Being admitted into SOT has been one of the highlights of my career so far, so I was really looking forward to attending my second Annual Meeting. The opportunity to listen to, and learn from, some of the best and brightest in our industry is always much appreciated, and this year was no different.
While we are all disappointed the meeting was canceled, I understand that it was for the best, especially because I live in the Bay Area and we have been on mandatory shelter-in-place for nearly two weeks now! However, I was delighted to learn that SOT had arranged for some of the sessions to be presented as webinars. Not only was I really excited to have the option to listen in, but also, it was one of the sessions I was most eager to attend—“New Frontiers in Dynamic Toxicology,” endorsed by the Exposure Specialty Section. I see a lot of different toxicology studies in my job so was really thrilled to delve into them more deeply and gain additional knowledge.
My career started in the vivarium, and I was lucky enough to work on a wide range of studies across the drug development spectrum. I started with basic pk screening in large animals and was able move into ADME (Absorption, Distribution, Metabolism, and Excretion), surgical support, ophthalmic studies, and eventually complex toxicology, including NHP (nonhuman primate) DART (developmental and reproductive toxicology). This was perhaps my favorite study type. The complexity of both the model and the design was fascinating to me, and I really enjoyed the details of setup and sample collection. Unfortunately, as a technician, I did not have the insight into the “why” of the study but was focused more on the “how” and the “when.” So, when this chance to delve into the “why” came up, I jumped at it.
John Wambaugh of the US EPA Office of Research and Development began the webinar, presenting for himself and Annie Lumen of the US FDA National Center for Toxicologic Research. Dr. Wambaugh discussed the history of chemical safety in the United States and how some population groups are at greater risk for adverse health effects from exposure to chemicals compared with others. One of these populations is pregnant women.
The risk to pregnant women and, thus, to the fetus is determined by the hazard, the dose-response, and the exposure. Assessing that risk is critical, and determining the window of susceptibility to that adverse reaction can be very difficult, not to mention time-consuming and expensive. DART studies span many months, if not years, and require untold staff hours and cost to complete just the in-life portion. It would be hard to for me to even imagine the overall cost and how many hours must be put in to bring a (hopefully) successful study to its conclusion. So, how can we potentially shorten the timeline and reduce costs while also maintaining safety?
However, Dr. Wambaugh pointed out some really exciting new methods for hazard screening, including the ToxCast Screening Program. He then focused on putting this hazard into a risk-based context. Because risk is one of the foremost considerations when conducting in vivo studies, this stood out to me. While some substances might be hazardous in micro doses, it’s difficult to convey that hazard in an everyday scenario. This is part of the reason that doses are generally in mg/kg/day—to make them applicable to daily life. Some of the new models that are available help extrapolate these minuscule quantities from in vitro studies to the exposures of in vivo models, thus allowing reverse dosimetry.
The data required are not available for every compound just yet, but there are a lot of open-source tools for high-throughput toxicokinetics, or HTTK, that can be used to build and run these models. Generic tools also can be utilized to make reasonable predictions, although there is a trade-off in accuracy. There are even some current models that simulate ADME in the human mother and fetus from 13 weeks of gestation onward.
I’m really thrilled to see how these models progress in the next few years and if they have the required accuracy to replace some of the current standards. Making more safe and effective treatments available to pregnant mothers also would lead to healthy children while reducing some of the health care costs that are associated with developmental exposures.
Highlighting the real risk of prenatal exposure, Brianna Rivera of Oregon State University then presented on “Time-Integrated Exposures to Identify Chemical Profiles between Health and Dysphagic Foals.” I really enjoyed this presentation, as it gave real-life context to the risk of exposure to hazards. In this case, the hazard is from unconventional natural gas development, or fracking, which releases polycyclic aromatic hydrocarbons (PAHs) into both the water and the air. PAHs have carcinogenic properties and have been associated with developmental and behavioral disorders. Because they have been shown to have the same effects on animals, we can utilize them as sentinels for exposure.
This presentation detailed a real-life example of a cluster of foals born in Pennsylvania during the 2014 season that presented with dysphagia and subdued mentation. These are indicative of central neurological dysfunction, and because they can also be present in human infants, we can possibly use foals as a sentinel.
Luckily, the farm in question had a sister farm in New York that had no nearby drilling activity, allowing it to act as a sort of control. The wells at both farms were shared by the employees living on the property as well as the horses, and both farms had the same source of feed. The only difference between the two was the pasture, air, and water sources.
The team involved utilized passive sampling to capture data and determine a time-weighted average. Over a duration of 21 months, the data showed that there was a higher concentration of many PAHs at the Pennsylvania location in the water, although there was not a statistically significant difference among the individual PAHs in the air. The well at that farm was capped in May 2016, which led to a decrease in PAHs in the air, but an increase in PAHs in the water. While the overall cancer risk at both farms was lower than those of large urban areas, the incidence of neurologic issues at the Pennsylvania farms is indicative of the hazards that accompany PAHs.
The PAHs that were found at elevated levels in Pennsylvania have been associated with an increased risk of neurotoxicity in mouse models. It would be interesting to see if the PAH levels at both sister farms change and continue to evaluate the impact on foals. It’s possible that there are other environmental chemicals that also are playing a role in the health of these animals, but perhaps risk could be evaluated based on the combined exposure of different chemicals as well as different routes of exposure.
Finally, Dr. Ann Pitruzzello of Northrop Grumman Corporation presented on “Modeling, Machine Learning, and Time-Series Data.” I was quite interested to hear how machine learning and modeling could potentially replace some of the in vivo models or even in vitro models that are currently in use.
There are a lot of complexities in the current range of toxicity studies that seem to be difficult to reproduce in a simulation. However, by utilizing certain methods of creating time series data, we can see some correlations and use them to improve predictive capabilities. While there are challenges associated with choosing a model, there also are a lot of potential benefits to its use. If there are sufficient training data and you understand the mechanisms underlying your observations, it is possible to use deep learning, network models, or classifiers to model the system. These models can have a wide range of applications, from cyber security to medical devices that predict seizures.
When looking at these three sections as a whole, I can see some immediate benefits for the decision-makers at major pharma companies during discussions of structure and compliance related to laboratory animal studies. While they all have different targets and pipelines, the drug approval process is largely identical across compounds. Because of this, they may encounter some of the same hurdles and face similar difficulties.
There is risk inherent in utilizing animals for research, and different pharma companies approach and manage this issue in a slightly different way. But with the goal of reducing risk exposure in mind, the question is raised whether it be possible for large pharma companies to utilize some of these assays and models to reduce that risk. Could it be taken a step further and be applied to the 3Rs of animal research (replacement, reduction, refinement)?
I am looking forward to addressing these questions in the coming months and trying to apply them in a way that reduces risk. I can’t wait to see what SOT 2021 has in store and to enjoy the opportunity for knowledge sharing. Until then, I wish everyone a year of success and good health. See you in Orlando!
This blog was prepared by an SOT Reporter and represents the views of the author. SOT Reporters are SOT members who volunteer to write about sessions and events in which they participate during the SOT Annual Meeting and ToxExpo or 2020 SOT Virtual Meeting. SOT does not propose or endorse any position by posting this article. If you are interested in participating in the SOT Reporter program in the future, please email Giuliana Macaluso.