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Brief history of how the beta-carotene & lung cancer link in smokers came about
Unlike gods, children of gods and mystics, pulling things apart to understand the whole is the flawed human way, no matter the whole often ends up more than the sum of its parts, beta-carotene being convenient case in point, courtesy this question.
Carrots? Yup. Pumpkins and sweet potatoes? Right again. Foods rich in beta-carotene. Research shows such carotenoids to be efficient scavengers of the reactive oxygen species that are often at play in pathologic processes in chronic diseases.
No wonder carotenoids like beta-carotene got caught up and subsumed into the antioxidant craze that supplement pushers have hawked for years and why wouldn’t they when it looks like they hit upon such a lucrative market?
Before all that came to pass though, in somewhat more innocent times, epidemiological studies showed those consuming diets rich in fruits and vegetables, especially foods rich in carotenoids like beta-carotene, to have lower rates of cancer compared to those who didn’t. Specifically, dietary beta-carotene intake correlated inversely with lung cancer risk (1, 2).
And off to the races we went! In no time, epidemiologists had planned and set in motion clinical trials to see if taking beta-carotene supplements could likewise reduce lung cancer risk.
Results were unexpected to say the least and not in a good way.
- Good news first. Beta-carotene correlated inversely with lung cancer in non-smokers.
- Contrary to expectation, beta-carotene correlated with higher lung cancer rates in smokers, especially among those with high smoking intensity and especially after long-term, high dose standalone supplementation.
Note that early epidemiological studies focused on dietary beta-carotene and not beta-carotene supplement. Obviously, foods rich in beta-carotene ≠ beta-carotene.
Beta-carotene correlates inversely with lung cancer in non-smokers, i.e., beta-carotene supplement good for non-smokers
Intake of beta-carotene-rich foods in non-smokers shows inverse correlation with lung cancer (3, 4).
Beta-carotene correlates with higher lung cancer rates in smokers, i.e., beta-carotene supplement bad for smokers
A double-blind, placebo-controlled randomized clinical trial of 22071 doctors began in 1982. 50 mg of beta-carotene on alternate days. In 1995 the study was forced to conclude (below from 5),
“virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease, or in overall mortality”
Story doesn’t end there because other studies showed worse in the form of insult to injury with high-dose beta-carotene supplementation correlating with higher lung cancer rates in smokers (6, 7, 8). A few years later, a meta-analysis (study of studies) put the nail in the beta-carotene-lung cancer coffin when it concluded (below from 9).
“High-dose beta-carotene supplementation appears to increase the risk of lung cancer among current smokers”
Further meta-analyses have removed the sheen off of antioxidant supplementation in general (below from 10),
“supplementation of antioxidants does not result in the presumed health benefit, but paradoxically a high intake of antioxidants is associated with increased mortality [6], [7], [8], [9]. More than 68 randomized control trials were analyzed for the effects of β-carotene, vitamin A and vitamin E on mortality. All these compounds, given in a relatively high dose as a single compound or in different combinations, had no beneficial effects. The supplements even increased all-cause mortality.”
Coda
What could be happening? Best guess appears to be that the oxygen-rich lung environment is fundamentally physiologically and biochemically different in smokers compared to non-smokers. This would normally remain invisible but pops up on the radar when smokers take standalone high-dose beta-carotene supplements which elicit pro- rather than antioxidant properties from them, an apparent physiological corollary of ‘nothing is good or bad but thinking makes it so’ (11).
We evolved eating certain whole foods in the form of fruits and vegetables. Those foods in turn evolved to have specific complex compositions, largely for their own benefit of course. Empirically over long time periods, we learned to associate specific foods with specific health benefits.
Fruits and vegetables seem to protect against cancer. Is it the beta-carotene in them that does this? Is the xyz in them that does it? Chasing such questions likely leads to fool’s gold. Meantime, the ever-dizzying arrays of supplements in grocery and health food stores suggest that supplement hawkers are still laughing their way to the bank.
Bibliography
1. Peto, R., et al. “Can dietary beta-carotene materially reduce human cancer rates?.” Nature 290.5803 (1981): 201.
2. Champan, S. “Dead customers are unprofitable customers: potential and pitfalls in harm reduction and product regulation.” En: Public Health Advocacy and Tobacco Control, editor. Making smoking history. Oxford: Blackwell Publishing (2007).
3. Le Marchand, LoIc, et al. “Intake of specific carotenoids and lung cancer risk.” Cancer Epidemiology and Prevention Biomarkers 2.3 (1993): 183-187. http://cebp.aacrjournals.org/content/cebp/2/3/183.full.pdf
4. Mayne, Susan Taylor, et al. “Dietary beta carotene and lung cancer risk in US nonsmokers.” JNCI: Journal of the National Cancer Institute 86.1 (1994): 33-38. http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.868.3656&rep=rep1&type=pdf
5. Hennekens, Charles H., et al. “Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease.” New England Journal of Medicine 334.18 (1996): 1145-1149. Lack of Effect of Long-Term Supplementation with Beta Carotene on the Incidence of Malignant Neoplasms and Cardiovascular Disease | NEJM
6. Omenn, Gilbert S., et al. “Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.” New England journal of medicine 334.18 (1996): 1150-1155. Effects of a Combination of Beta Carotene and Vitamin A on Lung Cancer and Cardiovascular Disease | NEJM
7. Albanes, Demetrius, et al. “Effects of alpha-tocopherol and beta-carotene supplements on cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study.” The American journal of clinical nutrition 62.6 (1995): 1427S-1430S. http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.860.4088&rep=rep1&type=pdf
8. Goodman, Gary E., et al. “The Beta-Carotene and Retinol Efficacy Trial: incidence of lung cancer and cardiovascular disease mortality during 6-year follow-up after stopping β-carotene and retinol supplements.” Journal of the National Cancer Institute 96.23 (2004): 1743-1750. https://academic.oup.com/jnci/article/96/23/1743/2521077
9. Tanvetyanon, Tawee, and Gerold Bepler. “Beta‐carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers: a meta‐analysis and evaluation of national brands.” Cancer 113.1 (2008): 150-157. Beta‐carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers
10. Vrolijk, Misha F., et al. “The shifting perception on antioxidants: The case of vitamin E and β-carotene.” Redox biology 4 (2015): 272-278. The shifting perception on antioxidants: The case of vitamin E and β-carotene
11. Goralczyk, Regina. “ß-Carotene and lung cancer in smokers: Review of hypotheses and status of research.” Nutrition and cancer 61.6 (2009): 767-774.