Educational Infographic produced by the Human Toxicology Project Consortium

THE FUTURE OF TOXICITY TESTINGHTP_infographic_FINAL_revised

A new infographic produced by the Human Toxicology Project Consortium shows in three sections how the future of toxicity testing promises a steady reduction in testing costs, increases in human relevance and confidence in safety assessments, and the eventual elimination of animal tests.

The first section provides a snapshot comparison of the current and future costs, efficiency and efficacy of toxicity testing, while the mid portion uses pesticide testing as a specific example of now, vs near-future, vs the optimal approach that, given the focus and resources necessary, will be envisioned within the decade.

The near-future and optimal approaches rely increasingly on our understanding of biology and using it to build a predictive systems biology platform that is comprised of an interrelated network of biological pathways. This platform is used to design and interpret tests that provide much more efficient and effective characterization of chemical activity that can be used to predict safe use of chemicals.

Finally, the results of this progression are captured in the summary graphic at the end – decreasing costs, animal use and time while human relevance and our confidence in safety decisions continue to improve.

As explained on our Project page, the Human Toxicology Project Consortium works on three areas critical for the successful, international implementation of a pathways-based approach to chemical safety testing: advancing the science, communicating the purpose and goals of pathway-based toxicology, and lobbying for funding and policy changes that will support pathway-based approaches in the US and around the world.

To advance our communication and education efforts, HTPC member organizations worked together to create this infographic, to quickly and effectively illustrate the differences between traditional animal-based toxicity testing and pathway-based testing in terms of predictive power, cost, and testing capacity.

Details on the numbers used in this comparison are available here (PDF).

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“Humans are not mice:” scientists use human cells to create a working model of a rare genetic disorder

In this TEDx talk, researchers from HemoShear Therapeutics and Children’s National Medical Center describe how they can use cells from a diseased human liver to test treatments for that disease more rapidly and effectively than they could through tests on animals.

Their patient, “Stacy,” suffers from a very rare genetic condition – proprionic acidemia (PA) – which affects her body’s ability to completely process proteins and fats. As a result, proprionic acid begins to build up to toxic levels in her blood. The condition affects 1 in 100,000 people, and can lead to a variety of serious health problems and even early death. Like other PA patients, Stacy’s liver was worn out by its efforts to clear the toxic build-up from her body, and she eventually needed a transplant.

As Brian Wamhoff from HemoShear points out in this video, scientists have tried to recreate PA in mice that have been genetically engineered to exhibit the disease – but the condition kills mice immediately, before they can be treated. And as Wamhoff says, “humans are not mice.” Researchers need a way to test treatments on viable liver cells taken from a human with proprionic acidemia. So HemoShear developed a technology that keeps cells alive in conditions that mimic those in the patient’s body. When Stacy recently got her new liver, doctors sent living cells from her diseased liver to HemoShear – allowing them to create the first working “model” of proprionic acidemia.

Says Marshall Summar, Chief of Genetics and Metabolism at Children’s National Medical Center, in the video: “What this means is we can cut literally years off the development of new treatments for our patients. Before, we would have to try to develop an animal model…that often wouldn’t work. Or we’d try serendipity – we would try, maybe there’s drug that would work here and there. Now we can take a systematic approach to developing new therapies for these patients. This literally is an order of magnitude improvement on what we’re going to be able to do. And it offers us, for the first time, hope for developing therapies rapidly for these patients with rare diseases, so we can tackle the other 6,999 of them.”

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“Mice are not men”

In a recent episode of Freakonomics Radio, the hosts asked guests to identify ideas “we cling to” that might actually impede progress. Oncologist Azra Raza points to the futility of using mouse models for human cancer research. In the podcast, Dr. Raza’s segment begins at 00:15:10, and ends at 00:19:31. Here is a transcript of her comments:

miceMy name is Azra Raza. I am an oncologist, professor of medicine and director of the MDS Center at Columbia University in New York. The scientific idea that I believe is ready for retirement is “mouse models” must be retired from use in drug development for cancer therapy because what you see in a mouse is not necessarily what you are going to see in humans. For example, one very simple mouse model would be we take a mouse and give it a drug and see what happens to it. Another, which is much more commonly used, is called xenograft mouse model in which what we do is that we will take a mouse and we will use radiation therapy etcetera to destroy its immune system completely. And now we will transplant a tumor taken from a human into this mouse model. So its own immune system is gone, so it won’t reject the tumor, and we can then test the efficacy of a drug to kill these human cells in the xenografted mouse model. Now, currently cancer affects one in two men and one in three women. It’s obvious that despite concerted efforts of thousands of investigators, cancer therapy is today like beating a dog with a stick to get rid of its fleas. It’s really, in general, quite primitive. In fact, the acute myeloid leukemia – the disease I’ve been studying – we are giving the same drugs today for the majority of patients that we were giving in 1977 when I started my research in this area. So when compared to let’s say things like infectious diseases or cardiac drugs, cancer drugs fail more often. Recently things have improved. From the mid-90s to now, about 20% of drugs are actually entering clinical trials and FDA approved. But 90% of the drugs still fail because of either unacceptable toxicity, or once we give them to humans we find that they’re not working the way they were supposed to. So why are these facts so grim? Because we have used a mouse model that is misleading. They do not mimic human disease well and they’re essentially worthless for drug development. It’s very clear that if we are to improve cancer therapy we have to study human cancer cells. But in my opinion too many eminent laboratories and illustrious researchers have devoted entire lives to studying malignant diseases in mouse models. And they are the ones reviewing each others’ grants and deciding where money gets spent. So they’re not prepared to accept that mouse models are basically valueless for most of cancer therapeutics. But persisting with mouse models and trying to treat all cancers in this exceedingly artificial system will be a real drawback to proceeding with personalized care based on a patient’s own specific tumor, its genetic characteristics, its expression profile, its metabolomics; all those things are so individually determined in cancer. And for a lot of patients the drugs are already there we just have to know how to match the right drug to the right patient at the right time, and in order to do that the answer is not going to come from mouse models, but its is going to come from studying human cancers directly. Mice just are not men.

 

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Computer model correctly predicts human liver failure – where rat studies didn’t

Using a computer model developed by HTPC partner, the Hamner Institutes for Health Sciences, researchers at UNC Eshelman School of Pharmacy were able to predict human liver failure induced by the diabetes drug, troglitazone.

Troglitazone was introduced in 1997, and withdrawn from the market three years later after 63 patients died from liver failure. Though the drug had been shown to be safe in rat studies, and had only mildly adverse effects in human trials, introduction to a larger human population revealed that some patients could not metabolize the drug.

The UNC research team used DILIsym, a computer model developed by scientists at the Hamner Institutes, to combine chemical information about troglitazone with clinical human liver data, to see if the model could predict which patients in a simulated population would develop liver failure.

The model correctly predicted those at-risk patients, and also predicted that rats would respond differently than humans. From the UNC press release:

“Before DILIsym, no one had been able to completely explain troglitazone liver injury or suggest improved approaches so drug companies could avoid similar problems in the future,” (study author, Dr. Kim) Brouwer says. “It turns out that animals do a poor job predicting human drug-induced liver injury. There are lots of explanations, but one important reason is that bile acids are different in each species. Recent data suggest that the use of humanized systems has greater predictive power for adverse events like DILI.”

[…]

“Rare liver toxicity is now the major safety concern with new drugs and can often be detected only after many thousands of patients have received treatment,” Watkins says. “We believe that the application of DILIsym will greatly improve drug safety while minimizing animal testing and reducing the costs of new medicines.”

Read more about the development of DILIsym software here.

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Study finds monkeys make poor models for drug-induced liver failure

A news release on the Fund for the Replacement of Animals in Medical Experiments (FRAME) website highlights a recent study showing that cynomolgous monkeys – long valued in drug-testing because of their genetic similarities to humans – in fact respond very differently to overdoses of the painkiller paracetamol (acetaminophen).

Though paracetamol is a relatively safe and widely used over-the-counter painkiller, overdoses of the drug are the leading cause of liver failure in humans.  The new study finds that cynomolgous monkeys are poor stand-ins for paracetamol-induced hepatoxicity, because their livers are better able to detoxify large doses than human livers.

Dr. Gerry McKenna, FRAME’s new director of research, writes that the study “raises significant concerns about the scientific validity to humans of drug safety studies undertaken in primates,” and – like the HTPC – urges further development of cell-based and computational approaches to toxicity testing.

 

Photo credit: “Macaca fascicularis” by André Ueberbach – Eigene Aufnahme von André Ueberbach/Own production. Licensed under Creative Commons Attribution-Share Alike 2.0-de via Wikimedia Commons

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