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Relationship: 3346

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

Decreased, Plasma sodium concentrations leads to Decreased, blood plasma volume

Upstream event

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

Decreased, Plasma sodium concentrations

Downstream event

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

Decreased, blood plasma volume

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
Decreased Sodium/Potassium ATPase activity leads to Heart failure	adjacent	High	Not Specified	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 Do not cite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
fish	fish	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

Decreased blood sodium plasma concentrations lead to decreased blood plasma volume through osmotic relationships in which fluid moves from a lower concentration solution to a higher concentration solution. As a major ion component of blood (Wichmann and Althaus 2020), plasma sodium concentrations are important in maintaining fluid concentration balance between blood and surrounding tissues. When blood plasma sodium concentrations decrease, ion concentrations in blood are lower than the surrounding tissue, causing water to flow into surrounding tissues, and causing a decrease in blood plasma volume.

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. Brix et al. (2022) focused on identifying Adverse Outcome Pathways associated with chronic copper exposure in aquatic vertebrates through review of existing literature, and provided initial network analysis.

Cited empirical studies are focused on blood sodium plasma concentrations and resulting decreased blood plasma volume in freshwater fish, in support of development of AOP 539 for Brix et al. (2022) content. Mechanisms of osmoregulation and the relationship between ion concentrations and fluid volumes, with sodium as an important ion contributor, refer to the active regulation of fluid volume and concentration of ions.

Authors of KER 3346 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

The relationship between blood sodium plasma concentrations and blood plasma volume has been studied in relation to movement associated with osmotic gradients, as well as active transport using adenosine triphosphate to move sodium across membranes against its electrochemical gradient. Through toxicant and electrophysical studies, evidence shows that decreases in blood sodium plasma concentrations lead to decrease in blood plasma volume. Hematocrit values are often used as an indirect measure of blood plasma volume based on the volume of red blood cells in total blood volume (Gordon et al. 2003).

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	Decreased sodium plasma concentration?	Decreased blood plasma volume?	Summary	Citation
Rainbow trout (Oncorhynchus mykiss)	24 hours	4.9 umol/L copper	yes	yes	Adult trout showed statistically significant decreased sodium plasma concentrations and resulting decreased plasma volume inferred by statistically significant increased hematocrit.	Wilson and Taylor (1993)
Rainbow trout (Oncorhynchus mykiss)	6 days	10.9 ug/L silver nitrate	yes	yes	Adult trout showed statistically significant decreased sodium plasma concentrations and resulting decreased plasma volume.	Wood et al. (1996)
Rainbow trout (Oncorhynchus mykiss)	6 days	9.2 ug/L silver nitrate.	yes	yes	Adult trout showed statistically significant decreased sodium plasma concentrations and resulting decreased plasma volume.	Webb and Wood (1998)
Carp (Cyprinus carpio)	96 hours	100 ug/L copper nitrate.	yes	yes	Juvenile carp showed statistically significant decreased sodium plasma concentrations and resulting decreased plasma volume inferred by statistically significant increased hematocrit.	De Brouck et al. (2001)
Rainbow trout (Oncorhynchus mykiss)	60 hours	20,40,80 ug/L aluminum chloride, low pH 5.1.	yes	yes	Rainbow trout showed dose dependence to exposure, at low pH and 80 ug/L statistically significant decreased sodium plasma concentrations and resulting decreased plasma volume inferred by statistically significant increased hematocrit.	Dussault et al. (2001)
Curimbata (Prochilodus scrofa)	96 hours	20, 25, 29 ug/L copper sulfate	yes	yes	Curimbata showed dose-dependence to exposure, at 25, 29 ug/L statistically significant decreased sodium plasma concentrations and resulting decreased plasma volume inferred by statistically significant increased hematocrit.	Mazon et al. (2002)

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.

Sex: Applies to both males and females.

Taxonomic: Freshwater true chordates, with evidence primarily from fish.

References

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

Brix, K.V., De Boeck, G., Baken, S., and Fort, D.J. 2022. Adverse Outcome Pathways for Chronic Copper Toxicity to Fish and Amphibians. Environmental Toxicology and Chemistry 41(12): 2911-2927.

De Boeck, G., Vlaeminck, A., Balm, P.H.M., Lock, R.A.C., De Wachter, B., and Blust, R. 2001. Morphological and metabolic changes in common carp, Cyprinus carpio, during short-term copper exposure: Interactions between Cu2+ and plasma cortisol elevation. Environmental Toxicology and Chemistry 20(2): 374–381.

Dussault, E.B., Playle, R.C., Dixon, D.G., McKinley, R.S. 2001. Effects of sublethal, acidic aluminum exposure on blood ions and metabolites, cardiac output, heart rate, and stroke volume of rainbow trout, Oncorhynchus mykiss. Fish Physiology and Biochemistry 25: 347–357.

Gordon, C.J., Fogarty, A.L., Greenleaf, J.E., Taylor, N.A.S., and Stocks, J.M. 2003. Direct and indirect methods for determining plasma volume during thermoneutral and cold-water immersion. European Journal of Applied Physiology 89: 471–474.

Mazon, A.F., Monteiro, E.A.S., Pinheiro, G.H.D., and Fernandes, M.N. 2002. Hematological and physiological changes induced by short-term exposure to copper in the freshwater fish, Prochilodus scrofa. Brazilian Journal of Biology 62(4A): 621-631.

Webb, N.A. and Wood, C.M. 1998. Physiological analysis of the stress response associated with acute silver nitrate exposure in freshwater rainbow trout (Onchorhynchus mykiss). Environmental Toxicology and Chemistry 17(4): 579–588.

Wichmann, L. and Althaus, M. 2020. Evolution of epithelial sodium channels: current concepts and hypotheses. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 319: R387–R400.

Wilson, R.W. and Taylor, E.W. 1993. The physiological responses of freshwater rainbow trout, Oncorhynchus mykiss, during acutely lethal copper exposure. Journal of Comparative Physiology B 163:38-47.

Wood, C.M., Hogstrand, C., Galvez, F., and Munger, R.S. 1996. The physiology of waterborne silver toxicity in freshwater rainbow trout (Oncorhynchus mykiss) 1. The effects of ionic Ag+. Aquatic Toxicology 35: 93-109.

NOTE: Italics indicate edits from John Frisch September 2024.