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Extreme carcinogenic doses for rats

Here is a defense of using those rat tests to judge what will cause cancer in humans:

The "junk science" they are referring to is the long-standing and well-confirmed practice of identifying chemicals likely to cause cancer in humans by testing them in animals. The animals (rodents) are a standard model for biological processes of relevance to humans (which is why drug companies and medical researchers have been using them for a century). They are well understood and are the only sentinels for detecting carcinogenicity of any use to public health. Since chemically induced cancer has a latency period of decades (typically 20 years or more), waiting for it to appear in human populations would meant that once detected, even if exposure would cease instantly (which can never happen), it would take another 20 or more years to eliminate the cancers from exposure (all the cancers induced in the 20 years exposure prior to detection). But even then, the chances of detecting any but the most powerful carcinogens in human populations (via epidemiology) is small. Epidemiology is a very insensitive tool. I say this with some authority, as I am a cancer epidemiologist specializing in chemical exposures and have authored numerous peer reviewed studies in that area over many years.

The main rhetorical lever ACSH employs is the use of high doses in the animal studies, doses that are much higher than usually faced by humans. But as ACSH knows well (but didn't divulge) there is a technical requirement for using these doses. If one were to use doses in animals predicted to cause cancer at a rate we would consider a public health hazard, we would need tens of thousands of animals to test a single dose, mode of exposure and rodent species or strain. This makes using those doses infeasible. Thus a Maximum Tolerated Dose is used, one that causes no other pathology except possibly cancer and doesn't result in more than a 10% weight loss. The assumption here is that something that causes cancer at high doses in these animals will also do so at low doses. This is biologically reasonable. It is a (surprising) fact, that most chemicals, given in no matter how high a dose, won't cause the very unusual and specific biological effect of turning an animal cell cancerous. Cancer cells are not "damaged" cells in the individual sense but "super cells," capable of out competing normal cells. It is only in the context of the whole organism that there is a problem. It is not surprising, then, that very few chemicals would have be ability to turn a normal cell into a biological super cell of this type. Estimates are that is far less than 10%, perhaps only 1% of all chemicals that have this ability. Thus western industrial civilization doesn't have to come to a screeching halt if we eliminate industrial chemical carcinogens from our environment.

We know of no false negatives with this process. Every chemical we know that causes cancer in humans also does so in rodents (with the possible exception of inorganic trivalent arsenic, which is equivocal).

Here is the full post.  I'm not close to having the expertise to evaluate these claims, but two points.  First, the author is highly qualified; as a blogger he is anonymous but I can vouch for his credentials.  Second, it should be the self-appointed task of bloggers to pass along arguments which either struck them or which might shake up their readers.

Posted by Tyler Cowen on December 13, 2005 at 04:52 AM in Science | Permalink

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Comments

Seems like a sensible defence of science against the claque of "junk science" hacks. Since economics is ontopic for this blog, though, I'm not so sure about this bit:

["Estimates are that is far less than 10%, perhaps only 1% of all chemicals that have this ability. Thus western industrial civilization doesn't have to come to a screeching halt if we eliminate industrial chemical carcinogens from our environment."]

Not all chemicals are equal, surely? I would be much less confident in a blanket pronouncement that there was no set of chemicals equal to 1% of all chemicals which could not be withdrawn without bringing Western industrial socity to a halt.

Posted by: dsquared at Dec 13, 2005 6:47:42 AM

A very well said argument.

But one thing worries me -- the author's own figures suggest that if there is a large class of chemicals that cause cancer in humans but not in rats, it would take 20 years for us to recognize it (if we are lucky with the epidemiological data), and another 20 to fix it.

Another good reason to use rat-based tests, though, is if we eliminate a large number of cancer-causing chemicals via rat tests, it should become easier for us to use epidemiological data to find other, more subtle causes of cancer.

Posted by: DK at Dec 13, 2005 7:59:50 AM

The real question, however, is "What is the safe dose of any chemical for humans?". These are the facts that allow us to determine risk of exposure, identify at-risk populations and apply meaningful regulations. The "high-dose in rats" experiments only identify the potential for human carcinogenic activity. It is a profound logical and biological error to assume that a compound which is harmful at high doses will exert the same effect at low doses; an assumption which is clearly made by this anonymous blogger.
"The assumption here is that something that causes cancer at high doses in these animals will also do so at low doses. This is biologically reasonable."

There are many things which at high doses are harmful, even lethal, for humans: water, salt, even excessive food consumption. Yet all of these things are safe and even necessary at low doses.

Posted by: DrQ at Dec 13, 2005 9:00:02 AM

Shorter version of the argument. Our methods are cheap, therefore, they work.

Posted by: Alex Tabarrok at Dec 13, 2005 9:33:17 AM

This is another area, like nuclear power, where scientists and engineers have frustrated the public good due to poor communication. The scientists assume everyone is clear regarding the meaning of the results, their scope and potiential uses so no abuse of the data will occur. Consumer advocates have proven this idea false.

This type of study has its merits to determine possible carcinogens but has little use with regards to risk to humans. Maximizing banifit to potential risk is the true end goal but the work seems to end at the identification of the offending substance. Instead of having clear advice for public health we have litigation against teh offenders and advertisements promoting(defending) chemistry on TV.

Posted by: sprice at Dec 13, 2005 9:36:50 AM

Bruce Ames (inventor of the Ames test, among other distinctions) does not agree. See, for example:

http://reason.com/amesint.shtml

Posted by: Steve Schwarz at Dec 13, 2005 9:48:26 AM

Dr Q: I'm no expert in any of this, but I think you responded to a different argument than the anonymous blogger made. He said that using high doses of chemicals on rats gave good information about whether they were carcinogenic--not whether they were generically harmful. He's trying to detect a specific effect of the chemical (causing mutations to the DNA in some cells that helps them along toward becoming cancerous), and because the effect is small at the low doses we usually see in the environment, he's trying to amplify the effect by using much higher doses. Now, how well this tracks to P(cancer|exposure at dose X) in humans is an empirical question, but it's not obviously unreasonable to use this technique to determine that probability / dose relationship.

Posted by: John Kelsey at Dec 13, 2005 10:05:35 AM

Unrealistically high doses of tested chemicals, metabolic differences between humans and rats (a much greater resistance to cancer in humans), the completely unwarranted assumption of linear dose-response relationship (known to be wrong in many specific cases), and the thousand-fold safety factors built in the maximum exposure levels derived from animal studies - all of these elements mean that such studies should be treated as *hints* about possible effects in humans, rather than definitive data.

Under no circumstances should they ever be used in court, or as a basis of legislation.

Rafal

Posted by: Rafal Smigrodzki at Dec 13, 2005 11:26:56 AM

The problem with using these tests in court is that they are well off point. Water is dangerous when consumed in large enough amounts. The question is whether or not a particular drug poses an unreasonable risk. These kinds of tests offer no insight into that question.

Posted by: Sebastian Holsclaw at Dec 13, 2005 11:41:13 AM

Cancer cells are not "damaged" cells in the individual sense but "super cells," capable of out competing normal cells....It is not surprising, then, that very few chemicals would have be ability to turn a normal cell into a biological super cell of this type.

Well, he's the expert, but this logic seems suspicious to me. As I understand it, cancer is what happens when genes which prevent regular cells from becoming cancerous "super-cells" are damaged. For example, a gene which suppresses telomerase, thus making a cell incapable of dividing indefinitely. And a gene which tells cells when to stop growing.

So it seems to me that if you throw enough of any mutagen at enough cells, it may just kill or damage 99.9999% of them. But if it knocks out the right genes in just one cell out of millions or billions, then it should be sufficient to cause cancer.

Don't take this as gospel; it's just what I gleaned from a couple of years of biology in high school and college. But I don't see how any mutagen, unless it preferentially favors certain parts of the genome, could fail to be carcinogenic.

Posted by: Brandon Berg at Dec 13, 2005 1:52:02 PM

Regarding the "anything can be toxic" argument: these tests distinguish between general toxicity and carcinogenesis.

The reason that we need these special tests for carcinogenesis is that it is such a delayed effect, so it's often hard to identify the cause of cancer.

The basic argument is that what happens in the lab is not the same as what happens in reality: guess what--that's true of ANYTHING done in a lab.

It's pretty obvious that the "American Council on Health and Science" is a corporate front-group that with no concern for "health and science"--and only views them as obstacles to making a buck.

Their problem is not with the science, per se, but with how that knowledge is applied in our social/legal system. However, for PR, it is much easier to attack "junk science" than it is to push the idea that they should be able to dump anything that they want into our environment until it has absolutely, positively, been shown to cause immense damage to humans.

Posted by: Adam at Dec 13, 2005 5:06:03 PM

I'm suspicious. The anonymous blogger says:

"It is not surprising, then, that very few chemicals would have be ability to turn a normal cell into a biological super cell of this type. Estimates are that is far less than 10%, perhaps only 1% of all chemicals that have this ability."

Would a scientist say that? What is the class of "all chemicals"? If it indeed is all possible chemical compounds, then 1% is a huge number of chemicals.

Posted by: Eric Rasmusen at Dec 13, 2005 5:10:44 PM

"We know of no false negatives with this process. Every chemical we know that causes cancer in humans also does so in rodents" answers the wrong question. Is it the case that everything that causes cancer in rodents causes it in humans?

Posted by: dearieme at Dec 13, 2005 7:59:58 PM

Everything that causes cancer in rodents should be expected to cause cancer in humans. We're very similar
in that respect. DNA is DNA. There could be exceptions but I doubt there would be many.

Posted by: Ronald Brak at Dec 14, 2005 4:44:05 AM

Had this discussion at Reason earlier today. Besides the Ames interview in Reason that Mr Schwarz linked, which is very good (Ames invented the Ames test, which is an important test for mutagens and often confused with a test for carcinogens), this article ( http://www.sciam.com/article.cfm?articleID=00019A70-0C1C-1F41-B0B980A841890000&sc=I100322 ) from Scientific American is very good. Simple summary: many chemicals and other effects that are harmful in large doses are actually beneficial in small doses; the body overcompensates for the damage and actually becomes less likely to suffer from cancer or toxicity. So the testing in rats may well give good information on whether a chemical can be a carcinogenI'm not qualified to judge, although it seems totally plausiblebut it doesn't tell you anything about which doses are helpful and which harmful. I suspect that we consistently tend to set thresholds far lower than we ought.

Add to this Dr Ames's point that you get exposed to more known carcinogens from a cup of coffee than you will from a years' worth of pesticides on produce, and I'm pretty skeptical.

Posted by: jadagul at Dec 14, 2005 5:51:31 AM

I just added a trackback to a long post on this. MR readers already make most of the key points, but I hope they'll still find something useful.

Posted by: Jim Hu at Dec 14, 2005 10:48:32 AM

After following jadaqul's link to the Sci Am article, MR readers may have made ALL the points in my long post!

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电话交换机
交换机
呼叫中心
测厚仪
测温仪
停车场
道闸

Posted by: xdrs at Jul 12, 2007 3:21:29 AM

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