AOPs, Space, and In-Silico
By Awurakua Asamoah-Mensah | October 16th, 2025
Adverse Outcome Pathways (AOPs) are hypothetical, modular frameworks. AOPs link stimulus exposure to an adverse outcome by showing the biological sequence of events spurred by the initial exposure. AOPs have been efficacious in different scientific fields. For example, they have offered critical information on DNA damage and mutations leading to metastatic breast cancer, as well as how excessive iron accumulation in neurons can cause neurological disorders, to name a few. Where there is a knowledge gap, an AOP can be implemented.
AOPs begin with a molecular initiating event, which is when the body first has an interaction with a chemical or physical stimulus. These molecular initiating events then cause key events, which are measurable responses that are primarily biologically dominant. Key events must occur in order for an adverse outcome to be realized. Between key events are key event relationships, which link one key event to another. Key event relationships cannot be conjectured; they depend on weight of evidence and are directional. All of these components lead to an adverse outcome which is an observed phenotypic change.
Adverse Outcome Pathways and Harm Reduction: PMI science. www.pmiscience.com. (2024). https://www.pmiscience.com/en/research/product-assessment-approach/toxicological-assessment/adverse-outcome-pathways-harm-reduction/
To build an AOP, one can use literature collation and filtration. This process enables researchers to identify key events and key event relationships, which helps in the formulation of the proposed adverse outcome. Weight of evidence is the foundation of an AOP, as it supports the key event relationships. Weight of evidence includes primary research (e.g. animal studies) and secondary sources (e.g. models). It is measured on a scale of low, medium, or high. To designate the level of the weight of evidence, one can use the modified Bradford Hill Considerations:
Becker RA, Ankley GT, Edwards SW, Kennedy SW, Linkov I, Meek B, Sachana M, Segner H, Van Der Burg B, Villeneuve DL, et al. 2015. Increasing scientific confidence in adverse outcome pathways: application of tailored Bradford-Hill considerations for evaluating weight of evidence. Regul Toxicol Pharmacol. 72(3):514–537
One area of interest is space and its impact on the human body. So far, 105 women have been to space, and this number will only grow. Curiosity about space and innovative flights have been increasing, as exemplified by the National Aeronautics and Space Administration’s upcoming Artemis Missions. The Artemis Missions are divided into four phases that will provide groundbreaking lunar information. It is also set to place the first woman on the moon, as well as the first person of color, Christina Koch and Victor Glover, respectively. This will be an incredible feat that will launch them into the space travel stratosphere, both literally and figuratively. There are currently other space missions in progress or in development, and as such, synthesized information on space ionizing radiation and its effects are imperative.
As of now, there is limited information on the long-term effects of space ionizing radiation, especially in the context of prolonged exposure. To address this, an AOP to study space ionizing radiation and its effects on female fertility is in progress under the guidance of Health Canada and in conjunction with the Organisation for Economic Co-operation and Development’s (OECD) Nuclear Energy Agency. Infertility is considered “a disorder of the reproductive system characterized by the inability to achieve a pregnancy after 12 months or more of regular unprotected sexual intercourse.” Current literature reflects that ionizing radiation exhibits a toxicological effect, impacting the uterus, ovaries, and/or the hypothalamic-pituitary-gonadal axis. This data must be analyzed to present clear information on this relationship, which will guide space agencies, governments, toxicology, and personal decision making.
Proposed AOP in development regarding ionizing radiation and its effects on female fertility
D’Urbano, J. (2024). Deposition of Energy leading to Decreased Fertility
AOP projects have the opportunity to harness new approach methodologies (NAMs) to a greater degree. Many AOPs use data gathered from literature based on animal studies. However, in contexts where literature is limited, such as in prolonged space radiation studies, NAMs can be of great use. In-silico models, which use computer simulations, could help predict the effects of toxicological stimuli on the human body without needing to use animals. These models can supplement known information and inform those encountering the stimuli, as it will serve as a predictor of adverse outcomes or other physiological effects on a micro (e.g. cellular) and macro (e.g. organ) scale. Especially with the recent advancements in technology, in-silico models can offer more applicable outcomes to humans and can be updated to encompass new data. In-silico models can be used as dynamic knowledge libraries, where researchers can input proposed molecular initiating events to understand the effects of various stimuli. They can connect key events, using the accurate pathophysiology of complex human biological processes. The widespread use of AOPs, in general, and in-silico models within AOPs will further emphasize the utility of NAMs, especially in fields like toxicology and exposure science.
AOP development is pivotal in guiding regulatory decisions, bridging knowledge gaps, and predicting stimulus impact. Further integrating new approach methodologies, such as in-silico models, into research will enhance AOP development, offering novel and relevant contributions to science, medicine, and policy.
Work Cited:
D’Urbano, J. (2024). Deposition of Energy leading to Decreased Fertility.
The views expressed do not necessarily reflect the official policy or position of Johns Hopkins University or Johns Hopkins Bloomberg School of Public Health.
