Disrupt toxicity testing

Abstract

Dimensions of time that are relevant to molecular mechanisms are not incorporated into conventional toxicity testing methodologies. Historically, this was due to technological limitations. These limitations no longer exist. Application of real-time imaging and chemical sensor technologies presents an opportunity to overcome the challenges that have stalled essential transformation of toxicity testing methodology.

Toxicologists know that chemical absorption, distribution, metabolism, and elimination pathways involve time-dependent molecular interactions. They understand too, that since rate and binding constants are involved, induction of adverse outcome pathways (AOPs) is dependent on dose rate (dose rate is used here to mean the dose or external exposure in unit of weight of a chemical substance per unit of body weight per unit of time). If the dose rate is high enough, any chemical substance, even caffeine and water, has the potential to be toxic. Although it is common knowledge among toxicologists that a chemical’s dose rate is an essential component of its safety assessment, relevant dimensions of time are not incorporated into tradition toxicity testing methodologies. Historically, this was due to technological limitations. These limitations no longer exist. Yet, relevant dose-rate parameters are still not being incorporated into the emerging toxicity testing strategies, including the mechanism-based in vitro and in silico assays advocated in the 2007 National Research Council report, “Toxicity Testing in the 21st Century.” ¹

The absence of the dose-rate parameter from the contemporary toxicity testing strategies is not because the essential technologies do not exist. They do! Real-time chemical sensors and real-time biomarker imaging devices are commercially available and measuring dose–response in real time, both in vivo and in vitro, is possible. Nor is the absence of the dose-rate parameter due to lack of insight, many of the essential toxicity testing technologies that are now available were developed with funding from the same federal agencies charged with conducting toxicity testing. We suggest that omission of the dose-rate concept is largely due to institutional inertia. The consequence is significant. Both “Toxicity Testing in the 21st Century” and the 2016 Frank R. Lautenberg Chemical Safety for the 21st Century Act are destine to fall short of achieving their goals of reducing the use of animals and reducing the costs of; screening chemicals, prioritizing chemicals for more extensive testing, and generating more informed risk management and safer designs. Some of the specific challenges are summarized in “Improving the human hazard characterization of chemicals: A Tox21 update.” ² It is telling that in 2013 when the paper was published, the authors anticipated it would take a decade or more to reach the goals of the Tox21 initiative. More recently, a 2017 SCIENCE policy forum article suggested that many of the same challenges remain, including technological, institutional, and legal challenges. ³ In these contexts, it is time to consider disrupting toxicity testing.

The term “disruptive technologies” is attributed to Clayton M. Christensen and Joseph Bower who used it in their 1995 Harvard Business Review article titled, “Disruptive Technologies: Catching the Wave.” ⁴ Since then, the term has evolved to include any innovation that disrupts conventional business models. Ripe for disruptive innovation is not only traditional toxicity testing, but also the alternative testing strategies promoted for the 21st century. The disruptive technologies are the real-time imaging and chemical sensor technologies. The dose–response curve is the current industry standard and the business model to be disrupted. The application of real-time chemical sensor and 3-D imaging technologies to toxicity testing has the potential to generate anatomical dose-rate–response topographies that change over time. By developing biomarkers of disease progression that can be imaged, it will become possible to observe chemical-induced adverse effects develop in real time (or in time lapse). By imaging exposure biomarkers and AOP biomarkers, it will become possible to reveal disruption of homeostatic pathway dynamics, for example, the dose rate at which a detoxifying pathway switches to an AOP. We envision that the benefits of capturing this extraordinary spatial-temporal precision will also extend into clinical practice as modeling for patient-specific dose rates becomes possible. To achieve the health benefits, time savings, and potential cost savings of the strategy suggested herein, we must first overcome institutional inertia. It will not be easy but let’s not miss the wave.