Linking To And Embedding “Supplement Use and Increased Risks of Cancer: Unveiling the Other Side of the Coin” From Cancers (Basil)

Posted on December 25, 2024 by Tom Wade MD

Today, I review, link to, and excerpt from Supplement Use and Increased Risks of Cancer: Unveiling the Other Side of the Coin from Cancers (Basil). [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. Cancers (Basel). 2024 Feb 22;16(5):880. doi: 10.3390/cancers16050880.

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Simple Summary

This study investigates the overlooked harmful effects of dietary supplements, particularly their potential association with increased cancer risk. In response to a rising trend in supplement consumption, we address the “more is better” mentality prevalent in marketing campaigns by focusing on the long-term and regular use of these supplements. Our findings reveal that beyond known toxicities at high levels, dietary supplements may contribute to increased risk of cancer. We consolidate evidence from studies highlighting the correlation between substantial micronutrient intake, supplement use, and the potential implications for cancer development and mortality. Recognizing the link between supplement consumption and increased cancer risk is crucial for informing consumers and empowering healthcare professionals in how to guide patients more effectively.

Abstract

There is a rising trend in the consumption of dietary supplements, especially among adults, with the purpose of improving health. While marketing campaigns tout the potential health benefits of using dietary supplements, it is critical to evaluate the potential harmful effects associated with these supplements as well. The majority of the scarce research on the potential harmful effects of vitamins focuses on the acute or chronic toxicities associated with the use of dietary supplements. Quality research is still required to further investigate the risks of long-term use of dietary supplements, especially the risk of developing cancers. The present review concentrates on studies that have investigated the association between the risk of developing cancers and associated mortality with the risk of dietary supplements. Such an association has been reported for several vitamins, minerals, and other dietary supplements. Even though several of these studies come with their own shortcomings and critics, they must draw attention to further investigate long-term adverse effects of dietary supplements and advise consumers and healthcare providers to ponder the extensive use of dietary supplements.

Keywords: vitamin, supplement, cancer risk, prostate cancer

1. Introduction

With the increasing trends in longevity, the conversation in healthcare is changing from lifespan to that of healthspan []. Several genetics and epigenetics studies have been dedicated to finding intrinsic and extrinsic factors that can improve both lifespan and healthspan []. Much emphasis has been placed on the importance of a healthy lifestyle and its epigenetic effects in decreasing the risk of several diseases, especially age-related diseases, including cancers [,]. A healthy diet and moderate physical activity have been introduced as cornerstones of leading a long, healthy life [,]. Among these, micronutrients have received special attention for their role in preventing diseases such as cancers []. Following recommendations of a balanced diet and physical activity might be hard, and therefore several shortcuts have been introduced to improve healthspan. A solution to ensure balanced nutrition, especially in the light of concerns for nutrient-depleted food due to soil exploitation [], is the use of dietary supplements. While dietary supplements have been available for decades, the recent increase in their use is alarming and requires investigations for potential risks associated with their frequent or excessive use. Most of the studies regarding dietary supplements have focused on their benefits, specifically in the light of their effect on a certain health concern. These beneficial effects are one of the driving forces behind the increased consumption of dietary supplements and the multibillion dollar growth in this expanding market. With new reports on the health benefits of various compounds and micronutrients, the nutraceutical industry now offers more than 90,000 dietary supplements to the market, a remarkable increase compared to the 4000 supplements marketed in 1994 []. Several marketing campaigns are now providing consumers with information on the health benefits of their dietary supplements. Many of these dietary supplements provide a range of micronutrients to ease the consumption of required micronutrients in one go. However, influential marketing as one of the main contributors to the increased consumption of dietary supplements may lead to the concurrent consumption of dietary supplements []. The target consumers may fall into one of two major categories: one group may try to compensate for the lack of a healthy diet by consuming dietary supplements. Even though these individuals may receive daily doses of several micronutrients, they may miss out on the phytochemicals a balanced diet composed of whole foods can offer, which have several health benefits including anticancer properties []. Another group of consumers may be those who are obsessed with health. This group might consume more than one multinutrient supplement, leading to the potential consumption of certain micronutrients above the recommended daily doses. The consumption of these micronutrients in the long term has generally been assumed to be safe; however, a limited body of literature suggests an increased risk of various diseases, including cancers, associated with the long-term consumption of dietary supplements. In this review, we provide a critical assessment (Table 1) and a concise overview of the studies that have reported an increased risk of cancers or their associated mortalities with different dietary supplements (Table 2). We aim to encourage more studies focusing on the potential adverse effects of dietary supplements, specifically in light of recent advances in the nutraceutical industry.

Table 1.

Standardized quality assessment of reviewed studies.

Clinical Trials
Study Randomized
and
Blinded?		 Allocation
Concealment		 Baseline
Group
Similarities		 Dropout
Rate		 Intervention
Control		 Adherence
Assurance		 Sample Size
and
Power
Reported
Mondul et al. [] Yes Yes Yes NR Yes Yes Yes
Omenn et al. [] Yes Yes Yes NR Yes Yes Yes
Klein et al. [] Yes Yes Yes NR Yes Yes Yes
Cohorts/Cross-Sectional Studies
Study Clear Objective
and Study
Population		 Sample Size
and Power
Reported		 Sufficient
Follow-Up
Period		 Leveling
of Exposure		 Exposure
Measured
before
Outcome		 Multiple
Exposure
Assessments		 Confounding
Variables
Considered
Brasky et al. [] Yes Yes Yes Yes Yes Yes Yes
Hirsch et al. [] Yes NR NA CD NA No Yes
Chen et al. [] Yes Yes Yes Yes Yes Yes Yes
Kefield et al. [] Yes Yes Yes Yes Yes Yes Yes
Zhang et al. [] Yes Yes Yes Yes Yes Yes NR

CD: Cannot Determine, NA: Not Applicable, NR: Not Reported.

Table 2.

Risk of cancer or cancer mortality associated with dietary supplements.

Nutrient Study
Design		 Study Population Follow Up Supplement Intake Risk of Cancer
(p < 0.05)		 Ref.
Vitamin A Double Blind RCT 29,133 White males
between 1985 and 1988		 5–8 years (1) α-tocopherol 50 mg/day),
(2) β-carotene (20 mg/day),
(3) both supplements,
(4) placebo		 Higher serum retinol at baseline led to higher risk of PCA incidence.
HR = 1.19
(95% CI: 1.03–1.36)		 []
Sustained high exposure to serum retinol led to greatest risk of PCA incidence.
HR = 1.31
(95% CI: 1.08–1.59)
Vitamin A Double Blind RCT 18,314 Men and women, high risk for lung cancer 24 months (1) combination of 30 mg beta-carotene and 25,000 IU vitamin A daily,
(2) placebo		 Beta-carotene and Vit A supp. resulted in excess lung CA incidence.
HR = 1.36
(95% CI: 1.07–1.73)		 []
Beta-carotene and vit A resulted in excess lung CA mortality.
HR = 1.59
(95% CI: 1.13–2.23)
Vitamin B6 Cohort Study 77,118 Men and women, 50 to 76 years between 2000 and 2002 6 years 10 years average daily dose (mg/d)
(1) non-user,
(2) 0.4–1.4,
(3) 1.4–3.0,
(4) 3.0–20,
(5) >20		 Higher risk of lung CA after 10 y Vit B6 supp.
HR = 1.82
(95% CI: 1.25–2.65)		 []
Vitamin B9 Population-Based Study Cancer discharge trends in Chile, 1992–1996 vs. 2001–2004 (before and after flour folic acid fortification) N/A Average consumption of 185 g of flour containing 410 μg folic acid B9 supp. program resulted in additional risk of colon cancer
HR = 2.9
(99% CI: 2.86–3.25)		 []
Vitamin B12 Cohort Study 77,118 participants 50–76 years, between 2000 and 2002 6 years 10 years average daily dose (µg/d)
(1) non-user,
(2) 0.1–5.00,
(3) 5.01–25.00,
(4) 25.01–55.00,
(5) >55.00		 Higher risk of lung CA after 10 y Vit B12 supp.
HR = 1.98
(95% CI: 1.32–2.97)		 []
Vitamin E Double Blind RCT 35,533 men between 2001 and 2004 7–12 years (1) Oral selenium (200 μg/d,
(2) Vitamin E (400 IU/d),
(3) both agents,
(4) placebos		 Increased risk of PCA Development with Vit E supp.
HR = 1.17
(99% CI: 1.004–1.36)		 []
Selenium Prospective Cohort Study 4459 men, 40–75 years initially diagnosed with non-metastatic prostate cancer 7.8 years Selenium supplement μg/day:
(1) non-user
(2) 1–24
(3) 25–139
(4) >140		 Increased PCA mortality, highest of
>140 μg/day selenium supp.
HR = 2.60
(95% CI: 1.44–4.70)		 []
Zinc Prospective Cohort Study 47,240 men, 40–75 years between 1986 and 2016 28.3 years Zinc (mg/d):
(1) non-user,
(2) 1–24,
(3) 25–74,
(4) ≥75		 >75 mg/day zinc supp led to increased risk of aggressive PCA.
HR = 1.80
(95% CI: 1.19–2.73)		 []
>15 years zinc supp led to increased risk of PCA mortality.
HR = 1.91
(95% CI: 1.28–2.85)
Omega-3 Case Cohort Design Nested within
SELECT trial		 834 men with PCA and 1393 men selected randomly at baseline 4.5 years (1) Oral selenium (200 μg/d,
(2) Vitamin E (400 IU/d),
(3) both agents,
(4) placebos		 Higher PCA risk in men with high Omega-3 serum level.
HR = 1.43
(95% CI: 1.09–1.88)		 []

Randomized controlled clinical trial (RCT), PCA: Prostate Cancer, Vit: Vitamin, CA: Cancer, supp: supplementation, N/A, not applicable, SELECT trial (Selenium and Vitamin E Cancer Prevention Trial).

2. Materials and Methods

This review aimed to investigate the risk of cancer development and/or mortality associated with dietary supplements. A comprehensive search strategy was devised, encompassing relevant studies from PubMed between 1990 and 2023. The search terms included vitamin A, vitamin B1 (or thiamine), vitamin B2 (or riboflavin), vitamin B3 (or niacin or nicotinamide or nicotinic acid or niacinamide), vitamin B5 (or pantothenic acid), vitamin B6 (or pyridoxine), vitamin B7 (or biotin), vitamin B9 (or folic acid/folate), vitamin B12 (or cyanocobalamin), vitamin C (or ascorbic acid), vitamin D (or calciferol), vitamin E (or alpha-tocopherol), vitamin K (or phylloquinone or phytonadione or menaquinone or menaphthone), copper, zinc, selenium, iron, calcium, manganese, and magnesium, combined with terms related to cancer (cancer, cancer risk, or cancer mortality). Herbal supplements were excluded from consideration due to their diverse nature and non-commercially accessible forms. Studies that reported a high risk of cancer or increased cancer mortality associated with a higher consumption of micronutrients or their dietary supplementation as well as high levels of plasma concentration of the micronutrients were included.

3. Vitamins

3.1. Vitamin A

Vitamin A (FDA daily allowance (DA): 900 mcg) has antioxidant properties and its supplementation is used to boost immune function and prevent respiratory infections [,]. Despite in vitro evidence of the protective role of vitamin A against cancer in many instances [], population-based studies have found an increased risk of certain cancers associated with vitamin A supplementation.

A randomized, double-blind, placebo-controlled clinical trial on 29,133 white male smokers receiving alpha-tocopherol, beta-carotene, alpha-tocopherol + beta-carotene, or placebo was conducted to find associations between circulating levels of vitamin A and prostate cancer development in males. Even though this study did not report a significant correlation between vitamin A intake and serum retinol concentrations, higher serum retinol concentrations were reported to be associated with a higher risk of developing prostate cancer and the aggressiveness of prostate cancer in a dose-dependent manner (hazard ration of 1.19 (95% confidence interval (CI): 1.03, 1.36) for serum retinol concentrations above 685 μg/L compared with that of below 483 μg/L) []. Another randomized, double-blind, placebo-controlled chemoprevention trial (Beta-Carotene and Retinol Efficacy Trial, CARET) on 18,314 individuals with a high risk of lung cancer due to a history of smoking or asbestos exposure found a higher incidence of lung cancer (RR of 1.36 (95% CI = 1.07–1.73), cardiovascular disease, and lung cancer mortality (RR of 1.59 (95% CI = 1.13–2.23)) in individuals who received daily doses of 30 mg beta-carotene and 25,000 IU retinyl palmitate (~10 times daily allowance) []. Even though the study had to be terminated earlier than scheduled due to the obvious harms of vitamin A supplementation, patients were followed up for five additional years, the results of which showed that adverse effects of the supplementation remained in high-risk individuals, even though the differences between the two groups were no longer significant [].

3.2. Group B Vitamins

Group B vitamins are cofactors for several enzymes involved in metabolism and nucleic acid synthesis []. Supplements of group B vitamins are mostly used for improving energy and for addressing their deficiencies in at-risk individuals. High levels of thiamine in the Western diet have been hypothesized to be one of the contributing factors to a higher incidence of cancers in Western countries compared to African and Asian countries, where high levels of thiaminase in the diet degrades thiamine []. The effects of thiamine degradation with thiaminase on the proliferation of cancer cells have been studied in vitro and shown to decrease tumor growth through degrading thiamine []. Animal studies have shown increased tumor growth with moderate thiamine supplementation []. Similar studies have also implicated the interaction of thiamine levels and other dietary aspects, such as high-fat intake, in tumor development [].

Niacin is required for the synthesis of nicotinamide adenine dinucleotide (NAD+), which is used by several redox enzymes such as poly (ADP-ribose) polymerases (PARPs) and sirtuins for DNA repair []. Some studies have shown that certain cancers, especially those with BRCAness, can take advantage of niacin by amplifying nicotinic acid phosphoribosyltransferase (NAPRT) and increasing niacin conversion to NAD+ [], allowing cancer cells to repair their DNA and ensure the progression of tumorigenesis. Therefore, lowering niacin levels, either through the restriction of dietary intake, or the alteration of the gut microbiota with antibiotics, may reduce the resistance of cancers to treatments targeting the DNA repair of cancer cells [].

The Vitamins and Lifestyle (VITAL) cohort of 77,118 participants suggested an increased risk of lung cancer in males with a higher intake of pyridoxine and cobalamin. Pyridoxine (DA: 1.7 mg) and cobalamin (DA: 2.4 mcg) supplementation from individual sources were associated with 30% and 40% increased risks of lung cancer in men, respectively (HR, 1.84; 95% CI, 1.01 to 3.36) []. Another study in Chile investigating the effects of mandatory flour fortification with folate (DA: 400 mcg) on the incidence of cancers was performed by comparing the rate of cancer hospital admissions in two periods before and after the fortification program. It was found that the risk of colon cancer had increased for specific age groups after folate fortification, with the highest RR of 2.9 for individuals 65–79 years of age (99% CI: 3.25–2.86) [].

3.3. Vitamin E

Vitamin E (DA: 15 mg), mostly known as tocopherol, is a fat-soluble, antioxidant vitamin protecting cells from oxidative stress. Even though several studies have suggested anti-cancer properties for this vitamin due to its scavenging of free radicals [], some studies have implicated potential harmful effects of vitamin E supplementation with increased risks of cancer development. In the Selenium and Vitamin E Cancer Prevention Trial (SELECT) investigating the effects of selenium and vitamin E supplements on the risk of developing various diseases in healthy men, it was found that vitamin E supplementation alone could increase the risk of prostate cancer in healthy men. A total of 35,533 men were divided into four groups to receive vitamin E supplementation, selenium supplementation, selenium + vitamin E supplementation, or placebo for approximately four years. After a median follow-up of 5.46 years, it was initially reported that vitamin E supplements could slightly increase the risk of prostate cancer in men []. A secondary report on the study participants four years after the initial report was indicative of vitamin E supplementation leading to a statistically significant increased risk of developing prostate cancer, with a hazard ratio of 1.17 (99% CI, 1.004–1.36, p = 0.008) [].

4.1. Calcium

Calcium (DA: 1300 mg) is most commonly known for its role in bone mineralization, and its physiologic roles expand to signal transduction, the activation of enzymes, and the contraction of muscles []. In a prospective cohort study of 30,899 adults of 20 years or older, it was found that the consumption of calcium supplements above tolerable upper intake levels was associated with increased risks of cancer mortality []. In this study, individuals provided information on their dietary and supplementary intakes through a questionnaire, and were followed up for a median of 6.1 years. An intake of calcium higher than tolerable levels (2500 mg/day) was associated with higher risk of death from cancer, with a multivariable-adjusted rate ratio of 1.62 (95% CI, 1.07 to 2.45) compared to those with a supplementary intake at or below tolerable levels. Such an observation was not reported for a higher intake of calcium from dietary sources, suggesting a potential effect from the source of nutrients [].

4.2. Selenium

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