ANTIOXIDANTS and RISKS -
A GLOBAL ANALYSIS
Abstract: The combined results from most of more than 160 research study comparisons confirm that dietary antioxidants can substantially reduce the risk of cardiovascular disease, most types of cancer, and risk of death from all causes. They also reduce risk of dementia and macular degeneration. Life Ahead combines the benefits of antioxidants Vitamin E, Beta carotene, Vitamin C and Selenium because their effects are mostly duplicative. A new antioxidant index quantifies the effectiveness of weighted totals of these individual antioxidants and provides a new and important health target for user diets. Antioxidants reduce risk of both cardiovascular diseases and cancer in accord with their duration of exposure. Risk ratios obtained from individual nutrients vary somewhat from about 0.975 or a 3% per year benefit per year of exposure. A minimum risk ratio taken as 0.95 per year, and a minimum risk ratio of 0.50 for any amount or duration of these multiple factors now used in Life Ahead may be identify benefits conservatively.
Deficiencies in antioxidants can be a #1 dietary health problem in the US, and usually is of larger importance than diet deficiencies related to cholesterol. Dietary supplements usually are needed to increase antioxidants to levels needed for best health. Antioxidants may not benefit the cancer risk of pre-menopause women. And they may not benefit those who have suffered heart and other diseases. This paper summarizes research results presented and analyzed in nine papers on antioxidants and disease and deaths from all causes . Antioxidants also were discussed in papers on Dementia and Macular Degeneration.
See other papers of antioxidants and CV disease for Vitamin E; Vitamin A; Vitamin C; and Selenium , papers of antioxidants and cancer for Vitamin E; Vitamin A; Vitamin C; and Selenium, and Antioxidants, Death from All Causes. Also Dementia and Macular Degeneration.
Background: Antioxidants are discussed in health letters and health advice of all kinds. An incredible 135,000 research papers relating to antioxidants are listed in Medline, the key internet site for peer reviewed health papers. Despite this, researchers have done little to help people know what antioxidants do and how much of them they need to take. We have specific goals for fiber, for salt, and for vitamins and minerals. But what about antioxidants? How do they improve our health? And how much of what should we be taking? The RDA values are minimum values to avoid diseases of insufficiency, and much higher values can protect against health. The approach used in Life Ahead may be the first useful approach yet developed for solving these key problems..
There are dozens of diet nutrient chemicals that have antioxidant function. But until we have sufficient research showing their effects on actual populations of people we cannot accept whether or not it is useful to take them. As of this writing just four have been found adequately tested for benefits in the Life Ahead project. These are Vitamins A, C, E and Selenium. The actual research results published on each of these antioxidants is included and analyzed on this Web site in nine different papers. For cardiovascular diseases these are Vitamin E; Vitamin A; Vitamin C; and Selenium; and for cancer the papers are Vitamin E; Vitamin A; Vitamin C; and Selenium, Another one is for Antioxidants and Death from all Causes.
The Summarized Results on Four Key Antioxidants: Results for most of an included 160 research studies show that each of these antioxidants probably can reduce risk of cardiovascular diseases, cancer and and death from all causes. It is likely that in combinations antioxidants can provide more important long range health benefits that any other nutrient health factor. Much about antioxidants is included in the separate papers, and particularly in the paper on Vitamin E and Heart Disease. Please see these papers because much of this information is not repeated following. Antioxidants also affect the risk of Dementia/Alzheimers (See 18 risk ratios from 9 studies) and Macular Degeneration (See 17 risk ratios from 13 studies).
A summary of the results from the above eight papers on antioxidants, cardiovascular disease and cancer follows:
For Cardiovascular Diseases
For Nutrient Vitamin E Beta-carotene Vitamin C Selenium
Amount in Research 200IU 15,000IU 400mg 100mcg
Avg Research Risk Ratio 0.67 0.76 0.75 0.60
Risk Ratio per Year of Use 0.980 0.986 0.986 0.975
No Research Risk Ratios from
Population studies included 23 10 9 8
For Cancer
For Nutrient Vitamin E Beta carotene Vitamin C Selenium
Amount in research 200IU 15,000IU 400mg 100mcg
Avg Research Risk Ratio 0.67 0.75 0.71 0.61
Risk Ratio per year of use 0.980 0.986 0.983 0.976
No Research Population
Study Risk Ratios used 25 21 14 31
The results here from 50 key study comparisons of antioxidants of cardiovascular disease and 90 comparisons of antioxidants and cancer are surprisingly similar. Vitamin E of 200 IU attained the same risk for each major class of disease at a ratio of 0.67 and 0.980 per year of exposure based on a 20 year term for benefit. . Beta-Carotene limited to 15,000 IU and Vitamin C at 400 mg above a usual amount of 200 mg/day contributed somewhat lower but significant risk reduction. Selenium actually produced the largest reductions in risk. And note the large number of studies and risk ratios available for selenium and cancer. The average risk obtained in the 11 research comparisons of antioxidants and death from all causes not included above was 0.70, a good confirmation of the above values by major disease type.
Two observations are of interest are. First, the average reduction in risk found for each of the nutrients is generally similar, ranging from a low of 0.60 to a high of 0.75. Vitamin A via Beta-carotene provides the least protection, selenium provides the largest protection. And most interesting, the risk ratios found independently and 'objectively blind' for each nutrient had nearly identical risks for cardiovascular diseases and averages of all causes of cancer tested.
The Mechanisms: Antioxidants are defined herein as nutrients that have biochemical antioxidant activity and that slow the progress of major disease. This slowing can be small each year, but the summation of a small annual slowing can produce substantial effects over the longer term. Antioxidants appear to reduce the effect of LDL cholesterol in producing atherosclerosis that over long time clogs arteries and produces cardiovascular disease. Its beneficial effect in slowing the progress of most cancer is remarkably similar to its effect on heart disease, but the mechanism by which this occurs is not known.
Research has now identified the actual chemical antioxidant potency of a wide variety of foods and other nutrients. Called the Oxygen Radical Absorbance Capacity, or ORAC, this valuation probably identifies a more specific level of true antioxidant potential than that obtained from risks of disease. Ideally it would be desirable to use this measure for antioxidant risk. Unfortunately, an exploration found that there was no evident relationship between the ORAC values and their probable effect on the major diseases as now developed. This lack of correlation may suggest that the benefits of nutrients we now call antioxidants may be produced in part by chemical processes other than antioxidation per se.
About Risks for Types of Cancer: An interesting observation from the studies of multiple research is that antioxidants appear to benefit most and perhaps all types of cancer. The results for Vitamin E and cancer shown below found benefits that mostly were well within statistical consistency of an average value. Results for Vitamin C, Vitamin A or Beta Carotene, and Selenium also show the same pattern of near similar benefits for each type of cancer studied.. One exception is that pre-menopausal women may not obtain lower risk of cancer from antioxidant supplements. This may be because their normal estrogen is another antioxidant. Life Ahead now accords cancer risk benefit from antioxidants only to post-menopausal women.
| Cancer Type |
Number of Comparisons |
Average Risk Ratio |
| All Cancer | 2 | 0.55 |
| Breast Cancer | 4 | 0.82 |
| Prostate Cancer | 3 | 0.67 |
| Lung Cancer | 2 | 0.53 |
| Colorectal Cancer | 9 | 0.70 |
| Ovarian Cancer | 3 | 0.73 |
| Cervical Cancer | 2 | 0.51 |
| Bladder Cancer | 2 | 0.86 |
Combining Risk Benefits from Antioxidants: Antioxidants are assumed to benefit risks via similar mechanisms. Thus is would be improper to value them individually because their benefits presumably will be duplicative. Using separate risks for each could substantially overvalue their potential benefit in combinations. Formulas that effectively combine the risks of all four antioxidants based on the above average risk ratios and amounts are:
For Cardiovascular Disease
Risk = Exp (0.669 - 0.0020 * Vit E, IU - 0.0000196 * Beta C IU - 0.00072 * Vit C mg - 0.0051 * Selenium mcg)
For Cancer:
Risk = Exp (0.6847 - 0.0020 * Vit E, IU - 0.0000205 * Beta C IU - 0.00085 * Vit C mg- 0.0049 * Selenium mcg)
These formulas reproduce the average risks shown in the previous tables and add them as per amounts of the antioxidants included. These formulas are used in Life Ahead with limitations imposed as follows:
Average maximums now accepted are those that appear reasonably well verified by the research found. These are 200 IU for Vitamin E, 750 mg for Vitamin C; 15,000 maximum for Beta Carotene and 180 mcg maximum for selenium. These maximums are adjusted for individual gender and weight. A useful ratio between Vitamin A and Beta Carotene is 1 to 3. Thus a maximum accepted amount for Vitamin A is 5,000 IU. Note that higher amounts than this for Beta Carotene or Vitamin A can be deleterious to health not only by causing bone loss but possibly reversing to increase risk of heart disease. The maximum risk benefit accorded any combination of the above antioxidants is now set at a risk benefit of 0.95 per year or 0.5 overall for both cardiovascular diseases and cancer.
Risks are Computed Conservatively: The results of Life Ahead in developing risks of diet often show antioxidants to be the most important of the 15 nutrient groups now valued in diets. This occurs because of their benefits in reducing risks for a wide range of different life limiting diseases. Life Ahead uses what is felt to a very conservative approach in valuing these antioxidants.
First each antioxidant is subject to limits as to amount accepted for benefit from a combinations of diet and supplements that is verified by research.. Second, the % per year method for computing risks produces far lower benefit during earlier years of use that would be obtained using a conventional type risk factor. Third, a maximum period of annual risk benefits is taken in Life Ahead as only 20 years. Duration related benefits appeared achieved for at least 30 years for risk of diabetes on heart disease, and it is likely that duration type benefits continue for life. Fourth, benefits are given only from present age forward. This will undervalue benefits for individuals who have been taking antioxidants in past years. Finally, a maximum risk benefit taken for any amount of all antioxidants taken is set at a risk of 0.50 or one half.. The few available research results on combinations of antioxidants do suggest that their benefits are multipliable. And a number of research results reach to well below a risk benefit of 0.50. A multiplication of the above risks for antioxidants would suggest a possible risk benefit of only 0.22 or less than a fourth of average as possible for maximum accepted amounts of each. The 0.50 as lowest now accepted is twice higher than this much lower risk possibility from the combined antioxidants.
The Antioxidant Index: An unexpected finding from Life Ahead is that a deficiency of diets in dietary food antioxidants may be today's #1 dietary deficiency. A key problem with antioxidants is that no valid guidelines have been available for judging when we are taking enough. The new Antioxidant Index solves this problem. The index that follows from the above research is:
Antioxidant Index = 0.002 * IU Vitamin E + 0.00002 * IU of Beta Carotene + 0.00078 * mg of Vitamin C + 0.005 * mcg selenium
This index computes from the above combinations of antioxidants the amounts needed to reduce their combined risk to the maximum of 0.50 now accepted after 20 years of their use. A value of zero means no antioxidants. A value of 100 means an overall amount sufficient to accomplish maximum now accepted benefit. A maximum value is set at 100. We can compute the antioxidant index of a total diet, and of any given food or included supplement using this index. Vitamin A can be used as 1 IU equivalent to 3 IU of beta carotene. It remains possible that antioxidants in amounts beyond the 100 level will produce further benefit. But acceptance of this will require more research.
These has been a widespread assumption by nutritionists that use of multiple fruits and vegetables in a diet will provide the antioxidant needed. This assumption appears false. There are very wide differences in the actual antioxidant amounts included in fruits and vegetables as for example index values ranging from 1 to 26 for single food portions. A typical US diet of foods includes only 50% of the antioxidants needed for best health, and this deficiency probably costs an average of about 1.5 years of Well-Days of life.
Use Antioxidant Combinations and Supplements: It is desirable to use combinations of these antioxidants in a diet. First, Vitamin E is fat soluble and Vitamin C is water soluble. The combination gives better pathways to inclusion in the blood. Second, they each probably provide somewhat differing biochemical activity and thus can complement each other. Some individuals may benefit from more from specific antioxidants. The maximum total amount and lowest risk accepted can be obtained by using the above maximums for any two of these four antioxidants.
It is recommended that Life Ahead users first develop healthful diets based on nutrients in foods. And it is possible to devise diets that include all needed antioxidants. But this can be difficult and it becomes more practical to use at least some inexpensive antioxidant supplements. A number of higher potency multi-vitamins include the added ntioxidants needed to reach the 0.50 risk level desired. Life Ahead includes an Antioxidant Index (to follow) that identifies antioxidant amounts in a diet. It is desirable to include at least the 200 IU of Vitamin E as a supplement as little of this is included in food. Near or sufficient Beta Carotene often is included in food, but extra Vitamin C and Selenium usually are needed from supplements. Life Ahead will compute the amounts of supplement values needed for any entered diet.
Those "Other" Antioxidants: The health press often extols some new biochemical in food as an 'Antioxidant' and as such this is implied as making the food 'Good'. This may - or more probably may not - be true. The problem is that antioxidants as bio-chemicals operate within limits, and cannot continually produce more and more 'Good' with any amount more that is eaten. An amount of antioxidant that is beyond the 100 antioxidant index amount that can be effective probably can easily be obtained by eating foods and supplements the above specified amounts. The real question becomes: "Will adding this new antioxidant to a maximum useful amount of these four now verified antioxidants achieve any more benefit?" This question can only be answered by multiple actual research on populations that is costly and time consuming to obtain.
It does remain possible, however, that some specific antioxidant might have unique benefits. Lycopene from tomatoes and Lutein are confirmed examples. Pholyphenols in some fruits may be another but this nutrient has not been confirmed by population research. The key question not answered, is this something that will produce benefit beyond what we can easily obtain via other means?
The Confusion: There has been much confusion recently about antioxidant benefits and especially about Vitamin E and Beta Carotene from some recent studies. These problem studies were discussed in the papers on individual nutrients. Despite this confusion, we find little if any analysis published of the actual results of available research on antioxidant vitamins. Please see the above hyperlinks on the individual Vitamins that explain reasons for this confusion. The benefits of antioxidants on cardiovascular disease, cancer, and death from all causes are well confirmed and results of the confusing papers are explained herein via that may be a most extensive study of antioxidants now available.
The 160 research study results of antioxidants included in this study were based on actual diets of foods, on dietary supplements, and on amounts of nutrients measured in blood. No difference was evident between benefits found from these different sources. Some have claimed that a nutrient in a food is better than that in a supplement. Can the human body somehow know which molecule of any discrete chemical came from a food and that which came from a supplement? And then disregard the molecule from the supplement and use only the one from the food? From chemistry 101 this seems unlikely.
And this key health benefit probably is obtained for all or nearly all types of cancer. The benefits of the four key supplements included in the antioxidant model for cardiovascular diseases are similarly defined for cancer from all key research published and found in the links herein for Vitamin E, Betacarotene and Vitamin C and Selenium. Interestingly, although antioxidants have most often been referred to as associated with cardiovascular diseases (CVD), more studies were located relating antioxidants to cancer than were found for heart diseases. Further their benefit to reducing risk of cancer appears quite similar to their benefits in reducing risk of CV diseases.
The Research: The research results on Vitamin E in reducing risk of cancer are impressive, suggesting a reduction in a risk of about one third for men and post-menopausal women. This is the average benefit from a total of 25 population study comparisons for amounts of about 200 IU per day. The averaged risk ratio benefit for 21 study comparisons relating about 14,000 IU of beta carotene to cancer was 0.75. The averaged benefit found in 21 comparisons relating 400 mg of Vitamin C supplements to cancer was 0.71. And most interesting, the average benefit found in a total of 31 different researched comparisons for Selenium was a low risk ratio of 0.61. See the above links for the actual data and discussions of the more than 90 different research study comparisons that in aggregate confirm the benefits of antioxidants in reducing risk of cancer with highest probability. For example, the risk ratio and error margin for Vitamin E alone from the 25 included research comparisons is 0.67 (5%-95% limits about 0.59-0.75). And this is for a typical 200 IU of the vitamin vs. the 400 IU often taken.
Much on how antioxidants reduce risk of cancer parallels the process by which they reduce risk of CVD disease. Thus this Global Analysis will not review the process of risk reduction in the detail that is included for Antioxidants and CVD disease. Antioxidants are components of diet that are involved in DNA and cell maintenance and repair. Vitamin E and other antioxidants have been found to inhibit human prostate cancer cells. And there is considerable laboratory evidence from chemical, cell culture and animal studies that antioxidant vitamins and related micronutrients are able to slow the carcinogenic process. Life Ahead assumes that pro and antioxidants respectively enhance or slow the growth of cancer cells over time. Thus their biochemical effects must be duration related for cancer as appears true for cardiovascular diseases and cigarettes. Antioxidants appear to benefit all types of cancer, and a likely hypothesis now is that all or nearly all types will be benefited near similarly.
A key demonstration of the large effect of duration of multi-vitamin use was shown in the large Nurses Study of colon cancer. (Giovannucci, E, Ann Intern Med 1998, 129:517 ). The trend suggested a risk of 1.2 initially, declining to 1.0 at 2.5 years and only 0.4 for >=15 yrs. This confirms directly the average effect of duration obtained from all other studies of a risk reduction of 0.95 per year of exposure. Interestingly this study suggested a risk above 1.0 and perhaps 1.25 for durations of use less than 2.5 years.
A summary of the average risk ratios for each antioxidant obtained from the more detailed analysis provided in the Life Ahead library follows. More detail and actual research information on each factor is available in the library at the indicated links. Risk ratios are summarized vs. a typical amount of factor used for both an estimated 10 years duration and per year of use:
For Nutrient Vitamin E Beta carotene Vitamin C Selenium
Avg Amount in research 200IU 14,000IU 400mg 100mcg
Avg Research Risk Ratio 0.67 0.75 0.71 0.61
Formula Value 0.67 0.75 0.71 0.65
Risk Ratio per year of use 0.961 0.972 0.966 0.958
No Research Population
Study Risk Ratios used 25 21 14 31
The Global Formula: The formula for relating antioxidants to risk of cancer is similar in concept to the formula for antioxidants and CVD diseases. Risk is taken as a ratio to that for average nutrient dietary inclusion in the foods of a typical US population. Coefficients differ somewhat based on the available research as follows:
Cancer risk = Exp( - 0.002 * (Vitamin E, IU - 8) - 0.000020 * (Beta carotene, IU - 6000)
- 0.00085 * (Vitamin C, mg - 250) - 0.0043 * (Selenium, mcg - 90)
The results for each of the antioxidants showed that most types of cancer researched benefited similarly from overall antioxidants. An exception was that risk of women's cancer for breast and genital areas did not appear to benefit from antioxidants until after menopause.
The benefits for Vitamin E, Beta carotene, and Vitamin C are taken by the formula as the average values found in the accompanying research. Benefits for Selenium which are potentially quite large are modified slightly for conservatism. The most pertinent values used in Life Ahead for these nutrients in both foods and dietary supplements are the risk ratios per year of use - as for CVD diseases. The benefits of antioxidants in foods are similarly compared with those of an average diet of a US person. Maximum values credited for supplements in benefiting cancer are 400 IU for Vitamin E, 15,000 IU of Beta-carotene, 400 mg of Vitamin C, and 100 mg of Selenium as these values are those now confirmed by actual research results.
A maximum benefit on risk of cancer now taken in Life Ahead for any amount of or kind or combination of antioxidants is a reduction in risk of 5% per year or use, or an annual compounding risk of 0.95. Duration of use is taken for only a maximum of 20 years of use, and then only to a minimum overall risk factor of 0.50. This is the same maximum benefit credited for heart disease. These limits may be conservative in view of much lower risks found for Vitamin E and Selenium combinations. But the use of some limit appears appropriate to recognize that there must a defined biochemical limit to what antioxidants can accomplish in slowing cancer, and actual available research does not convincingly confirm overall risk benefits much beyond these arbitrary limits imposed.
A combination of any two of the above antioxidants at the above maximum accepted amounts should eventually produce these maximum credited benefits. But it is suggested that to assure adequate benefit all four antioxidants be taken, in at least 1/2 and preferably for the maximum amounts suggested for each individually. The different antioxidant nutrients may act via supplementary mechanisms. As noted for individual supplements, Life Ahead does not credit any cancer benefit to antioxidant supplements for pre-menopausal women. And amounts larger that the maximums specified in Life Ahead should not be used. It is possible that excessive amounts of beta carotene can be harmful, and no benefit may be obtained from Vitamin E when used in larger amounts than 400 IU. Also, no credit for beta-carotene is given to smokers. But overall benefits to heart disease alone for dietary supplements should be more than sufficient to convince any health-interested man or woman that they should take them regularly.
As for their effect on CV diseases, practical diets rarely will include sufficient antioxidants to reduce risk of cancer by more than about 15%. Thus use of these dietary supplements becomes an essential need to achieve adequate reduction of cancer risk by diet.
The effect of antioxidants in risk is remarkably similar for both heart disease and various types of cancer. Further, antioxidants benefit each group of diseases as a risk modifier per year. Despite repeated controversy among researchers about antioxidants the effects appear clearly established beyond reasonable question from a total of 141 studies and it is unlikely that a few more studies could change this picture.. A comparison of these risks follows:
For Nutrient Vitamin E Beta carotene Vitamin C Selenium
Avg Amount in research 200IU 14,000IU 400mg 100mcg
CANCER
Avg Research Risk Ratio 0.67 0.75 0.71 0.61
Risk Ratio per year of use 0.961 0.972 0.966 0.958
No Research Population
Study Risk Ratios used 25 21 14 31
Coefficient as x in -0.0020 -0.0000205 -0.00085 -0.0049
exp(amount * x)= Risk Ratio
HEART DISEASE
Avg Research Risk Ratio 0.67 0.76 0.75 0.60
Risk Ratio per Year of Use 0.961 0.973 0.972 0.973
No Research Risk Ratios from
Population studies included 23 10 9 8
Coefficient as x in -0.0020 -0.0000196 -0.00072 -0.0051
exp(amount * x)= Risk Ratio
No known mechanism explains these similar risks. Because the risks do not differ by a significant margin, average value coefficients for the effect of antioxidants are now used Life Ahead for each group of diseases involved. .
