Abstract

Widespread use of antioxidant supplements-vitamins (A, C, E), provitamin A carotenoids, selenium, coenzyme 
Q10, and numerous polyphenolic preparations-has been driven by epidemiological associations between dietary 
antioxidants and reduced chronic disease risk, and by the intuitive appeal of “neutralizing” oxidative stress. 
However, a growing body of preclinical and clinical evidence indicates that long-term or high-dose 
supplementation may carry toxicological risks, particularly when it perturbs physiological redox signaling, acts as 
a pro-oxidant in certain contexts, interacts adversely with environmental exposures or medications, or is given to 
susceptible populations. This review synthesizes mechanistic and experimental findings from animal models, 
cellular systems, and randomized clinical trials, and examines observational data and meta-analyses that document 
adverse outcomes including increased cancer incidence in specific subgroups, higher all-cause mortality at 
supraphysiologic doses, interference with chemotherapy and radiotherapy, impaired exercise adaptations, and 
developmental toxicity. We analyze underlying mechanisms-hormetic disruption of redox signaling, pro-oxidant 
chemistry, altered phase I/II metabolism, and genomic instability-and discuss how dose, form (synthetic versus 
food matrix), duration, timing, and host factors (smoking, existing disease, age, pregnancy, and genetic 
polymorphisms) determine safety. Finally, the review outlines pragmatic clinical guidance, regulatory and 
quality-control concerns, and research priorities needed to define safe use and to develop precision approaches that 
balance potential benefits against demonstrable risks.