In plain terms: Beta-Carotene (supplemental) has been tested in human trials aimed at the relevant outcome and did not show benefit at the doses and durations studied. The animal research may be encouraging, but it has not yet translated to humans in these trials.
Beta-Carotene (supplemental)
The evidence as the record states it
Harm: Alpha-Tocopherol Beta-Carotene Cancer Prevention Study Group (N Engl J Med, 1994; PMID 8127329): 29,133 male smokers, beta-carotene 20 mg/day alone for 5 to 8 years, lung cancer incidence 18 percent higher (95% CI 3 to 36) and total mortality 8 percent higher. CARET, Omenn et al. (N Engl J Med, 1996; PMID 8602180): 18,314 smokers, former smokers and asbestos workers, beta-carotene 30 mg/day PLUS retinyl palmitate 25,000 IU/day, a combination; lung cancer relative risk 1.28 and death from any cause 1.17; stopped 21 months early. Goodman et al. (J Natl Cancer Inst, 2004; PMID 15572756): CARET post-intervention follow-up to 2001; the excess continued as a nonsignificant trend (lung cancer 1.12, 95% CI 0.97 to 1.31; death 1.08, 0.99 to 1.17). Null outside heavy smokers: Physicians' Health Study, Hennekens et al. (N Engl J Med, 1996; PMID 8602179), 22,071 men, 11 percent current and 39 percent former smokers, 50 mg on alternate days for 12 years, no difference in cancer, cardiovascular disease or mortality; Women's Health Study, Lee et al. (J Natl Cancer Inst, 1999; PMID 10601381), 39,876 women, no difference in cancer or cardiovascular disease. Pooled: Druesne-Pecollo et al. (Int J Cancer, 2010; PMID 19876916), 9 trials, no effect on cancer overall, lung (RR 1.16) and stomach (RR 1.34) cancer increased at 20 to 30 mg/day in smokers and asbestos workers; Zhang et al. (Nutr Rev, 2023; PMID 36715090), 8 trials, lung cancer RR 1.19, no effect on other sites; O'Connor et al. (JAMA, 2022; PMID 35727272), the USPSTF evidence review, beta-carotene with or without vitamin A raised lung cancer (OR 1.20) and cardiovascular mortality (OR 1.10). D Route 2: tested, harm found in smokers and asbestos workers, no benefit in anyone.
Trials showing no benefit
High. Large randomized, double-blind, placebo-controlled primary-prevention trial. Lung cancer incidence 18 percent higher (95% CI 3 to 36) and total mortality 8 percent higher on beta-carotene.
High. Randomized placebo-controlled trial stopped 21 months early: lung cancer relative risk 1.28 (95% CI 1.04 to 1.57), death 1.17 (1.03 to 1.33). The combination, not beta-carotene alone, was tested.
High. Relative risk of any malignancy 0.98 (95% CI 0.91 to 1.06); no difference in lung cancer, cancer death, cardiovascular disease or overall mortality.
High for a null over the period studied: cancer relative risk 1.03 (95% CI 0.89 to 1.18), no difference in cardiovascular disease or mortality; the beta-carotene arm was stopped early after the ATBC and CARET results.
Why Grade D Route 2 and not Grade C
Grade D Route 2 applies when a compound has been tested in humans and benefit was not shown. Beta-Carotene (supplemental) has been tested in 4 human trials on endpoints relevant to the claim being evaluated, and the primary endpoint was not met.
A randomized, placebo-controlled trial pre-specifying a meaningful clinical or functional endpoint and demonstrating statistically significant benefit would move this to Grade C or higher, depending on effect size, population size, and whether it is independently replicated.
What this grade covers and what it does not
What would move this grade
A randomized, placebo-controlled trial pre-specifying a clinical aging endpoint and demonstrating statistically significant benefit on that primary endpoint would be sufficient to move this to Grade C or higher, depending on effect size and population.