Mason

My colleague, Dr. Robert Russell, is an internationally-acknowledged expert in the field of retinoids and carotenoids. Today, he will help guide us through the latest advances in this field, try to clarify several of the controversies that confuse both health professionals and patients alike and provide some perspectives on how advances in this field might impact on our clinical practices today.

Rob, please begin by telling us about the recently revised Recommended Daily Allowances set by The National Academy of Sciences.

Revised RDAs

Russell

The National Academy of Sciences actually has a Recommended Dietary Allowance only for vitamin A (retinol). They set no RDAs for any carotenoid (such as beta-carotene) and there are no Recommended Dietary Allowances set for any vitamin A derivative, such as retinoic acid. The new Recommended Dietary Allowance for vitamin A is slightly lower than the old Recommended Dietary Allowance for vitamin A. For adults, the RDA is now 900 ug/d (3000 IU) for males and is 700 ug/d (2300 IU) for females. These are 100 ug/day less than the old 1989 RDAs for vitamin A.

The revised Recommended Dietary Allowances for vitamin A were established on the basis of new knowledge of the average rates at which vitamin A is destroyed in the body as well as the average efficiency of absorption of vitamin A from the diet.

Mason

I know that the RDAs have always included a retinol equivalent dose to take into account the biologic conversion of carotenes to vitamin A once they enter the body. My understanding, also, is that these conversion rates have been altered. This has significant implications in regard to how much carotenoids might be appropriate for supplementation. Can you fill us in on this?

A Less Efficient Carotene Conversion

Russell

The efficiency of conversion of carotene (and I am going to use beta-carotene as the prototype carotene here since it is the most common carotene that appears in vegetables and fruits) has always been known to be rather poor. For the past 30 years, it was thought that it takes six ug of beta-carotene in the diet to yield one ug of vitamin A in the body. However, in the past few years, there have been several studies that have shown this carotene conversion is much less efficient than 6 to 1.(1) Using sophisticated stable isotope studies, as well as field studies of efficacy of beta-carotene feeding on vitamin A status, it is now estimated that it takes 12 ug of beta-carotene to yield one ug of retinol; thus, the efficiency of conversion is only half of what was previously thought.

This means that vegetarians are going to have to pay attention to eating more carotene-rich fruits and vegetables (which are, generally, the most deeply colored fruits and vegetables) in order to get enough vitamin A. That said, if a person chooses the right fruits and vegetables (that is, the most carotene-rich ones), it is still quite easy to obtain the RDA for vitamin A. For example, all it takes is 1/2 c of cooked carrots to meet the 900 ug/d of vitamin A that is required for an adult male.

However, if you particularly like non-colored fruits and vegetables, or light colored ones such as white potato, iceberg lettuce, white asparagus or apple, it is important to be aware that these foods have little or no carotene or vitamin A value. Tomatoes contain a carotene (called lycopene) which cannot be broken down to vitamin A. We can talk about lycopene later.

Labeling: Confusion

Mason

Rob, given this transition in regard to what is the accepted rate of conversion from carotenoids to vitamin A, what should people be aware of when they read the label of a vitamin supplement that says part of the vitamin A in the supplement is being given as B-carotene?

Russell

You are right that many vitamin supplements contain at least part of their vitamin A content as beta-carotene. Unfortunately, there is a lot of confusion about this at the present time, since the Food and Drug Administration has not mandated any new regulations that would make the vitamin companies change their labels, even though we now know that the efficiency of beta-conversion to vitamin A is only half as good as what we once thought. It is going to take a year or two, I think, before the labeling catches up with the science here.

For now, the consumer can be assured that the total vitamin A content in the vitamin supplement will not pose any toxicity dangers as long as the preformed vitamin A contained in it does not exceed the upper limit of 10,000 IU (3000 ug). Some vitamin companies are changing, or have changed, the calculations on their labels, some have not. The consumer cannot really tell if that change has been made. It is best to go with what is on label and know that it is safe [if the preformed vitamin A (retinol) is under 10,000 IU], although it might not have all the vitamin A that the label implies.

In the United States, there is more of a danger of over-supplementing yourself with vitamin A than under-supplementing. So I would not worry too much about whether or not one is getting enough vitamin A.

Tolerable Upper Limits

Mason

Rob, I know you have written much about vitamin A toxicity, particularly in the elderly. In that regard, the National Academy established for the first time, "Tolerable Upper Limits" (TUL) for all the RDA nutrients. Perhaps, you could tell us a little bit about the Tolerable Upper Limits for vitamin A.

Russell

The three major detrimental effects from taking too much vitamin A on a chronic basis are:

1. liver disease
2. teratogenicity and birth defects and
3. bone demineralization.

The Vitamin A Panel decided that there was sufficient information on the first two (liver disease and birth defects) to provide a good estimate on what a Tolerable Upper Level should be. The Upper Level is based on looking either at "lowest observed effect level" or at a "no observed effect level." For example, if one were looking at the "lowest observed effect level," one would look at the lowest dose of vitamin A that a bad effect (such as liver disease) was seen. If one were looking at a "no observed effect level," one would be looking for the highest amount of vitamin A that one could take in without seeing any bad effects whatsoever. These "lowest observed effect levels" or "no observed effect levels" are then corrected by a fudge factor known as an "uncertainty factor" in order to make very sure that there will be absolutely no risk of vitamin A intoxication to the population.

With this background of how a Tolerable Upper Level is derived, the final TUL for vitamin A for an adult has been set at 3000 ug/day (10,000 IU) on the basis of liver disease and birth defects. One can be sure that if you are eating vitamin A at the TUL or below on a daily basis, you are not running any risk whatsoever of having an adverse effect.

If you consistently go over the TUL, then you are increasing your risk of having an adverse effect (e.g., liver disease). The higher you are above the Upper Level, the more you increase your risk. It should be said that the Upper Level for vitamin A applies only to preformed (retinol) vitamin A that would be in a supplement or in a food but does not refer to vitamin A that is derived from carotenes, (whether or not it comes from a fruit, vegetable or a supplement).

Mason

So, if I understand correctly, one doesn't need to be concerned about precursor vitamin A in the form of carotenoids when examining the possibility of exceeding the Tolerable Upper Level. One thing I think is worth adding is acute vitamin A toxicity, which we rarely see these days. You were talking about toxicity from chronic ingestion. It is also worth noting that one can develop acute vitamin A toxicity with a single dose of 100,000 I.U.s or more of preformed vitamin A. This acute toxicity syndrome includes nausea, vomiting, exfoliating dermatitis, pseudo-tumor, cerebri, coma and possibly death.

Cancer Prevention Action

Mason

A lot of the interest in these compounds over the past decade has centered around their possible utility in cancer prevention or treatment. I know that the evidence is very distinct between the use of vitamin A and retinoids and the use of carotenoids. Perhaps, you could update us on both of these groups of compounds in regard to cancer?

Russell

There is not much interest in vitamin A (retinol) per se in the treatment of cancer. On the other hand, there is interest in avoiding vitamin A deficiency for the prevention of cancer because we know that animals deficient in vitamin A are more prone to get cancers after being exposed to various carcinogens. In the U.S., we want to have a population that is well nourished but not over-nourished with vitamin A. In general, our population in the United States is quite well nourished with regard to vitamin A.

On the other hand, we know that vitamin A derivatives (e.g., retinoic acids) do play an important role in cell differentiation. The problem with using preformed vitamin A (retinol), rather than the derivatives, for this cell differentiating effect is that the necessary dose is so high that it would have other toxic effects. Thus, vitamin A (retinol) itself, as I have already said, is not of much interest as a chemotherapeutic agent.

Retinoic acid derivatives of vitamin A are well known to bind to nuclear receptors that influence gene transcription. All trans-retinoic acids have been found to be very useful for treating promyelocytic leukemia.(2)

Other research protocols use retinoid derivatives in the secondary prevention of certain cancers, (for example, in the prevention of head and neck cancer), but these are ongoing studies. Suffice it to say, no one should be taking retinol or vitamin A derivatives for cancer treatment or secondary prevention unless they are being treated by a physician and/or part of an ongoing study in a medical center.

The Lycopene Story

Mason

I am particularly interested in lycopene since it is a carotenoid that cannot be broken down to vitamin A and is one that has been tied, at least in an epidemiologic sense, to a number of cancers.

Russell

Unfortunately, our state of knowledge is still "epidemiologic," although there are many ongoing in vitro and animal studies that are studying lycopene's anticancer properties. We have some very intriguing epidemiologic observations that high lycopene (from tomatoes) intake and blood levels are linked with lower levels of prostate, breast and cervical cancers. There is probably most interest in prostate cancer, since several large epidemiologic studies tend to show that the higher the lycopene in the diet, the less the risk for this cancer.

The problem with lycopene is that we know very little about its metabolism (how it is broken down in the body) and what are its actual active biologic derivatives. We don't want to get into the same situation with lycopene in prostate cancer that happened a few years ago with respect to using beta-carotene to prevent lung cancer in smokers. As you remember, in a series of intervention trials, beta-carotene supplementation actually was found to result in greater numbers of lung cancers rather than fewer in smokers and asbestos-exposed workers, even though, theoretically, this compound should have been effective in preventing these cancers. We now know that this was a dose phenomenon. That is, the high doses of beta-carotene that were used in these studies produced a number of breakdown products of beta-carotene that were actually having detrimental effects on the cells' metabolism and, ultimately, provoking carcinogenesis.

So, we are left with some intriguing observations on lycopene but we need to better understand the biologic properties of lycopene's breakdown products. Eventually, it might be possible to start an intervention trial using lycopene to prove once and for all whether or not this compound is useful in the prevention of prostate, lung and breast cancers.

Lutein and Macular Degeneration

Mason

Rob, another carotenoid that is in both the public eye, as well as in focus in the scientific community, is lutein. Could you tell us a little about what clinical effects this compound might have?

Russell

There has been most interest in lutein for its possible effects in preventing age-related macular degeneration, which is the biggest cause of permanent blindness in the elderly population. Lutein is particularly concentrated in the macula of the eye and is thought to have photoprotective properties such as it has in plants. Thus, the theory is a good one that lutein might protect against chronic light induced damage to the macula as well.

As with lycopene, we know very little about how lutein is actually acting. Is it acting simply as a light filter or is it working at a more molecular level via one of its metabolic products? We don't, in fact, even know that lutein will protect against macular degeneration since the intervention studies have not yet been carried out. However, we do have several epidemiologic studies(3) that have linked high dietary lutein levels and blood levels to lower prevalences of macular degeneration.

I would not advise people to take large amounts of lycopene or lutein in dietary supplements since we know so little about either. However, if one were interested in safely raising blood and tissue levels of lycopene or lutein, a patient could do so simply by eating diets that are richer in tomato or tomato products (for lycopene) and dark green leafy vegetables, e.g., spinach (for lutein).

Mason

Rob, I think it is fair to say that fields of very active research such as this are very confusing for both the public and the health professional. It necessitates that all of us keep up with knowledge and the periodic literature because what we say today is not necessarily going to be held to be true three or five years from now. I look forward with great interest to what further studies about these compounds will show in the upcoming years.

Because this is an evolving field, I would like you, as an expert, to give us clinicians a few "bullets" that really represent suggestions that you have as to how we ought to change our approach to patients in the year 2001, given our present state of knowledge on retinoids and carotenoids.

Clinical Pearls

Russell

• Number one, we now have Tolerable Upper Levels set by the National Academy of Science for preformed vitamin A (retinol). The physician should advise his/her patients not to go above this Tolerable Upper Level on a daily basis (3000 ug/ or 10,000 IU).
• We now have information from several large randomized trials on beta-carotene and lung cancer prevention. We can definitively tell people that they should not be taking "megadoses" (no more than 15 mg of beta-carotene per day) This advice extends to include lycopene and lutein. I would not advise patients to take supplements of these chemicals at the present time, since we don't know enough about them. The patient should be advised to increase their intake of tomatoes for lycopene or dark green leafy vegetables for lutein, if they are interested in safely increasing their blood and tissue levels of these compounds.
• The final point is for vegetarians: it is easy to get enough vitamin A from plant sources simply by choosing the darkly colored fruits and vegetables. People will ingest more than enough vitamin A from those food sources if they simply think "deep color."