In alternative animal testing, a pessimist really is a well-informed optimist

Back in March in Toxicological Sciences there was a great LTE from Dr David Basketter regarding an in vitro sensitization assay. The part I thought most on the money was this:

Overall, a prediction accuracy of about 82% was achieved, which is only a little lower than was obtained during the validation of the local lymph node assay (LLNA) (NIH, 1999), although some might be concerned by the failure of this in vitro system to detect almost 20% of the sensitizers. The authors address this issue by invoking the conduct of complementary assays, such as peptide binding or in silico methods. For example, an example of a chemical class that is not well predicted is aldehydes, where the possibility of employing an existing predictive Quantitative structure activity relationships is suggested. Of course, such devices are most easily implemented for chemicals where we already know what the answer should be, whereas the most critical assessment is for new substances where we do not already know the answers.

Preach on. With out huge and complete data sets we are only training a system to catch stuff we only know about. A reply (not by the authors of the critiqued article) that was published this month contains, among other arguments, the argument that boils down to, "Hey, it actually works near 100% of the time for the right chemical classes". Now, I get their point, that it could be restricted for use in those classes but that's not really where the need or the problem exists for alternative animal testing. We need something that's comprehensive. Beyond that they say that you could use other models, structure/activity models (QSAR), for the classes that don't work. But, that's why they're trying to develop in vitro tests in the first place! Because QSAR doesn't work well enough! I'll end by saying, 'keep trying guys and gals!' and echoing the statements of Dr Basketter in his reply to the reply:

I note an accusation of pessimism and I would simply respond that generally speaking, a pessimist is merely a well-informed optimist.

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Interesting. A little while back some newspapers were reporting on concerns that the regulatory system for new "cosmaceuticals" is not adequate, due to these cosmetics containing ingredients such as nanoparticles that potentially have effects that current animal and in vitro tests don't look for.

I'm not sure if the story reflected genuine widespread concern or was something of a scare story.

I wonder if you could tell me if there is any real concern among toxicologists that the non-animal testing methods currently under development are not up to identifying problems with these new compounds?

"We need something that's comprehensive."
Surely that could be "things" in the plural? The point about QSARs is that, by their nature they are domain-specific. So for example under the European REACH regulations, one approach is to develop a whole range of QSARs with overlapping domains so that most classes of compound are covered. Alternatively one can use hybrid models, (see: http://www.caesar-project.eu/) that accomplish the same thing mathematically. Also complaining about 20% false negatives may be ironoic because most of the databases of animal experimental tests we have looked at have about the same level of variability when checked against replicate or alternative test protocols.

Paul,
I think there is a real concern but also an acknowledgement that we need to move forward. There is a large group, and I would count myself in that group, that are worried that by wanting to get somewhere so bad we'll take whatever model we can get (let's face it, alternative methods are easy and cheap compared to live animal tests; there is huge pressure to move to them even outside the political/cultural pressure sphere). This is likely to backfire, in my opinion, if a high profile chemical makes it through one of these things and causes a disaster for a company.

Profnick,
You make some good points but I would point out that the critical measure for live animal tests is how well they predict what's happening in humans, not how well they correlate with other alternative or live tests. That's the reason some agencies require a rodent and non-rodent study. They know they're not always the same so they get both to make sure they've covered their based in terms of possible human toxicity. Consistency is not relevancy.

Well just how comprehensive are the animal tests for predicting human health problems anyway? Is a rat developing bladder cancer after being exposed to gigantic doses of a chemical really going to predict whether I might develop cancer after a chronic lifetime low dose exposure? Okay, so do the test in another species...what if the rat gets bladder cancer and the dog doesn't. Then am I more like a rat or like a dog?
Animal testing has never undergone the extensive validation that in vitro tests are undergoing now. After 60 years we're just so darned comfortable with them.
I personally like the approach of ToxCast...they're evaluating a whole bunch of high throughput in vitro assays to see just how comprehensive they can get.

Interesting. A little while back some newspapers were reporting on concerns that the regulatory system for new "cosmaceuticals" is not adequate, due to these cosmetics containing ingredients such as nanoparticles that potentially have effects that current animal and in vitro tests don't look for.

Interesting. A little while back some newspapers were reporting on concerns that the regulatory system for new "cosmaceuticals" is not adequate, due to these cosmetics containing ingredients such as nanoparticles that potentially have effects that current animal and in vitro tests don't look for.

You make some good points but I would point out that the critical measure for live animal tests is how well they predict what's happening in humans, not how well they correlate with other alternative or live tests.

It's not the ER's fault. It was allowing primary care socialized medicine to be destroyed that caused the ER mess you're all stuck with.

interesting commentary.

as the number of potentially interacting chemicals increases, so the number of potential interactions goes up exponentially. Do you think that might impact on your idea of testing chemicals if there is an (effectively) infinite number of combinations

Interesting. A little while back some newspapers were reporting on concerns that the regulatory system for new "cosmaceuticals" is not adequate, due to these cosmetics containing ingredients such as nanoparticles that potentially have effects that current animal and in vitro tests don't look for.

Interesting. A little while back some newspapers were reporting on concerns that the regulatory system for new "cosmaceuticals" is not adequate, due to these cosmetics containing ingredients such as nanoparticles that potentially have effects that current animal and in vitro tests don't look for.

You make some good points but I would point out that the critical measure for live animal tests is how well they predict what's happening in humans, not how well they correlate with other alternative or live tests.