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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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January 4, 2006

Mice, Humans, and Cancer

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Posted by Derek

Via Tyler Cowen at Marginal Revolution I came across this post earlier in the year from a blog called EffectMeasure on the use of rodent models to predict human cancer risks. It's a broadside against the American Council on Science and Health and a petition they filed against the use of high-dose rodent carcinogenicity tests.

Quote the anonymous "Revere":

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). The reverse question, whether everything that causes cancer in animals also is a human carcinogen, is not testable without doing the actual natural experiment: waiting to see if people get cancer on exposure, an experiment ACSH is only too happy to conduct on the American people to make their corporate sponsors happy."

I've left out (as did the MR post) the part where he called the ACSH "right wing whores", which is the kind of thing that doesn't enhance the statistical arguments very much. Dropping the invective, I want to take up Tyler Cowen's question: is there anything to this critique? My answer: there might be. But there might not be. It's certainly not as clear-cut as the author would like to make it, cancer epidemiologist though he is, which would seem to be one of the criticisms he's making against the ACSH petition.

Here are some complicating details:

1. The effects of high doses of compounds can be due to their effects on cell division. At such levels, test substances cause irritation and inflammation that promotes cell proliferation. The more cells are forced to divide, the more opportunities there are for the defects that lead to cancer. These effects do not scale well to lower doses. It's the opinion of Bruce Ames (inventor of the Ames test genotoxicity screen) that this problem has completely confounded the interpretation of high-dose animal data. (His article in Angew. Chem. Int. Ed. 29, 1197, 1990 is a good statement of this argument).

2. The statement 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" is not accurate. As Revere surely knows, there are many mutations and pathways that can turn a cell cancerous (which is why I keep harping on the idea that cancer isn't a single disease). Somewhere between one-third and one-half of all synthetic chemicals tested in cell assays or in high-dose animal assays show up as possible carcinogens, depending on your definitions. Interestingly, basically the same proportion of natural products (isolated from untreated foods and other sources) show up as positives, too.

Now, if you want to talk confirmed human carcinogens, then Revere may have a point. There are only some three or four dozen specific chemicals that are confirmed as causes of human cancer. Here's the list. If you read through it, you'll note that many of the 95 agents on it are radioactives or broad categories such as "alcoholic beverages." (Mention should be made of things like nickel, all compounds of which are under suspicion. Check your pockets, though, for your most likely exposure). Specific compounds known as human carcinogens are quite rare. But doesn't that fact support the ACSH's point more than Revere's?

3. Revere's statement that "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" is also inaccurate. Cancer cells are indeed damaged, right in their growth-regulation and/or apoptosis pathways. A car whose throttle is damaged will run at a higher RPM than a normal model, but I wouldn't call it a "super car". And cancerous cells are often quite recognizably problematic, whole animal or not. They divide like crazy in petri dishes, the same as they do in an animal.

4. The majority of the cancers seen in rat and mouse models are in the liver (which supports the idea that these tumors occur through general strain on their metabolic systems). Human liver cancer is much more rare. The most common human cancer in many countries is lung, caused to a great degree by smoking (which is also likely to have constant-irritant cell-proliferation component). Of the agents on that ICAR list in point #2, only three or four are chemicals (or mixtures) known to induce human liver cancer specifically. This is a significant mismatch.

5. Revere states that "We know of no false negatives with this process. Every chemical we know that causes cancer in humans also does so in rodents. . ." But how about false positives? There are hundreds of compounds that seem to cause cancer in rodents that (as far as we can tell) do not pose a risk to humans. I say "seem to", because these are almost always high-dose studies. But I can even think of some compounds (the PPAR-alpha ligands) that cause all sorts of trouble (including tumors) in rodent livers at reasonable doses, but don't do so in humans. Rodent tox is necessary, but it sure isn't perfect.

There, that should be enough to complicate things. It doesn't make for as dramatic a story as the evil henchmen poisoning America on behalf of their corporate masters, I have to admit. But we'll have to try to get along without the excitement.

Comments (11) + TrackBacks (0) | Category: Cancer | Toxicology


COMMENTS

1. revere on January 4, 2006 11:11 PM writes...

Derek: Thanks for the thoughtful response to my blog post. Both you and Tyler quoted from my shorter post about ACSH (and what I consider their outrageous petition). The part you quoted was just a sketch of the accepted justification for the practice of animal bioassays for carcinogenesis and wasn't meant as a full explication. As a result of Tyler's sensible questions, I expanded on it a bit in a series of three additional posts which start here and have their follow-ups linked at the end of the post. Since I write an opinion blog, I do make what some might consider editorial comments, like referring to ACSH as "right wing whores," which many who have worked in the field of environmental and occupational health as long as I have (40 years) would consider mainly an accurate description. Elizabeth Whelan and her science director (who served jail time for defrauding the government) are notorious. I mention it again because you made a point of referring to it.

I have already addressed several of your points in the follow up posts, noted above. Ames's view on the effects of cell proliferation have been around for more than a decade and are nothing new. It relates to an issue I take up in the posts, i.e., what is a reasonable and prudent basis for regulating carcinogens from a public policy perspective.

Regarding your point that cancer is not one disease, but many, this is a trickier question than it is given credit for. From the nosological perspective it may or may not be true, because cancer is a manifestationally classified disease, not an etiologically classified one (to use a very serviceable distinction of Brian MacMahon's form the 1960s). Consider the question of organ inflammation. By one perspective, there are as many organ inflammations as there are organs or tissues that can be inflamed. By another perspective, they are all the pathophysiologic process of inflammation. With regard to cancer, we know many cancers in disparate organs have the same underlying mutations (e.g., in p53), while the "same" cancer in the same tissue might have a lot of different cell types or sub-types (e.g., the non-Hodgkin lymphomas). Since most manifestational and even histological classifications are clinical, i.e., their purpose is not etiology but because they are important for management and prognosis, the fact that different cancers have different names may (or may not) be significant. I point this out only to say that this is a more complex question than you are allowing here. To take an example, fractures of the humerus and fractures of the femur are managed very differently and have different prognoses. They have different clinical appearances. They may have the same or different causes. They are both fractures (discontinuities in the bony matrix).

My definition of neoplastic behavior (as opposed to a normal phenotype) is a cell that divides when it wants to and where it wants to, i.e., a cell whose reproductive behavior is dysregulated from the standpoint of the organism. This relates to the "super cell" argument. This is also a truncated argument of a bigger issue. You correctly point out that it is a question of whether we are looking at this from the standpoint of the cell or of the organism. From the cell's point of view, its objective is to make another cell, i.e., to reproduce. It is competing for resources to do this with other cells and tissues which constrain it. The cancer cell, however, is a social deviant. It doesn't care about the other cells or the welfare of the collectivity. It is super selfish and out competes all the other cells. It is in that sense that it is a "super cell" and the reason I chose "cell" as the frame of reference. It is also a very specific and unusual biological ability. There you and I might differ, but I note that it is certainly not the usual "toxic" effect.

This also explains another difference we have. You have deftly elided "animal carcinogen" with "possible carcinogen in an in vitro test" as Ames invented. My post was quite clearly about in vivo assays, which I consider superior for the reasons I give in the posts. I do not believe what you say is accurate with regard to animal carcinogenicity. The property of causing cancers in whole animals is unusual. By the way, your list of "confirmed" human carcinogens is small because it requires epidemiological evidence, which, as I point out in several of the posts, is monumentally insensitive, and from the policy perspective, inadequate because it is also too late once it shows up.

Many chemicals are hepatic carcinogens, true. But what is being tested is the ability to cause neoplasia in a whole animal, not the target organ. I am not sure the proportion that are hepatic versus other organs and am not ready to concded that this is true for the majority (do you mean 51% or 90% or what?). But most pathologists experienced in bioassay work do not believe that there has to be a direct correspondence between the target organs in species. Indeed it isn't unusual to see different target organs in rats and mice for the same confirmed animal carcinogen. Your example of the PPAR-alpha agonists statement is controversial (although adheres closely to industry claims that they can't possibly be human carcinogens). The papers of Ron Melnick at NIEHS have addressed this many times and certain chlorinated ethylenes (e.g., TCE) I believe are renal and human carcinogens by a PPAR independent mechanism (via a glutathione-dependent pathway). Your claim that they are clearly false positives is not accurate and TCE and PCE are good examples. Both are class 2A carcinogens by the IARC classification and both "reasonably anticipated to be human carcinogens" by the National Toxicology Program. And both are hepatocarcinogens via your alleged high dose PPAR alpha mechanism. You have glossed over some very significant controversies and disagreements, just as you accuse me of doing.

But, again, the bottom line is what will be the prudent public health policy position here? For reasons I have indicated in the posts I referenced above, I believe that the use of rodent bioassays as a gold standard still is the proper position. I look forward to the day when we understand enough of the carcinogenic process that we can use Structure Activity Relationships. We aren't there yet.

Permalink to Comment

2. UndergradChemist on January 5, 2006 10:25 AM writes...

I'm curious; if some PPAR-alpha ligands are carcinogenic or toxic in rodent studies, how did they decide to move ahead with clinical development? Did they use an alternate animal model and find out that the main modes of toxicity was rodent-specific?

Permalink to Comment

3. biff on January 5, 2006 11:37 AM writes...

Quoting revere: "referring to ACSH as "right wing whores," which many who have worked in the field of environmental and occupational health as long as I have (40 years) would consider mainly an accurate description."

Ironically, when I did field work in environmental toxicology and chemistry quite a few years ago, it seemed that most of my colleagues could be accurately characterized as "left wing whores", although they would not have used the label on themselves. Since we all appear to be whores of one sort or another, I like to focus on the facts where they are discernable. Thanks to Derek and to Revere for at least attempting to share some data with sourcing...Let's see how long we can go without argumenta ad hominem. ;-)

Permalink to Comment

4. Derek Lowe on January 5, 2006 1:13 PM writes...

UC, the only PPAR-alpha compounds on the market are the fibrates, and they're not particularly potent at that target. They were developed before the general connection was made. By the time people got interested in the other PPAR subtypes, a lot of work had been done on the differences between rodent and human responses, which increased confidence.

That said, PPAR drug development is still a major minefield. . .

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5. revere on January 5, 2006 5:40 PM writes...

biff: Probably not very long as lives are at stake. Does the "left" have an axe to grind? Undoubtedly. Most of us are highly biased in favor of public health. I say this objectively. It is not the only bias one can have. One can have a bias in favor of shareholder profits, economic efficiency, jobs, property rights, inidividual liberties, etc. The folks I would call whores, however, are those just do it for the money. If that is your interest, the "left" is not a strategically good decision. There are many on the "right" that are driven by ideas, principles, ideology and I wouldn't call them whores, although I disagree with them. "Nuff said.

Permalink to Comment

6. Jim Hu on January 5, 2006 6:48 PM writes...

I had a post on this last month, also noting a NYT piece blogged by Volokh Conspiracy.

http://dimer.tamu.edu/simplog/archive.php?blogid=3&pid=2973

This was written before Revere posted followups (or I missed them), though...off to read those now.

Permalink to Comment

7. daen on January 6, 2006 6:03 AM writes...

Cancer cells are not "damaged" cells in the individual sense but "super cells," capable of out competing normal cells.

Cancer cells break the implied "multicellular organism contract" by giving up their tidy ordered existence and throwing off the shackles of controlled growth/division. They are certainly damaged from the organism's perspective but from another viewpoint are simply responding to evolutionary pressures that predate multicellularity.

Permalink to Comment

8. Maria on January 9, 2006 4:41 PM writes...

It seems to me that one could select one of these substances which animal studies suggest is carcinogenic but has not been confirmed as such, and run a large scale experiment with low doses. Doing it once or twice could help to see if this is indeed a good methodology.

Permalink to Comment

9. Sebastian Holsclaw on January 9, 2006 8:50 PM writes...

"It seems to me that one could select one of these substances which animal studies suggest is carcinogenic but has not been confirmed as such, and run a large scale experiment with low doses. Doing it once or twice could help to see if this is indeed a good methodology."

This seems like an excellent idea. Why not take three or four very different subtances that exhibit a moderate effect at super-high doses and test them out over the thousands of animals which would be required to note a low-level?

I'm a huge fan of the free market, but I see an important place for university research. This is exactly the type of experiment that a university would be great at. It is great basic science, it has broad implications, it is methodologically important, where is Maria's grant?

Permalink to Comment

10. revere on January 11, 2006 5:02 PM writes...

Sebastien and Maria: Well here are some of the technical statistical issues. Say the risk you are worried about is 1 in 100,000 (10-5). Suppose you want to be sure that if there are no cancers in the test animals your chance of being wrong is less than 5%. Then (1 - 10-5)x needs to be less than .05, i.e., x=log(.05/log( (1 - 10-5)). In this case you would need about 300,000 animals (assuming that you have historical controls that never get a tumor at that site in that strain of animals). If you have ever done lab work with rats, you immediately see this is not feasible. Moreover it is only for one dose via one route of exposure.

I made the statistics easy here for illustrative purposes. Of course if you wanted to do a power calculation with a more realistic test and a control group things are worse.

Now a risk of 10 might seem very small to you. But in the water supply of Boston that risk per year is about 20 people. If it is something in everybody's water (like a disinfection by-product) the pile of bodies gets bigger. If it is something the whole population can be exposed to, including fetuses--say saccharin, then the exposed population of the US is 300,000,000, so a risk of one in 100,000 becomes 3000 people, about the number that died in the WTC catastrophe.

The arithmetic works against you very quickly.

Permalink to Comment

11. revere on January 11, 2006 5:04 PM writes...

Sebastien and Maria: Well here are some of the technical statistical issues. Say the risk you are worried about is 1 in 100,000 (10^-5). Suppose you want to be sure that if there are no cancers in the test animals your chance of being wrong is less than 5%. Then (1 - 10^-5)^x needs to be less than .05, i.e., x=log(.05)/log( (1 - 10^-5)). In this case you would need about 300,000 animals (assuming that you have historical controls that never get a tumor at that site in that strain of animals). If you have ever done lab work with rats, you immediately see this is not feasible. Moreover it is only for one dose via one route of exposure.

I made the statistics easy here for illustrative purposes. Of course if you wanted to do a power calculation with a more realistic test and a control group things are worse.

Now a risk of 10^-5 might seem very small to you. But in the water supply of Boston that risk per year is about 20 people. If it is something in everybody's water (like a disinfection by-product) the pile of bodies gets bigger. If it is something the whole population can be exposed to, including fetuses--say saccharin, then the exposed population of the US is 300,000,000, so a risk of one in 100,000 becomes 3000 people, about the number that died in the WTC catastrophe.

The arithmetic works against you very quickly.

Permalink to Comment


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