Toxicology Research and Application

Review Article

Toxicology Research and Application

Volume 1: 1–2
ª The Author(s) 2017
Disrupt toxicity testing: It’s the dose Reprints and permissions:
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rate that makes the poison DOI: 10.1177/2397847317723571
journals.sagepub.com/home/tor

Janis E Hulla1 and A Wallace Hayes2

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.

Keywords
Adverse outcome pathways, toxicity testing, disruptive technologies, real-time imaging, dose–response, Frank R. Lauten-
berg Chemical Safety for the 21st Century Act

Date received: 9 June 2017; accepted: 24 June 2017

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, induc-
tion of adverse outcome pathways (AOPs) is dependent on
dose rate (dose rate is used here to mean the dose or exter-
nal 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 knowl-
edge 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 toxi-
city testing methodologies. Historically, this was due to
technological limitations. These limitations no longer exist.
Yet, relevant dose-rate parameters are still not being incor-
porated into the emerging toxicity testing strategies, includ-
ing 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 con-
temporary 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 exten-
sive testing, and generating more informed risk manage-
ment and safer designs. Some of the specific challenges are
summarized in “Improving the human hazard characteriza-
tion 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
1
US Army Corps of Engineers, Sacramento, CA, USA
2
Department of Environmental Health, Harvard University, Andover,
MA, USA
Corresponding author:
Janis E Hulla, US Army Corps of Engineers, Sacramento, CA 95814, USA.
Email: janis.e.hulla@usace.army.mil

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2 Toxicology Research and Application
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 disrupt-
ing toxicity testing.
The term “disruptive technologies” is attributed to Clay-
ton 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 conven-
tional business models. Ripe for disruptive innovation is
not only traditional toxicity testing, but also the alternative
testing strategies promoted for the 21st century. The dis-
ruptive technologies are the real-time imaging and chemi-
cal 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 poten-
tial to generate anatomical dose-rate–response topogra-
phies 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 expo-
sure biomarkers and AOP biomarkers, it will become pos-
sible 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.
Authors’ note
Opinions expressed do not necessary represent that of the US
Army Corps of Engineers, US Army, or US Department of
Defense.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
References
1. NRC. Toxicity testing in the 21st century: a vision and a strat-
egy. USA: The National Academies Press, 2007.
2. Tice RR, Austin CP, Kovlock RJ, et al. Improving the human
hazard characterization of chemicals: A Tox21 update.
Environ. Health Perspect 2013; 121: 737–743.
3. Nel AE and Malloy TF, Science, 355, 6329, 1016–8, March 10,
2017, ¼http://www.sciencemagazinedigital.org/sciencemaga
zine/10_march_2017?pg¼30#pg30.
4. Bower JL and Christensen CM. Disruptive Technologies:
Catching the Wave. Harvard Business Review 73, no. 1
(January–February 1995): 43–53.