While high doses of vitamin A can be toxic, the use of beta-carotene as a source of vitamin A is safe. The conversion of beta-carotene ─ also called ‘provitamin A’ ─ to vitamin A is influenced by the vitamin A status of the individual and some other host factors (50). The molecular regulation of the beta-carotene conversion to vitamin A was elucidated some years ago by von Lintig and Wyss (66). The intestinal factor ISX is responsible for the down-regulation of beta-carotene uptake and cleavage as soon as the vitamin A supply is sufficient. This explains why high doses of beta-carotene have never been found to cause vitamin A toxicity.
High doses of beta-carotene (up to 180 mg/day) have been used without toxic side effects (1).
Unlike vitamin A, high doses of beta-carotene taken by pregnant women have not been associated with increased risk of birth defects 1). However, the safety of high-dose beta-carotene supplements in pregnancy and lactation has not been well-studied.
Lung cancer risk
Three large randomized controlled trials evaluated the effect of long-term high-dosed beta-carotene supplementation on the risk of developing lung cancer. In Finland, the Alpha-Tocopherol Beta-Carotene (ATBC) cancer prevention trial evaluated the effects of 20 mg/day beta-carotene and/or 50 mg/day alpha-tocopherol (vitamin E) on more than 29,000 male smokers (29), and in the United States, the beta-Carotene And Retinol Efficacy Trial (CARET) evaluated the effects of a combination of 30 mg/day beta-carotene and 25,000 IU/day retinol (vitamin A) in more than 18,000 men and women who were smokers, former smokers, or had a history of occupational asbestos exposure (51).
In the groups of heavy smokers (more than 20 cigarettes per day) taking high doses of beta-carotene supplements (5 to 10 times the recommended dose), the risk of lung cancer was increased by 16% after six years in the ATBC participants and increased by 28% after four years in the CARET participants.
A possible explanation for such a finding is that the oxidative environment of the lung, created by smoke or asbestos exposure, gives rise to unusual carotenoid cleavage products, which are involved in cancer development (60). Further the group of X.-D. Wang at Tufts University tried to explain the detrimental effects of high dose beta-carotene supplementation on a molecular level. They concluded that a high dose of beta-carotene interferes with the retinoid signalling in lung cells and leads to the change of expression levels of genes involved in cancerogenesis (67,68). However, other large studies did not show such effects: The Physicians’ Health Study examined the effect of beta-carotene supplementation (50 mg every other day) on cancer risk in more than 22,000 male physicians in the U.S., of whom 11% were current smokers (30). In that population, beta-carotene supplementation for more than 12 years was not associated with an increased risk of lung cancer.
More recently, the Women's Health Study (WHS) in 40,000 women, including 13% smokers, receiving 50 mg beta-carotene per day showed no increased lung cancer risk for two years and two years follow-up (52).
Although the reasons for the increase in lung cancer risk in some studies are not fully clear, experts advise against high-dose beta-carotene supplementation in smokers or other high-risk populations (53, 54).
In 2012, the European Food Safety Authority (EFSA) concluded that epidemiological studies had reported no increased lung cancer incidence in heavy smokers who consumed beta-carotene in supplemental dose levels varying from 6 to 15 mg/day over the course of 5 to 7 years (62). Exposure to beta-carotene from its use as a food additive and as a food supplement at levels below 15 mg/day did not give rise to concerns about adverse health effects in the general population, including heavy smokers.
More importantly, smoking itself remains the strongest risk factor for lung cancer. The fact is that no micronutrient can compensate for an unhealthy lifestyle.
High doses of beta-carotene supplements (30 mg/day or more) and the consumption of large amounts of carotene-rich foods may result in a yellow discoloration of the skin known as ‘carotenodermia’. Carotenodermia is not associated with any underlying health problems and resolves when beta-carotene supplements are discontinued or dietary carotene intake is reduced.
Beta-carotene plus other antioxidants
A meta-analysis of 67 selected studies concluded that it did not find convincing evidence that antioxidant supplements reduce mortality (55). Additionally, the authors stated that beta-carotene, vitamin A, and vitamin E may increase the risk of death. They suggested this again for beta-carotene and for vitamin E doses which are higher than the RDA in a meta-analysis from 2013 (63). However, experts raised serious doubts about the conclusions as they were drawn from a flawed meta-analysis pooling data from trials with varied populations (healthy and diseased individuals) and different methodologies (61) (see also Expert Opinion). The ATBC and CARET study, that were included in this meta-analysis have an over proportional weight and influence the outcome.
An evaluation of data from the VITamins And Lifestyle (VITAL) cohort study discussed the connection between antioxidant supplements and the incidence of lung cancer (56). The authors speculated that longer duration of use of individual beta-carotene, vitamin A (retinol) and lutein supplements was associated with elevated risk of total lung cancer. However, experts commented that the retrospective study was flawed due to an invalid design, biased questionnaire methodology, and questionable statistical evaluations (see also Expert Opinion).
A randomized controlled trial of antioxidants for cancer prevention (SUVIMAX study) found that daily supplementation with nutritionally appropriate doses of vitamin C and vitamin E, beta carotene, selenium and zinc appeared to increase the risk of skin cancer (melanoma) in women fourfold (57). However, the analysis was criticized as it was limited only to a subsample of participants who agreed to answer a single question on their lifetime sun exposure ("How would you describe the intensity of your skin's exposure to the sun during your lifetime?"), which could introduce selection bias and limit generalizability (58).
In addition, a more recent large prospective cohort study did not observe increased melanoma risk in women and men using supplemental multivitamins or beta carotene long-term at doses comparable to those of the SUVIMAX study (59).
Tolerable upper intake levels
Existing evidence from human trials indicates that supplemental beta-carotene (20 mg/day or more) is not recommended for use in current, heavy smokers. However, the European Food Safety Authority and the U.S. Food and Nutrition Board have decided that there is insufficient scientific data from human intervention trials to set a precise figure for a tolerable upper intake level (UL) of isolated beta-carotene (46, 1). Moreover, it has not been possible to be more specific in distinguishing different forms of beta-carotene or specific formulations.
In the U.K., the British Expert Committee on Vitamins and Minerals (EVM) recommends a ‘safe upper level’ for supplementation of 7 mg/day.
The Nutrition Societies of German-speaking countries (German, Austrian, and Swiss Nutrition Society) have concluded that a daily intake of up to 10 mg beta-carotene from all sources is safe and the Norwegian Scientific Committee on food Safety, VKM, has introduced an upper safe level of 4mg/d.
Because of the potential for interactions, dietary supplements should not be taken with medication without first talking to an experienced healthcare provider.
Authored by Dr Peter Engel in 2010, reviewed and revised by Dr. Adrian Wyss on 03.10.17.