As Paracelsus put it, "the dose makes the poison."
November 6, 2013 3:06 AM   Subscribe

Dr Bruce Ames, a toxicologist and one of the world's most cited scientists, discusses the impact of his Ames test, "toxic chemicals," and scaremongering

The Ames test (Helpful explanation) is an elegantly clever way to cheaply and conveniently test for detecting mutagenicity, and thus potentially carcinogenicity, that made it possible to test a wide array of industrially used chemicals in the 70s. The large number of positive results generated outrage from environmental groups and regulation from however, as Ames continued his work he found that natural compounds found in foods are just as, if not more, likely to trip his assay in relevant concentrations.
Ames, BN & Kammen HO (1975). Hair Dyes Are Mutagenic: Identification of a Variety of Mutagenic IngredientsPDF PNAS
We have previously described a sensitive bacterial test for dectecting carcinogens as mutagens. We have previously described a sensitive bacterial test for detecting carcinogens as mutagens. We show here that 89% (150/169) of commercial oxidative-type (hydrogen peroxide) hair dye formulations are mutagenic in this test. Of the 18 components of these hair dyes, nine show various degrees of mutagenicity:2,4-diaminoanisole, 4-nitro-o-phenylenediamine, 2-nitro-p-phenylenediamine, 2,5-diaminoanisole, 2-amino-5-nitrophenol, m-phenylenediamine, o-phenylenediamine, 2-amino-4-nitrophenol, and 2,5-diaminotoluene. Three hair dye components (p-phenylenediamine, 2,5-diaminotuluene, and 2,5-diaminoanisole) become strongly mutagenic after oxidation by H2O2: the mutagenic product of p-phenylenediamine is identified as the known trimer, Bandrowski's base. 2,4-Diaminotoluene, a hair dye component until recently, is also shown to be mutagenic: this compound has been shown to be a carcinogen in rats and is used in large amounts in the polyurethane foam industry. About 20,000,000 people (mostly women) dye their hair in the U.S. and the hazard could be considerable if these chemicals are actually mutagenic and carcinogenic in humans.

Ames BN & Gold LS. 1990 Misconceptions on Pollution and the Causes of CancerPDF Angew. Chem.
The public has numerous misconceptions about the relationship between environmental pollution and human cancer. Underlying these misconceptions is an erroneous belief that nature is benign. In this article we highlight eight of these misconceptions and describe the scientific information that undermines each one.

Ames BN & Gold LS. (1997) Environmental pollution, pesticides, and the prevention of cancer: misconceptions.PDF FASEB J
The major causes of cancer are: 1) smoking, which accounts for about a third of U.S. cancer and 90% of lung cancer; 2) dietary imbalances: lack of sufficient amounts of dietary fruits and vegetables. The quarter of the population eating the fewest fruits and vegetables has double the cancer rate for most types of cancer than the quarter eating the most; 3) chronic infections, mostly in developing countries; and 4) hormonal factors, influenced primarily by lifestyle. There is no cancer epidemic except for cancer of the lung due to smoking. Cancer mortality rates have declined by 16% since 1950 (excluding lung cancer). Regulatory policy that focuses on traces of synthetic chemicals is based on misconceptions about animal cancer tests. Recent research indicates that rodent carcinogens are not rare. Half of all chemicals tested in standard high-dose animal cancer tests, whether occurring naturally or produced synthetically, are "carcinogens"; there are high-dose effects in rodent cancer tests that are not relevant to low-dose human exposures and which contribute to the high proportion of chemicals that test positive. The focus of regulatory policy is on synthetic chemicals, although 99.9% of the chemicals humans ingest are natural. More than 1000 chemicals have been described in coffee: 28 have been tested and 19 are rodent carcinogens. Plants in the human diet contain thousands of natural "pesticides" produced by plants to protect themselves from insects and other predators: 63 have been tested and 35 are rodent carcinogens. There is no convincing evidence that synthetic chemical pollutants are important as a cause of human cancer. Regulations targeted to eliminate minuscule levels of synthetic chemicals are enormously expensive: the Environmental Protection Agency has estimated that environmental regulations cost society $140 billion/year. Others have estimated that the median toxic control program costs 146 times more per hypothetical life-year saved than the median medical intervention. Attempting to reduce tiny hypothetical risks has other costs as well: if reducing synthetic pesticides makes fruits and vegetables more expensive, thereby decreasing consumption, then the cancer rate will increase, especially for the poor. The prevention of cancer will come from knowledge obtained from biomedical research, education of the public, and lifestyle changes made by individuals. A reexamination of priorities in cancer prevention, both public and private, seems called for.
In The Pipeline discusses the Ames test and its relevance to the pharmaceutical industry
posted by Blasdelb (22 comments total) 27 users marked this as a favorite
Okay, cigarette smoking is obviously a major cause of cancer, but "lack of sufficient amounts of dietary fruits and vegetables"? It seems quite a stretch to lump that in with smoking.

I don't doubt that lower consumption of fruits and vegetables is associated with higher rates of cancers, but I would be very surprised if there aren't a number of confounding variables that make it very difficult to tease out a causal relationship.
posted by Pararrayos at 3:59 AM on November 6, 2013 [2 favorites]

lack of sufficient amounts of dietary fruits and vegetables

I think it's associated with colon cancer specifically
posted by thelonius at 5:16 AM on November 6, 2013 [2 favorites]

van Duijnhoven FJB et al. (2009) Fruit, vegetables, and colorectal cancer risk: the European Prospective Investigation into Cancer and NutritionPDF Am J Clin Nutr
Background: A high consumption of fruit and vegetables is possibly associated with a decreased risk of colorectal cancer (CRC). However, the findings to date are inconsistent.
Objective: We examined the relation between self-reported usual consumption of fruit and vegetables and the incidence of CRC.
Design: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 452,755 subjects (131,985 men and 320,770 women) completed a dietary questionnaire in 1992–2000 and were followed up for cancer incidence and mortality until 2006. A multivariate Cox proportional hazard model was used to estimate adjusted hazard ratios (HRs) and 95% CIs.
Results: After an average follow-up of 8.8 y, 2,819 incident CRC cases were reported. Consumption of fruit and vegetables was inversely associated with CRC in a comparison of the highest with the lowest EPIC-wide quintile of consumption (HR: 0.86; 95% CI: 0.75, 1.00; P for trend = 0.04), particularly with colon cancer risk (HR: 0.76; 95% CI: 0.63, 0.91; P for trend < 0.01). Only after exclusion of the first 2 y of follow-up were these findings corroborated by calibrated continuous analyses for a 100-g increase in consumption: HRs of 0.95 (95% CI: 0.91, 1.00; P = 0.04) and 0.94 (95% CI: 0.89, 0.99; P = 0.02), respectively. The association between fruit and vegetable consumption and CRC risk was inverse in never and former smokers, but positive in current smokers. This modifying effect was found for fruit and vegetables combined and for vegetables alone (P for interaction < 0.01 for both).
Conclusions: These findings suggest that a high consumption of fruit and vegetables is associated with a reduced risk of CRC, especially of colon cancer. This effect may depend on smoking status.
posted by Blasdelb at 5:38 AM on November 6, 2013

A high consumption of fruit and vegetables is possibly associated with a decreased risk of colorectal cancer (CRC). However, the findings to date are inconsistent.

That's exactly the type of result I would expect. For that reason, the bold assertion in Ames and Gold (1997) that lack of fruits and vegetables is the number 2 cause of cancer in the US (behind smoking!) makes me wonder about their other conclusions.
posted by Pararrayos at 6:14 AM on November 6, 2013

Wait, did you get past the abstract? There was indeed more reason to think fruit and vegetables were associated with a reduction in colon cancer in 1997 than 2007, as well as incidentally more reason to think so today than in 2007. There is stronger evidence for diets rich in complex carbohydrates, as well as lacking in red meats, being protective; but there was really nothing inappropriate about Ames' recommendations there.
posted by Blasdelb at 6:34 AM on November 6, 2013


*nerds out*

*comes back to actually read article later*

Ames is still alive? Huh.
posted by maryr at 7:13 AM on November 6, 2013 [1 favorite]

As Parcells put it, " the rest of your life, nobody can tell you that you couldn't do it."
posted by Senator at 7:25 AM on November 6, 2013

That's exactly the type of result I would expect.

What you quoted ("However, the findings to date are inconsistent.") is the background of the experiment. Inconsistent prior data was the reason they did a larger, presumably better study, which concluded that increased fruit & vegetable consumption is indeed associated with a lower incidence of colorectal cancer.

NB: the study only found an association, it was not a randomized trial in which some people were required to eat more fruits and vegetables for several years, so that should be borne in mind.
posted by jedicus at 7:38 AM on November 6, 2013 [2 favorites]

Thanks for posting this.
posted by JoeXIII007 at 2:44 PM on November 6, 2013

I've only had time to skim through the video, but already I have an idea for a rage-baiting petition demanding that certain chemicals be banned ... but have it actually be for banning tomatoes or coffee.
posted by kanewai at 6:30 PM on November 6, 2013

I know a lot of people who could stand to watch — and understand — this video.
posted by cthuljew at 9:03 PM on November 6, 2013

Plants contain a lot of toxins that are there to protect them against plant predators. Humans eat plants and have evolved defenses against the plant toxins. A general defense against the enormously broad variety of plant toxins is to clear damaged cells from the body. Eating more vegetables exercises this defense mechanism. A side effect of clearing damaged cells is to eliminate precancerous cells, since they are one type of damaged cell. Eliminating precancerous cells reduces later incidence of cancer. So an effect of eating vegetables is to protect you from cancer. There's a dose-response relationship where the more vegetables you eat, the lower your cancer risk. As a benchmark, eating a pound of vegetables a day cuts your cancer risk in half.

no cites, sorry, but I did used to do cancer research, and this story makes sense
posted by kadonoishi at 2:29 AM on November 7, 2013

"A general defense against the enormously broad variety of plant toxins is to clear damaged cells from the body. Eating more vegetables exercises this defense mechanism."

"A side effect of clearing damaged cells is to eliminate precancerous cells, since they are one type of damaged cell."

"There's a dose-response relationship where the more vegetables you eat, the lower your cancer risk. As a benchmark, eating a pound of vegetables a day cuts your cancer risk in half."
Each of these statements are pretty radically opposed to the conventional understanding in environmental oncology and I think would really need citations.

I mean,
Biological clues to potent DNA-damaging activities in food and flavoring
Population differences in age-related diseases and cancer could stem from differences in diet. To characterize DNA strand-breaking activities in selected foods/beverages, flavorings, and some of their constituent chemicals, we used p53R cells, a cellular assay sensitive to such breaks. Substances testing positive included reference chemicals: quinacrine (peak response, 51×) and etoposide (33×); flavonoids: EGCG (19×), curcumin (12×), apigenin (9×), and quercetin (7×); beverages: chamomile (11×), green (21×), and black tea (26×) and coffee (3–29×); and liquid smoke (4–28×). Damage occurred at dietary concentrations: etoposide near 5 μg/ml produced responses similar to a 1:1000 dilution of liquid smoke, a 1:20 dilution of coffee, and a 1:5 dilution of tea. Pyrogallol-related chemicals and tannins are present in dietary sources and individually produced strong activity: pyrogallol (30×), 3-methoxycatechol (25×), gallic acid (21×), and 1,2,4-benzenetriol (21×). From structure–activity relationships, high activities depended on specific orientations of hydroxyls on the benzene ring. Responses accompanied cellular signals characteristic of DNA breaks such as H2AX phosphorylation. Breaks were also directly detected by comet assay. Cellular toxicological effects of foods and flavorings could guide epidemiologic and experimental studies of potential disease risks from DNA strand-breaking chemicals in diets.
posted by Blasdelb at 4:36 AM on November 7, 2013

Dear god, not liquid smoke too? How will I make my barbecue sauce now?!
posted by mittens at 8:34 AM on November 7, 2013

There are some things that, while they may be unhealthy for the body, remain essential for the health of the soul.
posted by Blasdelb at 9:18 AM on November 7, 2013

"DNA strand-breaking activities."

When you start from the action of one chemical on another, and then draw conclusions about disease epidemiology, you're probably making a few assumptions along the way, ne?

I got to musing about this and wrote a tome. This isn't aimed at you, Blasdelb, it's just a bunch of stuff I've been thinking about for a long time, and you reminded me of it.

In the mechanism-meaning hierarchy in the natural sciences, starting at what you're studying, you can look down to understand how it works, and up to understand why it works that way.

Evolutionary ecology
Population biology
Cell biology

Starting observed fact: eating vegetables cuts cancer incidence. One looks down at mechanisms and finds that implausible. Another looks up at reasons and thinks it's quite plausible. Humans exist in a context of evolutionary biology, and the relevant bit here is we're plant predators and so are in an arms race with plants like any other predator.

If all this DNA-breaking activity were that serious we'd obviously all be dead, so there must be other mechanisms countering. Such as all our DNA repair mechanisms, but also reproduction, since we do eventually break down and die and only continue as a species by starting over periodically.

Ames's whole talk was about how we freak out too much over test results that seem to show a lot of chemicals are dangerous. Environmental oncology sounds like one of the fields that institutionalizes the excessive freakout. Ames even directly mocked the concern over chemicals (around 9:00 in the video) as mostly benefitting contract laboratories, lawyers and conference organizers.

Cancer is caused by viruses, anyway. That's what cancer _is_: old viral infections that fester and crop up years or decades later as malignancies.

Cancer, if it's caused by buildup of random damage as commonly conceived, has to obey this equation:

# cancer cases = population * # susceptible body parts/person * # damaging events/body part * cancer conversions/damaging event

The nature of the damaging event determines the kind of susceptible body part, and number of parts. If the damaging event is gamma radiation, the susceptible part is an individual atom, since gamma rays act on electrons. If it's a small chemical like benzene, then it's a molecule. If it's a large molecule like a protein, then the susceptible part could be a gene or organelle.

Then the issue is the last term, the number of cancerous conversions per damaging event. Gamma radiation can't distinguish between electrons in points of cancer vulnerability vs points involved in respiration and other maintenance activities; it's not _aimed_. So a lot of random gamma radiation will hit in spots that just result in general radiation damage.

Cancer is a specific, complicated mechanism where the cell has to retain all the complex machinery that allows it to grow. If a cell is too damaged, it can't become cancer, because it just dies.

I did some testing around possible values of these ratios, and the only way gamma radiation can cause cancer is if there's a single spot that can be damaged and turn a cell cancerous. If cancer requires two conversions, then, to hit those two spots enough times to result in observed cancer incidence, there would have to be so much radiation, and thus so much non-carcinogenic damage, that organisms would just die from radiation poisoning rather than develop cancer.

The same is true for small carcinogenic molecules, e.g. benzene. It only works if there are just two spots that need to be damaged to turn a cell cancerous. If it has to hit three, then again, hitting those specific three spots entails hitting so many other spots that the vast majority of organisms would just die of benzene poisoning rather than getting cancer.

And it doesn't seem likely that a single atom, or two molecules, could be the critical triggers of cancer. But three larger structures does start to seem plausible. A large biomolecule could act with specificity on three genes, and then it would be possible to get to the total number of observed cancer cases without killing the whole population with noncancerous damage. This is working within the constraints imposed by the equation above, which is derived by deduction as one logical consequence of the common conception that cancer is caused by buildup of _random_ damage.

A large molecule, capable of acting on a specific large unit of the cell mechanism, is too large to pass a cell membrane, an effective barrier. Only a large molecule can cause the observed incidence of cancer. So what's the likely mechanism here.

Viruses specifically inject large biomolecules through the cell membrane, biomolecules specifically evolved to take over cell machinery and make it go into overdrive while preserving the cell's ability to live and grow.

Viruses cause cervical cancer, HPV is basically the only cause of cervical cancer. More viral culprits keep getting identified.

The long lag time between the initial viral infection, which is countered by the body's defense mechanisms which shut down infected cells, which are in turn countered by the virus's mechanisms to block immune attacks on infected cells by withdrawing identifiable proteins sticking out of the cell to make it smooth, featureless, and difficult to identify and attack -- the long lag times make it hard for cancer researchers to connect the observed cancer with the original cause that might've happened 20 years before and looked like a simple passing illness.

When the immune response that jammed the infected cell in stasis eventually weakens and wears off, then the badly-damaged viral machinery can cough back into life and start the cell growing and multiplying without any checks, becoming a malignancy.

One mathematical model of cancer development fit the data well with an initial event, a long lag, then a second event. They were doing abstract math fitting models with various numbers of terms, without saying anything about what these events were, but it fits the festering-viral-infection idea well. The first event is the initial infection, and the second is the wearing-off of the known immune response of shutting down the infected cell.

Those cells sitting there, damaged by viruses, put into stasis by one of our immune responses as one way of stopping the infection, are damaged cells; and if our mechanism for removing cells damaged in other ways, as by plant toxins, gets revved-up by eating a whole lot of vegetables, then it's entirely plausible to me that more of those cells would get cleared out of the body, reducing the chance of one coming out of stasis in just the wrong biochemical configuration and becoming cancer.

Everyone knows that medicine doesn't actually cure people directly, but rather helps the body heal itself. No doctor can put all those billions of tiny bits of machinery back in order, of course, but they can kill enough bacteria to let the body take care of the rest, or set a bone so it can knit.

Looking up the mechanism-meaning hierarchy of the natural sciences, it seems to me that taking your immune system out for some exercise is a quite reasonable way to help your body protect itself from cancer. Looking down the hierarchy at cancer mechanisms should be fruitful, eventually, but it's a huge amount of extremely hard work and it's still, after 80 years of the war on cancer, not all that far along.

So I think, for now, for guidance on things like what I eat, I'll rely more on a worldview assembled in the upper regions of the mechanism-meaning hierarchy of the natural sciences, and less on the fragments of knowledge coming out of work in the lower regions.
posted by kadonoishi at 3:00 AM on November 8, 2013

I did some testing around possible values of these ratios, and the only way gamma radiation can cause cancer is if there's a single spot that can be damaged and turn a cell cancerous. If cancer requires two conversions, then, to hit those two spots enough times to result in observed cancer incidence, there would have to be so much radiation, and thus so much non-carcinogenic damage, that organisms would just die from radiation poisoning rather than develop cancer.

Radiation is an interesting example, because, as you pose it, it really does seem unlikely that there is a single sweet spot on the cell where, once hit, the cell becomes both immortalized and hidden from the body's clean-up processes. But what's wrong with the example is that it assumes there are only two levels of radiation--one low level, flicking at the cell, and one high level, killing the tissue (or entire body), and that this happens as a one-time event. It leaves off the fact that our cells are being assaulted all the time, and that many do die, in the kind of ferociously high numbers that make you wonder how we're surviving at all. In those numbers, there is plenty of room for a few lucky cells to survive with their all-new superpowers.

So, while yes, lots of cancers may turn out to have viral etiologies, I don't think you could make the leap and say that all cancer is caused by viruses. It leaves out too many interesting environmental exposures, like tobacco or asbestos in lung tumors. Or, say, nitrosamines in processed meat in stomach cancers (which, sadly, eating veggies does not seem to offer much protection from).
posted by mittens at 4:47 AM on November 8, 2013

(A group of renegade scientists, in an effort to spread optimism and hope, should replace all those cancer-prone lab rats with cancer-proof naked mole rats, perhaps putting them in little white fur coats so no one will notice!)
posted by mittens at 7:48 AM on November 8, 2013

kadonoishi: It would take too long to refute all of your points. You misunderstand how cancer is caused, how cell division works, how programmed cell death works, the immune system's role in programmed cell death, how viruses work, and how viruses cause cancer. There's a start.

I do not know what this "mechanism-meaning hierarchy" you keep referring to is. Is it the list at the top of your post?

Your formula is simplistic at best and you misunderstand your own variables.

You are so wrong on some of these points that I think you may be trolling me.

I'm so tired.
posted by someone is wrong on the internet at 12:10 PM on November 8, 2013 [2 favorites]

Hey SiWotI, not trolling, this is actually what I think, which of course may be wrong as that's the only rational stance toward claims about empirically observable reality.

I would observe that you do not know how cancer is caused, either. If we understood the precise mechanism, we could either intervene to stop it, or we'd know clearly why we can't.

Cell division and apoptosis aren't relevant. Viruses are shotguns where only a few pellets have to hit for the blast to be effective. The details of how viruses cause cancer are highly relevant and if you have more info, lay it on me (high-level non-technical please, I'm several years out of this field).

The mechanism-meaning hierarchy of the natural sciences is an idea from a biology professor of mine in college. He was looking at trees, and saying To know how this tree grows, look at cell biology, and to know why this tree is growing here, look at ecology. This framing (to know "how" look at one discipline, to get an idea of "why" look at a different discipline) puts the natural sciences into an ordered list.

I'm maybe not as tired as you, so if you have a particular point where I'm seriously wrong, I'll listen and learn.

Note that my main point is an attack on the idea that cancer is caused by an accumulation of "random" damage. People use "random" as a more respectable term for "I don't understand what's going on." I'm aiming to take seriously the idea of "random damage" and explore its consequences. "Random" here requires a set of objects that can be affected, and then impacts on those objects.

If the damage is from gamma radiation, then the objects are atoms because that is, physically, what gamma radiation acts on.

If the damage is from benzene, then the objects are molecules.

If the damage is from RNA, then you have to explain where this specifically cancer-causing RNA came from.
posted by kadonoishi at 7:28 PM on November 8, 2013

mittens: Yes, point well-taken that it's a leap from some cancers having viral etiologies to all cancers being caused by viruses. There may very well be many paths to cancer, and viruses are only one. I'd posit that viruses might be more understandable and are worthy of a focused research effort, as was attempted in the 1970s.

Radiation cannot possibly attack a whole tissue. Radiation is changes in single atoms, where some charge is violently flung out and the remainder sits in place and reconfigures. My main point here, I guess, is that you have to reconcile these atomic events with observed consequences in the population.
posted by kadonoishi at 7:54 PM on November 8, 2013

Cell division and apoptosis aren't relevant.

To cancer?
posted by mittens at 10:29 AM on November 10, 2013 [1 favorite]

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