Review:OECD EAGMST March, 2015 - Aop:25

From AOP-Wiki
Jump to: navigation, search

AOP Information


Reviewers

Primary Reviewer (PR): Name: Taisen Iguchi; OECD Country/Org.: Japan; Email: taisen@nibb.ac.jp

Date review completed:

April 20, 2015

Secondary reviewer 1 (SR1) Name: Tom Knudsen; OECD Country/Org.: US; Email: knudsen.thomas@epa.gov

Date review completed:

April 16, 2015

Secondary reviewer 2 (SR2) Name: Bette Meek; OECD Country/Org.: Canada; Email: bmeek@uottawa.ca

Date review completed:


Review

Section 1:

AOP identifier/Title

Does the name of the AOP follow the right convention (MIE or first KE leading to AO)?

Does the name of the AOP reflect its content/domain?

Responses

PR:

Yes

SR1:

Yes: the name of the AOP follows the right convention with MIE first (aromatase inhibition) as a KE leading to AO (reproductive dysfunction (in fish)). The fish qualifier is added to this AOP, but not others in the bundle. The name reflects content/domain, although I have a comment about terminology 'reproductive dysfunction'. Abstract uses different terms from the OECD fish reproduction arsenal (cumulative fecundity, reproductive impairment). Fish population trends would be ultimately be adversely affected by inhibition of aromatase activity, and I wonder if they should title the AO from apical endpoints in the OECD 229 or OECD 2012 assays.

SR2:

Yes

Author response:

I agree with the reviewer's comment regarding the title. The key event of reproductive dysfunction could encompass a variety of different endpoints and measurements including cumulative fecundity, fertility, spawning, etc. This is part of the reason the actual KE/AO title was defined more specifically as cumulative fecundity and spawning. Reproductive dysfunction was used in the title as a bit of a bridge between the individual level AO of reduced cumulative fecundity and spawning and the population-level AO of population trajectory, decrease. The title could be revised to match more precisely with the KE title, but this should probably be coordinated through the wiki-gardeners.



Section 2:

Authors

Is it clear who the authors/developers of the AOP are?

Contact information for one or more corresponding author(s) should be included.

Responses

PR:

Yes

SR1:

Yes: one author is listed.

SR2:

Yes

Author response:


Section 3:

Date of updating

Reviewer should indicate the date stamp on the PDF snapshot under review.

Responses

PR:

2/27/2015

SR1:

2/27/2015

SR2:

2/27/2015

Author response:


Section 4:

Abstract

Does the abstract concisely describe the main content of the AOP?

Responses

PR:

Yes

SR1:

The Abstract is brief, organized around OECD 229 and OECD 2012 assays for fish populations. Variance in terminologies with the title were noted above. Although dysfunction and impairment can perhaps be used interchangeably, if 'reproductive dysfunction' is to remain in the title, then the Abstract should elaborate on its relationship to 'cumulative fecundity', which seems to be the actual AO in this AOP.

SR2:

Yes

Author response:

The text of the abstract was revised slightly to draw a stronger linkage between the term reproductive dysfunction and the focus of the KE and abstract on cumulative fecundity.


Section 5:

Molecular Initiating Event

Is a MIE described? If yes, then:

Is the MIE description clear and is it biologically plausible?

Is the MIE described in a way that allows its use in other AOPs?

Are measurement/prediction methods specified and adequately described/referenced?

Is the biological context (inc. taxonomic applicability/relevance, level of biological organisation) specified and explained sufficiently?

Have chemical initiators (prototypical chemicals or chemical features) been identified?

Responses

PR:

Yes to all.

SR1:

Yes: MIE described is inhibition of fish CYP19 (specifically cyp19a1a in fish). There is good detail on the mechanism of xenobiotic inhibition, as well as the cellular target (ovarian granulosa cells).

SR2:

Yes to all.

Author response:

Key Events

Are the KE descriptions clear on how the events work and are they biologically plausible?

Are the KEs described in a way that allows their reuse in other AOPs?

Are measurement methods specified and adequately described/referenced?

Is the biological context (inc. taxonomic applicability/relevance, level of biological organisation) specified and explained sufficiently?

Responses

PR:

Yes to all.

SR1:

Yes: 6 KEs are listed. They are well-established and linearly arranged in a logical order, extensible and well-supported by literature references (albeit mostly 2010 and earlier).

SR2:

Yes to all.

Author response:

Adverse Outcome

Is an AO described? If yes, then:

Is the AO description clear and is it biologically plausible?

Is the AO described in a way that allows its use in other AOPs?

Are measurement methods specified and adequately described/referenced?

Is the biological context (inc. taxonomic applicability/relevance, level of biological organisation) specified and explained sufficiently?

Has the regulatory relevance of the AO been described?

Responses

PR:

Yes to all.

SR1:

AO description (population trajectory, decrease): clear and plausible (an accepted regulatory endpoint). AO maybe is described in a way that allows its use in other AOPs; however, as noted above the Title of this AOP is based on 'Reproductive Dysfunction' and so there is some variance with the AO described. 'Maintenance of sustainable fish populations' is certainly indicated as the level of biological organization, whereas this can have underlying mechanisms that are not related to reproductive impairment.

Yes: the regulatory relevance of the AO been described.

SR2:

Yes to all.

Author response:

The term reproductive dysfunction was used in the title as an alternative to either of the final two KEs. The AO of "population trajectory, decrease" is of significance from a regulatory standpoint, but will nearly always be a modeled rather than measured endpoint, therefore we went with something intermediate between the final two KEs for the title. The AOP title could be revise for greater concordance with the KE titles, but if done this should probably be coordinated with the wiki gardener to make sure all the links update appropriately.


Section 6:

Key Event Relationships

Are the KERs well described and in a way that allows their use in other AOPs?

Are the KERs biologically plausible and is there sufficient evidence presented?

Is the level of empirical support adequately described in accordance with the OECD AOP Handbook?

Are inconsistencies, uncertainties and level of confidence adequately described?

Is the quantitative understanding of the KER described?"

[refer to Tables 2 & 3 in the handbook]

Responses

PR:

Yes: I agree with comments of SR1 and SR2.

SR1:

Yes: KERs are well-described, extensible and plausible.

Incomplete: for some KERs, sections still empty on 'how does this key event relationship work' and 'weight of evidence', 'empirical support for linkage', 'quantitative understanding of the linkage', and 'evidence supporting taxonomic applicability'.

SR2:

Yes to all, with some suggestions presented here (Some comments relate to potential implications for the Users Handbook/wiki, since this AOP is a model for its application). Suggest to consider whether any content on weight of evidence can be streamlined, to avoid duplication with the content of Section 7 ("Overall Assessment of the AOPs). While it's apparent that it's the relevant supporting or discrepant data being presented here (generally, specific studies)rather than an evaluation, per se, inclusion of a section entitled "Uncertainties or Inconsistencies" normally relates to assimilation or evaluation across the database (as per Section 7). If retained here, where no discrepant data are identified based on available data, it might be helpful as well to indicate this (rather than leaving the section blank). Normally, such conclusion would also be qualified to indicate the author's consideration of the extent of available data (e.g., On the basis of limited/extensive data, no discrepant results identified).

For the KER "Plasma vitellogenin concentrations, Reduction Directly Leads to Vitellogenin uptake into oocytes and oocyte growth/development, Reduction", the identified "inconsistency" that not all fish reproduction studies showing reductions in plasma vitellogenin have caused visible decreases in yolk protein content in oocytes and overall reductions in ovarian stage (Ankley et al. 2005; Sun et al. 2007; Skolness et al. 2013)is actually the expected pattern, recognizing that key events are essential but not necessarily sufficient. Rather, the incidence of later key events being greater than that for (rather than less than or perhaps not observed) earlier key events would constitute an inconsistency.

Author response:

Text was added to the "uncertainties or inconsistencies" section of each KER page to indicate that these had at least been considered. Additionally, brief responses were added to each "Evidence supporting taxonomic applicability". However, we would note that the "evidence supporting taxonomic applicability" for the KERs is really largely defined by the taxonomic applicability of the two KERs it connects. Therefore, this may seem a bit redundant, although the combination of the two events can lead to an applicability domain that is narrower than that of either KE alone.



Section 7:

Overall Assessment of the AOP

Is the domain of applicability of the AOP defined appropriately?

Is the level of support for essentiality of the KEs adequately described and assessed?

Has the degree of quantitative understanding of KERs been assessed properly?

Has consideration been given to the overall weight of evidence for the AOP?

Are the calls on Overall WoE and Quantitative Understanding supported?

Responses

PR:

Applicability of the AOP has been defined appropriately and the KEs are well described. The biological plausibility for the AOP is well-documented. 'unpublished data' to support weight of evidence should be published sooner.

SR1:

The domain of applicability of the AOP has been defined appropriately as ecological, and the level of support for essentiality of the KEs are nicely described. The biological plausibility for the AOP is well-documented, with caveats noted based on lack of data and discordance where few studies are available. A number of 'unpublished data' are used to support weight of evidence and it is assumed this will move forward into the peer-reviewed literature in time. Some biological questions remain, as pointed out, to be filled by additional research. The role of compensatory responses is noted.

SR2:

The relevant considerations regarding biological plausibility are robustly explained, with uncertainties clearly identified. Addition of the supporting table on dose-response concordance is extremely helpful, in providing a snapshot of the relevant extent of supporting data and identifying seemingly discordant information. If available, inclusion of benchmark doses would more clearly illustrate relevant patterns. Can any conclusions be drawn from the compiled table on temporal concordance?

And while the considerations for biological plausibility and empirical support are well described and qualified, it would be helpful to add explicit rationales for the resulting confidence calls based on the considerations in Annex 1 of the Handbook. This is very well addressed for the essentiality of key events (though it might be helpful to additionally address consistency with the nomenclature of the key events in other parts of the text).

There is a considerable amount of text included on documentation of dose-response for individual key events (concentration dependence). Since we're interested in the concordance of dose-response relationships between and among KERs, in my view, this text is largely irrelevant to the overall assessment of the AOP and could be streamlined or deleted here (It might, for example, be considered as supporting information relevant to the KERs in Section 6, but even there, refocus from individual KEs to KERs would be required - e.g., the extent of the database on concentration dependence of KEs which serves as a basis for considering empirical concordance of KERs?).

For the WOE of KERs, the subsection entitled "Consistency" is unnecessary, in my view. Most of the content here seems to relate to the subsections entitled "Dose-Response Concordance", taxonomic considerations and/or Uncertainties.

In the subsection entitled "Consistency", the meaning of the phrase "...the cumulative fecundity endpoint can be less sensitive than key events measured at lower levels of biological organization” is unclear. Does this mean that the available data are consistent with the pattern that in all cases where impact on fecundity was observed, incidence was less than that for early key events? This is the expected pattern for dose response concordance data which support the hypothesized AOP.

In the subsection entitled "Uncertainties, inconsistencies, and data gaps" (This now should address "critical" data gaps based on most recent content of the Handbook, I believe, though a subtitle not included - might be good to collectively reconsider relevant subsections here and their titles, based on most recent content of the Handbook), would it be possible to consider relevant experimental design for the identified major uncertainty (i.e., direct biological linkage between impaired VTG uptake into oocytes and impaired spawning/reduced cumulative fecundity).

In the subsection on "Quantitative Considerations", the basis for inclusion of the following sentence is unclear: “The present models are also unable to account for pharmacokinetic considerations (e.g., adsorption, distribution, metabolism/biotransformation, and elimination)” since AOPs are chemical independent. Although it is early days in relation to assessment of quantitative understanding of KERs, there is international (WHO) guidance available that we could potentially consider as a basis to characterize reliability (as a function of variability in parameter estimates and their sensitivity) and performance (proximity of modeled to measured estimates)of the models, as part of the evaluation. (See, e.g., Meek et al., Reg. Tox. Pharmacol. 66:116-129 (2013).

Author response:

Explicit rationale for each confidence call, based on Annex 1 from the handbook was added. The Annex 1 table was completed, a pdf copy uploaded to the wiki, and a link created on the AOP page.


Section 8:

Potential application of the AOP (optional):

Is any context provided as regards the reason for development or the intended use?

Responses

PR:

SR1:

SR2:

Author response:


General Observations and Conclusions of the Reviewer

Responses

PR:

This AOP has been improved and stronger now. References support this AOP need to be up-dated.

SR1:

This was a strong AOP when last reviewed, and since then essentiality has been incoporated into the model. A general comment is that much of the supportive literature is based on references from 2010 and older. While a some newer references are present, overall the AOP could benefit from updated literature especially with regards to the current state of the EDSP screening program. These features would assume to follow in time, especially for the quantitative relationships.

SR2:

The previous version of this AOP was highly evolved and the author has carefully considered and taken into account comments from the previous round. Almost all aspects seem to be very clearly described (with the exception of a small number of aspects as noted above). The review and comments here are focused on continuing evolution/improvement of the weight of evidence considerations in the evaluation of AOPs, for which this AOP provides a rather advanced model.

Author response: