This past Thursday marked the one-year anniversary of The Curious Case of Campbell’s Rats, wherein we took a wild ride through over two decades of animal research in which Dr. T. Colin Campbell of China Study fame showed that dietary protein, whether it comes from animals or plants, protects against aflatoxin toxicity and the initiation of new precancerous lesions while simultaneously promoting the growth of precancerous lesions that have already formed. Most of these lessons promptly disappeared down the memory hole, so that the picture left to us in The China Study — where consuming animal protein is the leading cause of cancer while plant protein is benign — is radically different from the one Campbell had sketched onto the canvas of his many scientific papers.
Thursday also marked the release of Denise Minger’s review of Forks Over Knives, a new movie in which Campbell and his curious rats resurface once again. If you haven’t read this review, I’d recommend hopping over there and giving it a look. It might take a couple hours to get through, but the rigorous deconstruction of some of the pseudoscientific silliness in the movie, the positive and generous attitude she presents towards the intentions of the producers and stars of the film, and the dozen or two laugh-out-loud points all make the time spent well worth it.
Denise sleuthed out a few forgotten papers wherein researchers studied how dietary protein interacted with aflatoxin exposure in rhesus monkeys. The results suggested that low doses of aflatoxin were both more toxic and more carcinogenic to monkeys fed low-protein diets. High doses of aflatoxin, by contrast, would cause cancer in the monkeys gorging out on protein and just kill the others.
The model of aflatoxin-dosing used in these studies, discussed in more detail below, was much more realistic than the model used in most of Campbell’s studies, and thus the balance of the evidence suggests that adequate protein likely offers very powerful protection against cancer in someone who hasn’t already developed the disease.
In this post, I’d like to take advantage of a year of reflection to elaborate more precisely on how protein provides its protective effects — and the exciting news is that it involves our favorite tripeptide, known more formally as our good friend glutathione (which is pronounced like this: glute-uh-THIGH-own). The role of glutathione suggests we should emphasize adequate protein, nutrient-density, raw foods, and plenty of polyphenol-rich fruits and vegetables — not that we should eschew animal foods. These newly unearthed studies of rhesus monkeys provide a good opportunity to first revisit the curious question of dose as a prelude.
The Curious Question of Dose
Campbell spends a good portion of chapter three in The China Study arguing that protein provides a more compelling culprit than chemical carcinogens when it comes to cancer simply because the doses of protein used in his experiments were so much more realistic than the doses of chemicals used in most other studies. Yet he and his graduate student George Dunaif asked the question, ‘at what dose of aflatoxin does protein begin to promote cancer?’ in a 1987 paper (1) and the answer may be a little startling.
It is difficult to say, however, whether it is the answer itself or the obfuscatory way in which Campbell describes this experiment in his book that is more remarkable. Here’s his description (pp. 54-55, my emphasis in bold, his italics):
Up to this point, all of the animals were exposed to the same amount of aflatoxin. But what if the initial aflatoxin exposure is varied? Would protein still have an effect? We investigated this question by giving two groups of rats either a high-aflatoxin dose or a low-aflatoxin dose, along with a standard baseline diet. Because of this the two groups of rats were starting the cancer process with different amounts of initiated, cancerous “seeds.” Then, during the promotion phase, we fed a low-protein diet to the high-aflatoxin dose groups and a high-protein diet to the low-aflatoxin dose group. We wondered whether the animals that start with lots of cancerous seeds are able to overcome their predicament by eating a low-protein diet.
Again, the results were remarkable (Chart 3.5). Animals starting with the most cancer initiation (high-aflatoxin dose) developed substantially less foci when fed the 5% protein diet. In contrast, animals initiated with a low-aflatoxin dose actually produced substantially more foci when subsequently fed the 20% protein diet.
A principle was being established. Foci development, initially determined by the amount of the carcinogen exposure, is actually controlled far more by dietary protein consumed during promotion. Protein during promotion trumps the carcinogen, regardless of initial exposure.
I read the middle paragraph over and over again and I have to admit that the experimental scientist within me was befuddled. If I wanted to investigate the interaction of two levels (high and low) of two different factors (protein dose and carcinogen dose) —I would have used a 2×2 design with four groups:
- Low-aflatoxin, low-protein
- Low-aflatoxin, high-protein
- High-aflatoxin, low-protein
- High-aflatoxin, high protein
I would be able to depict the results in a table looking something like this:
Yet Campbell only describes using the second and third groups. Thus, he’s changed two factors at once, leaving neither with an appropriate control. He presents the results in Chart 3.5:
The scientist in me is still scratching his head trying to understand why Campbell would have designed the study in this way. The NIH isn’t known for its skimpy research funding. Surely, he could have used four groups of rats, so why would he have used two? It would appear that there is a simple answer: he didn’t.
Campbell doesn’t cite any reference in direct association with Chart 3.5 or in the three-paragraph passage I quoted above. He does, however, cite a study in which he varied the dose of aflatoxin (1) in the paragraph immediately preceding this passage, and in that study there were nine groups, not two. Here is the graph shown in the actual paper (you can click on it to enlarge it, if you’d like):
Campbell and his graduate student George Dunaif fed all nine groups 20% casein for two weeks prior to aflatoxin-dosing, during the two-week dosing period, and for one week afterwards. Then they switched the rats to a number of different diets. As we move right-ward on the graph, we see the effect of increasing doses of aflatoxin. As we move upward, we witness a greater incidence of precancerous lesions. There are two lines. The top line represents the groups that stayed on 20% casein, and the bottom line represents groups switched to progressively lower amounts of casein ranging from 16% at the second point to 4% at the last point.
It seems rather obvious now that dose matters as much as protein. For the rats fed 20% casein, the rule is simple: more aflatoxin, more lesions.
Campbell acknowledges this on pages 58 and 59, but his statements on page 54 that “foci development was almost entirely dependent on how much protein was consumed, regardless of how much aflatoxin was consumed!” (his italics and exclamation point) and on page 56 that “protein during promotion trumps the carcinogen, regardless of initial exposure” seem difficult to justify.
In fact, if we wish to compare a high-aflatoxin, low-protein group to a low-aflatoxin, high-protein group, as Campbell does in Chart 3.5, we should compare the point on the far left with the bottom point on the far right:
The point circled in red represents the high-protein, low-aflatoxin group. The point circled in blue represents the low-protein, high-aflatoxin group. Great Scott! There is no difference. No difference at all.
Yes, Dr. Campbell, about that graph. . . .
The original paper shows no difference, and the graph above shows an enormous nine-fold difference. Good ol’ Chart 3.5, my friends, appears to be science fiction.
But wait! It turns out that Campbell almost presents the real graph (as Chart 3.7) on page 59!
Almost. Except he takes a few liberties.
On the far left, he takes a single group fed the lowest dose of aflatoxin and 20% casein, waves his magic wand, and splits it into two separate groups fed 20% or 5% protein. Behold! The fictitious group receiving 5% protein actually has a lower lesion response. That’s a convenient magic wand.
Then he tells us that the groups represented by the entire bottom line received 5% protein, when in fact as we move from left to right these groups received 16%, 12%, 8%, and 4% casein. This allows him to state in the text that “In the animals fed 5% protein . . . There was no foci response, even when animals were given the maximum tolerated aflatoxin dose.” In fact all of the groups represented by the bottom line developed some foci response, with about 0.3% of their livers being occupied by foci, and some of them received as much as 16% casein.
The original graph made the lesion response in the lower-protein groups look smaller than it really was by beginning the vertical axis at 0.2 instead of zero. Chart 3.7 doesn’t put any numbers on the axis at all, but it makes the response in the low-protein group look even closer to zero. Thus you have to squint your eyes just to see that the difference in lesion response between the high-protein, low-aflatoxin group and the low-protein, high-aflatoxin group has morphed from no difference at all to a three-fold difference. How it morphs even further into a nine-fold difference in Chart 3.5 is something only a magic wand could know.
Unlike Chart 3.5, which has no reference, Campbell cites the paper he published with Dunaif (1) in direct association with Chart 3.7. Charts 3.5 and 3.7 conflict with one another because on a scale of science to fiction, Chart 3.7 is about 60% science and Chart 3.5 is about 80% fiction.
No doubt, Campbell was likely under pressure from his editor to simplify things for the lay reader and to tell the story more smoothly. The problem here is that the message is fundamentally altered as the inconvenient details are glossed over.
Fiction aside, the science part raises two important questions. First, why did Campbell choose these doses? Why 200-350, and not 0.1, 5, or 5,000? Second, just how realistic are these doses? Are we likely to ever encounter this type of aflatoxin poisoning in everyday life, such that this experiment may have some actual relevance to the range of human experience?
The answer to the first question is that he first performed a preliminary study with a wider range of doses, reported in the same paper. That study itself can help shed some light on the second question.
Dose-Response Curve or Death-Response Curve?
Before testing the protein-aflatoxin interaction displayed above, Campbell and Dunaif first tested a range of doses between 0 and 400 micrograms of aflatoxin per kilogram of bodyweight per day. Each dose was given ten times during the initiation period. All of the rats were fed 20% casein during this experiment. Here are the results:
As Campbell and Dunaif had explained, the first two doses yielded no lesions at all, and the third dose yielded “a barely detectable, but significant, response.” Once again, dose matters.
And just how high are these doses? We can get a sense of this if we look at the “death-response” curve:
We can see that the amount of aflatoxin required to produce precancerous lesions in rats fed 20% casein is quite close to the dose required to begin killing them. Each group started out with twelve rats, but the last three groups saw one, four, and seven of them die.
As Campbell and Dunaif noted, “The total dose for the highest dose group (4.0 mg/kg) approaches the median lethal dose of 5.0 mg/kg for male F344 rats.” The median lethal dose, or LD50, is the dose required to kill half the animals.
In the second experiment, discussed in the previous section, Campbell eliminated the highest-dose group, but kept the next two highest doses which had killed one and four out of twelve animals in the preliminary study. Even so, none of the animals died, and lesion development was only half that seen with similar doses in the first experiment. This may have represented less susceptibility in the second litter of rats. Regardless, these doses, so close to the deadly dose, are mighty high. As I noted in Curious Case, even to obtain the “barely detectable, but significant, response” you would have to eat over a million peanut butter sandwiches contaminated with the maximum allowable concentration of aflatoxin in just a few days time.
These data make it impossible to accept Dr. Campbell’s contention that “foci development was almost entirely dependent on how much protein was consumed, regardless of how much aflatoxin was consumed!” (his italics and exclamation point). The dose required to cause foci development in rats fed 20% casein was just under the dose required to begin killing them.
Who Knew? “Standard Baseline Diets” Are Full of Powerfully Protective Casein
Campbell writes in The China Study that the rats received a “standard baseline diet” for the first five weeks of the experiment, without noting that this “standard” diet happens to be 20% casein. This was a wise choice of words, considering Campbell managed to entirely avoid discussing a fact he full well knew: that high-protein diets promote proper detoxification of aflatoxin.
Here is the reasoning that Campbell and Dunaif gave for feeding the high-protein diet during the initiation period:
You’ll probably need to click on the picture to read it. Here’s the key part:
Animals . . . continued on the same 20% casein-based diet for 1 week thereafter to clear tissues of AFB1 and its metabolites and to terminate most, if not all, initiation.
AFB1 is an abbreviation for the type of aflatoxin they used. This almost sounds like an admission that high-protein diets promote detoxification of aflatoxin. And why wouldn’t Campbell admit this? He discussed it explicitly in a 1983 paper he published with his graduate student Scott Appleton (2).
Protein Promotes Detoxification
This is the paper in which Campbell and Appleton showed that protein promotes the development of precancerous lesions if fed after the dosing period, but protects against these lesions when provided before and during the dosing period, as discussed in Curious Case. They also showed in this paper that feeding the low-protein diet during the dosing period led to serious cases of liver toxicity:
Some degree of bile duct proliferation was observed in all animals dosed with AFB1. However, the groups fed the 5% casein diet during the dosing period had relatively severe bile duct proliferation and cholangiofibrosis. In these groups, the architecture of the liver was often distorted by fibrous septa. Groups fed the 20% casein diet during the dosing period had mild bile duct proliferation and no cholangiofibrosis.
These changes basically mean that the bile ducts had gotten unusually large and developed scar tissue in the animals fed the low-protein diets during the dosing period. These are signs of acute liver toxicity.
Campbell and Appleton offered the following explanation:
We reported. . . that AFB1, as the parent compound, inhibited rat liver mitochondrial electron transport at the antimycin A-sensitive site (10) and postulated subsequently (5) that the enhanced liver cell necrosis and acute toxicity observed in the low-protein animals could be due to the low rate of metabolism and clearance of AFB1 with a consequent effect on mitochondrial respiration.
Campbell’s experiments showing that unmetabolized aflatoxin is itself toxic and seriously destroys the energy metabolism of our cells (3) are very valuable, but seem to undermine one of his principle theses presented in the third chapter of The China Study: that we should reduce the activity of the enzyme system that metabolizes this toxin by eating a low-protein diet, and thereby protect ourselves from its harmful effects.
As it turns out, the little conundrum our livers face when confronted with a massive dose of aflatoxin is not how to keep the activity of this enzyme system low enough to avoid toxicity. It is, rather, how to grab hold of enough glutathione to complete the detoxification process. Unfortunately, glutathione should appear in the index of The China Study right between “Glaucon” and “gluten,” but any mention of this little tripeptide is conspicuously absent.
Detoxification — It’s Mo’ Than the MFO
Campbell gives us the impression that enzymatic detoxification of aflatoxin is basically a one-step process (pg. 49):
Here we see an enzyme of the “mixed-function oxidase” (MFO) family transmogrifying a relatively harmless chunk of aflatoxin into an evil monster about to gnaw away at our DNA with its terrifying fangs. Campbell acknowledges on page 51 that this enzyme system actually produces “mostly normal, safe products” and that it is only a small handful of byproducts that are “exceptionally dangerous.” And again, we could excuse Campbell for simplifying a complicated biological process for the lay reader and limiting the details to those necessary to make his point, if only the simplification didn’t fundamentally alter the message.
Scientists currently see detoxification broadly as a three-phase process (4). In the first phase, an enzyme will oxidize a portion of the toxin in order to make it more reactive and prepare it for the second phase. This is the part attributable to the “mixed-function oxidase” family. In the second phase, a special detoxification molecule such as glutathione, sulfate, or glucuronate is added to the toxin. This phase is called “conjugation.” It makes the toxin more water-soluble and tags it for excretion. The third and final phase is to get rid of the conjugated toxin, either into the urine or into the bile.
A problem arises when some poorly behaved toxin doesn’t follow the rules and actually becomes more toxic during part of the detoxification process. Sometimes this happens during the second phase, but it happens more often during the first phase. Yet the solution is never to stop the detoxification process — stopping it can’t stop the toxicity. The solution is to complete the detoxification process by inactivating the more dangerous metabolite and getting rid of it (4). In the case of aflatoxin, this all comes down to our good friend glutathione.
As we’ll see in the section below, a fuller summary of the detoxification process would look like this:
This graph is also a tremendous simplification. There are many reactive metabolites, and glutathione is not the only molecule that can complete the second phase. It presents a fuller picture, however, because it presents all three phases, and as we will see below the glutathione pathway appears to be the most protective way of completing the detoxification process.
Glutathione Is a Rat’s Best Friend
In the late 1970s researchers discovered that rats excrete aflatoxin into the bile largely as the glutathione conjugate (5). This clued investigators in to the importance of the second phase of the detoxification process and raised the question of whether the balance between the first two phases might determine the chemical’s toxicity and carcinogenicity.
Comparing aflatoxin metabolism in the rat and mouse proved to be a fruitful way of investigating this question (6). Toxicity is three to five times worse in rats than in mice, and mice won’t develop cancer even when fed over 60 times the dose needed to produce the disease in rats. Yet mice have three times the activity of the MFO system, the very system Campbell suggests we should suppress by eating a low-protein diet. So what’s their secret weapon? Turns out their GST enzymes (see the above figure) are super-powered: they’re over 50 times better than the ones rats have at hooking up aflatoxin to glutathione.
Depleting mice of their glutathione (6) or genetically altering them to rob them of their most powerful GST enzyme (7) both make these little buggers just as vulnerable to the toxic and DNA-damaging effects of aflatoxin as rats.
Even in rats, whose GST enzymes are so impotent, glutathione provides powerful protection against the initiation of precancerous lesions. We can demonstrate this by injecting rats with BSO, a highly specific inhibitor of glutathione synthesis, a few hours before we inject them with aflatoxin. A group of researchers did exactly this in 1997, and here are their results (8):
BSO only depletes glutathione maximally for about six hours. After a day glutathione levels mostly recover, and after two days they fully return to normal (9). Thus a single bout of glutathione depletion during the very moments of aflatoxin dosing massively increases the development of precancerous lesions over the course of three or ten weeks, but even after almost a year — half a lifetime for a rat — a very substantial effect remains.
This should lead us to wonder, just how does glutathione status fare when a rat is fed on 5% casein?
Good Grief! Campbell’s Rats Have No Glutathione!
Lucky for us, Campbell investigated this question and published his results in 1981 (10). The full-text of the study is available free on his web site. Those 5% casein diets he praises throughout The China Study slashed glutathione levels by 70% in the livers of male rats and by 40% in the livers of female rats.
These results are comparable with what BSO injections achieve (9, 11, 12, 13, 14, 15, 16, 17). This is remarkable. BSO is used as an experimental tool to demonstrate certain biological phenomena are dependent on glutathione status. It’s a very powerful tool for mechanistic studies, not a nutritional supplement. I doubt any toxicologist would ever dream of eating it, even though that would have virtually no other effect than to deplete glutathione to the same extent as we see in Campbell’s rats.
This would also neatly explain why these 5% casein diets increased the formation of precancerous lesions when they were fed before and during aflatoxin-dosing, as explained in Curious Case, just like BSO does when injected hours before aflatoxin-dosing.
Campbell cites this study on page 56 (chapter three) of The China Study but the word “glutathione” appears neither in this chapter nor in the index.
And If We Don’t Fall Into the Aflatoxin Pool?
In Curious Case, I wrote that one would need to eat 270,000 peanut butter sandwiches per day for four days, each containing 100 grams of peanut butter contaminated with the maximum allowable concentration of aflatoxin in order to obtain the amount of aflatoxin that produced a “barely detectable, but significant, response” in Campbell’s studies. After a year of reflection, I consider this an unrealistic scenario. I don’t believe that peanut butter sandwiches are high enough in reward factors to induce anyone to eat this much.
In most of Campbell’s animal studies, he used an acute dose of aflatoxin, usually consisting of about ten doses over a period of two weeks. This was useful as a reductionist measure, because it allowed him to analyze the initiation and promotion periods separately. But it’s quite irrelevant to human experience, except for industrial accidents. If someone were to somehow accidentally fall into a vat of aflatoxin they would receive an acute dose where precancerous lesions may be initiated in a short period of time, followed by a lifetime in which their growth and development can be promoted by various dietary factors. The rest of us are exposed to small doses of carcinogens every day.
What is the effect of protein in animal models where aflatoxin is fed in small amounts every day? In Curious Case, I cited the “obscure study from India” that Campbell says launched him on this track (18) wherein rats fed low-protein diets were completely protected from cancer and precancerous lesions, but half of them died, while half of the rats fed high-protein diets developed precancerous lesions or cancer and none of them died. This suggests that about half the animals in each group were vulnerable to these doses of aflatoxin, and that it was death itself that rescued the vulnerable half of the low-protein rats from this fate.
In Denise Minger’s review of Forks Over Knives, she discussed two enlightening studies conducted in rhesus monkeys (19, 20). In these studies, a chronic low dose of aflatoxin produced precancerous lesions in monkeys fed 5% casein but not in those fed 20% casein; a chronic medium dose saved the low-protein monkeys from precancerous lesions by — yup, you guessed it — killing them, while the high-protein monkeys suffered neither plight; and a chronic high dose was finally able to give the high-protein monkeys pre-cancerous lesions. In the latter group, the preneoplastic lesions were able to transform to neoplastic lesions, meaning their potential to begin proliferating abnormally was realized.
A simple way to view this would be to suggest that adequate protein promotes proper detoxification of aflatoxin by providing sufficient glutathione to complete the detoxification process. This protects against both its toxic and carcinogenic effects. It takes a lower dose to give an animal precancerous lesions than to kill the animal, so in animals fed low-protein diets increasing the dose will shift the effect from precancerous lesions to death. Only when the dose is large enough — and as we’ve seen, these are massive, almost lethal doses — can the aflatoxin overwhelm the glutathione pools of rats fed on high-protein diets and cause cancer. Once cancerous or precancerous lesions are initiated in these animals, protein supplies the lesions with the raw materials they need to grow and progress.
Granted, as Campbell argues, we are probably always walking around with some initiated “cancerous seeds,” so it is not as if no initiation at all takes place until we get to near-lethal doses. It is simply that among the many competing biological events that occur when we are chronically exposed to low doses of carcinogens in everyday life, the protective, detoxification-promoting effect of protein prevails.
We could summarize the chronic aflatoxin-dosing experiments as follows:
Insofar as we can generalize from these animal experiments to humans, they provide a potential rationale for using low-protein diets to treat cancer patients, and raise the important clinical question of how to best maintain proper detoxification in these patients. For the rest of us, these data emphasize the need to eat adequate protein, not to eat vegan “plant-based” diets devoid of animal foods.
Indeed, oral glutathione can reverse fully developed liver cancer in aflatoxin-dosed rats (21), raising the survival rate from zero to 81%, suggesting that maintaining robust glutathione status may especially be of interest to the cancer patient, despite any possible benefits to protein-restriction.
Boosting Glutathione Status
As I largely covered in “The Biochemical Magic of Raw Milk and Other Raw Foods: Glutathione,” maintaining robust glutathione status comes down to a few basic points:
- Eating adequate protein, defined thus far as one gram per day for every kilogram of body weight.
- Obtaining sufficient nutrients for the synthesis and recycling of glutathione, especially riboflavin, niacin, and magnesium.
- Eating plenty of raw foods, especially raw milk or raw fruits and vegetables, and possibly raw egg whites, to provide dietary glutathione or its precursors.
- Eating plenty of polyphenol-rich foods, such as fruits and vegetables, to stimulate glutathione synthesis.
- Having robust energy metabolism by cultivating an optimal hormonal milieu.
- Preventing oxidative stress by minimizing inflammation, optimizing metabolism, and eating a broad range of nutrient-dense foods.
(The usual warnings apply that some people don’t tolerate fruits and vegetables well, some don’t tolerate milk well, and some could develop a biotin deficiency or digestive troubles when consuming raw egg whites.)
In the future, I’ll expand on some of these points, and write more about glutathione with an emphasis on human studies.
Unfortunately, it seems Dr. Campbell missed most of these points when writing The China Study, which I suppose isn’t that surprising considering he wrote almost 25 pages about his decades of research on aflatoxin without ever mentioning the word “glutathione.”
Nevertheless, Dr. Campbell’s own research showing that adequate protein is needed to maintain robust glutathione status, to promote proper detoxification of aflatoxin, and to protect against the initation of precancerous lesions will provide valuable health information for generations to come for those of us who look beyond the pages of The China Study.
Read more about the author, Chris Masterjohn, PhD, here.
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