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Relationship: 3355

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

Demyelination, increased leads to Delayed neuropathy, increased

Upstream event

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

Demyelination, increased

Downstream event

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

Delayed neuropathy, increased

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 of neuropathy target esterase leading to delayed neuropathy via lysolecithin cell membrane integration	adjacent	High		Brooke Bowe (send email)	Under development: Not open for comment. Do not cite
Inhibition of neuropathy target esterase leading to delayed neuropathy via increased inflammation	adjacent	High		Brooke Bowe (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 Do not cite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
Homo sapiens	Homo sapiens		NCBI

Sex Applicability

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

Sex	Evidence
Unspecific

Life Stage Applicability

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

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

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

Literature reviews were conducted by searching through databases including PubMed and Google Scholar. Search terms included “organophosphates”, “OPIDN”, “OPIDP”, and “delayed neuropathy” used in combination with a variety of phrases such as “enzyme inhibition”, “demyelination”, “demyelinating lesions”, “weakness”, and “endogenous substrate.” After establishment of the general outline for the AOP, search terms broadened to commonly include the words “neuropathy target esterase”, “irreversible aging”, “lysolecithin”, “lysophosphatidylcholine”, “inflammation”, “chemokines”, “surfactant”, “membrane disruption”, “oligodendrocyte susceptibility”, and “oligodendrocyte death.” Exclusion criteria included publications that focused on nervous tissue damage that did not involve changes to oligodendrocytes or myelin considering that this pathway focused on a single mechanism of a larger overall AOP network, and the goal was to specifically focus on progression of demyelination causing delayed neuropathy. Additional resources were also identified in the references of publications explored during database searches and were used to further develop KEs.

Evidence Supporting this KER

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

Modified Marchi staining of spinal cord slices from hens administered the organophosphate chemicals diisopropyl fluorophosphate (DFP), mipafox, or TOCP orally or via subcutaneous injections noted that animals presenting with a late paralysis that occurred 2-3 weeks after exposure also had demyelinating lesions that were especially apparent in the spinal cord (Barnes & Denz, 1953). Further analysis of the most affected regions in the spinal cord track indicates that regions of demyelination correspond with nerve tracts of both sensory and motor nerves, which could help explain the presentation of symptoms. For example, as seen in figure 5A there is a concentration of demyelination around the posterior median fissure in a region thought to correspond to the gracile fasciculus in humans, which is a sensory spinal cord tract. Meanwhile figure 5B displays focused demyelination laterally in the spinocerebellar tract of hens, which corresponds to proprioception and motor functions and has homologous structures in humans (Barnes & Denz, 1953).

Figure 5: Marchi method staining for demyelination following organophosphate administration in hens, wherein dark stains represent demyelination. (A) Upper dorsal cord, showing demyelination of gracile fasciculus in posterior columns; (B) upper cervical cord, showing damaged fibers grouped in lateral columns. Image adapted from: (Barnes & Denz, 1953).

Similar results were seen in studies using mallards orally administered the organophosphates ethyl p-nitrophenyl phenylphosphorothioate (EPN) or leptophos, which indicated that demyelinating lesions and clinical OPIDN symptoms are closely related. In this second study, evidence supporting the biological plausibility of this KER is notably apparent as the severity of demyelination has a linear relationship not only to the administered dose of EPN but also to the number of ducks exhibiting ataxia or paralysis.

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

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

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

While no test animals displayed neuropathy symptoms at the lowest dose, this concentration was capable of producing barely detectable demyelination. At higher doses, delayed neuropathy was present in all test animals along with clear evidence of demyelination (Hoffman, Sileo, & Murray, 1984). This appears to suggest that demyelination occurs as a first step and at lower exposure doses before being followed by neuropathy at higher doses dependent upon the initial demyelination.

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

References

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

Barnes, J. M., & Denz, F. A. (1953). Experimental demyelination with organo-phosphorus compounds. Journal of Pathology and Bacteriology, 65(2), 597-605.

Hoffman, D. J., Sileo, L., & Murray, H. C. (1984). Subchronic organophosphorus ester-induced delayed neurotoxicity in mallards. Toxicology and Applied Pharmacology, 75(1), 128-136.