In this next section, I'm going to talk about how you would build, evaluate and use AOPs in safety decisions. Say you'd like to start building an AOP, and it would be great if you would. How do you begin? Well, you can start anywhere, at the molecular initiating event from the adverse outcome, or from somewhere in the middle toward one of the anchors. Where you start usually depends on your field of expertise but the basic process is the same regardless. First, you gather all existing information, you document and capture this information as elements of an AOP in the wiki. Once you have the information in the form of KERs and KEs, you evaluate the KERs. When you are ready and if you so desire, you then enter the OECD evaluation process described in the previous section. What's involved in evaluating a key event relationship? There are three elements of the evaluation, the biological plausibility, the essentially and the strength of the empirical evidence. The evaluation is qualitative binned into weak, moderate, or strong, but still gives transparent communication of the level with strength, or confidence in the underlying information. To provide consistency between authors and reviewers, OECD guidance provides a detailed description on how to evaluate the information. This description is only briefly summarized in this table. As briefly mentioned in the previous section, the key event relationship page of the AOP wiki contains fields for entering specific details about species, chemicals and conditions, under which the supporting evidence for the relationship was generated. It also contains fields for entering evidence supporting the KER, as well as the evaluation criteria including biological plausibility, empirical evidence, and any uncertainties or inconsistencies in the data. During the evaluation process of the AOP, the same criteria used to evaluate KERs are applied to the AOP overall. Other considerations during AOP evaluation are, the appropriate domain of application, for example the species, the sex, or the life stage, the overall confidence or certainty, and any key data gaps or data needs that are left unaddressed. Although optional, the AOP page also contains a field to add considerations for the use of an AOP. So how can AOPs be useful? As we've learned AOPs can be useful in organizing data. They can also be useful in generating biological hypotheses that can be tested. AOPs can also provide a biological rationale for weight of evidence interpretation of the data. They can help with test strategy design, since tests can be identified that measure changes in key events to determine whether the adverse outcome is likely. AOPs can support transparent communication of the current level of biological knowledge, and as quantitative information is added to the key event relationships. For example, information about how much of a change in one key event is needed to lead to the change in the next key event. Predictive modeling can follow. AOPs can be used within the context of an IATA to increase certainty and safety decisions. What does that mean? According to OECD, an integrated approach to testing and assessment or IATA is, a structured approach that statistically integrates in weights all relevant data to inform regulatory decisions regarding potential hazard, and or risk, and or the need for further targeted testing, and therefore optimizing and potentially reducing the number of tests that need to be conducted. IATA begins with a problem formulation. What question are you trying to answer? Is It hazard assessment? Or risk assessment? Human health, or eco talks. Next, you gather, organize and evaluate all existing information. Do you have enough to answer your question? If not, design a non-testing strategy using available predictive tools like the OECD QSAR toolbox. Can you now answer your question, or do you still need more information? If more is needed, design a testing strategy to get that information. Repeat this process until you have enough information to answer your question with the required certainty. AOP support every step of the IATA process. Within the context of an IATA, AOP information provides the biological rationale for weight of evidence interpretation, and for the design of integrated iterative testing strategies. Once again if quantitative information is available for KERs, downstream events can be predicted from upstream events allowing safety decisions to be supported by molecular information, which is the objective of the 21st century toxicology. It Is the IATA that are used in safety decisions by regulators. The AOP supports the IATA, and facilitates decisions by doing all of the things we've talked about, providing a transparent way to communicate certainty of decisions. This is really not a new way of thinking. Regulators have been doing this naturally. What is new, is the creation of a formal system to standardize this process.
