Response to " What I've Learned is Wrong about Bacon and Cancer"

Hi Everyone,

One of y'all asked for a rebuttal to the video of 'Mic the Vegan' 's stating that I got the facts wrong in my recent video on bacon/processed meat. Even if you didn't see the video, I think this will be a fun read because it lets me further highlight the type of rigor and critical thinking I try to encourage with my videos.  
[PDF attached for easier reading]
Mic's arguments seem pretty compelling if you don't dig into the video too much, but ... 

Flaws with Mic’s video at a glance:
-While I did not mean to suggest “sodium nitrite added to bacon makes it good for the arteries” in my video, Mic does not present sufficient evidence to claim nitrate/nitrite from the plants is good whereas nitrite from bacon is bad. (Fun fact: 93% of the total ingestion of nitrite is derived from saliva)
-Skips over some very complicated science presented by a PhD in Pharmocology & Physiology with ad hominem logic.
-Misinterprets me as saying ‘nitrosamines cannot be formed in the body,’ I didn’t say this.
-Confuses red meat with processed meat.
-Uses studies that are looking at “apparent total nitrosamines” rather than specific nitrosamines in meat. This is important because there are several types of nitrosamines with different severity of effects on the body.
-His data for endogenous formation of NDMA is based on in vitro studies looking not at red meat, but fish, and in specific, a type of fish that has the specific precursor to NDMA (DMA) in its muscle. Meat does not typically have this precursor. The study even found no NDMA formation from grilled meat.
-Mic confuses total endogenously formed NDMA with NDMA formed endogenously as the result of eating red meat/processed meat. (The study he references makes no mention of endogenous NDMA formation via meat consumption.)  

1:45 - Mic: ‘WIL claims sodium nitrite in bacon is beneficial like the nitrates/nitrites found in plants. This is false.’ (Paraphrasing)

Actually, I was trying to get the viewers to think of why it would be that when a compound comes from plants is good, but when the exact same happens to be present in bacon, it is then bad for you. As Mic acknowledged, I purposely tried to be neutral in my narration to avoid such misinterpretations like “bacon is the food of choice to improve artery function,” but considering I didn’t explicitly say “I’m not saying bacon is the food of choice for improving endothelial function,” I think it’s fair to address this as Mic did.

✳︎My point - Mic doesn’t provide sufficient evidence to say nitrite in bacon is bad for arterial function where nitrate/nitrite from plants is good for arterial function.

Consider the following quote from this paper: NO-Rich Diet for Lifestyle-Related Diseases
“In fact, cured meats have been reported to generally comprise only 4.8% of the daily nitrite intake, and surprisingly, 93% of the total ingestion of nitrite is derived from saliva [114], suggesting that cured meats provide minimal contributions to the human intake of nitrite, even if they are frequently consumed.”

Mic the vegan says:
-It’s well documented that the nitrates in plants turn into nitric oxide, which is good.
[Mic study 1 - Red and processed meat consumption and risk of incident

coronary heart disease, stroke, and diabetes: A systematic review

and meta-analysis]

-The idea that “processed meat is associated with increased heart disease risk” suffers the exact same criticisms I presented in my video:
(1) The data relies heavily on questionnaires.
(2) The relative risk for processed meat and heart disease in this paper is far under 2 at 1.46. Look up “Bradford Hill Criteria” and see my comment at the very end of this document.

-Mic says “however plants that are high in these nitrates are associated with lower risk," while referencing this study: [Mic study 2 Association of dietary nitrate with atheroscleratic vascular disease mortality.]
This is another association study meaning another observational study meaning they used a “a validated food-frequency questionnaire to evaluate dietary intake.” So the study finds that nitrates from plants are associated with less chance of death. The study authors didn’t extract the nitrate from the plants, randomize people into two groups where one group ate specially modified plants that were “de-nitrated” and the other group got normal nitrate containing vegetables… so this study is subject to the same criticisms I presented in my video. People who are likely to eat more vegetables are likely to follow other pieces of health advice: don’t smoke, exercise, drink enough water etc, but the people who say “screw it, I want my bacon and hot dogs, coca cola never killed anyone” are the type of people who drink more coca cola and don’t exercise. Look at the comment at the end of this document.

Mic Quote at 3:07: “So no it doesn’t appear bacon is good for your arteries.”
Again, while I did not say “bacon is good for the arteries” in my video, Mic’s evidence for bacon not being good for the arteries (these two studies above) is not sufficient at this point.

Quoting mics narrative from 3:11 in the video: “Well there is a major difference between the nitrates in plants and the nitrates and nitrites in processed meats in terms of what happens within the body. There is a fork in the road if you will, a fork where these nitrogen compounds can either go the way of the dark side or the light side. ...Let's compare these nitrogen compounds from meat or plants as they enter the body with plants it’s quite simple:
That nitrate gets turned into nitrite by your saliva, and then a portion of that in your body can be turned into nitric oxide, which again is very beneficial for your arteries. So again, that nitrate to nitrite to nitric oxide - and then in terms of the nitrates and the nitrites that are added to processed meat (I know this gets confusing) the nitrates will also be turned into nitrite, so to keep it simple- everything past the mouth is gonna be a nitrite which will then be turned into one thing or another thing. It doesn't appear that those plant nitrates are gonna be turned into nitric oxide at all. I haven't found any evidence for that.”

✳︎In response to: “It doesn't appear that those plant nitrates are gonna be turned into nitric oxide at all.”

[Mic Study 3 - Inhibitors of endogenous nitrosation. Mechanisms and implications in human cancer prevention.]
At 4:37 Mic points out that certain compounds in plants inhibit nitrosation, and that these compounds are why plant nitrates don’t cause nitrosation.  The 1988 study he refers to is done by Ohshima and Bartsch: "Such inhibitors of nitrosation include vitamins C and E, phenolic compounds, and complex mixtures such as fruit and vegetable juices or other plant extracts." 

The same two people did a study 7 years earlier in 1981 which found that nitrate, with proline, caused the urinary excretion of the nitrosamine N-Nitrosoproline. The nitrate containing liquid they gave the volunteer was ...beet juice. Beets are a source of vitamin C but not enough perhaps?

Cabbage has plenty of proline (almost as much as beef) and plenty of nitrate - the combo the 1981 paper used to form N-Nitrosoproline. Cabbage has around 718 mg/kg of nitrate, 5% of nitrate is converted into nitrite in the body, so we’ll say there’s 36mg/kg of nitrite in cabbage. Bacon has an upper sodium nitrite concentration of 27 mg/kg - less than cabbage.
Of course cabbage has vitamin C - a lot more than beets, in fact. Is that enough vitamin C to cut the nitrosamine formation down to zero? Well, according to this paper, No. Even when you hit an amount of vitamin C ten times the amount expected to halt all nitrosamine formation ...there is still some nitrosamine being formed.

This leaves us with a couple interesting options:
(1)Bacon and cabbage are both carcinogenic, but cabbage is less so thanks to vitamin C and perhaps other compounds.
(2)Bacon eaten with enough of the right greens (or green tea...) can be rendered not carcinogenic or only as carcinogenic as cabbage. (Wouldn’t it be nice if the IARC said something like “...though, ½ cup of green tea and 2 tablespoons of lemon juice mitigate 90% of the negative effects of 50g of bacon.”)
(3)Neither are carcinogenic (or, if bacon is carcinogenic, it’s not through the action of nitrites).

Let me point out however, that we are left at this point with the same questions that I sought to address in my video:
(a) How is nitrite from vegetables/drinking water/saliva different from nitrite in processed meat?
(b) We understand nitrite itself is not the cancer causing agent, but the downstream compound of a reaction with nitrite (nitrosamine). How much of which nitrosamine will give you cancer at what rate?
(c) What is a realistic amount of this cancerous agent you can acquire from food.

While I do not explicitly say it in the video, this is the point of the video: to encourage this type of critical thinking. Despite saying things like “I’m not saying we should all eat more bacon” or “I rarely eat processed meat myself,” my aim with the video seems to have been misconstrued as “let’s all eat more bacon.” Let’s maintain this level of vigilance in our thinking as we move on.

[Mic study 4 - Red Meat-Derived Nitroso Compounds, Lipid Peroxidation Products and Colorectal Cancer]
Going back to my point (1) under “a couple interesting options,” Mic says at 4:48 that this study: Red Meat-Derived Nitroso Compounds, Lipid Peroxidation Products and Colorectal Cancer says that "...heme iron helps this process of [forming nitroso compounds] take place..."
The study shows that as you eat more red meat, there is more formation of nitroso compounds



And, it seems to be the heme iron that is causing this.


As a counter argument to my video, this is not as relevant as it seems. I didn’t talk about heme iron in my video. The paper only mentions nitrite/nitrate once. It says “in germ-free rats, the endogenous formation of nitroso compounds only occurs in the presence of intestinal microflora,” and certain strains of bacteria could make use of a nitrate or nitrite reductase at a neutral pH to form nitroso compounds. “However, this activity strongly varies among humans[18]…” Reference 18 refers to Dietary modification of intestinal bacterial enzyme activities--potential formation of toxic agents in the gut.

Then, the study finding increased nitroso compounds from eating more red meat (rather than sodium nitrite containing processed meat) was measuring ATNC - “apparent total nitroso compounds.”

This is not a perfect analogy, but for the sake of painting a mental picture, think about it like this. A celebrity is found dead in their apartment from an apparent overdose. The coroner reports that “the deceased took a total of 10 milligrams of drugs.” So, we can assume at least 10mg of drugs is lethal for some percentage of people. ...obviously we want to know which drug it was.

While it’s not cancer data, we can say that based on LD50 data, N-Nitrosodimethylamine is 10 times more toxic than N-Nitrosoproline. This is why I take issue with the fact that this study was looking at “apparent total nitroso compounds” rather than specifically which nitroso compounds were found in the feces.

So, at this point we can say that red meat increases the amount of nitroso compounds excreted in the feces. What component of red meat is doing this? Probably the heme iron. Is the amount of endogenous formation of nitroso compounds from red meat enough to realistically cause cancer? This paper is far from answering that question.

5:45 - Mic skips over the Dr. Mark Miller article

In my video, I directed viewers to an article Dr. Mark Miller posted to his linkedin page. Dr. Mark Miller has a PhD in Pharmacology & Physiology (Honors) from the University of Adelaide, was a fellow of the American College of Nutrition for 6 years, has 3 decades of experience in academic research. He has been published many times with over 6000 citations on research gate. I came across his article when looking at his paper Nitric Oxide III. A molecular prelude to intestinal inflammation in the American Journal of Physiology - Gastrointestinal and Liver Physiology. I chose to include Mark Miller’s article because of his qualifications, but more importantly, his research is specifically relevant to the topic at hand.

In the article, Mark Miller made these four points:

“In short, dietary nitrate and nitrite do not provoke cancer via nitrosamines because they are:

•too stable

•the wrong charge 

•must be converted to other reactive nitrogen species

•the rates that nitrate and nitrite are converted to nitric oxide can support cardiovascular functional optimization but are inadequate for nitrosamine formation, for the same reasons that endogenous production from either nNOS or eNOS do not support nitrosamine formation, and neither does saliva.”

One other point which will become relevant later on is that the physiological state of a person will also change endogenous nitrosamine formation, particularly in states of immune activation.

...but Mic didn’t address any of these points apparently because he didn’t like that Mark Miller is apparently affiliated with MLM’s? Not sure what to say if he wants to ignore these points with ad hominem logic, so let’s move on.

[Mic Study 5 - Processed meat and colorectal cancer: a review of epidemiologic and experimental evidence]

At 7:02 Mic puts on screen a quote from this study: "Decarboxylation of amino acids by gut bacteria yields amines and amides that can be N-nitrosated in the large bowel (65). Heme from meat strikingly increases NOC formation(66)..."

✳︎Mic misunderstands my video: Yes, N-nitroso compounds are formed in the body, I never said they cannot be formed in the body. Red meat seems to increase the amount of N-nitroso compounds formed in the body. Again. I did not refute (or even address red meat) in the video.

Again, Mic is confounding sodium nitrite containing processed meat (the subject of my video) with red meat (not the subject of my video). As per the quote, amino acids can lead to the formation of N-nitroso compounds thanks to the action of gut bacteria. Heme iron also increases NOC formation. This is very different from “sodium nitrite is directly turned into N-nitroso compounds in the body and then causes cancer.”  

What is reference 66 from the above study looking at? Apparent total nitroso compounds in feces. Do we know which nitroso compounds? No.

This is interesting, by the way. Look at the individual variation in apparent total nitroso compounds found in feces:


Could nitroso compound formation be dependent on the physiology of the individual person?

✳︎Mic misunderstands my video:
7:42 [Mic Quote] "point is, increasing that red meat intake actually put your fecal nitrosamine content on par with people who smoke, which is really not a good thing, and further more he is just patently false saying that you aren't making nitrosamine endogenously within your own body."
Re: highlighted portion - I didn’t say you can’t make nitrosamine endogenously.

[Mic Quote] “He then continues the entire video with the assumption that endogenous nitrosamines aren’t a threat or aren’t part of the equation.”

I didn’t say this outright either, but my video could be interpreted as saying ‘exogenous intake of nitroso compounds from processed meat is more important than the endogenous formation of nitroso compounds as a result of eating processed meat’, so let’s move on assuming I did say that.

Mic criticizes the rat study I used to make my point that you would need an unrealistically large amount of processed meat to give you a dose analogous to that which induced cancerous tumors in rats. Mic’s criticism stands - rat studies have their limitations, but you’re not going to find a study where they give humans a known carcinogen just to know what the minimum amount to cause cancer is.

He points out that I only looked at one Nitrosamine, NDMA, which is true. As made clear in my video, the reason I did this is because NDMA seems to be the most toxic based on LD50 data and the other reason is that this is the compound used in the study I referenced.

9:10 - Mic points brings up studies looking at total nitrosamine content of processed meats.

[Mic quote] “But there are several nitrosamines that cause cancer, we have NDEA, which is in notable amounts in meat, you add all these together and…”

Yes, other nitrosamines are also carcinogenic. But the point of my video was to investigate the amounts of specific nitrosamines in processed meat, then compare that with data we have on the amount that would give you cancer.

[Mic Study 6 - Determination of total N-nitroso compounds and their precursors in frankfurters, fresh meat, dried salted fish, sauces, tobacco, and tobacco smoke particulates.]

Mic brings up the above study on screen and says:
"Here's doctor Greger's summary of the findings: ‘4 hot dogs has more [Nitrosamines] than a pack of 20 cigarettes...’"

So here we have to go to the Greger video to see that Greger is pointing at these two data points:

Wow. That is pretty compelling - 4 hot dogs has more Nitrosamines than a pack of cigarettes.

Three things:
(1) If that were a worthwhile comparison, why do we see a tremendously different risk from smoking cigarettes and eating processed meat? The IARC said eating 50g of processed meat a day incurs a 18% increased risk of colon cancer (this is a relative risk of 1.18), whereas depending on which study looking at which population of smokers, you’ll find up to 3000% percent increased risk of lung cancer. The relative risk of small-cell lung cancer in Korean smokers in this study was 21.7

(2) Do you eat your hot dogs or  light them up and inhale the hot dog smoke into your lungs?

(3) We again run into a familiar problem: In the study they are looking at total N-Nitroso compounds. Which nitroso compounds? That’s not listed in the table. Here are the four nitrosamines the IARC lists in their table of nitrosamines found in processed meat:


N-Nitrosodimethylamine
LD50 Rat oral 27-41 mg/kg

American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991., p. 1128

N-Nitrosodiethylamine
LD50 Rat oral 280 mg/kg

Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2708

N-nitrosopiperidine
LD50 Rat oral 200 mg/kg

Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2723

N-Nitrosopyrrolidine
Oral LD50 rat = 900 mg/kg

O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1148

Just looking at the toxicology, we can assume their effects on the body are drastically different. N-Nitrosodimethylamine is 30 times more toxic (in rats) than N-Nitrosopyrrolidine.

9:50 - Mic: ‘It is really the endogenously produced nitrosamines we should be worried about.’

[Mic Study 7 - N-Nitrosodimethylamine (NDMA) in Food and Beverages: A Comparison in Context to Drinking Water]
Mic brings up this study and pulls this quote on screen:
“Another in vitro study showed that 0.37 μg of NDMA was formed endogenously for each gram of nitrate and/or nitrite-rich food ingestion (Fristachi and Rice 2007)” 

The 2007 Fristachi and Rice study actually comes up with that calculation based on data from this study. Here is the in vitro study:

In vivo means “in an organism.” In vitro literally means “in the glass,” i.e. outside the biological context. Here’s the gastric model used in that in vitro study to check NDMA formation:

There are four issues with this study:
(1) This is not looking at what happens in a person or even an animal.
(2) While the study referencing this study comes up with a calculation of how much NDMA (0.37 micrograms) is produced per gram of “nitrate rich foods,” this is not what the study is simulating. It is simulating the amount of nitrite you would get from swallowing your own saliva. (As you’ll remember, part of the nitrate to nitrite to nitric oxide cycle takes place in the saliva)
(3) This is not looking at processed meat or even meat. In fact, quoting from the study: “Pike perch, as an example of a non-gadoid fish species, and grilled steak tartar, as an example of meat (data not shown), did not result in NDMA formation above the background level.”
(4) Why did they specifically look at non-gadoid fish? Probably because gadoid fish form Dimethylamine (DMA) in their dark muscle. Maybe that stuff is in meat then? Nope.

Uh oh. Maybe we need a new IARC report: “Thanks to compounds naturally occurring in your saliva, eating cod fish increases your risk of colon cancer.”
Except, a 6 month intervention trial found no effect on colon cancer from cod fish.

[Mic quote] “Back to endogenous NDMA creation, which is real!” Again, I didn’t say nitrosamines or NDMA couldn’t be formed in the body.

Here’s another quote from Mic from the study:
“The data reported in Hrudey et al. (2013) were approximately 70 times the estimates in Fristachi and Rice (2007).”

That quote comes from this study:
Drinking Water as a Proportion of Total Human Exposure to Volatile N-Nitrosamines

This study is interesting. Here are some highlights:
(1) Does this study discuss the formation of NDMA from processed meat or even red meat? No.

[Abstract]
(2) “Our analysis, based upon human blood concentrations, indicates that endogenous NDMA pro- duction is larger than expected.” Interesting. But what is the cause of this endogenous formation? We don’t know.

[Section 2.3 Endogenous Formation of Volatile N-Nitrosamines]
(3) The precursor to forming NDMA, Dimethylamine (the same stuff found in dark muscle of cod), was found already in saliva, blood, gastric juice, feces and urine. See the following table:

Did the study say where these precursors came from? No. Was it from meat or processed meat? The data presented above would suggest no, because dimethylamine wasn’t found in meat.  

(4)Wait a minute... Reading further in the article, I came across something that sounded familiar. Something that sounds a lot like what Dr. Mark Miller was talking about in the article that Mic brushed off: “In Wales, patients who had bladder infections were found to have measurable levels of NDMA, NPIP, or NPYR in their urine, whereas none was detected in 10 control subjects on the same dietary regimen.”

Quote from Mark Miller’s article: “Those results in gastric cancer identify that the nitrogen oxides may well be linked to gastric cancer, but the source of the problem lay in the immune response, not the generation of nitrogen oxides in the lumen of the stomach through interactions with acid.”

Could it be the case that the physiological state of the body, in particular the amount of immune response activation has more to do with the formation of Nitrosamines and less with the amount of bacon you eat?

Quote from the study Mic brought up (emphasis is mine):
“There are papers in the biomedical literature that have associated various disease states with increased endogenous formation of nitrosamines. The literature is too large to review in detail, but selected papers that associate systemic infections with increased nitrosamine formation in humans and experimental animals are cited to make this point.
・Leaf et al demonstrated that stimulation of tissues with Escherichia coli lipopolysaccharide increased NO synthesis from L-arginine and this was associated with an increase in NMOR in the urine of the rat.
・Elicited (activated) rat neutrophils nitrosated 2,3-daminoanaphthaline, whereas circulating, nonelecitic neutrophils did not.
・Experiments with woodchucks infected with woodchuck hepatitis virus showed increased NDMA levels in urine by a process that was dependent upon L-arginine.
・In a follow up study, a 10-fold increase in the nitrosation of morpholine by infected hepatocytes was found with stimulation by lipopolysaccharide.
・Ohshima et al. found that nitrosamine biosynthesis mediated by nitric oxide synthase was increased by infection with liver flukes.
・Humans infected with liver flukes were found to have increased nitrosation of proline and thioproline in an extragastric site relative to noninfected controls.
・Urinary excretion of both volatile and nonvolatile N-nitroso compounds was increased in humans infected with schistomiasis relative to noninfected controls.”

Sounds like the inflammatory response could be more important than bacon for nitrosamine formation.


11:14 - Lastly, Mic brings up this table to say exposure to NDMA from endogenous sources is quite significant.

Is data presented showing how the endogenous exposure is thanks to red meat or processed meat? No.

Quote from Mic: "So clearly, endogenous NDMA matters - it's a real threat and the amount that you could create from an actual amount of meat that you would eat is clinically relevant."

The papers he has presented in this video do not support the notion that NDMA creation from meat is clinically relevant.

Maybe that’s why the IARC report itself on page 497 says “there is inadequate evidence in experimental animals for the carcinogenicity of consumption of processed meat.”


[11:36 - 12:51 Mic’s sponsor message]

12:52 onwards
Mic says that studies with a relative risk under 2 should still be taken seriously.
I won’t spend too much time on this because he hasn’t addressed the criticisms of observational studies I presented in the video:
-They are often based on questionnaires that ask people to estimate their average consumption of select foods over a period of months to years.
-Healthy User Bias: It is a massive challenge to separate the effect of one food from the effects of the other foods likely to be eaten with that food. I.e. If you are the type of person to eat a lot of hot dogs, you are probably not the type of person to take other health advice to exercise, not smoke.
The IARC report itself says: “For example, intake of processed meat was associated with intake of French fries, sweets, cakes, desserts, snacks, and alcoholic beverages (Fung et al., 2003; Dixon et al., 2004; Kesse et al., 2006).”

Mic gives the example: “Let's say you have a 20% increase risk of heart disease with some compound that we've been adding to the water nationally, well if that's a 20% increase risk of heart disease death that would translate to about 120,000 more heart disease deaths in the US."

The point of not investing people’s time on studies that find a relative risk under 2 is not to say “not enough people are dying so let’s forget it,” but to say “These types of studies have serious flaws, so unless the RR is over 2, it’s hard not to discount the results as noise so we should investigate something else.”

I recommend to check out this presentation by John Ioannidis, at 5:55 he begins to talk about the Bradford Hill criteria and observational studies.

Recap: Mic’s video:
-Doesn’t sufficiently address the criticisms I brought up for observational studies in my video, then uses two observational studies at the start of his video.
-Skips over some very complicated science with ad hominem logic.
-Misinterprets me as saying ‘nitrosamines cannot be formed in the body,’ I didn’t say this.
-Confounds red meat with processed meat.
-Uses studies that are looking at “apparent total nitrosamines” rather than specific nitrosamines in meat.
-His data for endogenous formation of NDMA is based on in vitro studies looking not at red meat, but fish, and in specific, a type of fish that has the specific precursor to NDMA (DMA) in its muscle. Meat does not typically have this precursor. The study even found no NDMA formation from grilled meat.
-Mic confuses “total endogenously formed NDMA” with “NDMA formed endogenously as the result of eating red meat/processed meat.” (The study he referenced made no mention of NDMA formation via meat consumption.)