Low Toxin Diet Grant Genereux's Theory Of Vitamin A Toxicity

[franko]

@Travis, in reference to my earlier question to you. Grant lays it out like this on p. 31 of PFP:

It makes sense to me, but I'm no biochemistry expert.

And as you can see in my above posts about the casein "deactivation" process described by Goldblatt and Moritz in 1926, it sure seems plausible to me that it had the requisite conditions to oxidize that retinol into retinoic acid.

 

[Travis]

> "Reason would dictate that the retinoic acid concentration of any food would be directly proportional to its retinol concentration."

Interesting.

Since you obviously have biochemistry knowledge, I would greatly appreciate if you weighed in on the matter of foods which may have their retinol converted into retinoic acid by oxidation.

Is it plausible that, as was done in many of the original VA deficiency diets, the process by which they "inactivated" casein (i.e. "destroyed" the retinol by heating and aeration) was actually just converting that retinol into retinoic acid?

It seems that the scientists at the time knew and understood they could "destroy" the retinol with heating and aeration, as you can read in this study:

Hopkins, 1920 - The Effects of Heat and Aeration upon the Fat-soluble Vitamine
The Effects of Heat and Aeration upon the Fat-soluble Vitamine

"It will be seen that the experiments described show in the clearest way that while the fat-soluble A factor is relatively resistant to the effects of heat alone, it is easily destroyed by aeration, presumably because it is a substance prone to oxidation."​

And in that study they demonstrated that the rats fed on this oxidized butter (heated and aerated) showed symptoms of xerophthalmia, which they interpret as proof they have "destroyed" the vitamin A.

But this fits Grant's theory too. Because his theory is that, in actuality, that processing converts retinol into retinoic acid. And the results were demonstrating retinoic acid poisoning.

So it is a cornerstone of Grant's theory that the explanation for many of these original deficiency experiments is that they unknowingly added retinoic acid into their "deficiency" diets by the heating/oxidation of some retinol source (e.g. casein or lard or what have you) and so their experiments were, in reality, demonstrating the effects of retinoic acid poisoning which they wrongly interpreted as being caused by VA deficiency. And that's what explains the dramatic disease effects seen so commonly in these studies — e.g. majority of the rats are sick and dead within 10 weeks time.

So it would seem the first step in backing up this theory, is to answer the question: Can heating and aeration of a retinol-rich food convert its retinol into retinoic acid?

About this Grant says:

"Remember, retinol is easily converted into retinoic acid via oxidation. All that’s needed to create the oxidation reaction is heat and oxygen."
​

So do you think it is plausible that these diets could be introducing retinoic acid via the oxidation of retinol? I've attached a screenshot from Grant's book describing one of these "deficiency" diets which could have RA from oxidized casein.

View attachment 10071

This is very interesting, and I think the type of oxidation the chemists had in mind was lipid oxidation. Of course the 'head group' can convert through the series (i.e. alcohol ⇌ aldehyde ⇌ acid), but just have a look at retinol's unsaturated 'tail:'

Even though it is conjugated, I think you could predict some lipid peroxidation. The methyl groups create tertiary carbon junctions that would stabilize a lipid radical, lowering the energy barrier for it's formation. Although not as unstable as linoleic acid on account of no bis-allyl hydrogen, I think you'd predict O₂ would also add to this lipid chain under certain conditions. There is a little iron in milk that could catalyze retinol peroxidation.

Peroxidized retinol would of course be totally inactive, yet when the terminal carbon alone is oxidized—once into the aldehyde, then again into the carboxylic acid—it would become the most active vitamin A.

In the 1960s, high pressure chromatography had become standard allowing all milk lipids to be fully-separated and characterized. For this reason, animal feeding studies conducted post-1960 are going to be more reliable here. Besides the oxidation/peroxidation of retinol given enough heat + O₂, you could also expect a degradation of other vitamins and even unusual polymerizations. I think feeding studies using boiled milk what be hard to fully-interpret due to diverse reactions.

 

[InChristAlone]

Why would a supposed very low VA diet cause retinoic acid toxicty and yet we have millions of lab rats for yrs and yrs who are NOT on a low VA diet and not getting all these toxic effects? Are you implying it's the oxidized VA causing all the effects and not retinol by itself because that seems to be where the logic is leading....

 

[franko]

Are you implying it's the oxidized VA causing all the effects and not retinol by itself because that seems to be where the logic is leading....

The oxidation of retinol results in retinoic acid.

And, yes, if you read Grant's books, you will learn that retinoic acid is at the core of his theory for explaining the toxicity of the Vitamin A family of compounds.

"Retinoic acid has about ten times the toxicity of vitamin-A (retinol). That is not to say that vitamin-A is not toxic. It is just not immediately toxic because it takes time to convert into retinoic acid. To better understand the relative toxicity between these two molecules, retinoic acid is by far the more toxic one. But, the conversion from vitamin-A (retinol) to retinoic acid is just a simple oxidation reaction. All that’s needed for the reaction to take place is a little activation energy and oxygen.

Therefore, since the conversion of retinol into retinoic acid is so simple, we can think of vitamin-A as just being the devil in disguise. The true sinister identity of retinol is only revealed after it has metabolized into retinoic acid. The takeaway here, and what’s critically important to remember is: Retinol is metabolized to retinoic acid in normal cells."
- p. 31, PFP​

This doesn't let retinol (or even beta-carotene) off the hook though, because they are essential precursors to retinoic acid.



Source: acute and chronic toxic effects of vitamin A | The American Journal of Clinical Nutrition | Oxford Academic

The oxidation of retinol into retinoic acid is a process that occurs both naturally in the body and also potentially via the synthetic processing of food (which is the theoretical explanation for the disease symptoms in the deficiency experiments).

But if you understand how consumed carotenes and retinol, can be converted into retinoic acid in the body, and how toxic retinoic acid is — as demonstrated clearly by the documented side effects of tretinoin (Retin-a) and isotretinoin (Accutane), which are essentially just pharmaceutical retinoic acid — then you can start to see the picture of how so-called "Vitamin" A can be so toxic.

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Btw, this may also explain the toxicity of fermented cod liver oil — not because of "rancid" or oxidized PUFAs but actually because of the oxidation of the retinol (which means converting retinol into retinoic acid). If the processing of the cod liver oil involves heat and oxygen then it's possible that a significant enough amount of the retinol was oxidized into retinoic acid.

And if that were the case then you'd expect to see that people who take FCLO may indeed get symptoms similar to the side effects of Accutane. So you could compare the symptoms people got from FCLO and to the side effects of Accutane. And then compare to the symptoms of hypervitaminosis A and you may start to see the whole picture.

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To back up this point about how intake of VA results in production of retinoic acid, here is a quote from a study that Grant features:

"An acute elevation of retinoids other than retinyl esters — eg, retinoic acid— occurs after the ingestion of a large amount of vitamin-A, possibly because the intestinal absorptive capacity is overwhelmed, which leads to the oxidation of retinol to retinoic acid by the intestinal enterocytes (30) and to the rapid formation of retinoic acid from retinol in certain cells (5). Whereas retinoic acid can be produced from excentric cleavage of beta-carotene in humans (31), it is generally considered a minor contributor to circulating concentrations, at least in normal, healthy persons."

Source: acute and chronic toxic effects of vitamin A | The American Journal of Clinical Nutrition | Oxford Academic​

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And retinoic acid is the key to understanding the Vitamin A connection with "auto-immunity" or immune system "flareups".

Grant explains:

"When there is retinoic acid in serum, or in the intercellular fluids, there is sure to be cellular damage. ​

Where’s this cellular damage going to happen most often? Well, once again it is going to be variable, and it depends, and it might be almost random. But, it is clearly going to most commonly show up in the eyes, and the adipose tissues, such as the skin.

The reason retinol and retinoic acid are so incredibly toxic is because being hydrophobic it easily slips through the cell’s fatty outer and nucleus membrane structures. From there the molecule’s cyclohexane group is a perfect fit into the cell’s RNA molecule 3.

The perfect fit allows the retinoic acid to quickly substitute itself into the RNA sequence. Once that happens, the cell’s DNA processing mechanism is severely damaged. This damaged mechanism then breaks the cell’s ability to properly and precisely weave together intricate proteins. The cell either detects this DNA damage, or just errantly due to the broken machinery, then starts generating damage alerting proteins. This action is what is called retinoid-induced apoptosis (cellular suicide). But, the damaged cell simply can’t hold its breath and kill itself off. No, it needs some help. Therefore, the damage alerting proteins are truly pleas for that help being sent out to the immune system. The immune system responds, calls in the troops and kills the now damaged and defective cell. There’s a bit more to it, but this process is what modern medicine has mistakenly termed “auto-immunity.” This fabricated term is especially wickedly evil because “auto-immunity” is just the downstream consequence of subtly overdosing on a so-called vitamin."

- p. 34, PFP​

 

[Travis]

The oxidation of retinol results in retinoic acid.

Not always. The conditions cited in that classic study could be expected to produce a hydroxylated lipid, or even the cleavage of the chain into two aldehydes. I can't believe you are still taking that book seriously.

 

[Travis]

And, yes, if you read Grant's books, you will learn that retinoic acid is at the core of his theory for explaining the toxicity of the Vitamin A family of compounds.

[...]

The reason retinol and retinoic acid are so incredibly toxic is because being hydrophobic it easily slips through the cell’s fatty outer and nucleus membrane structures. From there the molecule’s cyclohexane group is a perfect fit into the cell’s RNA molecule...​

Wait a minute . . . retinoic acid doesn't have a cyclohexane group, it has a 2,6,6-trimethylcyclohexen-1-yl group.

 

[Brother John]

@franko, I really appreciate you sharing this information with the forum. I'm sure it doesn't apply to everyone but there are people that are struggling with autoimmune issues that have tried everything to no avail or with only partial improvement and perhaps this could give them an additional avenue to explore on their healing journey.
I've suspected for many years that retin-a was a contributing environmental factor in my development of celiac disease. I learned it is advised against for people with celiac disease because it increases intestinal permeability via one of the interleukins.
It's also interesting that people with autoimmune diseases are reporting substantial improvements from the carnivore diet. It does make me wonder if vitamin A could be a factor for them. I could personally never go back to carb restriction but sadly the carnivore diet proponents are blaming everything on the carbs. This seems like a much safer approach.
Do you use eggshell or oyster shell calcium since you aren't eating dairy?

 

[Brother John]

@franko, I really appreciate you sharing this information with the forum. I'm sure it doesn't apply to everyone but there are people that are struggling with autoimmune issues that have tried everything to no avail or with only partial improvement and perhaps this could give them an additional avenue to explore on their healing journey.
I've suspected for many years that retin-a was a contributing environmental factor in my development of celiac disease. I learned it is advised against for people with celiac disease because it increases intestinal permeability via one of the interleukins.
It's also interesting that people with autoimmune diseases are reporting substantial improvements from the carnivore diet. It does make me wonder if vitamin A could be a factor for them. I could personally never go back to carb restriction but sadly the carnivore diet proponents are blaming everything on the carbs. This seems like a much safer approach.
Do you use eggshell or oyster shell calcium since you aren't eating dairy?

Good thoughts there Blossom!
Thanks,
Brother John

 

[InChristAlone]

I still think there is some kind of cofactor that may be missing for people with apparent vitamin A overload. I mean @Amazoniac banged on about how it can be difficult to supplement nutrients alone because they all work together in some way. I still think food retinol isn't likely to be toxic and that sunlight and thyroid are factors.

 

[franko]

Not always. The conditions cited in that classic study could be expected to produce a hydroxylated lipid, or even the cleavage of the chain into two aldehydes. I can't believe you are still taking that book seriously.

Wait a minute . . . retinoic acid doesn't have a cyclohexane group, it has a 2,6,6-trimethylcyclohexen-1-yl group.

I'm a big picture guy. And the big picture of his theory makes sense to me. If some minor details here and there are mistaken — that doesn't bother me.

As I've said, I'm no biochemistry expert. But you admit that it can oxidize into retinoic acid so it's at least plausible that some of it did, right?

And that's not the only piece of evidence that retinoic acid was present — because the fact that the symptoms produced were so sudden and severe (e.g. things like organ failure, blindness and death within 90 days) suggests that what was being demonstrated was no mere "deficiency", but a poisoning. And the symptoms shown are a match for the symptoms of retinoic acid poisoning, as shown by tretinoin and isotretinoin side effects.

So yeah, I don't just take his theory seriously, my judgement at this point is that his theory is probably correct, but obviously, it still has to be proven.

And, of course, the most convincing piece of evidence, for me, was that I tried the VA elimination diet experiment and it worked. And many people report similar healing by going on minimal VA diets. So there's something going on here. Most of these people don't even know why their carnivore diet worked – they just know it worked. And Grant's theory offers the best explanation — by far — as to why it works. Like, 1000x better than the next best explanation.

If someone out there has a better explanation as to why going on an all beef diet cures autoimmune disease — I'd like to hear it.

 

[Travis]

I still think there is some kind of cofactor that may be missing for people with apparent vitamin A overload. I mean @Amazoniac banged on about how it can be difficult to supplement nutrients alone because they all work together in some way. I still think food retinol isn't likely to be toxic and that sunlight and thyroid are factors.

But what causes what?

Arai, M. "Effects of retinoids on iodine metabolism, thyroid peroxidase gene expression, and deoxyribonucleic acid synthesis in porcine thyroid cells in culture." Endocrinology (1991)

'For example, vitamin A deficiency in rats was found to be associated with increased serum concentrations of thyroid hormones (3, 4). In contrast, excess vitamin A appears to have an inhibitory effect on thyroid functions.' ―Arai

'Figure 2 illustrates that TSH-induced iodide uptake was markedly reduced in cells cultured in the presence of 10⁻⁶ M retinol.' ―Arai

'The effect of retinol was dose-dependent, as shown in Fig. 3. Significant inhibition was detected at 10⁻⁸ M, and iodide uptake stimulated by 50 IU/ml TSH decreased to less than 30% by 10⁻⁵ M retinol.' ―Arai

'The potency of retinoic acid to inhibit iodide uptake was comparable to that of retinol.' ―Arai

'Analysis of the medium by TLC revealed that the TSH-induced release of [¹²⁵I]-T₃ or [¹²⁵I]-T₄ was markedly reduced in the presence of retinol.' ―Arai

'It can be seen that the TPO gene expression was reduced when thyroid cells were incubated with these stimulators in the presence of 10⁻⁶ M retinol.' ―Arai

'Inhibition of iodide uptake as well as release of organic ¹²⁵I by retinoids is compatible with earlier in vivo observations that vitamin A has suppressive effects on thyroid functions (5, 6).' ―Arai

'The inhibitory effect of retinoids on iodine metabolism was detected at 10⁻⁸ M, which is similar to levels of retinol found in rat or human serum (29).' ―Arai

'However, it is clear that inhibition of cAMP accumulation is not the whole explanation for the inhibitory effects of retinoids on iodine metabolism. Retinol was able to inhibit iodide uptake and TPO gene expression induced by 8-bromo-cAMP.' ―Arai
​

Reading this article, you would get the impression that retinol suppresses the transcription of thyroid peroxidase mRNA at nanomolar concentrations—likely via a nuclear receptor. Without this mRNA, the enzyme needed for thyroxine (T₄) synthesis cannot be produced and hormone synthesis cannot proceed.

Carotene cleavage has been shown to be under the control of retinoic acid, not thyroid hormone. Unless it can be demonstrated that thyroid hormones can transcriptionally regulate the cleavage of carotenes, it would be reasonable to assume that the historical association of carotenemia with hypothyroidism is not caused by β-carotene. In fact, those two conditions appear not to be causally-associated at all—or that is, not directly with each-other. Carotenemia and hypothyroidism are both symptoms of a different cause, hypervitaminosis A.

 

[Travis]

I'm a big picture guy.

Well I'm a bigger picture guy, and these are not merely 'minor details:' These are blatant errors that reveal a profound lack of comprehension. Yet I do think he's probably correct about the main thrust, and that more people probably do have subclinical hypervitaminosis A than is commonly believed. I have personally talked to three people on this forum who've mega-dosed vitamin A to the point of toxicity.

The milk & meat promoters hype-up retinol because it cannot be found in plant foods, as such, even to the point of recommending unsafe doses. I see retinol-mongering as irresponsible, and nobody in America supplemental amounts of this.

 

[franko]

Well I'm a bigger picture guy, and these are not merely 'minor details.' These are blatant errors that reveal a profound lack of comprehension.

Which error of Grant's is more than just minor detail?

 

[Frankdee20]

I was going to say earlier that the pizza isn't proof vitamin A causes mouth ulcers. Typically ulcers result from acidic foods too. I used to get at least a few a yr, I don't remember the last time I had one and I still eat liver occasionally (and pizza!).

That had to be the funniest ***t I’ve ever heard. I eat tons of liver, no mouth or genital ulcers here.

 

[franko]

That had to be the funniest ***t I’ve ever heard. I eat tons of liver, no mouth or genital ulcers here.

Welp, read this:

Hypervitaminosis A - Wikipedia

And if you get any of these symptoms some day, maybe you'll remember that wacky theory about Vitamin A.

 

[Travis]

Sharma, R. L. "Hypervitaminosis A Causes Degenerative Changes in Thyroid of Mouse." Research Journal of Recent Sciences (2012)

 

[InChristAlone]

Sharma, R. L. "Hypervitaminosis A Causes Degenerative Changes in Thyroid of Mouse." Research Journal of Recent Sciences (2012)

What kind of dosage does that translate to in humans? I really don't think lab rats are good indicators. Are lab rats even given access to UV light? Because humans need sunlight to thrive.

 

[Travis]

What kind of dosage does that translate to in humans? I really don't think lab rats are good indicators. Are lab rats even given access to UV light? Because humans need sunlight to thrive.

It's the sum of data that counts. Retinol has been shown to downregulate thyroid peroxidase in nanomolar concentrations by Arai et al., in cells of the pig, who's above-cited article has many citations demonstrating its anti-thyroid effects. Perhaps you should read some of these experimental studies and tell us what you think.

 

[InChristAlone]

It's the sum of data that counts. Retinol has been shown to downregulate thyroid peroxidase in nanomolar concentrations by Arai et al., in cells of the pig, who's above-cited article has many citations demonstrating its anti-thyroid effects. Perhaps you should read some of these experimental studies and tell us what you think.

Yes I see that, but what about humans who are given ample accesss to sunlight? Would it show the same toxic effects to the thyroid? I am not so interested in in vitro and lab albino rats. As Peat has said he notices the toxicity of A when under low UV conditions. I think those who are experiencing the toxic effects should take a vacation to the tropics. I think this thread has given me more cause for concern with A in the winter and to never supplement it.

 

[Travis]

Yes I see that, but what about humans who are given ample accesss to sunlight? Would it show the same toxic effects to the thyroid? I am not so interested in in vitro and lab albino rats. As Peat has said he notices the toxicity of A when under low UV conditions. I think those who are experiencing the toxic effects should take a vacation to the tropics. I think this thread has given me more cause for concern with A in the winter and to never supplement it.

I'm not trying to excessively fearmonger, I just had to point this out because many people on this forum concentrate on the presumed antithyroid activity of β-carotene while retinol is given a free pass. [?] I can not find one study indicating that β-carotene has antithyroid effects of any kind, yet retinol shows a direct dose-dependent inhibition on iodine uptake in the nanomolar range. Retinol also reduces expression of thyroid peroxidase and inhibits thyroxine synthesis.

The study below reports circulating retinol concentrations in 16,058 humans expressed as means of percentiles.

Ballew, Carol. "Serum retinol distributions in residents of the United States: third National Health and Nutrition Examination Survey, 1988–1994." The American journal of clinical nutrition (2001)​

The range of circulating retinol in males between the 1 and 99 percentiles—nearly all Americans—is between .87–3.42 μM. I think we can all agree that this is a surprisingly-narrow range, and is approximately the width of the red line below. The interpersonal variance in vitamin D, sex steroids, and growth hormone concentrations are all much larger than this; the range of retinoic acid is even tighter.

The liver is so efficient at sequestering retinol from the serum that large fluctuations are not observed until it becomes saturated and spills-over. Nonetheless, excessive retinol is correlated with osteoporosis within this narrow threefold range in the Nordic countries—yet this was on account of extreme intakes. Milk had been heavily-fortified with vitamin A in Sweden and Norway in the 1990's, and fish liver oil is somewhat popular there.

Autopsy data reveal widely-variable liver concentrations:

Huque, T. "A survey of human liver reserves of retinol in London." British Journal of Nutrition (1982)

'Median retinol stores (Table 5) were highest in individuals who had met sudden, accidental death.' ―Huque

​

Retinol can be stored in the liver, yet pre-retinol can exist as inactive dimers of β-carotene nearly everywhere in the body. Carotenes are cleaved into retinol as needed, and serve as antioxidants before that point.

I am still waiting for evidence that β-carotene can also inhibit the thyroid (@Amazoniac).