NUTRITION
June 1, 2001

Vitamin A, Retinoids and Carotenoids: What's the Bottom Line?

A dialogue between Robert Russell, M.D., and Joel Mason, M.D.
In the last three years, Dr. Russell has received grant/research support from BASF and Roche Vitamins. Dr. Russell has also served as a consultant for Whitehall Robbins-Quaker; Dr. Mason has received grant/research support from Mead-Johnson Nutritional and also served as a consultant for Mead-Johnson Nutritional.


Mason
My colleague, Dr. Robert Russell, is an internationally known expert in the field of vitamin A, also known as retinol, and the related substances called retinoids and carotenoids. Some of these, such as beta-carotene, are thought to have anti-cancer and other health benefits; and many people take one or more of them as a diet supplement. Today, Dr. Russell will guide us through the latest advances in our knowledge about the positive and negative effects of these substances. Rob, please begin by telling us about the newly revised Recommended Dietary Allowances (RDAs) set by The National Academy of Sciences.

Revised RDAs

Russell
Actually, the National Academy of Sciences has issued a Recommended Dietary Allowance only for vitamin A (retinol). They have set no RDAs for any carotenoid, including beta-carotene, and there are no Recommended Dietary Allowances set for retinoic acid or any other retinoid, or vitamin A derivative. The new Recommended Dietary Allowance for vitamin A is slightly lower than the old one. For adults, the RDA for vitamin A is now 900 micrograms per day [3000 IU (international units)] for males and is 700 micrograms per day (2300 IU) for females. These are 100 micrograms per day lower than the previous RDAs, which were issued in 1989.

These latest Recommended Dietary Allowances for vitamin A are based on new findings about how long vitamin A lasts in the body as well as a better understanding of how efficiently the body absorbs vitamin A from food.

A Less Efficient Carotene Conversion

Mason
I know that the RDAs have always taken into account the fact that carotenes can be converted, or broken down by the body, into vitamin A. My understanding is that these conversion rates have been altered in the latest RDAs. A lot of people are now taking pills or other diet supplements that contain carotenoids. Do these new conversion rates change our understanding of what level of carotenoids people should be taking?

Russell
Carotene (and I am going to use beta-carotene as the prototype carotene here since it is the most common carotene in food) is converted rather poorly by the human body. For the past 30 years, it was thought that it took six micrograms of beta-carotene in the diet to yield one microgram of vitamin A in the body. In the past few years, however, we have discovered that carotene conversion is really much less efficient than 6 to 1. It is now estimated that it takes more like 12 micrograms of beta-carotene to yield one microgram of retinol, In other words carotene is converted only half as efficiently as was previously thought.

This means that vegetarians are going to have to be careful to eat more carotene rich fruits and vegetables (generally, these are 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, it is still quite easy to obtain the RDA for vitamin A. For example, it takes only half a cup of cooked carrots a day to meet the 900 micrograms per day of vitamin A that is recommended for an adult male.

Keep in mind that if you are particularly fond of non-colored or light-colored fruits and vegetables, such as white potato, iceberg lettuce, white asparagus and apple, be aware that you are not getting much carotene or vitamin A from these foods. And, also, remember that tomatoes are an exception to the dark colored rule; they contain a carotene, called lycopene, which cannot be broken down to vitamin A. We will talk about lycopene later.

Mason
Rob, now that we have a different understanding of how efficiently carotenoids convert to vitamin A, how should people interpret a label on a vitamin supplement that says part of the vitamin A in the supplement is being given as beta-carotene?

Russell
That is a good point — many vitamin supplements contain at least part of their vitamin A content as beta-carotene. This is a very confusing situation at the present time, since the Food and Drug Administration has not issued new regulations that would make the vitamin companies change their labels to reflect the discovery that the efficiency of beta conversion to vitamin A is only half what was once thought. It is going to take a year or two, I think, before the labels catch up with the science here.

Few consumers, however, have a realistic worry about getting too little vitamin A. In the United States, there is more of a danger of over doing than under doing vitamin A. This is because given the American diet, most of us are closer to the levels at which vitamin A becomes toxic, or poisonous, than they are to the minimum requirements for good health. Until all vitamin companies have changed their labels to reflect the real conversion rates, it is safest for most people to go with what is on label, and not worry too much if they might not be getting all the vitamin A that the label states.

As for upper limits, you can be assured that the total vitamin A content of a supplement is not toxic as long as the vitamin A contained in it does not exceed 10,000 IU (3000 micrograms).

Table 1.
Age and Sex Specific RDAs for Vitamin A

RDA for Children 1-3 years
4-8 years
300 µg/day
400 µg/day
RDA for Boys 9-13 years
14-18 years
600 µg/day
900 µg/day
RDA for Girls 9-13 years
14-18 years
600 µg/day
900 µg/day
RDA for Men 19+ years 900 µg/day
RDA for Women 19+ years 700 µg/day
RDA for Pregnancy 14-18 years
19+ years
750 µg/day
770 µg/day
RDA for Lactation 14-18 years
19+ years
1200 µg/day
1330 µg/day

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," or 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 bad effects from taking too much vitamin A over time are liver disease, birth defects and bone demineralization. The National Academy decided that there was sufficient information on the first two (liver disease and birth defects) to estimate a Tolerable Upper Level. This TUL is based on two things: the "lowest observed effect level" and the "no observed effect level." For example, if we were looking at the "lowest observed effect level" for vitamin A, we would use the lowest dose of vitamin A at which a particular bad effect, say liver disease, was seen. But if were looking at the "no observed effect level," we would be looking for the highest amount of vitamin A that a person could take without suffering any bad effects whatsoever. Both of these numbers are then corrected downward by a fudge factor known as the "uncertainty factor" in order to make very sure that there will be absolutely no risk of vitamin A toxicity.

The TUL for vitamin A in an adult has been set at 3000 micrograms per day (10,000 IU) for liver disease and birth defects. If you are eating vitamin A at or below the TUL, then you are running no known health risk. If you consistently go over the TUL, then you are increasing your risk of liver disease or some other health problem. And the risk is proportionate; the higher you go above the TUL, the more you increase your risk.

In your TUL count, you can ignore any vitamin A that may come from carotene. Just keep track of your daily intake of pure vitamin A from supplements and animal products.

Table 2.
Age and Sex Specific Tolerable Upper Levels for Vitamin A

UL for Infants 0-12 months 600 µg/day of preformed vitamin A
UL for Children 1-3 years
4-8 years
9-13 years
600 µg/day of preformed vitamin A
900 µg/day of preformed vitamin A
2800 µg/day of preformed vitamin A
UL for Boys and Girls 14-18 years 2800 µg/day of preformed vitamin A
UL for Men 19+ years 3000 µg/day of preformed vitamin A
UL for Women 19+ years 3000 µg/day of preformed vitamin A
UL for Pregnancy 14-18 years
19-50 years
2800 µg/day of preformed vitamin A
3000 µg/day of preformed vitamin A
UL for Lactation 14-18 years
19-50 years
2800 µg/day of preformed vitamin A
3000 µg/day of preformed vitamin A

Mason
So, if I understand correctly, we don't count any vitamin A in the form of carotenoids when examining the possibility of exceeding the Tolerable Upper Leve.

One thing I think is worth bringing up is acute vitamin A toxicity, which we see only rarely these days. You mentioned that a person can develop toxicity from long-term, or chronic, overingestion of vitamin A. I should add that a person can also develop acute vitamin A toxicity with a single dose of 100,000 IUs or more of vitamin A. This would cause symptoms including nausea, vomiting, a type of skin inflammation called exfoliating dermatitis, coma and possibly even death.

Cancer Prevention?
On another topic, there has been a lot of talk over the past decade about the possibility that these compounds may be used to prevent or even treat some forms of cancer. I know that the evidence is very different for vitamin A and for retinoids and carotenoids. Perhaps, you could update us on these in regard to cancer?

Russell
There is not much interest in vitamin A (retinol) as a cancer treatment. The amounts necessary to have any kind of positive effect would do too much harm elsewhere in the body. On the other hand, we do tell people to avoid vitamin A deficiency because animals low in vitamin A are known to be more prone to cancer. In the U.S., the goal is to have a population that is well nourished but not over nourished with vitamin A; and in general, that goal is being reached.

On the other hand, we know that a group of vitamin A derivatives called retinoic acids do play an important role in certain cellular processes that are involved in some cancers. For instance, retinoic acids have been found to be very useful for treating a type of leukemia. Research is currently under way into whether some vitamin A derivatives may prevent certain cancers, including head and neck cancer, but we do not yet have definitive results. Still, because of the health risks from vitamin A toxicity, NO ONE should take retinol (vitamin A) or vitamin A derivatives either for cancer treatment or for prevention unless they do so as part of a medical treatment or as part of a research study at a reputable medical institution.

Mason
I am particularly interested in lycopene, which is abundant in tomatoes. Some have suggested that lycopene may be able to help prevent some cancers.

Russell
Right now, we just do not have a whole lot of hard data about lycopene and cancer or cancer prevention, although there are many studies under way on lycopene's alleged anticancer properties. There have been some very intriguing statistical hints that high lycopene intake from tomatoes is linked with lower levels of prostate, breast and cervical cancers. For prostate cancer, several large epidemiological studies have shown that the higher the amount of lycopene in a man's diet, the lower his likelihood of having cancer.

The problem with lycopene is that we know so little about how it is broken down in the body and what substances it breaks down into. We don't want to get into the same situation with lycopene and prostate cancer that we got into a few years ago with beta-carotene and lung cancer in smokers — although beta-carotene in theory should have helped prevent lung cancer, in practice a series of studies found it did the opposite. We now know that this was a dose problem. In other words, the high doses of beta-carotene that were used in these studies broke down in the body into substances that actually stimulated the growth of cancer.

So, in short, we're not really sure about lycopene's possible benefit yet.

Mason
Rob, another carotenoid that is often in the media is lutein, a yellow pigment found in egg yolks, spinach and green leafy vegetables. Could you tell us a little about what health effects this compound might have?

Russell
There has been a lot of interest in using lutein for the prevention of age related macular degeneration, which is the biggest cause of permanent blindness in the elderly. There is quite a lot of lutein in the human eye. Because it helps protect plants from damage caused by sunlight, scientists have speculated that lutein might protect against light induced damage to the eye as well.

As with lycopene, we know very little about how lutein actually acts inside the body. Is it acting as a simple light filter or is it working on some deeper level? We actually have no conclusive evidence that lutein can protect against macular degeneration, since intervention studies have not yet been carried out. Several epidemiological studies, however, have linked high dietary lutein levels and blood levels to lower incidences of macular degeneration.

At this time, I would not advise anyone to take large amounts of lycopene or lutein in supplement form, because we know so little about them. However, if you are interested in safely raising blood and tissue levels of lycopene or lutein, it is perfectly all right to do so by eating diets that are richer in tomato or tomato products for lycopene and spinach or other dark green leafy vegetables for lutein.

Mason
Understanding that this is an evolving field, I would like you, as an expert, to give us a few things to remember about vitamin A, retinoids and carotenoids, given our present state of knowledge.

Take Aways for the Consumer

Russell
Number one, we now have Tolerable Upper Levels, or TULs, set by the National Academy of Science for vitamin A (retinol). Everyone should be careful not to go above 3000 micrograms per day (10,000 IU).

We now have information from several large studies on beta-carotene and lung cancer prevention. People should definitely not be taking "megadoses" and in any case, no more than 15 milligrams of beta-carotene per day. The same would be true of lycopene and lutein. If people want to safely increasing their levels of lutein or lycopene, the way to do it is to increase their intake of tomatoes and dark green leafy vegetables.

My final point is for vegetarians who might think they need to take vitamin A supplements. It is easy to get enough vitamin A from plant sources simply by choosing the darkly colored fruits and vegetables. You will get plenty of vitamin A from these food sources if you remember, when you are food shopping, to think "deep color."
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