Vitamin and Supplements Safety and Dangers – A Few Examples

Results of several large studies suggest that supplemental beta-carotene increases the risk of developing lung cancer in heavy smokers:

Alpha-tocopherol beta-carotene cancer prevention study group: The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. (N Engl J Med 1994, 330: 1029-1035).

Risk factors for lung cancer and for intervention effects in CARET, the beta-carotene and retinol efficacy trial. (J Natl Cancer Inst 1996, 88: 1550-1559).

Beta-carotene exacerbates DNA oxidative damage and modifies p53-related pathways of cell proliferation and apoptosis in cultured cells exposed to tobacco smoke condensate. (Carcinogenesis 2004, 25: 1315-1325).

Thus, it has been recommended that subjects with a history of smoking avoid supplemental beta-carotene.

However, an increased intake of foods rich in beta-carotene has not been found to pose a heightened risk for the development of lung cancer among current and non-smokers:

Dietary carotenoids and risk of lung cancer in a pooled analysis of seven cohort studies. (Cancer Epidemiol Biomarkers Prev 2004, 13: 40-48).

Other carotenoids derived from whole foods (lutein, zeaxanthin, and lycopene) are also not associated with increased risk for lung cancer:

Dietary carotenoids and risk of lung cancer in a pooled analysis of seven cohort studies. (Cancer Epidemiol Biomarkers Prev 2004, 13: 40-48).

The supplement prescribed in the TOZAL study was designed to address the risk of lung cancer among smokers receiving supplemental beta-carotene by focusing on beta-carotene derived from whole foods. The TOZAL supplement contained 18,640 IU of natural beta-carotene and 10,000 IU of vitamin A.


Recent data link high doses of vitamin E to a 13% increase in the risk for heart failure:

Harvard Health Publications: Research linking high doses of vitamin E to heart failure is causing new worries about the AREDS vitamins for macular degeneration. (Harv Health Lett 2005, 30: 6).

In addition, a separate study found that doses of 400 IU or more of vitamin E increased the chance of early death or, according to the authors, “all-cause mortality” and should be avoided:

Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. (Ann Intern Med 2005, 142: 46).

In an attempt to address these potential risk factors, the TOZAL supplement was designed with 200 IU vitamin E.


High doses of zinc were included in the AREDS supplement (80 mg as zinc oxide), as well as copper (2 mg) to help prevent copper deficiency associated with zinc supplementation.

In the AREDS study, 7.5% of participants receiving a zinc-containing nutritional supplements vs. 5.0% of participants receiving no zinc in their nutritional supplement reported urinary tract problems that required hospitalization, as well as increased rates of anemia (anemia results were found not to be statistically significant):

Age-Related Eye Disease Study Research Group: A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no 8. (Arch Ophthalmol 2001, 119: 1417-1436).

In an effort to limit the adverse effects associated with high-dose zinc, the TOZAL supplement was designed with 69.6 mg zinc and 1.6 mg copper. No urinary tract adverse events or anemia were reported during the TOZAL trial.


In 1998, van den Berg et al found that lutein negatively affected beta-carotene absorption when the two were given simultaneously:

Effect of simultaneous, single oral doses of betacarotene with lutein or lycopene on the beta-carotene and retinyl ester responses in the triacylglycerol-rich lipoprotein fraction of men. (Am J Clin Nutr 1998, 68: 82-89).

This decrease in absorption may affect the amount of beta-carotene available for conversion to retinol.

In the AREDS study, lutein was not a constituent of the formula, thereby circumventing the issue.

As newer formulas are developed that contain lutein, consideration must be given to administering vitamin A in addition to beta-carotene.

In the TOZAL study, this adjustment was made by administering 18,640 IU of natural beta-carotene and 10,000 IU of vitamin A.

Extracted and adapted from: Francis E Cangemi. TOZAL Study: An open case control study of an oral antioxidant and omega-3 supplement for dry AMD. BMC Ophthalmology 2007, 7:3 doi:10.1186/1471-2415-7-3. © 2007 Cangemi, licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (