disintegrating epithelial lining, fibrous exudation) starting at day 3.	Haschek et al. (1983)
Laboratory rats (Rattus norvegicus) and mice (Mus musculus)	5 days	9.1 ppm chlorine for 6 hours per day.	yes	yes	Male rats and mice had increased nasal cell death leading to increased nasal lesions (cellular exfoliation, erosion, ulceration, squamous metaplasia) at day 1, day 3, day 5.	Jiang et al. (1983)
Laboratory rats (Rattus norvegicus)	9 days, 2 years	175 ppm Dimethylamine for 6 hours per day	yes	yes	Male F-344 rats in both acute (9 day) and chronic (2 year) study had increased nasal cell death leading to increased nasal lesions (respiratory metaplasia, fenestration, erosion, mucostasis, ciliastasis).	Gross et al. (1987)

Uncertainties and Inconsistencies

Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references. More help

Quantitative Understanding of the Linkage

Captures information that helps to define how much change in the upstream KE, and/or for how long, is needed to elicit a detectable and defined change in the downstream KE. More help

Response-response Relationship

Provides sources of data that define the response-response relationships between the KEs. More help

Time-scale

Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help

Known Feedforward/Feedback loops influencing this KER

Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Life Stage: Applies to all life stages after development of the nose.

Sex: Applies to both males and females.

Taxonomic: Primarily studied in humans and laboratory rodents. Plausible for most mammals due to similar nose architecture.

References

List of the literature that was cited for this KER description. More help

Goyak, K.O. and Lewis, R.J. 2021. Application of adverse outcome pathway networks to integrate mechanistic data informing the choice of a point of departure for hydrogen sulfide exposure limits. Critical Reviews in Toxicology 51(3): 193-208.

Gross, E.A., Patterson, D.L., and Morgan, K.T. 1987. Effects of acute and chronic dimethylamine exposure on the nasal mucociliary apparatus of F-344 rats. Toxicology and Applied Pharmacology 90(3): 359-376.

Hardisty, J.F, Garman, R.H., Harkema, J.R., Lomax, L.G., and Morgan, K.T. 1999. Histopathology of nasal olfactory mucosa from selected inhalation toxicity studies conducted with volatile chemicals. Toxicologic Pathology 27(6): 618–627.

Harkema, J.R., Carey, S.A., and Wagner, J.G. 2006. The nose revisited: a brief review of the comparative structure, function, and toxicologic pathology of the nasal epithelium. Toxicologic Pathology 34(3): 252–269.

Haschek, W.M., Morse, C.C., Boyd, M.R., Hakkinen, P.J., and Witschi, H.P. 1983. Pathology of acute inhalation exposure to 3-methylfuran in the rat and hamster. Experimental and Molecular Pathology 39: 342-354.

Jiang, X.Z., Buckley, L.A., and Morgan, K.T. 1983. Pathology of toxic responses to the RD50 concentration of chlorine gas in the nasal passages of rats and mice. Toxicology and Applied Pharmacology 71: 225-236.

Reznik, G., Stinson, S.F., and Ward, J.M. 1980. Respiratory pathology in rats and mice after inhalation of 1,2-dibromo-3-chloropropane or 1,2 dibromoethane for 13 weeks. Archives of Toxicology 46(3-4): 233-240.

NOTE: Italics indicate edits from John Frisch March 2025. A full list of updates can be found in the Change Log on the View History page.