The Dose Makes The Poison

When I started work as Public Health Toxicologist with the California Department of Public Health a little more than fifty years ago, the word “toxic” was seldom heard much less used as a topic of conversation. In recent years, the word has been discovered and become a fashionable adjective for a wide variety of undesirable things.

This has bothered me because ‘toxic’ has a very specific meaning that makes it an unacceptable adjective to use except when applied to harmful chemicals. Its use otherwise only confuses people and needlessly frightens them. I usually ignore the matter, but when specific foods are labeled as toxic, I can no longer remain silent.

The toxicity of chemicals may seem an odd subject for a website devoted to all things ketogenic. However, when one realizes that most things ketogenic are chemicals and that all chemicals obey the natural laws that govern toxicity, the idea of an article on toxicology in Ketopia may not be too far a stretch. To keep the discussion relevant, what makes chemicals toxic (harmful) will be explained using fructose and its imprudent “toxic” label for illustration.

A food, by definition, cannot be toxic. A food is a plant or animal product that is accepted by fact or custom as a substance that sustains life, supplies energy, and provides for growth, repair, and maintenance when taken into the body, usually by mouth. A toxic chemical is defined as a poison, which is a substance that destroys life or impairs health. These two categories are mutually exclusive. Despite the fact that the two are categories are exclusive of each other, they both obey the same natural laws of the science of toxicology.

The most recent nutrient to be tossed into the toxic pile is fructose. There is no argument that fructose is a harmful food when consumed in excessive amounts. What are excessive amounts? That has not yet been established, but the tremendous increase in unanticipated health problems accompanying consumption of high fructose products has alerted nutritional science that something really bad about dietary fructose is afoot.

We know that the metabolic breakdown of fructose bypasses glycolysis and joins the glucose pathway as it forms pyruvate for entry into the Krebs cycle. To this extent, fructose has the same inflammatory outcomes in kind if not in degree as glucose. Because of the structural difference between glucose and fructose, fructose has a very low glycemic index and is invisible to insulin. For these reasons, fructose was once considered to be a good sweetener for use by diabetics. This was the extent of what was known about the biochemistry of fructose when sugar was expensive and availability of fruits was only “in season.”

We have learned in recent years that consumption of large amounts of fructose is associated with high uric acid levels and gout. This was quite a puzzle because biochemists knew there is no way for the body to make uric acid from fructose. Good biochemical detective work revealed that the activation of dietary fructose by the enzyme fructokinase was an extremely energy expensive process that significantly depleted the body’s chemical energy pool.

In brief: The energy pool depletion results in local deficiencies of energy that cause massive numbers of cell deaths; cell death disintegration causes release of genetic material from the dead cells; disposal of genetic material involves breakdown to uric acid; the large amount of uric acid formed overwhelms the ability of kidneys to excrete uric acid, with resulting kidney damage and gout. Serious questions remain. What other more subtle biochemistry is dietary fructose engaging in? What other damage is fructose doing to consumers about which we have yet to learn?

Fructose is a perfect example of a basic tenet of modern toxicology that came from the writings of Paracelsus(1) “What is it that is not poison? All things are poison and nothing is without poison. It is the dose that makes a thing not a poison.” A dose has two parts; “how much” and “how often.” This is true of all chemicals, independent of their source (animal or plant), whether they are natural or synthetic, or what their function is.

The monosaccharide fructose is not known to have any unique role in human biochemistry, but in the small doses of a hundred years ago, it was not known to be harmful. The “how much” was small and the “how often” was infrequent. In fact, fruits were a highly valued food because of the essential micronutrients they contained; the fructose component was not an issue.

Unlike small doses, the large doses of fructose in the modern American diet have been shown to be very harmful. The “how much” is large and the “how often” is frequent. How much fructose consumed in one dose is harmful? How often can an amount of fructose that is thought to be harmless be eaten without eventually causing harm? The answers to these two critical questions are not known, but they must be dealt with to protect the health of the high-carbohydrate consuming public.

The “how much” and “how often” questions about fructose suggest that toxicity is not a simple concept. In fact, the toxicity of chemicals is of two kinds, neither of which actually bears any relationship to the other. Paracelsus was the first to recognize the existence of acute toxicity and chronic toxicity. Acute toxicity refers to the harm done by a chemical as a result of a onetime exposure. Chronic toxicity refers to the harm done by a chemical as a result of many repeated exposures. The Hazardous Substances Labeling Act (HSLA) of 1960 defines categories of toxicity and specifies procedures for toxicity testing.

The acute toxicity of chemicals is not relevant to foods. No substance that produced immediate illness or death from a onetime exposure would ever be considered for use as a food. With regard to chronic harmful effects, such as those now being found with fructose, the methods used for studying chronic toxicity would probably not be precise enough to detect adverse effects in sufficient time to be of value in preventing illness. In any event, the matter of toxicity of foods was resolved by the HSLA. It formalized the long-standing practice of exempting foods from toxicity testing.

There are a few micronutrients that do require exemption from HSLA for use in food because of their toxicity. The one I used often in trying to give people a perspective on “the dose makes the poison,” is actually a poison. That nutrient is vitamin D.

Any chemical that has an LD50 (Lethal Dose for 50 percent of the test animals) of 50 milligrams per kilogram of body weight must carry a Poison label. For a70 kilogram person, 50 milligrams per kilogram is the equivalent of about 1/16th of a teaspoon – a very tiny amount. Pure vitamin D has an LD50 of about 10 milligrams (400,000 International Units) per kilogram; if it were not exempted from HSLA as a food it would have to be labeled as a poison.

Yet vitamin D is an essential nutrient. Humans cannot live without at least 10 micrograms (400 IU) of vitamin D per day(2). This is an eye-opening example for people who think that a chemical that is toxic in any amount is also toxic in every amount. Incidentally, pure vitamin D is not available to the general public, and the vitamin D content in supplements is tremendously diluted.

The exemption of foods from toxicity testing should be of little concern because there are many scientific methods for studying potentially harmful chronic effects of chemicals other than those specified by HSLA. The problems like those of fructose do not come from the foods we have long known, but from new foods that are products of food engineering designed to enhance some commercially valuable quality, such as high fructose corn syrup synthetically concentrated from sugars to enhance their natural sweetness. The blame lays with the food regulatory agencies that permit products of food technology to be classed as foods before adequate investigation justifies their need and safety.

Further, it is criminal for any government agency charged with protecting the health of its people to reject science and support pseudoscience. Official sanction of the unrestricted use of fructose as a substitute for sugar is unacceptable. It is proper to publicize and protest such agency’s malfeasance. But there can be no remedy until someone goes beyond protest and examines the “why” of the malfeasance.


  1. Paracelsus was a Swiss physician who lived in the early 1500s. His observations concerning harmfulness or harmlessness of chemicals applies to all chemicals, regardless of their source or use. He is considered the Father of Modern Toxicology.
  2. Frank P, Ottoboni MA. The Dose Makes the Poison: A Plain Language Guide to Toxicology, 3rd Edition. John Wiley & Sons, Hoboken, NJ. 2011

16 Responses to “The Dose Makes The Poison”

  1. Great insight. I remember reading in the 1970s that a scientist–I wish I could remember his name–said if sugar were invented today it would be a controlled substance. That stayed with me all these years; I just wish I had believed it at the time.

    • I bet you it was Prof John Yudkin who said that. He was one of the people to waged war to sugar and its overlords for pushing it into everything to start a new generation of addicts (exactly how they did with todacco jsut during and after WWII). He questioned time and again why it was not a controlled substance…..

    • Alice and Fred Ottoboni

      We bet you are both right; Yudkin was a scientist with wisdom, honesty, AND courage. Unfortunately, he was overwhelmed by the pseudoscience of Ancel Keys and peers.

      We are so glad for you, Digby, you will never regret the change. All of us who follow Ketopia have a peak through the door at some wonderful things the low-carb/ketogenic diet will someday bring forth. Just as one example, check back to the great review of Thomas Seyfried’s Cancer as a Metabolic Disease by Michael O’Neill (June 30, 2013). There will be cures for all of the chronic inflammatory diseases including cancer.

  2. Alice and Fred Ottoboni

    Many thanks for your comment. We recall that quote too – but cannot recall its author. Perhaps someone out there will remember.

    However, have no regrets, Digbyde, it is NEVER too late. We did not learn of the dangers of a high carb diet until we were in our 60s. We changed our diet, improved our general wellbeing, and are now starting our 90s med-free, with NO chronic diseases.

    • We, my spouse happily joined me in this, started about three years ago, and it has made a great difference. We too are in our 60s, take no meds, and want the elder years to be as good or better than our younger days. I keep saying we were not meant to age into decrepit pill-popping elders which seems to be the norm nowadays.

  3. I think you a couple of things are not quite right. “breakdown of fructose bypasses glycolysis and joins the glucose pathway…” is not right. Fructose is incorporated into glycolysis at the level of the trios-phosphates.

    “We have learned in recent years that consumption of large amounts of fructose is associated with high uric acid levels and gout.” I think that the associations are with high uric acid but this has not been shown to cause gout. “activation of dietary fructose by the enzyme fructokinase was an extremely energy expensive process that significantly depleted the body’s chemical energy pool” The process is not any more energetically expensive than processing glucose. The depletion in ATP is seen when fructose is given alone which is not the normal way it is ingested.

    “the large amount of uric acid formed overwhelms the ability of kidneys to excrete uric acid, with resulting kidney damage and gout.” This is not true. It is what might happen but doesn’t. “Serious questions remain” is correct but no good research will be done if we are sure we know the answer. Current fructose research is embarrassingly poor.

    “What other more subtle biochemistry is dietary fructose engaging in? What other damage is fructose doing to consumers about which we have yet to learn?” Asking the question that way assumes that harm exists.

    “Official sanction of the unrestricted use of fructose as a substitute for sugar is unacceptable” I know of no movement to replace sugar (sucrose) with fructose. Replacing sugar with high fructose corn syrup is neutral but replacing either with glucose, that is starch, may actually be worse.

    • Alice and Fred Ottoboni

      We appreciate very much that Dr Feinman has taken the time to read our post

      In reference to his first comment, we show in Figure 6-1 Glycolysis, page 109, The Modern Nutritional Disease, 2nd Ed., that triose formation occurs at steps 4 and 5 of glycolysis, and at this level, fructose-1 phosphate enters the glycolytic cycle. Dr Feinman is correct. We should have been more specific and said that “fructose bypasses the first half of glycolysis and then joins the glucose pathway…,” but because we were writing for a lay audience who would not know what a triose is, we wanted to simplify the matter. Actually, the step at which fructose enters glycolysis is not germane to the subject of the post.

      In reference to “consumption of large amounts of fructose is associated with high uric acid levels and gout,” we have read a number of media reports of the association of both uric acid and gout with high fructose intake. (We did not use the words ’cause gout’; we know that associations cannot prove cause.) The fact that medical science accepts that high levels of uric acid cause gout (1) makes it logical for scientists who find an association between high fructose intake and high uric acid concentrations to assume that fructose would also be associated with gout.

      Dr. Feinman points out that fructose activation and glycolysis require approximately the same energy expenditure. We have not had time to evaluate this, but giving it credence makes the next statement a bit puzzling. “The depletion in ATP is seen when fructose is given alone which is not the normal way it is ingested.” Perhaps we are misinformed, but it is our understanding that high fructose corn syrup is often used alone as the sweetener source, such as in soft drinks. HFCS is also a component of many commercial foods – even hot dogs! – sans sucrose.

      Dr Feinman suggests that we are unfair to fructose when we wonder if the uric acid problem may foretell of another health problem related to fructose metabolism. We consider that it would be unfair to the fructose-consuming public to assume that the fructose/uric acid problem is a unique occurrence that does not require any further investigation. Studies of potential adverse effects of products designed for human consumption would not be undertaken if the possibility that the products might cause harm were rejected.

      Finally, Dr. Feinman’s comment “I know of no movement to replace sugar (sucrose) with fructose” brings us to suggest very respectively that Dr. Feinman read Ketopia more carefully and more regularly. The very next post after “The Dose Makes the Poison” is “Lustig, EFSA, Fructose, and Poison.” In the latter post, Dr. Ludwig states:

      The European Food and Safety Agency has just weighed in, in favour of the substitution of sucrose (table sugar: a disaccharide composed of the monosaccharides glucose and fructose) with fructose alone, the sweeter of the two – even to the point of allowing health claims for fructose on the packaging of processed foods.


      1. Mayo Clinic statement on cause of gout: l
      • First, I forgot about the European decision on fructose which seems truly whacko. On the rest, I am just giving you my perspective. So the reason that I think the step at which fructose enters glycolysis is germane is that the at some point, it is impossible to tell which glycolytic intermediate came from fructose and which from glucose. Our review is available without subscription at Studies of fructose should be undertaken but they should be designed to tell us what the harms and benefits are. I am concerned about a rush to judgement of the type we had (and are still stuck with) in saturated fat where we now recognize the unseen consequences (trans-fat) but we are now too far down the line to get general acceptance for the saturated fat that they replace. I thought your post at least started out trying to keep perspective but you seem to be drifting in the direction of being sure you know the answer. That’s the first step in rejecting science which you correctly warn about.

  4. What I meant to say was that it has not been shown that high fructose causes gout. Gout is not a disease. It is a symptom that is more or less identical to high uric acid. Dietary fructose is associated with increased uric acid but frequently so are the glucose controls, but neither are out of the normal range. The original studies were I believe in perfused liver and pure fructose was used. This does seem to have unique detrimental effects. It seems that the liver expects the two sugars to come in at the same time.

  5. I wanted to add that I am on your side. It is the threat to low-carbohydrate diets whose successes you have posted about that I see as the biggest problem here. Almost all of the studies indicting fructose compare into glucose rather than to replacing total carbohydrate with fat whose efficacy is established. If we take out sugar and put in those high fiber healthy starches, I don’t think that we will have accomplished anything.

  6. It might interest you to know that vitamin D is used in New Zealand as a poison for controlling possums. It may be that because these marsupials are nocturnal herbivores they are especially sensitive to vitamin D toxicity.
    “In New Zealand, possums have become a significant pest animal, and cholecalciferol has been used as the active ingredient in lethal gel baits and cereal pellet baits “DECAL” for possum control. The LD50 is 16.8 mg/kg, but only 9.8 mg/kg if calcium carbonate is added to the bait”

    • Alice and Fred Ottoboni

      Hi George,

      Please accept our apologies for not responding more promptly to your interesting note. The holidays have kept us hopping. We were fascinated by your comment about the use of cholecalciferol as a pesticide for possums. We have never heard of vitamin D being used as a pesticide at all. However, it is quite logical. We wonder if it is a fast kill or whether. like warfarin. is takes a few exposures.

      We wonder too, if possums, like rats and mice, cannot throw up, so they cannot voluntarily eliminate a food that makes them feel ill.
      Repeated exposures are finally lethal.

      Again, many thanks.

  7. MITBeta

    Incidentally, most essential chemicals that we ingest on a regular basis have a HUGE range between necessary and toxic. There is one chemical, however, that only needs to be doubled or quadrupled from normal ingestion levels to become acutely toxic. That chemical is water.

  8. Regarding fructose, I wish to add the element of biochemical individuality to the discussion. I react so poorly to fruit that I did a great deal of investigation into this subject.mwhat I learned is that there are some people who have what is called hereditary fructose intolerance and even the smallest amount of fructose can actually kill them. This is the reason intravenous feeding does not include fructose. I did not test positive for HFI (there are over 40 genetic variations known to date and only a few of them are tests for), but it is my belief that some of us can have partial impairment of fructose metabolism…much like people can have low thyroid or adrenal function without being completely deficient. There are also people who do not have HFI, but the fructose does not get metabolized due to another genetic variation and the result is that fructose does not cause any negative effects on their body. There is a family in Switzerland with this genetic anomaly that is being studied. I have an acquaintance who has lived on fruit for over 20 years and raised two boys on a fruit only diet. Her Uric acid level is in the low normal range. However, when I tried to eat a fruit-based diet my Uric acid level increased significantly. So, Roger Williams is correct: There is substantial biochemical individuality and one man’s poison may be another man’s harmless pleasure.

  9. ceteague

    Some one please clarify the need for dietary saturated fat in infants and children to Mrs. Oboma. As a teenager As a preteen, I was impressed that fat had twice the calories of other foods. So I essentially neutered myself and intentionally created a deficient diet that resulted in uncontrollable secret binging on everything, but especially, dry cake mix, of all things. Besides creating guilt and shame, it also changed my test scores which were far higher in grade school than high school and well, we just will not even discuss my dismal performance in college. I married a brilliant, and unrepentant fattish man, raised on braunschwager and converted him to skim milk and low fat items. NOW we are retired and are much happier and seemingly growing healthier with whole milk, grass fed meat, butter and blessed coconut oil. I recall all the smart guys in the back row in algebra looked like my guy. Thanks to their Moms who gave them whole milk.


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