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Relationship: 3290

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, Abnormal osmoregulation leads to Increased, Blood viscosity

Upstream event

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

Increase, Abnormal osmoregulation

Downstream event

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

Increased, Blood viscosity

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

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
Animals	Metazoa	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 this key event relationship we are focused on abnormal osmoregulation and increased blood viscosity. Plasma osmoregulation involves active and passive transport of ions and fluid volume from movement of water across membranes in response to ion concentration gradients. A loss of fluid or increased red blood cells, white blood cells, and blood proteins results in increased blood viscosity., Increase in red blood cells is often assessed by hematocrit as the volume of red blood cells in total blood volume.

Cited empirical studies are focused on osmoregulation and blood viscosity in freshwater fish, in support of development of AOP 539 for Brix et al. (2022) content. The mechanisms of ion transport and fluid dynamics in osmoregulation are present throughout the animal kingdom, with a consistent relationship between fluid volume and blood viscosity.

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.

Authors of KER 3290 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 osmoregulation and blood viscosity has been studied in relation to regulation of ion concentrations and transport across membranes, with related changes to fluid volume and resulting blood viscosity. Due to osmotic gradients, there is a well-established relationship between ion concentrations and the movement of fluids, with resulting increases in blood viscosity due to loss of fluids. Additionally, viscosity is known to increase based on increases in red blood cells, white blood cells, and plasma proteins.

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	Increased abnormal osregulation?	Increased blood viscosity?	Summary
Rainbow trout (Oncorhynchus mykiss)	24 hours	4.9 umol/L copper	yes	yes	Adult trout showed abnormal osmoregulation with statistically significant decreased plasma sodium and chloride and increased plasma potassium, calcium, magnesium, and ammonium concentrations and resulting increased blood viscosity with statistically significant increased hematocrit.
Carp (Cyprinus carpio)	96 hours	100 ug/L copper nitrate.	yes	yes	Juvenile carp showed abnormal osmoregulation with statistically significant decreased plasma osmolarity, sodium, potassium, and calcium concentrations and resulting increased blood viscosity with statistically significant increased hematocrit.
Rainbow trout (Oncorhynchus mykiss)	60 hours	20,40,80 ug/L aluminum chloride, low pH 5.1.	yes	yes	Rainbow trout showed dose dependent abnormal osmoregulation to exposure, at low pH and 80 ug/L statistically significant decreased sodium plasma, chloride and calcium concentrations and increased potassium, lactose and glucose and resulting increased blood viscosity with statistically significant increased hematocrit at low pH and 80 ug/L and up to 60% increased blood viscosity.
Curimbata (Prochilodus scrofa)	96 hours	20, 25, 29 ug/L copper sulfate	yes	yes	Curimbata showed dose-dependent abnormal osmoregulation to exposure, at 25, 29 ug/L statistically significant decreased sodium plasma concentrations, chloride at all concentrations and increased potassium at 29 ug/L and resulting increased blood viscosity with statistically significant increased hematocrit at 25, 29 ug/L.

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; not specific to any life stage.

Sex: Applies to both males and females; not sex-specific.

Taxonomic: Present broadly in animals that have blood as a circulatory fluid.

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. Lauren, D.J. and McDonald, D.G. 1985. Effects of copper on branchial ionoregulation in the rainbow trout, Saimo gairdneri Richardson: Modulation by water hardness and pH. Journal of Comparative Physiology B 155: 635-644.

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.

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.

NOTE: Italics indicate edits from John Frisch.