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July 23, 2002
Rats, For Fear of Worse
I've had some mail asking a good (and Frequently Asked) question: how good are the alternatives to animal testing? How close are we to not dosing animals to get toxicology information?
My short answer to the second question is, simultaneously, "A lot closer than we used to be" and "Not very close, for all that." The root of the problem is complexity. Toxicological properties are, to use the trendy word, emergent. You need the whole living system to be sure that you're seeing all there is to see.
You could try to mix and connect cell cultures, where the compound, after being exposed to one type of cell, then flowed off to another, and the original cells got a chance, if they'd been changed, to affect other different cell types. . .and so on. But by the time you got all the connections worked out, you'd have built an animal.
An example of a emergent tox problem is the recent withdrawal by Novo Nordisk of a clinical candidate that they were developing with the Indian company, Dr. Reddy's. Bladder cancer was the problem, seen in long-term dosing. But it's mostly a problem in rats - mice showed enough to notice, but it was the rat data that really set off the sirens.
There aren't a lot of good in vitro methods to predict carcinogenic potential. It's for sure that this compound had been through screens like the well-known Ames test for mutagenicity, for example. If it hadn't passed, it's unlikely that they would have carried the compound as far as they did. (I'll be writing more on the Ames test at a later date.)
Bladder cancer's a bit unusual. Playing the percentages, you'd have to guess that the problem isn't the compound itself, but some metabolite produced in the body which concentrates in the urine. And the rodent differences might suggest that rats produce more of this metabolite than mice do (or, alternatively, that they produce the same one, but that rat bladders are more sensitive to it.) Something like this would be the way to bet.
How much are you willing to bet, though? Are you willing to give people bladder cancer, or even put them at risk for it? (And are you willing to invite some many liability suits to land on you that you'll think it's snowing?) Your chances of getting through (and the chances of your customers!) depend on what the mechanism of the tox might be, and whether it operates in humans, as opposed to rats.
Novo and Dr. Reddy's are certainly going to take their time to thoroughly investigate what the problem might be, and whether it can be fixed. There was really no way to anticipate it without animal testing, though, since we don't have an in vitro system that mimics the bladder. Even if we did, they might have run their compound through it and gotten a green light, if the problem is in fact some later metabolic product. There's no substitute for the whole animal.
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