Angry Toxicologist

Reading my Chemical and Engineering News (nerd alert!), I came across the article: “Toxicity Testing Without Animals” by Celia Henry Arnaud. “Oh no, here we go again”, I thought. It may come as a surprise to some of you but cells in a dish don’t equal whole bodies and even more shocking, we don’t know everything about how bodies work and how they are disrupted.

So what does the article have to say? It starts off with the normal animal testing is long, expensive, a pain in the butt, and restrictive to the number of chemicals that can be evaluated. Fair enough. Then it points out that

The pharmaceutical industry uses high-throughput screening methods to identify compounds that can be starting points for drugs. But for drug toxicity testing, the industry still turns to the old standby of rodent tests. Several government organizations are working to adapt high-throughput methods for toxicity testing, with the goal of developing in vitro assays that can predict toxicity.

The two aren’t comparable for two reasons. 1) In a Pharma screen you are looking through a whole lot of chemicals for one certain characteristic. In toxicology you are looking through a whole lot of chemicals for thousands of possible endpoints, including ones you don’t know of and 2) we’ll get to #2 later.

A recent report from the National Research Council (NRC) recommends the development of cell-based screening methods as a replacement for animal testing (C&EN, June 18, page 13). Although toxicologists share the vision that cell-based assays will eliminate the need for animal testing, they suspect it will take many years to become a reality. In the shorter term, high-throughput methods could help prioritize chemicals for current time-consuming methods of toxicity testing

I’m about to blow a gasket. The NRC report is all very well put together for the middle sections but the conclusions come from the soon to be classic “The NRC in Wonderland”. More on that some other time but you’ll understand why I disagree here. I do like how she says that most suspect it will become a reality many years from now, however, I would like to add this point: it will never happen. The hubris of these people is stunning to think that they can devise a cell-based screen to predict possible toxicities when we don’t even understand completely how cells work, much less how they interact, much less how millions of processes are interrelated in a whole animal. If we understood all this stuff don’t you think we’d know how to cure diseases and develop drugs that only targeted what you wanted them to target? The other problem with screening is that you are basing the toxicity on what was already known to work (i.e. the assay was validated using known toxicants). Well, what happens when a chemical comes along that is toxic but doesn’t work in the same way as the known toxicants? You’re up a creek that’s what. (along this line was a study published recently that found that one of our hallowed methods for predicting concentration of toxics through the food chain doesn’t always work) And for another thing…

ANOTHER CHALLENGE is the unacceptability of false negative results in environmental toxicology. Screening in the pharmaceutical industry can tolerate a small percentage of false negatives-instances in which a compound is deemed safe when it is actually toxic-so long as safe compounds also are identified for further development. But such false negatives are unacceptable for environmental toxicology. If false negatives create an illusion of safety that diverts toxic chemicals from further testing, those misleading results could become “problematic,” Kavlock says.[italics mine]

Exactly. This is the #2 I referred to earlier. “Problematic” is an understatement the size of Nebraska, though. Getting the more nuanced view, here in the story. Good technique in further drawing you into the article. Let’s skip to the last paragraphs:

Even if in vitro tests reduce rather than eliminate animal tests, they will be a success. Further animal testing might be unnecessary for those compounds that cause obvious toxicity in many cell lines.
“We hope we will provide EPA a science-based system that’s capable of prioritizing chemicals for animal testing,” Kavlock says. “If we’re exceptionally good, we’ll be able to pinpoint what animal tests should be done.”

This is an interesting contradiction in the ending. I can’t tell if it was intentional or not by Ms Arnaud, but it clearly wasn’t on the case of Kavlock. The first two sentences is what you want. Eliminate certain tests or chemicals or prioritize the ones that need to be tested first. The first sentence is a startling admission that the chances of any of this taking over animal studies is slim. The last sentence is dreaming. It won’t happen and is especially dangerous for the EPA. This is another reason why this works in the drug world but not for environmental chemicals. If you have a drug that passes a tox screen (say the hERG assay for QT prolongation risk – that’s a heart toxicity), it will still have to undergo the real whole animals study with ECGs and then hearts will be monitored in people through clinical trials. If you have an industrial chemical/pollutant that passes a tox screen, end of story – the chemical is still made, nobody ever finds out if anything is going on.

A better way of going about things is to start testing the chemicals that we know are in people’s blood, then move on to what we are exposed to. The thing is, we don’t need high-throughput methods to figure out the priorities, we already know which ones to go after first: the ones we’re exposed to; Because frankly, if we’re not exposed, who gives a crap?

Grade: A. Although I don’t agree with a lot of the people she quoted, I think that Ms Arnaud represented the diversity of opinion pretty well and no science mistakes that I caught. I would prefer to have a curmudgeon like me represented in there too, but you can’t have everything. Plus, it’s really hard to figure out how to fit the ‘ain’t gonna happen’ gal/guy into the story without tying a millstone around it’s neck. C&EN continues to impress.

Angry Conclusion: Toxicologists will be killing animals for a long time. Not because we like doing it (live animal work is a pain, no one I know likes it), because it’s the only way to know what the heck chemicals do.

Comments

  1. #1 Johnny Chimpo
    August 8, 2007

    I’ve always said, if there’s any truth to karma, I’m screwed, considering the sheer numbers of organisms I’ve killed in my time. Of course, hopefully fish and invertebrates don’t count for too much karma-cly.

  2. #2 ozzy
    August 8, 2007

    Your karma will be alright. His Holiness the 14th Dalai Lama spoke at an AACR conference a few years ago and stated that as long as your animal research was aimed at ending human suffering and was not frivolous you will be fine karma-wise. And we all know that fish and invertebrates don’t count…

  3. #3 MarkH
    August 8, 2007

    Awesome, I’ve got a pass from the Dalai Lama!

    Good essay AT. But let’s see if we can’t get an ARA troll to come in and say we should do all biology on computers.

  4. #4 cooler
    August 8, 2007

    What if a new species evolved that was much more intelligent than we are, would they have a right to expirement on us?

    We evolved from the monkey………..no we experiment on them…….say in 5000 years a new species evolves superior to humans………..uh oh, that would not be fun! I would not think that they would have this right…………..

  5. #5 cooler
    August 8, 2007

    now

  6. #6 angrytoxicologist
    August 13, 2007

    Ozzy and Mark got me thinking. I think I will print out Dalai Lama passes and hand them out to reseachers. Then when the animal extreme activists show up, all you have to do is show your Dalai Lama pass. What activist is going to argue with the Dalai Lama?!

  7. #7 Aliceanna
    August 14, 2007

    Animal testing is not needed…….I just started working for Animal Replacement Technologies……..they are making SYNTHETIC cadavers, tissues and body parts that REPLACE the need for animal testing! It is truly amazing! The website for those interested is http://www.Anireptec.com

  8. #8 Phil Boncer
    August 15, 2007

    Except that when I tried to go to that website, I got a HTTP403 (Forbidden) message; You are not authorized to view this page.

    Nonetheless, I doubt that Animal Replacement Technologies is building fully functional animals. Until you have the knowledge and ability to build an actual replacement animal with all systems go, you will not have eliminated the use or need for at least some animal testing.

    Testing in actual live organisms often (maybe even usually) gives surprising and not entirely predictable results,due to the complexity and interactions within a fully functioning organism. We do not know nearly enough to simulate this in the lab or in the computer model.

    Perhaps in fifty years or so, when we’ve decoded and understood the proteome, we’ll actually know how biology works on the deepest levels, and can then figure out how a substance will affect an organism without direct testing. But that’s a long ways fom what we can do now.

    PhilB

  9. #9 angrytoxicologist
    August 15, 2007

    I’m with you PhilB.

    Also, a thought experiment: what do you get when you assemble all the cells of an animal that interact with each other that are essential for predictive capabilities towards other animals?

    That’s right. An animal.

    So, wouldn’t it be easier to breed them then?

    (Okay so the A.R.T. folks do this with human cells but it’s not a replacement, it’s more of a addition.)

  10. #10 Anna
    August 16, 2007

    I was able to go to the anireptec site by clicking on Aliceanna’s name link.

  11. #11 Dr. Christopher Sakezles
    August 18, 2007

    My apologies to anyone who cannot get into our website (www.anireptec.com), but it is currently restricted to U.S. residents only. At any rate, the products my company (Animal Replacement Technologies) provides to industry are designed for medical device testing and surgical simulation only . . . not toxicology testing. We do have products under development that incorporate living cells to allow limited medical device – drug interaction testing, but we are not quite there yet.