Help: Why

Introduction


What determined current AOP development principles and best practices?

This page provides additional information on why certain AOP development practices have been adopted.  It is not intended to replace the vast amount of published literature on this topic, but simply to provide a brief summary for new users on why things are done a certain way.

Examples of Essentiality Evaluations

This section provides some examples of essentiality evaluations from AOPs that have been described in the AOP-KB.

 

Example 1.  from AOP:21  AhR activation leading to early life stage mortality

 Rationale for essentiality calls:

  • AhR, activation: [Strong] Knockdown of AhR prevents TCDD induced alteration in cardiovascular development and function (Clark et al 2010; Hanno et al 2010; Karchner et al 1999; Prasch et al 2003; Van Tiem & Di Giulio 2011).
  • AhR/ARNT, dimerization: [Strong] Knockdown of ARNT prevents TCDD induced alteration in cardiovascular development and function (Antkiewicz et al 2006; Prasch et al 2004). Depletion of ARNT lessens or prevents TCDD induced alteration in cardiovascular development and function (Prasch et al 2004).
  • COX-2, increase: [Strong] Knockdown of COX-2 and selective antagonists of COX-2 prevent TCDD induced alteration in cardiovascular development and function (Dong et al 2010; Teraoka et al 2008; 2014). COX-2 inducers that are not agonists of the AhR cause altered cardiovascular development and function that is consistent with activation of the AhR (Huang et al 2007). Knockdown of and selective antagonists of thromboxane A synthase 1 (CYP5A), which is down-stream of COX-2 in the prostaglandin synthesis pathway, prevents TCDD induced alteration in cardiovascular development and function (Teraoka et al 2008). Exposure to the substrate for COX-2, arachidonic acid, causes an up-regulation in COX-2 and altered cardiovascular development and function that is consistent with exposure to TCDD (Dong et al 2010).
  • Cardiovascular development and function, altered: [Strong] Isosmotic rearing solution prevents yolk sac edema, but has no effect on TCDD induced alteration in cardiovascular development and function or mortality (Hill et al 2004). This indicates that mortality is not caused by yolk sac edema. Knockdown of cytochrome P450 1A (CYP1A) or injection with antioxidants decreases oxidative stress but has no effect on TCDD induced alteration in cardiovascular development and function or mortality (Carney et al 2004; Scott et al 2011). This is suggestive that mortality is not caused by oxidative stress. Exposure to agonists of the AhR post-heart development lessens or prevents alteration in cardiovascular development, decreased blood flow, and cardiac failure (Carney et al 2004; Lanham et al 2012). Exposure to agonists of the AhR post-heart development dramatically reduces mortality (Carney et al 2004; Lanham et al 2012). This suggests that mortality is caused by circulatory failure as a result of cardiovascular teratogenenesis.

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Example 2:  from AOP:25 Aromatase inhibition leading to reproductive dysfunction

Rationale for essentiality calls:

• Aromatase, inhibition: [Strong] There is good evidence from stop/reversibility studies that ceasing delivery of the aromatase inhibitor leads to recovery of the subsequent key events.

• 17beta-estradiol synthesis by ovarian granulosa cells, reduction: [Strong] In both exposure studies and stop/reversibility studies, when ex vivo E2 production (as measure of this KE) recovers either through compensation or due to removal of the stressor, subsequent KEs have been shown to recover after a lag period.

• plasma 17beta-estradiol concentrations, reduction: [Strong] In both exposure studies and stop/reversibility studies, when plasma E2 concentrations recover either through compensation or due to removal of the stressor, subsequent KEs have been shown to recover after a lag period.

• vitellogenin production in liver (transcription, translation), reduction: [Moderate] This endpoint was not specifically examined in stop/reversibility studies with aromatase inhibitors, but biological plausibility provides strong support for the essentiality of this event.

• plasma vitellogenin concentrations, reduction: [Strong] Shown to recover in a predictable fashion consistent with the order of events in the AOP in stop/recovery studies.

• vitellogenin accumulation into oocytes and oocyte growth/development, reduction: [Weak] Some contradictory evidence regarding the essentiality of this event. No stop/reversibility studies have explicitly considered this key event.

• cumulative fecundity and spawning, reductions: [Moderate] By definition, some degree of spawning is required to maintain population.

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Lessons Learned from Challenging AOP Development Projects


First challenging project

This will be replaced with the first example before release of the new version of the OECD AOP developer's handbook. 

Note to OECD handbook authors. To edit, click the edit button, edit the sub-section field to provide a title for the lessons learned example and update the text in the message box to describe the example.  My convention is to increment the message order by 10 each time to make it easier to insert new messages between existing messages.