Main Content

Adverse Outcome Pathways (AOPs) for Toxicology and Risk Assessment

As chemical toxicity testing moves toward the use of in vitro and shorter-term tests to evaluate chemicals more quickly and replace/reduce the number of animals used therein, mathematical/computational models will be needed to extrapolate results of those tests and predict effects in whole organisms. An adverse outcome pathway (AOP) spans multiple scales of biological organization from a molecular initiating event (e.g., enzyme inhibition or ligand-receptor binding) to effects on cells, organisms, or populations. An AOP describes qualitatively key events that are measureable and necessary for the adverse outcome to occur along with experimental evidence to support the key event and relationships between key events. A quantitative AOP (qAOP) is a mathematical model or set of models that predict the adverse outcome based due to perturbations in the AOP.

Acetylcholinesterase Inhibition Leading to Neurodegeneration

Acetylcholinesterase inhibition AOP figure

Acetylcholine regulates a wide variety of processes in our bodies such as muscle activation. An enzyme called acetylcholinesterase (AChE) eliminates acetylcholine, but some chemicals (e.g., pesticides and nerve agents) inhibit AChE. Too much acetylcholine causes a variety of adverse effects such as seizures, and paralysis. Our goal is to understand the range of sub-lethal adverse outcomes that arise due to AChE inhibition by developing a quantitative AOP (qAOP). The qAOP can be used to extrapolate changes measured in acetylcholinesterase activity and predict effects upon key events in the AOP. For a full description of the AOP visit the AOP Wiki. This research is supported by a cooperative agreement with the U.S. Army Corps of Engineers.

Aromatase Inhibition qAOP

Aromatase inhibition AOP figure

Aromatase is an enzyme that is needed to transform testosterone (an androgen) to estradiol (an estrogen). Some chemicals inhibit aromatase, and reduce the production of natural estrogens in many species. This qAOP represents how aromatase inhibitors affect fish reproduction and populations that are concerns for ecotoxicology and risk assessment. This qAOP comprises three independent mathematical models that are linked through their input and output values. Our goal is to develop predictive, multiscale models that represent the uncertainty and biological variability observed in fecundity data. This research was supported in part by a cooperative agreement with the U.S. Environmental Protection Agency.

qAOPs and Dynamic Energy Budget Models

NIMBioS workgroup paper image

NIMBioS workgroup, "Modeling Molecules to Organisms." Living organisms require energy to maintain biological process and grow or reproduce. However, biologically based mathematical models rarely account for energy requirements (e.g., food) in addition to chemical effects on outcomes such as reproduction. Our workgroup integrated Dynamic Energy Budget theory with quantitative AOPs for chemical effects upon a variety of endpoints such as growth and reproduction in fish. A case study focused on estrogen effects upon reproduction in salmon and demonstrated a method to integrate these two modeling approaches. To our knowledge, this was the first attempt to bring these two modeling fields together. This research was supported in part by the National Institute for Mathematical and Biological Synthesis (NIMBioS).

Main Content

Reproduction and Toxicology

This section highlights the development of mathematical models simulating reproductive processes and the impact of endocrine active chemicals on reproduction.

Cell-based Model of Early Ovarian Development

PGC migration to gonadal ridge figure

Endocrine Active Chemicals and Reproduction

Fish sex reversal figure

Main Content

Research and Education

This section highlights activities focused on undergraduate student projects and educational outreach. We are committed to lifelong learning and promoting scientific and math literacy in learners of all ages and backgrounds.

NCEHSS Projects in Dr. Watanabe's Lab


If you enjoy math, science and want to learn more about how chemicals in the environment affect living organisms, this is the research group for you. Depending on your research interests a summer project may focus on (i) evaluating the ability of a model to predict effects of estrogen and androgen mixtures on reproduction; (ii) evaluating the ability of a cell-based ovarian development model to predict data from knock-out mice; or (iii) developing a mathematical model of how pesticides affect the nervous system. My lab will provide research and professional development training for careers in Computational Toxicology. Visit the NCEHSS website for more information and application instructions. This program is supported by the National Institute of Environmental Health Sciences grant 1R25ES030238.

Human Health Risks from Fish Consumption

AZ fish catch limits

Fish are a good source of lean protein. Some fish that we eat bioaccumulate chemicals that are known to cause adverse effects. To protect public health, Federal and State regulatory agencies provide fish consumption advisories limiting the number of meals per week of fish species with high levels of contaminants such as mercury or polychlorinated biphenyls (PCBs). In Dr. Watanabe's lab, students work in collaboration with scientists from state agencies to assist with a variety of tasks related to developing fish consumption advisories. Two students, Rand and Muhammed Jaafar, learned how to program and wrote a VBA macro to identify sampling data gaps from the Arizona Department of Environmental Quality (ADEQ) Fish Consumption Advisory Program. Email for the VBA macro and a sample data set. This research is a collaboration with S. Rector at ADEQ.