Advancing Species Extrapolation: EPA’s “Sequence Alignment to Predict Across Species Susceptibility” | Science

…SeqAPASS provides us with a fast, efficient screening tool. Using it, we can begin to extrapolate toxicity information from a few model organisms (like mice, rats, zebrafish, etc.) to thousands of other non-target species to evaluate potential chemical susceptibility.

SeqAPASS provides an example of how EPA Chemical Safety for Sustainability researchers are leading the effort to usher in a new generation of toxicology practices that aspire to reduce the number of animals used, decrease costs, and increase the efficiency of chemical toxicity testing. The 21st century chemical toxicity testing strategy incorporates these ideals and has given rise to adverse outcome pathway (AOP) development and rapid, high-throughput chemical screening programs such as EPA’s ToxCast program.

Read more on the EPA’s science blog: Advancing Species Extrapolation: EPA’s “Sequence Alignment to Predict Across Species Susceptibility” | Science.

alternative toxicity testing AOPs computational toxicology databases EPA ToxCast
microscopic image of lab-grown muscle tissue

Contracting human muscle tissue grown in a lab

Duke University scientists have grown functional human muscle tissue in the lab. The team grew the muscle tissue from “myogenic precursors” – cells that have developed beyond stem cells but are not yet muscle cells, and then tested the tissue’s contractile and other responses.

From the Duke University press release:

To see if the muscle could be used as a proxy for medical tests, Bursac and Madden studied its response to a variety of drugs, including statins used to lower cholesterol and clenbuterol, a drug known to be used off-label as a performance enhancer for athletes.

The effects of the drugs matched those seen in human patients. The statins had a dose-dependent response, causing abnormal fat accumulation at high concentrations. Clenbuterol showed a narrow beneficial window for increased contraction. Both of these effects have been documented in humans. Clenbuterol does not harm muscle tissue in rodents at those doses, showing the lab-grown muscle was giving a truly human response.

microscopic image of lab-grown muscle tissue

A microscopic view of lab-grown human muscle bundles stained to show patterns made by basic muscle units and their associated proteins (red), which are a hallmark of human muscle. Photo credit: Duke University; used with permission

Read more about the work and its implications for toxicity testing and disease modeling here. Watch video of the engineered muscle tissue below:

3D cell & tissue culture alternative toxicity testing
vascular photo

Pfizer and HemoShear partner to predict toxicity in early stages of drug discovery

Pfizer Inc. and HemoShear, a privately held biotechnology company, are collaborating to develop methods to predict drug-induced vascular injury (DIVI) – a complication that slows or stops the development of many promising new drug candidates.

As Hemoshear’s press release explains:

Drugs in development may cause DIVI, such as inflammation or vascular lesions, in animals during testing for drug safety and toxicity. When this occurs, significant program delays and additional costs are incurred to investigate and explain the underlying biology and determine whether the compound is safe to move forward to human testing, or to determine if another compound would be safer. In some cases, decisions are made to stop the program altogether in the absence of a clear understanding of the injury and whether an animal response translates to human response.

The collaboration will make use of Hemoshear’s computational models and “translational tissue systems” — species-specific multidimensional tissue structures that replicate circulation and other physiological dynamics. Using these tissue systems, Hemoshear is able to run comparative studies (human tissues versus other animal tissues) that show whether, and how, human and animal responses differ.

The Pfizer/HemoShear collaboration has the potential to prevent unnecessary additional animal testing, and to reduce the cost and time it takes to bring new medications to market.


Read more about HemoShear’s translational tissue systems here.

alternative toxicity testing computational toxicology drug discovery
organovo bioprinter

“L’Oreal at work on bioprinted skin for cosmetics testing”

In the span of just a few years, 3D-bioprinting (3D-printing of biological cell and organ components) has moved from the realm of science fiction to scientific reality – a technology capable of printing viable skin, liver, and other organ tissues that can be used for more human-relevant drug testing, disease-modeling, and even transplantation research.

This article from highlights the collaboration between 3D-bioprinting pioneer Organovo and HTPC corporate partner L’Oreal, who are working together to create a bioprinted skin tissue that can be used in cosmetics testing:

L’Oreal at work on bioprinted skin for cosmetics testing.

(For more on Organovo’s bioprinting technology, watch this video.)

alternative toxicity testing HTPC members in the news
Tools for PCR amplification of DNA

Growing in vitro toxicity test market catches investor attention

Increased demand for non-animal chemical safety evaluations and for greater efficiency in testing has led to a burgeoning new market for in vitro and in silico methods, and financial investment research companies are beginning to take notice.

In January, a report by BCC Research estimated that the combined in vitro/in silico test market – valued at $4 BILLION (USD) in 2011 and $4.9 BILLION in 2012 – will reach $9.9 BILLION in 2017.  The report also discusses the potential for continued growth in the market; quoted in one news release, report author Robert Johnson noted, “Our research indicates that the current wave of in vitro adoption globally will take at least five to seven years, and it could be decades before animal testing is replaced entirely.”

In April, Markets and Markets projected a market of $17,227 MILLION by 2018 (though this report seems not to include in silico tests). According to this analysis, “Europe was the largest contributor to the global in vitro toxicology testing market in 2013. It will also be the fastest growing region till 2018. The European market is witnessing growth as a result of strong government directives to altogether stop animal testing and replace in vivo testing by in vitro methods. The Asian countries…are also expected to register double-digit growth from 2013 to 2018 due to the low costs offered by the developing nations to conduct studies.”

In October, an analysis by Persistence Market Research reinforced these broad patterns (note that dollar figures are not provided in the summary available to the public).  The report notes that the market drivers are slightly different for the pharmaceutical and cosmetics industries: in pharmaceuticals, there is a growing trend “towards detecting the toxicity during initial stages of production,” while for cosmetics “support from regulatory authorities for using in-vitro and in-silico methods for studying toxicity of a substance is driving the in-vitro toxicity testing market…”  Persistence Market Research is also tracking growth in industry use of microfluidics: the market is projected to increase from $1,531.2 MILLION (USD) in 2013, to $5,246.4 MILLION in 2019, with Asia experiencing the highest growth. Microfluidic devices (such as the organs-on-chips being developed by the Wyss Institute, and 3-dimensional cell “co-cultures” such as those produced by Hepregen and HuRel) are increasingly used by pharmaceutical companies in their drug development and safety screening process, and are used in other health and manufacturing industries, as well.

For the purposes of predicting human responses to chemicals, non-animal test methods are proving to be as good as or better than the animal tests they are intended to replace. In addition, in vitro methods exponentially reduce the cost and time involved in identifying and safety- testing potential new pharmaceutical compounds.  This is no small matter; a recent study by the Tufts Center for the Study of Drug Development reports that it costs $2.6 BILLION (USD) to bring a new drug to market. Government initiatives to profile tens of thousands of already-marketed household and industrial chemicals stand to gain from improved speed and cost effectiveness, as well, and are among the key market drivers identified by these reports – along with regulatory activities such as REACH, and increasing public concerns about the ethics of animal research.

alternative toxicity testing computational toxicology
Male thyroid anatomy

Paper encouraging non-animal approaches to metabolism wins award

Among the awards bestowed at the 9th World Congress for Alternatives and Animal Use in the Life Sciences in August, a paper co-authored by consortium director Catherine Willett was named the journal ALTEX’s “Best ALTEX article of 2013.”

In vitro Metabolism and Bioavailability Tests for Endocrine Active Substances: What is Needed Next for Regulatory Purposes?” by Miriam N. Jacobs, Susan C. Laws, Kate Willett, Pat Schmieder, Jenny Odum, and Toine F. Bovee, revisits and expands on recommendations put forth in a 2008 OECD review paper that argued for the assessment of human metabolism in in vitro assays used to screen endocrine-active substances.  Although that earlier paper showed that many of the necessary screening tools were already available, little progress has been made by the European, US, or Japanese validation agencies toward validating such methods for use in a regulatory context.  In the ALTEX paper, Jacobs et al. outline a series of projects designed to accelerate validation, continue to expand the number of available metabolism-enhanced screening assays, and improve and expand predictive tools.


alternative toxicity testing AOPs OECD Publications
john wikswo_neurovascular unit on a chip

NIH announces funding for the next phase of its Tissue Chip for Drug Screening program

This week, the National Institutes of Health (NIH) announced funding for the next phase of its Tissue Chip for Drug Screening program. In this phase, $17 million will be distributed to 11 projects that will refine and integrate existing 3-D human tissue chips (developed in the first phase of the program) into a system that mimics the physiology of the human body.  The resulting “human body-on-a-chip” will be used to predict the toxicity of potential drugs or other biological agents, ultimately with much greater relevance, accuracy, and efficiency than is possible with traditional animal test procedures.  From the NIH press release:

“The development of tissue chips is a remarkable marriage of biology and engineering, and has the potential to transform preclinical testing of candidate treatments, providing valuable tools for biomedical research,” said NIH Director Francis S. Collins, M.D., Ph.D.

Among the projects funded are a neurovascular-unit-on-a-chip (Vanderbilt), a female reproductive tract system (Northwestern University), a micro-physiological model of metastasis (MIT), and a human cardio-pulmonary-system-on-a-chip (Harvard University).  Read more about these and seven other projects here.

The Tissue Chip for Drug Screening program is a collaboration between NIH, the Defense Advanced Research Projects Agency (DARPA) and the US Food and Drug Administration (FDA), coordinated by the National Center for Advancing Translational Sciences (NCATS).

For a deeper dive into the potential of microphysiological systems, see the September 2014 issue of Experimental Biology and Medicine, especially the opening article by John Wikswo, “The relevance and potential roles of microphysiological systems in biology and medicine” (open access).

alternative toxicity testing organs-on-chips