Researchers have conducted both observational studies and randomized controlled trials to look at possible links between someone’s vitamin D level or use of vitamin D supplements and their risk of developing or dying from cancer (11). Randomized trials are considered a stronger design because they control for the possibility that other differences between people, rather than their vitamin D status, explain associations seen in observational studies. However, vitamin supplementation trials are typically limited to testing one daily dosage, as compared with the measurement of a range of blood levels in observational studies. 

Evidence from observational studies

Cancer risk. Observational studies have examined a number of individual cancer sites for possible associations of risk with vitamin D level. Higher vitamin D levels have been consistently associated with reduced risks of colorectal cancer (12) and, to a lesser extent, bladder cancer (13). Studies have consistently shown no association between vitamin D levels and risk of breast, lung, and several other, less common cancers (14–17). By contrast, opposite (i.e., harmful) associations of risk with higher blood vitamin D levels have been suggested for prostate cancer (18) and possibly pancreatic cancer (19, 20).

Cancer mortality. Possible associations between vitamin D status and cancer mortality have generally been studied for all cancers combined. Most meta-analyses (i.e., studies that combine multiple individual studies) of observational studies have found that lower serum vitamin D levels are associated with higher overall cancer mortality (11, 21–24). For example, a meta-analysis of 12 cohort studies found a 14% higher cancer mortality among people with the lowest 25-hydroxyvitamin D levels than among those with the highest levels (22). Similarly, an analysis of approximately 4,000 cancer cases within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial found a 17% lower cancer mortality among men and women in the highest category of vitamin D than in the lowest category (25). 

Evidence from randomized controlled trials

Cancer risk. Most randomized controlled trials have found that vitamin D supplements, with or without calcium, do not reduce the risk of developing cancer overall or of developing specific cancers (11, 26–29). An evidence report prepared for the United States Preventive Serves Task Force (USPSTF) in its assessment of nutrient supplements to prevent cardiovascular disease or cancer found little or no benefit for vitamin D in preventing cancer, cardiovascular disease, and death (30). 

For example, the early large randomized Women’s Health Initiative trial found that supplementation with 400 IU vitamin D plus 1000 mg calcium had no effect on the incidence of breast or colorectal cancer among postmenopausal women (31–33). 

More recently, the largest trial of vitamin D supplementation, VITAL, assigned more than 25,000 participants aged 50 and over (men) or 55 and over (women) to receive a daily dose of 2000 IU vitamin D plus fish oil omega-3 fatty acids or of placebo. After 5 years of follow-up, the vitamin D/omega-3 group had the same overall cancer incidence as the placebo group (29). The incidence of breast, prostate, and colorectal cancer was also the same in both groups. Another large trial of vitamin D supplementation, ViDA, conducted among New Zealanders aged 50–84, also found no association between supplementation and the risk of cancer overall (34).  

In addition, findings from several trials cast doubt on the idea that taking vitamin D supplements prevents the development of colorectal adenomas, which can become colorectal cancer. In the VITAL trial, people who took vitamin D supplements did not have a lower risk of colorectal adenomas or serrated polyps at 5 years of follow-up (35). An ancillary study of a randomized trial in US adults with prediabetes and overweight or obesity found that vitamin D supplementation was not associated with incident cancer or colorectal polyps (36). And in the Vitamin D/Calcium Polyp Prevention Study, which studied people who had had at least one adenoma removed during colonoscopy at the start of the study, taking a daily vitamin D supplement did not reduce the risk that adenomas would recur during the following 10 years (37).

Cancer mortality. Several randomized controlled trials have studied whether vitamin D supplements lowers the risk of death from cancer, with varying results (11, 27, 29, 38, 39). For example, in the VITAL trial, vitamin D did not reduce cancer deaths overall, although a mortality reduction was seen in analyses that excluded deaths in the first few years of follow-up (28). In the D-Health trial, which included Australians 60 years and older, a monthly dose of 60,000 IU vitamin D for 5 years also did not reduce cancer mortality (40). 

However, a meta-analysis of 10 randomized controlled trials through 2018 (including the VITAL trial) found that vitamin D supplementation was associated with a slight (13%) reduction in cancer mortality over 3–10 years of follow-up (27). A meta-analysis of 21 randomized trials found no evidence that vitamin D supplementation was associated with reduced mortality from all causes combined or from cardiovascular disease (41). 

Many participants in these trials had blood levels of vitamin D that are considered adequate for overall health. This has led to speculation that any effects of vitamin D supplementation on cancer mortality might be more evident in people with low vitamin D levels (42), and researchers are pursuing this question.

Clinical trials are being conducted to examine the potential benefit of adding vitamin D supplements to other treatments for people with cancer. For example, the phase 3 SOLARIS trial is testing whether adding high-dose vitamin D3 to chemotherapy and bevacizumab would extend the length of time patients with advanced or metastatic colorectal cancer live without their disease getting worse. 

Researchers are also studying vitamin D analogs—chemicals with structures similar to that of vitamin D—which may have the anticancer activity of vitamin D but not the toxic effects of high doses (43). For example, ongoing clinical trials are testing both vitamin D and its analog paricalcitol alone or in combination with other treatments, including immunotherapy and chemotherapy, in patients with pancreatic cancer (44).

Another research question relates to the differing prevalence of vitamin D deficiency among racial/ethnic groups and whether these may contribute to some cancer disparities (45, 46). According to NHANES data for 2011–2014, the prevalence of vitamin D deficiency (defined as a serum 25-hydroxyvitamin D concentration of less than 30 nmol/L) among adults in the United States was 18% among non-Hispanic Black people, 2% among non-Hispanic White people, 8% among non-Hispanic Asian people, and 6% among Hispanic people (4). Black people are also less likely to use vitamin D supplements than White people (47).

Observational studies and investigations of biological mechanisms through which vitamin D status and supplementation influence cancer risk are ongoing. Also under study is whether any beneficial effects of vitamin D on cancer outcomes may be restricted to people who have certain genetic variants in genes that metabolize or transport vitamin D (48, 49). For example, a recent analysis of a US population found improved cancer survival primarily among women and men with a specific form of a vitamin D binding protein called GC (25). 

A possible relationship between fluoridated water and cancer risk has been debated for years. The debate resurfaced in 1990 when a study by the National Toxicology Program, part of the National Institute of Environmental Health Sciences, showed an increased number of osteosarcomas (bone tumors) in male rats given water high in fluoride for 2 years (4). However, other studies in humans and in animals have not shown an association between fluoridated water and cancer (5–7).

In a February 1991 Public Health Service (PHS) report, the agency said it found no evidence of an association between fluoride and cancer in humans. The report, based on a review of more than 50 human epidemiologic (population) studies produced over the past 40 years, concluded that optimal fluoridation of drinking water “does not pose a detectable cancer risk to humans” as evidenced by extensive human epidemiologic data reported to date (5).

In one of the studies reviewed for the PHS report, scientists at NCI evaluated the relationship between the fluoridation of drinking water and the number of deaths due to cancer in the United States during a 36-year period, and the relationship between water fluoridation and number of new cases of cancer during a 15-year period. After examining more than 2.2 million cancer death records and 125,000 cancer case records in counties using fluoridated water, the researchers found no indication of increased cancer risk associated with fluoridated drinking water (6).

In 1993, the Subcommittee on Health Effects of Ingested Fluoride of the National Research Council, part of the National Academy of Sciences, conducted an extensive literature review concerning the association between fluoridated drinking water and increased cancer risk. The review included data from more than 50 human epidemiologic studies and six animal studies. The Subcommittee concluded that none of the data demonstrated an association between fluoridated drinking water and cancer (6). A 1999 report by the CDC supported these findings. The CDC report concluded that studies to date have produced “no credible evidence” of an association between fluoridated drinking water and an increased risk for cancer (2). Subsequent interview studies of patients with osteosarcoma and their parents produced conflicting results, but with none showing clear evidence of a causal relationship between fluoride intake and risk of this tumor.

In 2011, researchers examined the possible relationship between fluoride exposure and osteosarcoma in a new way: they measured fluoride concentration in samples of normal bone that were adjacent to a person’s tumor. Because fluoride naturally accumulates in bone, this method provides a more accurate measure of cumulative fluoride exposure than relying on the memory of study participants or municipal water treatment records. The analysis showed no difference in bone fluoride levels between people with osteosarcoma and people in a control group who had other malignant bone tumors (7).

More recent population-based studies using cancer registry data found no evidence of an association between fluoride in drinking water and the risk of osteosarcoma or Ewing sarcoma (8, 9).  

The CDC has information at https://www.cdc.gov/fluoridation/index.html on standards for and surveillance of current fluoridated water supplies in the United States.

The Environmental Protection Agency has more information about drinking water and health at https://www.epa.gov/ground-water-and-drinking-water. The information on this page includes details about drinking water quality and safety standards.

Acrylamide is a chemical used primarily to make substances called polyacrylamide and acrylamide copolymers. Polyacrylamide and acrylamide copolymers are used in many industrial processes, such as the production of paper, dyes, and plastics, and in the treatment of drinking water and wastewater, including sewage. They are also found in consumer products, such as caulking, food packaging, and some adhesives.

Acrylamide is also found in some foods. It can be produced when vegetables that contain the amino acid asparagine, such as potatoes, are heated to high temperatures in the presence of certain sugars (1, 2). It is also a component of tobacco smoke.

Food and cigarette smoke are the major sources of acrylamide exposure for people in the general population (3, 4).

The major food sources of acrylamide are French fries and potato chips; crackers, bread, and cookies; breakfast cereals; canned black olives; prune juice; and coffee.

Acrylamide levels in food vary widely depending on the manufacturer, the cooking time, and the method and temperature of the cooking process (5, 6). Decreasing cooking time to avoid heavy crisping or browning, blanching potatoes before frying, not storing potatoes in a refrigerator, and post-drying (drying in a hot air oven after frying) have been shown to decrease the acrylamide content of some foods (7, 8).

People are exposed to substantially more acrylamide from tobacco smoke than from food. People who smoke have three to five times higher levels of acrylamide exposure markers in their blood than do non-smokers (9). Exposure from other sources is likely to be significantly less than that from food or smoking, but scientists do not yet have a complete understanding of all sources of exposure. Regulations are in place to limit exposure in workplaces where acrylamide may be present, such as industrial settings that use polyacrylamide and acrylamide copolymers.

Studies in rodent models have found that acrylamide exposure increases the risk for several types of cancer (10–13). In the body, acrylamide is converted to a compound called glycidamide, which causes mutations in and damage to DNA. However, a large number of epidemiologic studies (both case-control and cohort studies) in humans have found no consistent evidence that dietary acrylamide exposure is associated with the risk of any type of cancer (9, 14). One reason for the inconsistent findings from human studies may be the difficulty in determining a person’s acrylamide intake based on their reported diet.

The National Toxicology Program’s Report on Carcinogens considers acrylamide to be reasonably anticipated to be a human carcinogen, based on studies in laboratory animals given acrylamide in drinking water. However, toxicology studies have shown that humans and rodents not only absorb acrylamide at different rates, they metabolize it differently as well (15–17).

Studies of workplace exposure have shown that high levels of occupational acrylamide exposure (which occurs through inhalation) cause neurological damage, for example, among workers using acrylamide polymers to clarify water in coal preparation plants (18). However, studies of occupational exposure have not suggested increased risks of cancer (19).

The U.S. Environmental Protection Agency (EPA) regulates acrylamide in drinking water. The EPA established an acceptable level of acrylamide exposure, set low enough to account for any uncertainty in the data relating acrylamide to cancer and neurotoxic effects. The U.S. Food and Drug Administration regulates the amount of residual acrylamide in a variety of materials that contact food, but there are currently no guidelines governing the presence of acrylamide in food itself.

Additional epidemiologic studies in which acrylamide adduct or metabolite levels are serially measured in the same individuals over time (longitudinal cohorts) are needed to help determine whether dietary acrylamide intakes are associated with increased cancer risks in people. It is also important to determine how acrylamide is formed during the cooking process and whether acrylamide is present in foods other than those already tested. This information will enable researchers to make more accurate and comprehensive estimates of dietary exposure. Biospecimen collections in cohort studies will provide an opportunity to examine biomarkers of exposure to acrylamide and its metabolites in relation to the subsequent risk of cancer.

For more information about acrylamide in food, contact the FDA at 1-888-SAFEFOOD (1-888-723-3366) or visit their Acrylamide page.

Free radicals are highly reactive chemicals that have the potential to harm cells. They are created when an atom or a molecule (a chemical that has two or more atoms) either gains or loses an electron (a small negatively charged particle found in atoms). Free radicals are formed naturally in the body and play an important role in many normal cellular processes (1, 2). At high concentrations, however, free radicals can be hazardous to the body and damage all major components of cells, including DNA, proteins, and cell membranes. The damage to cells caused by free radicals, especially the damage to DNA, may play a role in the development of cancer and other health conditions (1, 2).

Abnormally high concentrations of free radicals in the body can be caused by exposure to ionizing radiation and other environmental toxins. When ionizing radiation hits an atom or a molecule in a cell, an electron may be lost, leading to the formation of a free radical. The production of abnormally high levels of free radicals is the mechanism by which ionizing radiation kills cells. Moreover, some environmental toxins, such as cigarette smoke, some metals, and high-oxygen atmospheres, may contain large amounts of free radicals or stimulate the body’s cells to produce more free radicals.

Free radicals that contain the element oxygen are the most common type of free radicals produced in living tissue. Another name for them is “reactive oxygen species,” or “ROS” (1, 2).

Antioxidants are chemicals that interact with and neutralize free radicals, thus preventing them from causing damage. Antioxidants are also known as “free radical scavengers.”

The body makes some of the antioxidants that it uses to neutralize free radicals. These antioxidants are called endogenous antioxidants. However, the body relies on external (exogenous) sources, primarily the diet, to obtain the rest of the antioxidants it needs. These exogenous antioxidants are commonly called dietary antioxidants. Fruits, vegetables, and grains are rich sources of dietary antioxidants. Some dietary antioxidants are also available as dietary supplements (1, 3).

Examples of dietary antioxidants include beta-carotene, lycopene, and vitamins A, C, and E (alpha-tocopherol). The mineral element selenium is often thought to be a dietary antioxidant, but the antioxidant effects of selenium are most likely due to the antioxidant activity of proteins that have this element as an essential component (i.e., selenium-containing proteins), and not to selenium itself (4).

In laboratory and animal studies, the presence of increased levels of exogenous antioxidants has been shown to prevent the types of free radical damage that have been associated with cancer development. Therefore, researchers have investigated whether taking dietary antioxidant supplements can help lower the risk of developing or dying from cancer in humans.

Many observational studies, including case–control studies and cohort studies, have been conducted to investigate whether the use of dietary antioxidant supplements is associated with reduced risks of cancer in humans. Overall, these studies have yielded mixed results (5). Because observational studies cannot adequately control for biases that might influence study outcomes, the results of any individual observational study must be viewed with caution.   

Randomized controlled clinical trials, however, lack most of the biases that limit the reliability of observational studies. Therefore, randomized trials are considered to provide the strongest and most reliable evidence of the benefit and/or harm of a health-related intervention. To date, nine randomized controlled trials of dietary antioxidant supplements for cancer prevention have been conducted worldwide. Many of the trials were sponsored by the National Cancer Institute. The results of these nine trials are summarized below.    

Overall, these nine randomized controlled clinical trials did not provide evidence that dietary antioxidant supplements are beneficial in primary cancer prevention. In addition, a systematic review of the available evidence regarding the use of vitamin and mineral supplements for the prevention of chronic diseases, including cancer, conducted for the United States Preventive Services Task Force (USPSTF) likewise found no clear evidence of benefit in preventing cancer (27).

It is possible that the lack of benefit in clinical studies can be explained by differences in the effects of the tested antioxidants when they are consumed as purified chemicals as opposed to when they are consumed in foods, which contain complex mixtures of antioxidants, vitamins, and minerals (3). Therefore, acquiring a more complete understanding of the antioxidant content of individual foods, how the various antioxidants and other substances in foods interact with one another, and factors that influence the uptake and distribution of food-derived antioxidants in the body are active areas of ongoing cancer prevention research.

Several randomized controlled trials, some including only small numbers of patients, have investigated whether taking antioxidant supplements during cancer treatment alters the effectiveness or reduces the toxicity of specific therapies (28). Although these trials had mixed results, some found that people who took antioxidant supplements during cancer therapy had worse outcomes, especially if they were smokers.

In some preclinical studies, antioxidants have been found to promote tumor growth and metastasis in tumor-bearing mice and to increase the ability of circulating tumor cells to metastasize (29–31). Until more is known about the effects of antioxidant supplements in cancer patients, these supplements should be used with caution. Cancer patients should inform their doctors about their use of any dietary supplement.