Beta Carotene, Cancer, and Smokers: A Warning

Do high beta carotene levels increase the risk of lung cancer in smokers? If so, what is the reason? Are antioxidants not the panacea for pre-cancerous free radical damage?

Beta carotene, the reddish-orange pigment found in fruits, has long been discovered to possess powerful antioxidant properties similar to vitamin C and vitamin E. Naturally, it was assumed dietary beta carotene as well as extra supplementation could be helpful in lowering the risk for cancer for nonsmokers and smokers alike. Only, trials did not garner the expected results … at least in smokers. The first  alarm was sounded in 1994 after results from the ATBC (Alpha-Tocopherol, Beta Carotene Cancer Prevention) trial reported an 18% increased risk in lung cancer in Finnish smokers assigned to receive 20mg of daily beta carotene compared to those who were not given the vitamin. (1) Considering that this trial was randomized, consisted of a total over 29,000 men, and was long in duration (5-8 years), while possibly entirely incidental, was not evidence to ignore. In effort to falsify seemingly nonsensical results, another trial of over 18,000 subjects was carried out in 1996 called the CARET (Beta Carotene and Retinol Efficacy Trial ) study that unexpectedly found a higher risk increase of 28% of lung cancer, and additionally, a 46% increased risk of death from lung cancer among those receiving 30mg beta carotene (alongside 25,000IU of retinol as  retinyl palmitate) for a period of 10 years. (2) This unexpected effect appears to emerge not so much in light smokers, but rather in those who smoke a pack or more a day. (3) Several explanations were spurred upon the dismaying data: 1. that beta carotene is just not as potent as fellow antioxidants vitamin C and E and in actuality had a null effect with observations of increased risk being explainable by elusive confounding factors 2. that cancer was already in development among the heavier smokers and thus antioxidants provided an enhancement of survival at this point 3. assuming the results were indeed conclusive, this only pertained to synthetic all-trans beta carotene and not the natural dietary form.

Doubts were put to rest after a ferret study elucidated the mechanism behind beta carotene’s pro-oxidant effect in the presence of tobacco smoke. The beta-carotene supplemented to the ferrets was a dose equivalent of approximately 30mg, which was around the average dose given in the human supplementation trials. As a result of 6 months of high beta-carotene supplementation coupled with exposure to cigarette smoke, a down-regulation of retinoid signaling was found and accompanied by an increase in pre-cancerous lesions compared to the controls that was explained by the generation of beta carotene’s oxidative metabolites spawned by the free radical-laden atmosphere induced by the tobacco smoke.  (4) Retinoic acid is protective against lung cancer by its inhibition of cancerous cell growth and ability to induce apoptosis in lung cancer cell lines. (5) With an increase of beta carotene and its oxidation products, a paradoxical localized deficiency of retinoic acid occurs, thus generating enhanced smoke-induced oxidative stress and resultant precancerous changes. Further, a direct damaging effect under high beta carotene load (60mg) was subsequently observed in humans in the form of DNA damage in smokers with opposite effects (protection from DNA damage) in nonsmokers. (6) This sufficiently puts the preposition that beta carotene is merely ineffective in smokers to bed and is, on the other hand, dangerous.

The Problem of Competition

A potential issue that will likely concern high doses of both all-trans and cis beta carotene (isomers of the carotenoid) is the potential for isolated replenishment to out-compete with other carotenoids and possibly other vitamins. These types of consequences are already recognized with mineral interactions (7-9), which is why single mineral supplementation in high amounts are discouraged independent of toxicity. In terms of carotenoids, high supplementation of beta carotene has been found to be reduce other carotenoids such as lutein and zeaxanthin in both plasma and in tissues. (10) Dietary lutein was seen to be dose-dependently inversely related to lung cancer, as was zeaxanthin. (11-13) As such, a drastic increase in the intake of one carotenoid – in this case beta carotene – will intensify the depletion of other carotenoids that already likely exists in most smokers.

Interestingly, when single carotenoids were assessed alone for lung cancer risk, findings indicate little to no protection; however, total carotenoid values consistently confer strong protective benefit against smoke-related lung cancer risk. (12)(14)

Besides other carotenoids, there may also be some antagonism with the tocopherols, otherwise known as vitamin E. Chronic high dosages (~30mg) of beta carotene were reported to decrease to serum vitamin E concentrations as well as well as its amount in tissues in several human studies consisting of both healthy and unhealthy subjects. (15-17) Intriguingly, the compromising effects of beta carotene supplementation on tocopherol seems to be enhanced with age. (16) It has been suggested that the imbalance brought about one fat soluble vitamin in high concentrations blocks the assimilation and usage of another to occur as a result of the competing for the same binding sites … this case being lipoproteins. (18)

So what about natural beta carotene?

A possibly salient point to note is all studies using supplemental beta carotene on animal models and humans included all-trans beta carotene, which is also the type found in the significant majority of health supplements available to consumers. Naturally-occurring beta carotene from food sources occurs as a mix of all-trans beta carotene and cis-beta carotene. However, the most popular sources of the carotenoid (carrots, sweet potatoes, tomatoes, etc.) have nearly  minuscule concentrations of the cis isomer compared to their all-trans content in their raw state.(19) Supplementing with all-trans beta carotene would therefore not be significantly different from supplementing with truly natural beta carotene, which would still contain a very high ratio of all-trans to cis isomers if it is intended to mirror beta carotene uptake some diet. Only algae from the Dunaliella species contains relatively equal amounts of cis-beta carotene to all-trans beta carotene isomers as all-trans beta carotene is by far the most common isomer in nature.(20) On the other hand, it may be worthy to consider that cis-beta carotene is only deceivably poorly absorbed in that it is majorly out-competed by the absorption of all-trans beta carotene in serum but is accumulated throughout tissue. (21-23) It is possible that the small portion of cis beta carotene in tissue is meaningful against the high oxidation potential of all-trans beta carotene. If that is the case, then near-pharmacological doses of all-trans beta carotene could theoretically override the cis beta carotene concentrations in tissue, increasing the high ratio of all-trans to cis isomers even more where it is no longer protective in a highly oxidative milieu. It already known that upon supplementation with synthetic beta carotene, the plasma ratio of trans to cis beta carotene increases dramatically. (24) The 9-cis beta carotene is demonstrably a more potent antioxidant, especially  in preventing carcinogenesis (25-26), and a higher ratio of 9-cis to all-trans beta carotene will have a sparing effect on all-trans beta carotene’s usage (27); thus, demand of all-trans beta carotene to react with cigarette smoke-induced free radicals will be reduced, which should lead to the prevention harmful oxidation products that result in suppression of retinoic acid … this is assuming that the chemically equivalent but geometrically different molecule (cis-9) reacts differently under the same circumstances.

Although research points to the fact that a mixture of both all-trans and cis beta carotene is superior to all-trans alone, it is not yet advisable to recommended cis products over all-trans product in pharmacological amounts. All-trans beta carotene, like cis isomers, has been repeatedly proven to be beneficial in vitro and in vivo at normal concentrations similar to dietary amounts in non-smokers, but effects of  suprapsysiological concentrations of the carotenoid  under conditions resembling  smoking is a whole different story altogether. At the current time there are no studies that have taken place that ensure high amounts of cis beta carotene with smoke exposure will not also generate equally troublesome metabolites that paradoxically will depress the retinoic acid protection in the lungs. For the time being, recommendations for pharmacological amounts of supplementary ‘natural’ cis form beta carotene cannot be recommended.

Do dietary amounts also pose a threat?

When only dietary beta carotene is assessed, the opposite relationship that is observed with high dose supplementation in smokers and nonsmokers disappears with apparent additive lung-protective (and generally chemoprotective) effects when replete with other carotenoids. (12,28,34) Among smokers, those who did not consume carrots – one of the greatest sources of beta carotene – displayed a three-fold higher risk compared to current smokers who consumed them more than once a week.  (28) Similar results were seen in a different study group where smokers in the lowest tertile of beta carotene (together with alpha carotene) intake were on average twice as likely to develop lung cancer. (12)

Contrary to expectations based on supplement studies, other than light female smokers, male participants who were heavy smokers were found to be most protected with higher beta carotene intake in a population-based study in Hawaii. (29) Other studies have reported very weak to null values for beta carotene consumption in current smokers, but no signs of harm. (30-31) These weakly beneficial to null effects were also found in the ferret model administered a physiological dosage equal to 6mg of beta carotene as a human dose whereas significantly reduced retinoic acid and suspicious lung cell growth was once again seen in the pharmacological dosage equal to 30mg in the ferrets. (32) Single beta-carotene supplementation with 9mgs also did not produce any deleterious effects in current smokers based on tests for oxidative stress (carbonyl content of proteins) and DNA damage (urinary 8-OHdG excretion). No additional benefit over dietary amounts in observed in humans. (34)

The Solution

  •   Achieve Balance with Antioxidants
    (I.E. Do Not Supplement with Beta-Carotene in Isolation)

This is crucial to all individuals. Contrary to popular assumption, different antioxidants have unique methods of action and therefore contribute to nonidentical benefits. Moreover, mega doses can transform safe, beneficial antioxidants into toxins irrespective of competition with other antioxidants. To achieve risk aversion rather than nil benefit or harm from intake of beta carotene, essential antioxidants vitamin C and vitamin E (natural/ ‘d-alpha tocopherol) are especially vital to smokers. These vitamins are effective against pre-cancerous oxidative damage and have an anticarcinogenic effect against lung cancer that is strengthened by synergy with one another. (33-36)

Independent of beta-carotene consumption, both of these vitamins become significantly depleted with the surge of oxidative stress derived from smoking. Upon exposure to cigarette smoke, vitamin C and E are rapidly emptied from human plasma, preceding the decrease of beta carotene. (37-38) Regardless of the effects of beta-carotene supplementation, higher serum values of beta-carotene at baseline actually are associated with a lower risk of lung cancer in smokers, and at worst, no increased risk. (1-2)(13) Beta-carotene in serum is diminished by smoking exposure (38-39), so what high baseline amounts of beta-carotene in smokers may actually be showing – other than higher intakes of beta-carotene –  is greater amounts of initial vitamin C and vitamin E and possibly other carotenoids preventing its oxidation. Therefore, these vitamins would serve as the first line defense for neutralizing free radicals , which would then spare the amount of beta-carotene that would otherwise vanish from  plasma.

Once vitamin C and vitamin E are incorporated along with beta-carotene, retinoic acid in the lungs increases rather than decreases, prooxidant pathways that are expressed during solo supraphysiological beta-carotene administration are deactivated, and in stark contrast to the development of precancerous lesions that formed in ferrets  given beta-carotene during cigarette smoke exposure, a lowered incidence of such development (and tumor formation) is observed. (40) When beta-carotene is together with vitamin C and E, both vitamins act synergically to dose-dependently inhibit the production of oxidative metabolites from beta-carotene and bolster its conversion to retinoids (41-42) Part of this synergetic relationship is imparted by the preserving effect vitamin C seems to have on the disappearance (oxidation) of vitamin E (43) that normally occurs with smoking and other triggers of oxidation stress and inflammation.  This co-antioxidant effect may be maintained as long as amounts beta-carotene do not outnumber vitamin C and vitamin E concentrations.

Positive effects of combined antioxidant supplementation (including beta-carotene) remain to be consistent in human studies. Specifically, a cocktail of vitamin C, vitamin E, and beta-carotene in tablet form containing 250mg, 200IU, and 6mg respectively taken twice a day in ‘heavy smokers’ (1 pack or over daily)  showed a more significant reduction of DNA damage compared to the placebo group. (44) Granted, the placebo group in this study also showed a deceased in DNA damage by the various test markers, lowering the calculated significance in the vitamin group, but it was suspected the placebo group improved their lifestyle during observation and the fact that a large number of placebo participants with higher baseline DNA damage dropped out was not overlooked by the researchers. (Ibid) In another study centered around beta carotene with vitamin C and E, 20 weeks of supplementation with the combination of antioxidants (vitamin C100mg/day, vitamin E 280mg/day, and beta-carotene 25mg/day) reduced oxidative damage to DNA by 65% in older male smokers. (45)

Antioxidant properties of minerals within their safe dosages should not be overlooked as well. Like vitamins, minerals have shown to have inverse relationships with lung cancer (55) and therefore might provide very strong protection when combined with adequate intake of vitamins and carotenoids. Workers exposed to environmental tobacco smoke were relieved of increased DNA damage according to the lowering (63%) of 8-OHdG values after administration of beta-carotene with multiple vitamins in small concentrations (3mg of beta-carotene, 60mg vitamin C, 30IU alpha-tocopherol/vitamin E, 40mg zinc, 40mcg selenium, and 2mg copper). (46)

Given the wide array of nutrients that possess anti-cancer activity and the number of positive interactions they may have with carotenoids, a large and diversified intake of fruits and vegetables is ultimately the easiest and most likely the most promising way to achieve maximum lung cancer protection. Fruits and vegetables both contain a host of vitamins, minerals, fiber, and thousands of potentially important phytochemicals (56) including unknown chemopreventative agents not yet discovered that could be mediating the consistent positive effect against fruit and vegetable consumption on lung and general cancer risk. Careful supplement is not discouraged, but it should not replace a diet containing fruits and vegetables.

  •    Beta-carotene

(Avoid Unnecessary High Amounts in Dietary Supplements)

As for smokers with low dietary intake of beta carotene, data indicates that cautious supplementation (mimicking dietary levels) will confer an antioxidative effect and therefore be helpful. (47) In these instances supplemental beta carotene should be around 6mg-12mg and not exceed those values for safety concerns. Those at risk are encouraged to practice punctilious vigilance when it comes to multivitamins, especially those geared towards eye health as several well known brands on the market can contain nearly 30mg of beta-carotene. (48)

  •   Other (Safe) Carotenoids

Smokers interested in preserving eye health and/or receiving chemoprotection from carotenoids should strongly consider prioritizing other carotenoids such as lycopene, lutein, zeaxanthin, and  cryptoxanthin in diet and in supplement regimes if need be. In the ATBC study group, those with the highest dietary intakes of lycopene, lutein/zeaxanthin, and cryptoxanthin compared the lowest intakes were found to have lower levels of lung cancer with strength of protection in that order. (13)

Lycopene is utilized to scavenge smoke-induced radicals before beta-carotene, preventing excess beta-carotene/smoke interaction from taking place. (38) Both low and high dose lycopene (equivalent human doses – 15mg/day and 6mg/day respectively) inhibited precancerous changes in the smoke-exposed ferret lung. (52) In one study, lycopene was the only carotenoid whose intake was significantly inversed correlated with lung cancer in current smokers. (53)

Lutein and zeaxanthin are equally protective against the development of eye-related disease in smokers as beta carotene without the added risk of lung cancer risk observed in the original formula containing 15mg. (49) Therefore, this combination would be a better choice as a high-dose carotenoid formulation to suppress macular degeneration development (or progression) without sacrificing cancer risk.  Additionally, there is evidence of antioxidative synergy between lutein and lycopene (54), possibly strengthening lycopene’s protective effect on lung carcinogenesis.

Cryptoxanthin, like beta carotene, has been studied in cigarette smoke exposed ferrets and in contrast to beta carotene, high dose cryptoxanthin decreased inflammation, oxidative DNA damage, and precancerous changes in the lung. (50) High cryptoxanthin detected in the serum of NHANES III participants was associated with a 61% reduced risk of lung cancer morality in the currently smoking group ,and opposite of the supplemental beta carotene associations, this strong protective effect was not found in never or former smokers.  (51)

Final Statements

According to the reported data, current smokers should  not feel encouraged to restrict balanced sources of beta carotene in the diet which are naturally mixed antioxidants and other carotenoids, but rather,  should err on the side of caution with any additional supplementation featuring high amounts of carotenoid – both natural and unnatural sources either as part of a general health formula or as a single ingredient. Protection against lung and other cancers will result from diets and supplementation that provide nutrients in modest amounts with synergy amongst each other to mimic a diet rich in fruits and vegetables. Alternate carotenoid formulations excluding beta-carotene may be safely used to promote eye health.

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