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Relationship: 3507

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, pulmonary edema

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, pulmonary edema

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
Inhibition, cytochrome oxidase leads to Increased, pulmonary edema	adjacent	High		John Frisch (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 Do not cite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
humans	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

In the lungs, increases in cell death lead to increased pulmonary edema, or buildup of fluid in lungs. Damage to the alveolar epithelium layer leads to fluid leakage resulting in fluid buildup in lungs (Herrero et al. 2018).

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 pulmonary edema in mammals, in support of development of AOP 573 for Goyak and Lewis (2021) content.

Authors of KER 3507 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 pulmonary edema have been investigated by addition of toxicants to induce trauma in laboratory mammals. Evidence from histological studies show a consistent response in increased cell death leading to increased pulmonary edema. In human subjects, pulmonary edema has been studied clinically in patients that have suffered traumatic injury from a variety of events, leading to cell death.

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 pulmonary edema?	Summary	Citation
Laboratory rats (Rattus norvegicus)	14 day	148 umol/L 3-methylfuran for 1 hour.	yes	yes	CD/CR rats exposed to 3-methylfuran had increased lung cell death starting at day 1, leading to pulmonary edema starting at day 3.	Haschek et al. (1983)
Laboratory mice (Mus musculus)	360 hours	0.5 g/kg body weight 3-methylindole via intraperitoneal injection.	yes	yes	Male CD-1 mice exposed to 3-methylindole had damage beginning at hour 2, with increased lung cell death, leading to pulmonary edema most severe at 24-48 hours.	Durham and Castleman (1985)
Laboratory rats (Rattus norvegicus)	4 hours	525-559 mg/m3 hydrogen sulfide for 4 hours, 14 days after half rats subcutaneously injected with 150 mg/kg body weight capsaicin.	yes	yes	Male Fisher 344 rats exposed to hydrogen sulfide and capsaicin had statistically significant lung cell death after 4 hours, leading to all rats exposed to hydrogen sulfide exhibiting pulmonary edema.	Prior et al. (1990)

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 lungs.

Sex: Applies to both males and females.

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

References

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

Durham, S.K. and Castleman W.L. 1985. Pulmonary lesions induced by 3-methylindole in mice. American Journal of Pathology 121(1): 128–137.

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.

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.

Herrero, R., Sanchez, G., and Lorente, J.A. 2018. New insights into the mechanisms of pulmonary edema in acute lung injury. Annals of Translational Medicine 6(2):32.

Prior, M., Green, F., Lopez, A., Balu, A., De Sanctis, G.T., and Fick, G. 1990. Capsaicin pretreatment modifies hydrogen sulphide-induced pulmonary injury in rats. Toxicologic Pathology 18(2): 279– 288.