The ABC's of confusion as a Weapol
Acronyms, ß-Carotene, And Capsaicin

JON 3(2), 1994
Editorial
Brian Leibovitz, Ph.D.

One of the Bad Science (BS) Award candidates this issue is John Hathcock, Ph.D., Office of Special Nutritionals, Center for Food Safety and Applied Nutrition, FDA. The reason? He is the sole author of a paper that, to the best of my knowledge, introduced the most absurd acronyms and ridiculous equations in a single article (1). This is true with respect to both quantity and quality.

This paper, published in Nutrition Reviews, introduced novel acronyms as well as toxicology acronyms adapted for nutrition:

ADI (acceptable daily intake)
SF (safety factor)
NOAEL (no-observed-adverse effect level)
LOAEL (lowest-observed-adverse effect level)
RfD (a reference dose that „probably will not cause deleterious effects over a lifetime of exposure‰)
UFs (uncertainty factors)
MF (modifying factor)
SI (nutrient safety index)
SL (safety limit)

Hathcock's definitions and calculations were equally unenlightening and senseless - not to mention confusing:

"For calculation of the RfD, the SF has been refined into multiple components described as uncertainty factors, UFs, and a modifying factor, MF. Thus, the RfD is defined by the following equation: RfD = NOAEL (or LOAEL) / (UF x MF), where UF represents one or the product of several uncertainty factors [emphasis added], generally tenfold each. An additional factor, the MF, is used as necessary to account for areas of uncertainty that are not explicitly addressed by the usual factors [emphasis added]."

"To assess the comparative safety of nutrients, a nutrient safety index (SI) has been defined as a ratio that is analogous in several ways to the therapeutic index (TI) for drugs. The SI was defined as the minimum toxic dose divided by the recommenced intake: SI = LOAEL / RI. This SI is useful for comparing the relative hazard posed by overconsumption of different nutrients. In this analysis, an SI of 10 does not indicate that an intake of up to 10 times the RDA is safe. Instead, it indicates that such an intake provides no margin of safety [emphasis added]." "If appropriate and adequate human data are available, a safety limit (SL) could be calculated as follows: SL = LOAEL / SF where LOAEL is the lowest-observed-adverse-effect level derived from clinical reports and SF is a safety factor that provides an acceptable margin of safety. The SF could be either fixed or variable [emphasis added]."

"Safety limits may be calculated by the SRM [square-root method] and MPM [midpoint method] as follows: Midpoint method:

SL = (LOAEL - (LOAEL - RDA) /2))
or equivalently
SL = (LOAEL + RDA) divided by 2 x (the arithmetic mean)
Square-root method:
SL = (LOAEL / SF) = LOAEL / SI0.5
where
SI = LOAEL / RDA
or equivalently
SL = (LOAEL x RDA)0.5 (the geometric mean).‰

"The confidence in and reasonableness of safety limits, regardless of the method used to define them, will be enhanced if the objectives [emphasis added], data criteria, and the quantitative method have been agreed upon ahead of time by groups responsible for nutrition and health policy [emphasis added]."

The scientific translation: agree on the policy (results) prior to conducting the research. Furthermore, why should "groups responsible for nutritionand health policy" - not bonafide nutritional scientists - be the final arbiters of scientific truth?

ß-CAROTENE, VITAMIN E, AND CANCER: SCIENCE BY DESIGN

ß-Carotene (and antioxidants in general) recently took it on the chin from a single study published in the New England Journal of Medicine (NEJM) (2) . The article reported a null effect of vitamin E, and a promoting effect of ß-Carotene, on lung cancer in heavy smokers.

Media Madness

Media coverage was horrendous. The LA Times (April 12, 1994) published a column entitled, "Study questions value of antioxidant vitamins." The front page of USA Today (April 13, 1994) contained a column with the headline, "Vitamins don't make smokers cancer-proof." Even worse was the cover story in the April 25, 1994 issue of Newsweek, entitled, "Are supplements still worth taking?"

Even Science (the most widely-read scientific journal) got into the act. " ß-Carotene
: Helpful or harmful?" (3) was the title of a recent editorial which concluded that the NEJM study provides "support for skepticism, and a moratorium on unsubstantiated health claims about ß-Carotene and other antioxidants." This editorial also stated that, "A more frightening explanation is that ß-Carotene itself is carcinogenic... In light of the Finnish results, is it safe to expose thousands of people to large doses of b- carotene?"

The NEJM article has successfully introduced an element of doubt regarding nutrient supplements that will linger long after the study has been thoroughly discredited. Therein lies the real danger: "confusion as a weapon" accomplished via "science by design."

Confusion: A Very Effective Weapon

The introduction of this abominable article, and the widespread media coverage, has left an indelible mark on the average person. When confronted with conflicting information, many people simply give up believing anything about nutrition: "If the experts can't even agree, why shouldI bother to listen to any of them?"

The concept of confusion as a weapon is described above, and was detailed in my article "Nutrition: At the crossroads" (4). Examples include: the oat bran study; the PDCAAS (the new measure of protein quality); the RDI, PDV, and DV (nutrient requirement and labeling acronyms);
Chaparral-induced "hepatotoxicity"; and L-tryptophan as the cause of the Eosinophilia Myalgia Syndrome (EMS).

Sadly, this paper has undoubtedly confused many people about the value, and safety, of ß-Carotene (and other nutrient) supplements. Confusion, in turn, acts to decrease supplement usage. This is really an example of "science by design."

The Danger of Hypothetical Mechanisms

I've heard a lot of speculation about mechanisms that might account for the reported ß-Carotene -associated increase in lung cancer. Some examples include: 1) Finns make poor subjects; 2) ß-Carotene -treated individuals, believing they were protected, smoked more; 3) ß-Carotene might prooxidize in lung tissue, as it can in vitro; and 4) radiation from Chernobyl somehow interacted (negatively) with ß-Carotene.

The NEJM study is a travesty of science - an experiment designed to fail - and does not deserve the honor of our speculation about possible mechanisms for its flawed findings.

Insufficient Doses: Designed To Fail

This study brings to mind an observation attributed to Louis Pasteur: "Be very careful when you look for something, or you will surely find it." This is exactly what occurred in the NEJM study, as the doses were simply too low to do the job.

ß-Carotene supplements provided only 20 mg/day - far too low a dosage to expect beneficial effects (especially in a challenged system, as described below). The investigators should have used at least 140 mg/day of ß-Carotene, as these intakes have proven effective.

The dose of vitamin E was even worse &Mac247; a measly 50 mg (or 50 IU) per day of dl-a-tocopheryl acetate! This is not even twice the RDA for vitamin E - hardly a therapeutic amount! The intake of vitamin E should have been in the 1,500 - 2,500 IU/day.

The effectiveness of any given dose, naturally, depends on the system. Heavily challenged systems, like smoking 20 cigarettes a day for 36 years (as in the present study), require intakes higher than the therapeutic doses routinely used. Because of its lack of applicability to the real human predicament, this article is not worth the paper it's printed on.

Scientific Snow Job?

There is a serious problem with the preparation (and presentation of) results in the present study. The authors designed a nice study protocol (the 4 groups listed below), save for the inadequate doses used. In the results section, however, the only comparisons were: with or without b- carotene and with or without vitamin E) . No tables or figures contained data for those receiving the supplement combination (the a-tocopherol and ß-Carotene group)!

"The participants were randomly assigned to one of four supplementation regimens: a-tocopherol alone (N=7286), a- tocopherol and ß-Carotene (N=7278), ß-Carotene alone (N=7282), or placebo (N=7287). Thus, a total of 14, 564 men received a- tocopherol, and 14, 560 received ß-Carotene."

Thus, any benefits of one nutrient (e.g., vitamin E alone) would be masked because the "without vitamin E" group contained data from those given ß-Carotene alone and from placebo-treated subjects. Incidentally, there was no mention of what placebo was used. They did, however, point out that "all formulations were colored with quinoline yellow" (a synthetic food dye with known toxicity) (5).

A Statistically-Significant Difference....By Chance?

The finding that "dumbfounded the experts" (3) was the statistically- significant increase in lung cancer in the ß-Carotene -treated group. But the authors weren't exactly convinced of their own work:

"In light of all the data available, an adverse effect of ß-Carotene seems unlikely; in spite of its formal statistical significance, therefore, this finding may well be due to chance."

This statement is an oxymoron: statistical significance, by definition, means that the results are not due to chance. If the authors don't even believe their own data, why should anyone else have confidence in their findings? The statement above is a type of academic insurance - insurance against the likelihood of being proven wrong about ß-Carotene and lung cancer.

The Guinness Book For Erroneous Extrapolations

Perhaps the worst responses to this publication were the blatantly- exaggerated extrapolations. The authors, and consequently the media, used the most outlandish extrapolations - and, not surprisingly, wound up with some incredible conclusions. The main finding, a null effect of vitamin E and a promoting effect of ß-Carotene, became, "Vitamins cause cancer", and then, "All supplements are worthless and possibly harmful" in the course of two or three days. To infer that all nutrient supplements are worthless and potentially harmful from any single article (especially the present one) can only be described as truly moronic.

THE CAYENNE-PEPPER CAPER

Capsaicin, the pungent principle of Cayenne pepper, is also the active ingredient in Zostrix - an analgesic cream from GenDerm Corporation, Lincolnshire, IL. Zostrix contains 0.025% capsaicin - a phenolic antioxidant similar to curcumin (from Tumeric). Zostrix is approved for the treatment of arthritis and other inflammatory conditions. The first page of an advertisement (6) in The New England Journal of Medicine stated in large print that Zostrix is:

"The Adjunct To NSAIDs That Works [emphasis added]"

The obvious implication is that other approved adjuncts don't work. The details were on the second page of the advertisement.

"Zostrix works safely and economically. Zostrix is free from systemic side effects, and has no known drug interactions. When used properly, Zostrix is inexpensive pain therapy. In fact, when treating a single knee joint, a 20-gm tube can last up to a month."

There is no problem with the concept of using capsaicin to treat inflammation; the data clearly show that it is effective for inflammation as well as pain relief (via a reduction in the levels of substance P). The concentration of capsaicin, however, is extremely low (0.025% by weight); hence, Zostrix is simply a very diluted form of this remarkable non- vitamin nutrient.

Cayenne pepper contains not less than 0.5 (dry weight) of capsaicin. A small, inexpensive (~$2) bottle (45.4 gm) of Cayenne at the grocery store contains ~227 mg of capsaicin. A similar amount is provided by ~45 tubes of Zostrix® (each 20-gm tube contains 5 mg capsaicin). The cost of 45 tubes - at $15.50/tube - is $698.

Thus, ~$2 worth of Cayenne pepper yields ~$700 worth of Zostrix. This astronomical markup of approximately 350-fold (35,000 percent) is yet another example of a nutrient (or herb) being converted to an expensive prescription item. FDA restrictions on Cayenne are likely, as the sales of Zostrix will suffer if the non-prescription form is allowed to remain on the market. The confusion, in the Cayenne pepper caper, is due to nomenclature: the name Zostrix's offers no clue as to the origin or nature of its active component.

Hathcock, JN. Safety limits for nutrient intakes: concepts and data requirements. Nutr Rev 51: 278-285, 1993.
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and ß-Carotene on the incidence of lung cancer and other cancers in male smokers. New Engl J Med 330: 1029-1035, 1994.
Nowak R. ß-Carotene : Helpful or harmful? Science 264: 500-501, 1994.
Leibovitz B. Nutrition: At the crossroads. J Optimal Nutr 1: 69-83, 1992.
Budavari S, O&Mac226;Neil MJ, Smith A, et al. (editors). The Merck Index, 11th Edition, Merck & Co., Inc., Rahway, NJ, 1989, pg. 1286.
The New England Journal of Medicine, December 9, 1993.

REFERENCES CITED

Nutritional Treatment Of Heart Disease CCME
The ABC's of Confusion as a Weapon
Beta-Carotene, Vitamin E, and Cancer: SCIENCE BY DESIGN
Nutrition at the Crossroads
A Forum On Nutrition And Health

By Claudio Capozza MBBS (Italy), Naturopathic Doctor (Australia) & www.laleva.cc