As the end of summer approaches, you love to grill your food on the open flame. You savor that char-grilled flavor on your meat or fish. Perhaps you fashion yourself as a modern-day caveman, inspired by the Paleo Diet and getting back to Nature.

At the same time, you’ve probably heard that eating grilled meat is a bad idea, because compounds in the meat char can cause cancer.

According to the National Cancer Institute, grilling meat to the point of charring causes the formation of heterocyclic amines (HCAs), polycyclic aromatic hydrocarbons (PAHs), and Maillard reaction products such as acrylamide (AA) or advanced glycation end-products (AGEs). HCAs and AGEs are formed when the amino acids, sugars and creatine in meat react at high temperatures. PAHs are formed when meat fats burn. Maillard reaction products are those tasty brown “caramelized” substances produced by the reaction of sugars and amino acids when meats and other foods are cooked by grilling, baking, frying or toasting.

The National Cancer Institute reports that HCAs, PAHs and acrylamide have been shown to cause cancer in laboratory animals. Added to this are a number of epidemiological studies purporting to show an association between consumption of cooked meats and cancer.

So you reluctantly curtail your inner caveman and carefully scrape the blackened parts off your meats, or grill them at a lower temperature. Or perhaps you avoid grilling altogether, retreating indoors and lightly sautéing or boiling your meat dishes.

Relax. I’m here to make the case that charred meat is not to be feared. It may actually be good for you, hormetically boosting your general ability to neutralize and dispose of dietary toxins. In this blog post, we will take a closer look at the animal and human studies, combined with a deeper look at the evolutionary record, aided by the perspective of modern toxicology. I think it may change your mind.

Conventional wisdom. It’s not just Mainstream Health that pushes the idea that charred meat causes cancer. Even Paleo advocates like Mark Sisson warn against the dangers of grilling and cooking meats at high temperatures:

But there’s a dark side to cooking. Depending on the methods and ingredients you use and the temperature you apply, cooking can create carcinogenic and toxic compounds, and oxidized fats – and these may be involved in some of the diseases studied. It may not be the meat itself, but how we treat the meat. …The easiest way to minimize your exposure to heat-related toxins is to emphasize gentle cooking methods and de-emphasize higher heat methods.

Sisson cites the usual culprits — HCAs, AGEs, acrylamide — and oxidized lipids. He cautions particularly againt “grilling over an open flame – the worst”, pointing to its association with higher levels of HCA. He recommends gentle methods such as steaming, poaching, boiling, braising, simmering and baking.

We should be a bit suspicious of these claims, given the fact that humans have been cooking meat over open flames for more than millenium, inevitably creating char. If these claims were correct, we’d expect to see elevated rates of cancer among modern hunter-gathers who cook their meat — but we don’t. Just as the demonization of meat and saturated fat as agents of disease has been challenged by reappraisals of epidemiological and biomedical evidence, I think we should take a closer look at the shibboleth that charbroiling meat or otherwise cooking it at high temperatures poses a health risk.

The studies. Let’s look more closely animal and human studies which gave rise to these concerns about the compounds in grilled meats. Here’s what the National Cancer Institute actually says about the studies of HCAs and PAHs:

In many experiments, rodents fed a diet supplemented with HCAs developed tumors of the breast, colon, liver, skin, lung, prostate, and other organs. Rodents fed PAHs also developed cancers, including leukemia and tumors of the gastrointestinal tract and lungs.

However, the doses of HCAs and PAHs used in these studies were very high—equivalent to thousands of times the doses that a person would consume in a normal diet.

Population studies have not established a definitive link between HCA and PAH exposure from cooked meats and cancer in humans. One difficulty with conducting such studies is that it can be difficult to determine the exact level of HCA and/or PAH exposure a person gets from cooked meats.

Although dietary questionnaires can provide good estimates, they may not capture all the detail about cooking techniques that is necessary to determine HCA and PAH exposure levels.

So the NCI concludes that there is no direct evidence in humans that HCA and PAH from cooked meats causes cancer in humans. The argument is based upon extrapolation from studies in mice and rats. Even if you are worried about PAHs, there is nothing distinctive about meats. A 2003 Spanish study of actual measured dietary exposures to PAHs, found that vegetables, fruits, cereals and milk all have comparable or higher levels of PAH than meat. The average male in Spain who consumes these foods raises his risk of cancer by a 5-in-a million chance.

What about acrylamide? According to the American Cancer Society, “Based on the studies done so far, it’s not yet clear if acrylamide affects cancer risk in people.” They further state:

Acrylamide has been found to increase the risk of several types of cancer when given to lab animals (rats and mice) in their drinking water. The doses of acrylamide given in these studies have been as much as 1,000 to 10,000 times higher than the levels people might be exposed to in foods. It’s not clear if these results would apply to people as well, but in general it makes sense to limit human exposure to substances that cause cancer in animals.

Writing for the American Council on Science and Health, Joseph Rosen of Rutgers University criticized the rodent studies as flawed, based on the extreme levels, the mode of administration, and key differences between the endocrine organs of humans and rats, where tumors were noted. Based on the animal studies, Rosen concluded that “There is no credible evidence that acrylamide in food poses a human cancer risk.”

What about studies of acrylamide specifically in humans? A 2007 Dutch study linked acrylamide consumption to cancer in women, finding that women who absorbed more acrylamide were twice as likely to develop ovarian or womb cancer as those who ingested a smaller amount. But a closer look at this study revealed that the measure of acrylamide was based upon a self-reported food questionnaire, not actual clinical measurements. And there was no clear linkage specifically to meat consumption. As noted by Dr. Lesley Walker of Cancer Resarch UK:

Women shouldn’t be unduly worried by this news…It’s not easy to separate out one component of the diet from all the others when studying the complex diets of ordinary people. And as acrylamide levels are highest in carbohydrate containing foods – such as chips and crisps – other factors need to be firmly ruled out, especially being overweight or obese, which we know is strongly linked to womb cancer and probably linked to ovarian cancer. As Dr. Walker notes, it is misleading to connect the potential dangers of acrylamide specifically to meat, since levels are much higher in other foods, particularly high carbohydrate foods. According to the American Cancer Society, “Acrylamide is found mainly in plant foods, such as potato products, grain products, or coffee. Foods such as French fries and potato chips seem to have the highest levels of acrylamide, but it’s also found in breads and other grain products. Acrylamide does not form (or forms at lower levels) in dairy, meat, and fish products.” For an eye opener, consult the FDA’s survey of acrylamide levels in food. If you are worried about acrylamide, you might start by cutting out Ore Ida french fries (with 1098 ppb acrylamide), Hershey’s cocoa (909 ppb), Health Valley Original Oat Bran Graham Crackers (1540 ppb), Ak-mak 100% whole wheat stone ground sesame crackers (343 ppb), Safeway pitted olives (226 ppb) or Starbucks coffee (175 ppb). By contrast, none of the meat products on the FDA list had more than 100 ppb; many had undetectable levels.

In short, if you are concerned about acrylamide, there are more worrisome places to look than meats.

Evolution and dietary adaptation. But are mice and rats a valid model for assessing the toxicity in humans of compounds from cooked foods? Rodents may indeed be suitable animal models for many aspects of human physiology and toxicology, such as testing the safety of drugs, synthetic chemicals, and evolutionarily novel compounds. But animal models are mainly useful for understanding human physiological responses only where there are shared metabolic, immune, or detoxification pathways. This is of particular importance in toxicology, because what is toxic to one species is often harmless or even beneficial to another. Detoxification pathways vary considerably across species. For example, chocolate can poison dogs because the active ingredient, theobromine, is highly toxic to canines, while humans typically tolerate it well, and even find it to be beneficial. So if you relied on dog testing to determine your food choices, you would never eat another piece of chocolate.

Organisms evolve detoxification processes that respond to what they are likely to encounter in their diets and their environments. Humans have been cooking (and burning) food over hot flames since they diverged from other primates half a millennia ago, so they have had ample opportunity to adapt their detoxification responses to the compounds present in charred meat. It’s just not novel for us.

However, to the best of my knowledge, mice and rats don’t cook their meat — with or without fire. Meat char represents a novel toxin to rodents, so they are unlikely to have developed a strong system for detoxifying HCAs, PAHs, or acrylamide. Thus, rodents are not a reasonable model for assessing the toxicity of compounds produced by cooking meat.

The barbecuing species. There is compelling evidence that humans evolved to eat and thrive on a diet that includes fire-cooked foods – both meat and plants.

The evidence comes from several independent and reinforcing lines of evidence. While the idea of “man as cook” goes back at least to the anthropologist Claude Levi-Strauss, his main interest was in how cooking changed social psychology. The most comprehensive and convincing argument for the “cooking hypothesis” is laid out by Richard Wrangham in his 2009 masterpiece, Catching Fire, How Cooking Made us Human.

Wrangham supports his contention that cooking shaped human biology with several independent lines of evidence — including the findings of archaeology, anthropology, nutrition, evolutionary biology and physiology. I’ll try to summarize here the key elements and implications of Wrangham’s argument:

Archaeology. Based on excavation of artifacts like burnt bones at campsites, archaeologists trace the origins of cooking by fire to physical evidence dated to less than million years ago, but other evidence suggests the advent of cooking may have been between 1 and 2 million years ago. The timing of these archaeological events are mirrored in simultaneous dramatic changes in the teeth, jaws, digestive apparatus and brain of our human ancestors, most particularly Homo erectus, between 1-2 million years ago, as elaborated in Point #4 below. Anthropology. Cooking is practiced in every human society, including by modern hunter-gatherers. Hunter-gatherers lived in a wide variety of environments including deserts, mountains, the arctic and rain forests — but cooking is universal. While foods like fruits, organ meats, grubs and fish are typically eaten raw, most hunter-gatherers prefer to cook their meat, eggs and tubers. Nutrition. Cooking food dramatically increases the palatability, digestibility, tenderness and available caloric value of both meat and plants. Cooking meat and other protein denatures it, rendering it more accessible to the action of digestive enzymes. The benefits of cooking are not restricted to meats — cooking also makes plant foods more digestible. Given the limited availability and lean composition of meat in the tropics, equatorial hunter-gathers also need to consume plant carbohydrates, such as starchy tubers. Cooking gelatinizes the starch, increasing its glycemic index, and making it easier to digest and absorb its sugars that one could otherwise obtain from raw starch. Raw foodism is effective as a weight loss diet because uncooked food provides less caloric value and requires more energy and time to digest than cooked food. Domestic animals grow faster and fatter on cooked food containing the same caloric content as the equivalent uncooked food. Evolutionary biology. More nutritive and tender cooked food “remodeled” the bodies of early humans, enabling the evolution of a weaker jaw, smaller teeth, and a smaller digestive tract. Gorillas and chimpanzee are mainly herbivores. They have large molars to chew plant foods, and voluminous stomachs and large intestines capable of digesting and fermenting fiber from plants. By contrast, humans are less able than apes to digest, ferment and utilize fiber — largely because eating cooked food reduces the need for this capacity. The tenderness of cooked food enabled the human jaw and teeth to shrink. Human jaws and molars are the smallest of any primate species, relative to body mass. As a result of their more nutrient-dense cooked diet, humans eat half as much per pound of body weight as do great apes. The shift to a cooked meat diet also coincided with a doubling of the size of the brain of Homo erectus relative to that of Homo habilis and earlier hominids. The “expensive tissue hypothesis” holds that more nutritive cooked food dramatically increased the energetic efficiency and intelligence of humans, freeing us from time spent gathering and digesting, increasing hunting and migration range and propelling reproductive success.

The evolution of toxicity. One of the corollaries of the shift from raw to cooked food by early humans was a re-tooling of their sensitivity to and tolerance for dietary toxins. Wrangham draws out some very important, but often overlooked, consequences of this evolutionary change:

Beyond reducing the size of teeth and guts, the adoption of cooking must have had numerous effects on our digestive system because it changed the chemistry of our food. Cooking would have created some toxins, reduced others, and probably favored adjustments to our digestive enzymes….Take, for example, Maillard compounds, such as heterocyclic amines and acrylamide…They occur at low concentration in natural foods but under the influence of heat their concentration becomes much higher than what is found in nature…They can also induce a chronic state of inflammation, a process that raw-foodists invoke to explain why they feel better on raw diets. The cooking hypothesis suggests that our long evolutionary history of exposure to Maillard compounds has led humans to be more resistant to their damaging effects than other mammals are. It is an important question because many processed foods contain Maillard compounds that are known to cause cancer in other animals. Acrylamide is an example. In 2002 acrylamide was discovered to occur widely in commercially produced potato products, such as potato chips. If it is as carcinogenic to humans as it is to other animals, it is dangerous. If not, it may provide evidence of human adaptation to Maillard compounds, and hence of a long exposure to heated foods.

So while humans have adapted to better tolerate “toxins” like Maillard compounds in cooked foods, the converse is true for certain plant toxins that we expect apes to tolerate better than humans. Wrangham observes how this shift is readily demonstrated by differences in palatability and food preference between our species and the apes:

In my experience of sampling many wild foods eaten by primates, items eaten by chimpanzees in the wild taste better than foods eaten by monkeys. Even so, some of the fruits, seeds, and leaves that chimpanzees select taste so foul that I can barely swallow them. The tastes are strong and rich, excellent indicators of the presence of non-nutritional compounds, many of which are likely to be toxic to humans—but presumably much less so to chimpanzees….The shifts in food preference between chimpanzees and humans suggest that our species has a reduced physiological tolerance for foods high in toxins or tannins. Since cooking predictably destroys many toxins, we may have evolved a relatively sensitive palate. By contrast, if we were adapted to a raw-meat diet we would expect to see evidence of resistance to the toxins produced by bacteria that live on meat. No such evidence is known. Even when we cook our meat we are vulnerable to bacterial infections….The best prevention is to cook meat, fish, and eggs beyond 140º F (60º C), and not to eat foods containing unpasteurized milk or eggs. The cooking hypothesis suggests that because our ancestors have typically been able to cook their meat, humans have remained vulnerable to bacteria that live on raw meat….We fare poorly on raw diets, no cultures rely on them, and adaptations in our bodies explain why we cannot easily utilize raw foods. Even vegetarians thrive on cooked diets. We are cooks more than carnivores.

Wrangham’s “cooking hypothesis” is certainly intriguing. But is there any hard evidence that humans and apes (to say nothing of mice) actually have different detoxification mechanisms going on in their bodies?

I believe the answer is yes, but we first need a brief detour into basic toxicology to understand how mammals deal with dietary toxins. Detox 101. All organisms process and detoxify “foreign” or poorly tolerated compounds (including alcohol, caffeine and prescription drugs) by a process called “xenobiotic metabolism. (“xeno” = foreign). While the liver is our primary organ of detoxification, cells throughout the body have the ability to detoxify. The key point to understand is that detoxification occurs in two steps — Phase I and Phase II: The Phase I detoxification system primarily employs what is known as the Cytochrome P450 system to modify toxins. The Cytochrome P450 (CYP) system varies by species and occurs in all life forms: animals, plants, microbes — even in viruses. In humans, CYP enzymes are located not just in the liver, but also in the mitochondria or endoplastic reticulum of cells in most tissues of the body. The CYP enzymes work by chemically modifying (hydrolyzing, oxidizing or reducing) the toxins into less harmful, more soluble compounds. However, the end products of Phase I are typically reactive a “free radicals” that are often potential carcinogens if they persist in excessive amounts .

primarily employs what is known as the Cytochrome P450 system to modify toxins. The Cytochrome P450 (CYP) system varies by species and occurs in all life forms: animals, plants, microbes — even in viruses. In humans, CYP enzymes are located not just in the liver, but also in the mitochondria or endoplastic reticulum of cells in most tissues of the body. The CYP enzymes work by chemically modifying (hydrolyzing, oxidizing or reducing) the toxins into less harmful, more soluble compounds. However, the end products of Phase I are typically reactive a “free radicals” that are . The Phase II detoxification system is a separate set of enzymes that render the products of Phase I less harmful by “conjugating” them – that is, combining their reactive groups with cysteine, glycine or sulfur molecules to create unreactive, water soluble compounds that are readily excreted in the urine or bile. So what do we know about how our Phase I and Phase II enzymes handle the compounds in our cooked food diet? Let’s look at Phase 1 and Phase II separately. Phase 1 enzymes and the human diet. As noted in an excellent study by Kumar et. al. (2009), the single most important and abundant Phase I enzyme is humans is called CYP3A4. It is found not just in the liver, but throughout our bodies. CYP3A4 accounts for 30% of all the P450 enzymes expressed in the liver and about 80% of the CYP enzymes in the intestine! According to Kumar et al, CYP3A4 is considered “the most important drug-metabolizing enzyme in humans, due to abundance, wide spectrum and indelibility.” Now here is an amazing fact. Despite the fact that we share 99% of our DNA with chimpanzees, we humans have developed a very different detoxification system. Our CYP system has changed enormously since the evolutionary split from chimps. Our most prevalent detox enzyme, CYP3A4, is found at about twice the level, and in a changed form, in humans relative to chimpanzees. According to Kumar et al. “CYP3A4 evolution in the human lineage would most likely reflect the adaptation to a change in the physiology or environment of our direct ancestors.” While the human CYP3A4 for the most part has similar breadth and specificity of activity against toxins as the chimp version, the is one interesting exception: unlike the chip enzyme, the human variant very active in deactivating (“de-benzylating”) a toxic bile acid compound known as lithocholic acid (LCA). As Kumar notes, The activation of human CYP3A4 by LCA reported in our present work would be expected to increase the detoxification of this and other bile acids metabolized by the enzyme, although this remains to be formally demonstrated. In contrast to LCA, no activation differences were detected in response to the less toxic LCA precursor chenodeoxycholic acid and the other major primary bile acid, cholic acid. This suggested a previously unknown defense mechanism against LCA-mediated cholestasis, which evolved after the split of the common human-chimpanzee lineage. The physiological necessity of such a mechanism may be related to our ancestors, beginning with Homo erectus some 1.8 million years ago, having adapted to an energy-dense, meat-based diet. Contemporary human foraging populations derive more than half of their dietary energy from animal foods, in comparison with 5 to 10% observed in chimpanzees. This adaptation may have been a prerequisite for the subsequent dramatic increase in the brain size in the human lineage. It is noteworthy that meat-based diet increased the load of animal steroids and thus the risk of cholestasis. In short, the explosive increase of a single detoxifying enzyme, CYP3A4 is a kind of “molecular archeology” that points to the human adaptation to a cooked meat diet. Interestingly, CYP3A4 is also induced by PAH compounds, one of those “compounds of concern” associated with charred meat. In other words, humans are much better adapted than chimpanzees to detoxifying potential meat toxins. Phase 2 enzymes and the human diet. Now let’s look at how well humans deal the the reaction products of the Phase 1 system. In Phase II, the altered toxins from Phase I are conjugated and neutralized to form easily excreted compounds by the Phase II antioxidant enzymes. The Phase II system, sometimes called the Antioxidant Response Element (ARE) consists of endogenous antioxidant enzymes such as glutathione reductase

glutathione transferase

glutathione peroxidase

glucuronysyl transferase

quinone reductase

epoxide hydrolase

superoxide dismutase

gamma glutamylcysteine In an earlier post, The case against antioxidants, I described how our body’s own Antioxidant Response Element is far more capable and nuanced in dealing with free radical oxidants, than the ingestion of exogenous antioxidant “vitamins” like Vitamins C and E. How do we activate the Phase II enzymes? The Phase 2 system is not so much “induced” as activated by Phase 1 products and by strengthened by nutrients. Different foods and nutrients activate different Phase II enzymes: Glutathione conjugation: Brassica family foods (cabbage, broccoli, Brussels sprouts); limonene-containing foods (citrus peel, dill weed oil, caraway oil)

Glutathione conjugation: Brassica family foods (cabbage, broccoli, Brussels sprouts); limonene-containing foods (citrus peel, dill weed oil, caraway oil) Amino acid conjugation: Glycine

Methylation: Lipotropic nutrients (choline, methionine, betaine, folic acid, vitamin B12)

Sulfation: Cysteine, methionine, taurine

Glucuronidation: Fish oils, limonene-containing foods In my earlier post, The case against antioxidants, I provided a more extensive list of phytochemical-rich plant foods, herbs and spices that have been shown to activate the Phase II enzymes, including curcumin, green tea, garlic, rosemary, ginko, bee propilis, and even…coffee! Dietary hormesis. Once we understand that the Phase II system is turned on in response to environmental exposure, it becomes logical to ask the question: Can the char compounds in cooked meat themselves, if consumed in moderation, actually improve our health by building our tolerance for potential toxins and carcinogens? There is some evidence that this is indeed the case. For example, a 2007 study by Hayes in the European Journal of Clinical Nutrition found evidence that for dietary acrylamide as a “hormesis-inducing agent”. Among the studies cited by Hayes Mucci (2003) found that that higher levels of acrylamide intake were associated with significant reductions in large bowel, colorectal and kidney cancers

Collins (1989) in a study of 9000 workers exposed to acrylamide over 50 years, found a statistically significant decrease in deaths from all causes More to the point, there is some evidence that consumption of grilled beef itself activates our endogenous Phase II anti-oxidant enzymes. In a 2013 study of grilled beef consumption by 29 healthy non-smoking males, without prior occupational exposure to PAHs, it was found that twice-daily consumption of charcoal-broiled hamburgers resulted in significant increases in serum levels of antioxidant enzymes GOT, GPT and ALP. Levels of non-enzymatic “sacrificial” antioxidants decreased, but that is not surprising given the “load” put on the detoxification system. The bottom line. It’s time to summarize the argument in this blog post: Unlike any other mammal or primate, humans evolved to specialize in eating cooked meats and plants There is no direct evidence that the compounds produced by grilling meat are toxic or carcinogenic to humans. Activating our xenobiotic detoxification system by moderate consumption of grilled meat may actually strengthen our generalized ability to neutralize toxins and carcinogens Therefore, embrace grilled meats — don’t fear them. If you have any remaining qualms, grill in moderation, and eat a side of broccoli or Brussels sprouts with your steak or burger, or mix a little turmeric, rosemary, or garlic into the recipe. Happy grilling! …

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