PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Cochrane Database Syst Rev. Author manuscript; available in PMC 2013 June 25.
Published in final edited form as:
PMCID: PMC3692366
NIHMSID: NIHMS472378

Selenium for preventing cancer

Abstract

Background

Selenium is a trace element essential to humans. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancers.

Objectives

Two research questions were addressed in this review: What is the evidence for

  1. an aetiological relationship between selenium exposure and cancer risk in women and men?
  2. the efficacy of selenium supplementation for cancer prevention in women and men?

Search strategy

We searched electronic databases and bibliographies of reviews and included publications.

Selection criteria

We included prospective observational studies to answer research question (a) and randomised controlled trials (RCTs) to answer research question (b).

Data collection and analysis

We conducted random effects meta-analyses of epidemiological data when five or more studies were retrieved for a specific outcome. We made a narrative summary of data from RCTs.

Main results

We included 49 prospective observational studies and six RCTs. In epidemiologic data, we found a reduced cancer incidence (summary odds ratio (OR) 0.69 (95% confidence interval (CI) 0.53 to 0.91) and mortality (OR 0.55, 95% CI 0.36 to 0.83) with higher selenium exposure. Cancer risk was more pronouncedly reduced in men (incidence: OR 0.66, 95% CI 0.42 to 1.05) than in women (incidence: OR 0.90, 95% CI 0.45 to 1.77). These findings have potential limitations due to study design, quality and heterogeneity of the data, which complicated the interpretation of the summary statistics.

The RCTs found no protective efficacy of selenium yeast supplementation against non-melanoma skin cancer or L-selenomethionine supplementation against prostate cancer. Study results for the prevention of liver cancer with selenium supplements were inconsistent and studies had an unclear risk of bias. The results of the Nutritional Prevention of Cancer Trial (NPCT) and SELECT raised concerns about possible harmful effects of selenium supplements.

Authors’ conclusions

No reliable conclusions can be drawn regarding a causal relationship between low selenium exposure and an increased risk of cancer. Despite evidence for an inverse association between selenium exposure and the risk of some types of cancer, these results should be interpreted with care due to the potential limiting factors of heterogeneity and influences of unknown biases, confounding and effect modification.

The effect of selenium supplementation from RCTs yielded inconsistent results. To date, there is no convincing evidence that selenium supplements can prevent cancer in men, women or children.

PLAIN LANGUAGE SUMMARY

Selenium for preventing cancer

Selenium is a trace element that is important for human health, but might also be harmful for humans when the taken in excess.

Fifty-five studies with more than one million participants were included in this systematic review. Forty-nine studies observed and analysed whether healthy people with high selenium levels in blood or toenail samples or with a high selenium intake developed cancer more or less often than other people. We found that people with higher selenium levels or intake had a lower frequency of certain cancers (such as bladder or prostate cancer) but no difference for other cancers such as breast cancer. However, it was not possible to determine from these studies that selenium levels or selenium intake were really the reason for the lower risk of cancer in some people. Factors apart from higher selenium levels could also influence the cancer risk: They might have had a healthier nutritional intake or lifestyle, have had a more favourable job or overall living conditions.

Six randomised controlled trials (RCTs) assessed whether the use of selenium supplements might prevent cancer. In general, there are two types of selenium supplements: one type uses the salt of selenium as main ingredient, the other type uses organic selenium. These two types may act differently in the human body when ingested. We assessed the quality of each trial according to four established methodological criteria. The trials with the most reliable results found that organic selenium did not prevent prostate cancer in men and increased the risk of non-melanoma skin cancer in women and men. Other trials found that participants using selenium salt or organic supplements had a decrease in liver cancer cases. However, due to methodological shortcomings this evidence was less convincing. We advise further investigation of selenium for liver cancer prevention before translating results into public health recommendations. We also recommend that there should be further evaluation of the effects of selenium supplements in populations according to their nutritional status as they may differ between undernourished and adequately nourished groups of people.

To maintain or improve health, access to healthy food and a healthy diet is important. Currently, there is no convincing evidence that individuals, particularly those who are adequately nourished, will benefit from selenium supplementation with regard to their cancer risk.

BACKGROUND

Selenium

Selenium is a trace element essential to humans. Humans usually ingest selenium with crop and animal products and sometimes as functional foods or supplements. Speciation and concentration of selenium in food sources vary considerably, depending on plant and animal metabolism and growth conditions or animal nutrition (Duffield 1999).

Selenium species can be classified into selenium-containing organic compounds (e.g. selenomethionine, selenocysteine) and inorganic forms (selenate, selenite) (Rayman 2008a). Selenium yeast refers to a selenium-enriched yeast medium which usually contains 80% to 90% organically bound selenium with a high proportion of selenomethionine (Rayman 2004). Whether selenium is linked to specific beneficial health effects in humans is suspected but unproven and the debate on those effects is controversial (Drake 2006; Rayman 2008a).

The recommended daily allowance differs between regulatory agencies. For example, the highest amount of daily intake (55 μg selenium for adults) has been recommended by the US Institute of Medicine (Institute of Medicine 2009), whereas the WHO (World Health Organization) recommendations range between 30 and 40 μg/day for men and women (WHO 2004).

To prevent the risk of developing selenosis, the US Institute of Medicine has set the tolerable upper intake level to 400 μg per day for adults (Office of Dietary Supplements 2009). Besides the acute and chronic toxicity of high selenium exposure, possible harmful effects of long-term intake of lower dosages have also been discussed. However, effects of long-term intake of lower dosages are not so well investigated or understood (Vinceti 2001) and there may be differences between organic and inorganic forms (Rayman 2008a). A recent publication has questioned the current upper limit of ’safe intake’ and proposed a far lower ’safe level’ for long-term usage (20 μg/day for organic selenium) and a differentiation between organic and inorganic selenium sources (Vinceti 2009).

An accurate estimation of selenium exposure in epidemiological research presents a challenge. Individual exposure is often assessed as the concentration in blood specimens or toenail clippings (Longnecker 1996) or as estimated dietary or supplemental intake, but the validity of dietary logs and recall questionnaires has been questioned (Patterson 1998). For the measurement in blood specimens, either whole blood or blood fractions (plasma = blood without the cells; serum = plasma without the clotting factors) are used.

Selenium levels found in human specimens (Rayman 2008b) as well as the estimated intake of selenium (Alfthan 1996) show a high global variability. Different selenium levels within populations have been found to be related to ethnicity (Kant 2007), gender, age or smoking behaviour. Smoking tends to lower selenium biomarker concentrations despite being a source of selenium exposure (Kafai 2003). Globally, however, there are also inconsistencies as to how these factors are associated with selenium levels. For example, selenium levels increased with age in women, but not in men, in the French SU.VI.M.AX cohort study (Arnaud 2007), decreased with age in a female population in Ohio (Smith 2000) and two studies from Switzerland and Austria could not find an association between age and selenium status in either gender (Burri 2008; Gundacker 2006). Gender-specific nutritional and health behaviours, as well as gender-specific differences in selenium metabolism, may contribute to the observed discrepancies in selenium levels between genders (Rodriguez 1995).

These global and within-population differences formed the early basis of investigations into the association of selenium exposure and cancer risk (Schrauzer 1977; Shamberger 1969).

The hypotheses about the potentially anticarcinogenic mechanisms of selenium include its effects on DNA stability, cell proliferation, necrotic and apoptotic cell death in healthy and malignant cells and its effects on the immune system (Whanger 2004). Selenium is involved in these processes as a source of selenometabolites and is part of selenium-containing enzymes (Hatfield 2001). The optimum level for the prevention and retardation of carcinogenesis in human cells has been discussed to be higher than the level commonly achieved under a diet not deficient in selenium (Whanger 2004). Gender differences regarding the effects of selenium on health, including cancer diseases, have been increasingly debated in recent years. Apart from gender differences in selenium levels, gender differences in selenium distribution in tissue or tumour biology might be involved in the differential health effects in women and men (Waters 2004).

However, selenium has also been shown to promote malignant cell transformation (Kandas 2009; Novoselov 2005; Su 2005) and protect cancer cells against stress-induced apoptosis (Sarada 2008) in animal and in-vitro studies and might therefore work as carcinogen.

Cancer

Cancer is a leading cause of death worldwide. According to WHO estimates, 11.3 million people developed and 7.9 million died of cancer in 2007, with more than half of all new cases occurring in middle-income or low-income countries (WHO 2008).

The role of diet and nutrition for carcinogenesis and, as a potentially modifiable factor, in cancer prevention is still under debate. The identification of a nutrient supplement with cancer preventive properties would be a major breakthrough for public health. However, cancer is not a uniform disease and the existence of such a nutrient, or combination of nutrients, has been debated.

Case-control studies as well as systematic and non-systematic reviews have found conflicting results on risks of specific cancers and selenium exposure. Zhuo 2004 found a summary risk estimate suggestive for a protective effect of higher selenium exposure against lung cancer in a systematic review and meta-analysis of epidemiological studies; Brinkman 2006 found similar results for prostate cancer. However, two other epidemiological reviews concluded that studies did not support an association between selenium status and breast cancer risk in women (Navarro Silvera 2007; Waters 2004).

Vinceti and colleagues observed an increased melanoma incidence (Vinceti 1998) and mortality from melanoma (Vinceti 2000a) in both genders in a cohort of people from Northern Italy who where accidentally exposed to long-term consumption of drinking water with a high content of inorganic selenium. The standardised mortality ratio for melanoma in comparison to the non-exposed individuals in the municipality was 4.15 (95% CI 0.21 to 20.47) in women and 10.98 (95% CI 1.84 to 36.27) in men.

The first indication from an RCT that selenium supplements may reduce risk of gastrointestinal (GIT) cancers came from the General Population Trial in Linxian, China (Blot 1993; Dawsey 1994; Wang 1994). Study participants were living in regions with a very high rate of GIT cancers and subclinical deficiencies of several nutrients. The RCT investigated the efficacy of vitamin and mineral supplements to reduce cancer incidence and mortality, especially of oesophageal and gastric cancer, in middle-aged adults with four treatment factors for a period of 5.25 years. Participants receiving one study supplement (containing 50 μg selenised yeast, beta-carotene, alpha-tocopherol) had a reduced mortality from, but not incidence of, gastric cancer. Oesophageal cancer risk was not altered.

In the more recent French SU.VI.M.AX trial (Hercberg 2004), a supplementation with beta-carotene, vitamin C, vitamin E and 100 μg selenium-enriched yeast did not alter the incidence of cancer of the digestive tract after a median period of 7.5 years in women. In men, the incidence rate was lower in the intervention group than in the placebo group, but risk ratios (RRs) with confidence intervals (CIs) were not calculated because of low numbers. Bjelakovic 2006 conducted a Cochrane Review on antioxidant supplements for the prevention of gastrointestinal (GIT) cancers. Nine RCTs that investigated mono-selenium or selenium-containing supplements were included in this review. The authors concluded that selenium may potentially possess beneficial effects, but the results required further research before any recommendation could be made.

Why it is important to do this review

Selenium is suggested to be involved in central anti-carcinogenic processes. Selenium supplements are widely marketed with many health claims, the prevention of cancer being one of them. There is a worldwide debate about the association between selenium exposure and cancer risk or whether selenium supplements are effective in decreasing the incidence or mortality of cancer. Epidemiologic and other data suggest differential effects in men and women and there are hints that selenium supplements might even have harmful effects, this especially being the case in certain populations. This review is timely and important as several meta-analyses and systematic reviews have been published, but a comprehensive summary providing evidence from both prospective studies and intervention trials which a) include all types of cancer and b) look for gender-related differences does not exist.

OBJECTIVES

Two research questions were addressed in this review: What is the evidence for

  1. an aetiological relationship between selenium exposure and cancer risk in women and men?
  2. the efficacy of selenium supplementation for cancer prevention in women and men?

METHODS

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and prospective observational studies (cohort studies and nested case-control studies) were included, irrespective of publication year, publication status or language.

Types of participants

All adult participants (aged 18 years and over) at risk of malignant neoplastic diseases.

Types of interventions

We considered prospective observational studies (cohort studies including sub-cohort controlled studies and nested case-control studies) for inclusion if they assessed baseline exposure to selenium in apparently cancer-free individuals either as biochemical selenium status or estimated selenium intake at study inception. We considered RCTs for inclusion if they used selenium supplementation at any dose or route of administration for a minimum of four weeks versus placebo or no intervention. We excluded trials using selenium supplementation as part of a multi-component preparation, without a study arm using selenium monotherapy supplementation.

Types of outcome measures

The primary outcome measures were

  1. the number of participants developing cancers (incidence of any cancer);
  2. the number of participants dying from cancers (cancer-related mortality).

Search methods for identification of studies

We conducted electronic searches in the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 1, 2011), MEDLINE (via PubMed, 1966 to February 2011), EMBASE (1980 to 2010 week 50), CancerLit (February 2004) and CCMed (February 2011). We conducted the initial search in 2004 and updates in July 2007, January 2009, October 2009, and February 2011. As MEDLINE now includes the journals indexed in CancerLit, no further searches were conducted in this database after 2004.

We also searched the following online clinical trials databases: Clinical Trials of the American Cancer Society (http://www.cancer.gov, February 2011), the metaRegister of Controlled Trials (mRCT, http://www.controlled-trials.com, February 2011) and the German Cancer Study Register (http://www.studien.de, February 2011). The search strategies are given in Appendix 1. We scanned conference abstracts to identify unpublished material and searched the database for grey literature SIGLE (February 2004). This electronic database was discontinued in 2005.

Data collection and analysis

Selection of studies

Two review authors independently checked all electronic search results for eligibility. When search results could not be rejected with certainty on the basis of title and/or abstract, we obtained full text material.

We scanned bibliographies of papers retrieved with the described search strategy, and included publications to identify additional studies. If additional information was necessary we tried to contact all the correspondent authors of the included studies and asked investigators for information about unpublished trials.

Two review authors (GD, MH) independently applied the inclusion and exclusion criteria, if necessary with the assistance of an interpreter. We resolved disagreements by discussion and with the involvement of a third review author.

Data extraction and management

We used pre-tested extraction forms for epidemiological studies and RCTs to document data from the original material and assess the quality of studies. GD and another review author independently extracted data unblinded. GD checked extracted data for discrepancies and any discrepancies were discussed between both extracting review authors. In a small number of cases, we sought the opinion of a third review author to reach a consensus. If several reports from the same study were available, we considered the most recent to be the primary publication, but study details available from other publications were also extracted if not reported in the primary study reference.

We entered data from the extraction forms into a Microsoft Access database by hand. GD double-checked completely for errors and MH and GD triple-checked using descriptive database methods and plausibility checks.

For comparisons of selenium exposure as measured in serum and plasma specimens, we converted all data into the unit μg/l. Results provided as ppm (parts per million) or μg/g were converted using the factor 1.026 g/ml (weight density of serum) and data provided as μmol/l using the factor 78.96 (molecular weight of selenium). In order to be included, prospective observational studies had to report estimates of relative risk (RR (e.g. odds ratio (OR)) for each selenium exposure level.

Assessment of risk of bias in included studies

Observational studies

The risk of bias in observational studies was assessed using an assessment form adapted from the Newcastle-Ottawa Quality Assessment Scale (NOS) for cohort and case-control studies (Wells 2004). The NOS was developed using a ’star system’ in which cohort or case-control studies are judged on the selection and comparability of the study groups and the ascertainment of either the exposure or outcome of interest.

The NOS form for cohort studies was used for all included observational studies. In addition, we assessed the risk of bias of nested case-control studies with the NOS case-control form. Both forms must be adapted a priori for use in a systematic review according to the research question and the review topic. For each question within this standardised assessment procedure either a ’star’ or ’no star’ is assigned to a study. A ’star’ indicates that study design was considered adequate and less likely to introduce bias.

We used the questions as reported in the appendices for study assessment; (*) means that for the corresponding item a ’star’ according to the NOS was assigned to the study. Key domains are the selection and comparability of the exposed and non-exposed cohort, the ascertainment of exposure and outcome and the length of follow-up. A study could receive a maximum of 9 stars in the cohort assessment (Appendix 2) and 9 stars in the assessment of the case-control part (Appendix 3).

The risk of bias assessment was based on the data provided in the included publications. We did not check other, not included publications for details. If an included study encompassed more than one publication with divergent rating in the NOS, we used the highest score.

Randomised controlled trials

We categorised generation of allocation sequence, allocation concealment, blinding and completeness of outcome data as adequate (low risk of bias), inadequate (high risk of bias) or unclear following the criteria specified in the Cochrane Handbook of Review of Interventions (Higgins 2009a). We considered these four items to be the key domains for bias risk assessment. Studies that were categorised as “adequate” in all four domains were considered to have a low risk of bias; studies with inadequate procedures in one or more key domains were considered to have a high risk of bias. Studies with unclear procedures in one or more key domains were considered to have an unclear risk of bias.

We assessed the fulfillment of ethical standards as follows:

  • Was informed consent obtained from patients? (yes/no/unclear)
  • Was approval obtained from an ethical board? (yes/no/unclear)

Dealing with missing data

When data were missing or discrepancies in study publications were found, we tried to make contact with the study investigators for further information. Contacting study authors helped to clarify discrepancies in several publications, e.g. differing data in text and tables within the same report, however, we retrieved no missing data or study details.

Data synthesis

Data synthesis and analysis

We performed data synthesis and analysis separately for RCTs and observational studies.

We restricted meta-analyses to cancers for which at least 5 studies were available. There were two reasons for this restriction. The first was practical and was to limit the number of analyses to be performed. The second was that we expected that results are heterogeneous, but heterogeneity cannot be described and quantified well if only very few studies are available (Higgins 2009b). Although the cut-off at 5 studies is somewhat arbitrary, this decision was made very early in the review process and was declared in the protocol.

Observational studies

This review includes only binary outcomes. If five or more studies were available for a specific type of cancer, we conducted a meta-analysis.

Study authors defined cancer cases either as diagnosis (i.e. cancer incidence) or death from cancer (i.e. cancer mortality) or as a combination of both. The term ’cancer risk’ is used in this paper as a generic term and refers likewise to cancer incidence, cancer mortality and combined incidence/mortality data.

A meta-analysis of highest versus lowest selenium exposure category was performed using a random effects model and by analysing the natural logarithm of the OR or RR, using the squared standard error of the natural logarithm of the OR or RR as weights. The latter was calculated from the reported upper and lower boundaries of the 95% CI of the OR or RR. If a 95% CI was not reported, we used the total number of cases and the total number of controls as well as the number of categories of selenium exposure to estimate the number of cases and controls per exposure category. We then used the standard normal approximation formula to calculate the standard error of the OR (comparing the highest versus the lowest exposure category (lnOR = (1/a + 1/b +1/c +1/d) where a, b, c, d are the four counts needed to calculate the OR via (a*d)/(b*c)).

We took the OR from the analysis that included the most extensive adjustment in the publication. For the calculation of the summary risk estimate, gender-aggregated data of mixed-gender studies were used when available.

We performed a Chi2 test for heterogeneity of study results. Additionally, we used I2 statistics (Higgins 2003) to quantify inconsistency. Meta-analyses were conducted using STATA 10.0 and STATA 11.0 software. We repeated meta-analyses that were included in this review publication using the Review Manager 5 statistical tool; for this, logarithmic data for the OR and the standard error were copied from STATA into Review Manager 5 and results were double-checked for errors.

We conducted sensitivity analyses to assess the effect of the methods used to assess selenium status/intake. We used gender-disaggregated data from mixed-gender studies together with data from single-gender cohorts for subgroup analyses by gender. We conducted the latter subgroup analyses to account for potential gender differences in selenium health effects (see Background).

Randomised controlled trials

We did not perform a meta-analysis of summary statistics with RCT data in this review as the minimum number of five studies, required for meta-analysis according to our review protocol, was not reached for any type of cancer.

Risk ratios (RR) of intervention trials that were not reported in the original publication were calculated on the basis of the number of participants and cases using the statistical tool for meta-analysis included in Review Manager 5. We also calculated the RR of adverse outcomes and its 95% CI, if sufficient data were available.

RESULTS

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

Table thumbnail
Characteristics of included studies [ordered by study ID]
Table thumbnail
Characteristics of excluded studies [ordered by study ID]
Table thumbnail
Characteristics of studies awaiting assessment [ordered by study ID]

Citation style: Please note that we reference the sources of relevant information in a certain way to increase traceability of our results for interested readers. When the source of information is not the primary publication of an included study, the specific publication of interest is also referenced. For example “Hakama 1990 in: Knekt 1990” indicates that the cited paper is “Hakama 1990” as part of the mentioned study.

Three full text theses published in the US, could not be accessed (Coates 1987, in: Coates 1988; Menkes 1986a, in: Menkes 1986; Schober 1986, in: Menkes 1986). However, later journal publications were available and included in this review as main study publications (Coates 1988, in: Coates 1988; Menkes 1986b, in: Menkes 1986; Schober 1987, in: Menkes 1986). Thus the retrieval of the full text theses was considered to be unnecessary.

Results of the search

After excluding duplicates, the electronic search retrieved 4082 hits (flow chart of literature search: Figure 1). Of these, we excluded 3802 references as being clearly irrelevant due to title and abstract. The reasons for exclusion were:

Figure 1
Flow chart literature search
  • the paper did not report a study on selenium and cancer with humans (n = 3184),
  • the paper dealt with selenium in the treatment of cancer (n = 278),
  • the study did not meet other inclusion criteria, e.g. retrospective case-control studies or RCTs using a multi component vitamin/trace element supplement (n = 340).

Twelve publications of potential relevance were identified in the latest update search in February 2011. Due to time restrictions, these publications could not be included in the current review version and are listed in the section “Classification pending references”.

The remaining 268 publications were considered of possible relevance and re-evaluated.

Included studies

One hundred and thirty-seven papers were identified for inclusion in this review: 80 papers referred to one ongoing and 49 completed observational studies. Fifty-seven papers referred to five ongoing and six completed randomised controlled trials.

A detailed description of the studies included is given in the table Characteristics of included studies.

1. Observational studies

Forty-nine completed observational studies were included in this review. Thirty-six studies were nested case-control studies, the others were sub-cohort controlled or cohort studies and one study used a cohort together with a nested case-control design. Sub-cohort controlled studies used (random) samples of the cohort as controls. The original papers were published between 1983 and 2009. Five studies were conducted in Asia (China, Japan and Taiwan), one in Australia, 19 in Europe (including data from Belgium, Denmark, Germany, Greece, Italy, Netherlands, Norway, Spain, Sweden, Channel Islands, Finland, France and the UK) and 24 in the US Overall, the studies included more than 1,078,000 participants. European study populations made up 45%, the US 45%, Asia 9.7%, and Australia 0.2% of all study participants. The median size of the study populations was 10,494. Twenty-six studies included men and women, one did not report gender, 17 included only men and five only women. For a substantial proportion of the study populations (38%), gender was not reported. Forty-one percent of participants were men, 21% were women. Six studies with gender-mixed populations reported results stratified by gender. The study populations were derived from 42 different cohorts. Twenty-three cohorts were non-randomly recruited, e.g. included volunteers, and 19 cohorts consisted of a random (or total) sample of the population of interest, which was either a specifically exposed population such as male tin-miners in China or the general population.

Thirty-seven studies specified the age range of their included participants, the majority of which included adults over 40 years. Five studies investigated nutritional and/or supplemental selenium intake, using food-frequency questionnaires or interviews. Forty-three studies assessed biochemical selenium status:

  • eight used toenail specimens,
  • 11 plasma specimens,
  • 23 serum specimens,
  • and one used both serum and plasma specimens.

One study measured both serum selenium levels and intake. The mean follow-up period was up to three years in five studies and longer than three years in the remaining studies. Generally, study authors grouped the cases following the ICD classification that was up-to-date at the inception of the cohort observation. The level of disaggregation of data varied remarkably between the studies. While some studies reported cancer risk according to organ systems (e.g. urinary tract, respiratory tract), others stratified their data by one or two organs (e.g. female breast, urinary bladder). Only in the case of skin cancer did studies also differentiate according to histological type (e.g. melanoma, basal cell carcinoma).

For the following outcomes, five or more studies were included in the review and observational data were meta-analysed:

  • any cancer (15 studies)
  • female breast cancer (7)
  • urinary bladder cancer (5)
  • lung cancer (13)
  • prostate cancer (14)
  • stomach cancer (5)
  • colon/colorectal cancer (5)

Table 1 provides an overview on the studies for each outcome. Five studies gave data for the group of “other” cancers, which encompassed any type of cancer not reported separately in the study publications. The definition of the group of “other” cancers varied between studies including predominantly rare cancers but also cancers of unknown origin. The results of the studies within the category “other cancers” are mentioned for the sake of completeness, however, due to the diversity of outcomes the results were not included in further analysis or discussion of this review.

Table 1
Included observational studies by outcome

2. Randomised controlled trials

Six randomised controlled trials with a total of 43,408 participants (94% men) were included in this review. All used parallel group designs with either two arms ( Li 2000; NPCT 1996; Reid 2008; Yu 1991; Yu 1997) or four arms (SELECT 2009). Three were conducted in China ( Li 2000; Yu 1991; Yu 1997), two in the US (NPCT 1996; Reid 2008) and one in the USA/Canada/Puerto Rico (SELECT 2009).

Selenium supplements and placebos were administered daily. As an active intervention, trials used 200 μg (NPCT 1996; Yu 1991; Yu 1997) or 400 μg (Reid 2008) selenium in the form of selenised yeast tablets. Li 2000 used 500 μg sodium selenite and SELECT 2009 used 200 μg L-selenomethionine.

2.1. Primary liver cancer

Three Chinese trials investigated the preventive efficacy of selenium supplementation against primary liver cancer in different high-risk populations. Participants were either carriers of the Hepatitis B surface antigen (HBs-Ag) with normal liver function or first-degree relatives of liver cancer patients. Two trials used se-lenised yeast (Yu 1991; Yu 1997) and one sodium selenite (Li 2000).

2.2. Non-melanoma skin cancer

The US Nutritional Prevention of Cancer Trial (NPCT) investigated the influence of selenium on the development of squamous and basal cell skin cancer in a high-risk group (NPCT 1996). Participants were men and women between 18 and 80 years. All had a history of two or more basal cell carcinomas or of one squamous cell carcinoma. All results were reported for two periods of follow-up: the intended study period (from 15 September 1983 to 31 December 1993: Clark 1996 see NPCT 1996) and the entire blinded intervention period (from 15 September 1983 to 31 January 1996: Duffield-Lillico 2002; Duffield-Lillico 2003 see NPCT 1996).

A sub-study of the NPCT (Reid 2008) investigated the efficacy of a higher selenium dose, supplied as selenised yeast orally, in the prevention of non-melanoma skin cancer in one of the NPCT study sites. Study design was similar to the NPCT study, except that 423 participants at this study site were randomised to placebo or intervention with higher selenium content.

2.3. Prostate cancer

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) investigated the preventive potential of selenium, as selenomethionine, and vitamin E supplementation in men of diverse ethnic backgrounds against prostate cancer (SELECT 2009).

2.4. Other cancers

In 1990 additional secondary endpoints were identified post-hoc in NPCT 1996 (total cancer mortality, total cancer incidence, incidence of lung, prostate, colorectal cancers). Furthermore, the incidences of female breast cancer, bladder cancer, oesophageal cancer, melanoma, haematological cancers and cancers of the head and neck were also reported in trial publications (NPCT 1996). Reid 2008 reported the incidence of internal cancers.

SELECT 2009 investigated several pre-specified secondary outcomes, including the incidence of and deaths from any type of cancer, lung cancer, colorectal cancer and other cancers (excluding prostate, basal cell and squamous cell skin cancer).

Excluded studies

Of these, 131 papers did not fulfil the inclusion criteria. Eighty-eight of these publications were rejected on the basis of abstract and title in the second evaluation, 43 papers were retrieved as full-text and their reasons for exclusion are described in the table Characteristics of excluded studies.

The main reasons for exclusion were:

  • The publication was a review or comment.
  • Cancer was not a study endpoint.
  • Selenium was not the exposure/intervention of interest.
  • The study was a retrospective case-control study.
  • The RCT had not been started.
  • A multi component supplement was used.
  • A control group was not included in the trial.
  • Observational studies did not report their results according to the inclusion criteria, e.g. only differences in the mean selenium exposure between cases and controls were provided.

Risk of bias in included studies

Observational studies

The median value of ’assigned stars’ was seven in the cohort study assessment and eight in the (nested) case-control study assessment out of a maximum of nine stars each (Figure 2 and Figure 3). A summary of the rating according to the Newcastle-Ottawa-Scale (NOS) is presented in Table 2.

Figure 2
Newcastle-Ottawa-Scale: number of studies by number of “stars” assigned in the case-control part of studies
Figure 3
Newcastle Ottawa-Scale: number of studies by number of “stars” assigned in the cohort part of studies
Table 2
Risk of bias: observational studies

All but one cohort study received five to nine ’stars’ in the NOS. The exception (two ’stars’) was an early investigation, which was only available in abstract form for assessment (Clark 1985). For three items of the NOS cohort assessment, less than 70% of the included studies were considered adequate: representativeness of the cohort for the target population (51% of the studies received a ’star’), demonstration that cancer was not present at study commencement (69%) and completeness of follow-up data (49%).

The representativeness of the cohort for the target population is a matter of external validity and generalisability of study results, but a systematic deviation of participants from the target population might also introduce bias to study results. The target population of included studies depended on the study objectives and could have been the general population, but also special occupational groups. Studies that did not identify their target population or recruited volunteers were not assigned a ’star’ to this question. Differential selection of study participants, e.g. volunteers, from the target population can lead to confounding by factors associated with selenium status and cancer incidence, e.g. nutritional behaviour or socio-economic position.

All included studies chose comparison groups (cases/controls or exposed/non-exposed) from the same study population. This approach increased the comparability between groups.

The presence of undiagnosed cancer at the beginning of the study, when specimens for selenium analysis were taken, might influence selenium levels. People with certain types of cancer have been found to have lower selenium levels than healthy controls. This might lead to an overestimation of the protective effect of higher selenium levels against cancer, if undiagnosed cancer cases are prevalent. Some studies tried to investigate this source of bias by excluding cases that occurred within a certain period from the beginning (mostly one or two years).

Follow-up data were considered either as complete or as missing data unlikely to introduce bias to study results in 50% of the included observational studies. In the other cohorts, losses to follow-up were more than 5% and a description of losses to follow-up was not provided. A high attrition may alter the characteristics of the population under investigation and impede generalisability of study results to the intended target population (external validity). The presence of attrition does not necessarily mean that the study results are biased. However, given the possibility that selenium status may be linked to sociodemographic variables and socio-economic position which may also influence participation in follow-up procedures, a differential effect of attrition may introduce bias towards under- or over-estimation of the true exposure effect.

Thirty-six included observational studies were nested case-control studies and therefore additionally assessed using the NOS case-control form. The number of ’stars’ in the NOS assessment of the case-control part of the studies ranged from six to nine, with more than 85% having received eight or nine ’stars’. Although the included prospective case-control studies were generally assessed as having a low risk of bias, in some studies concern arose due to case definition and the question of representativeness of the cases. Definition of cases was considered inadequate in 19% of the nested case-control studies as cases were identified by self-reporting, linkage to databases with unclear validity of data or procedures were not described. The magnitude and direction of bias that might have been introduced to the study results is unclear.

In 19% of studies, not all identified cases (or an appropriate sample of them) were included in the trial analyses or selection procedures for analysed cases were not reported. In some studies, blood specimens were lost due to technical problems (e.g. cooler breakdown in one study centre), others did not have enough material available for analysis or cases for analysis were otherwise selected in a non-random manner. This might bias the estimates of association in either direction.

There was no obvious asymmetry (as an indicator of publication bias) in the funnel plots of the studies on total and prostate cancer risk (Figure 4; Figure 5).

Figure 4
Funnel plot of comparison: 1 Highest versus lowest selenium exposure, outcome: 1.17 Total cancer incidence and mortality.
Figure 5
Funnel plot of comparison: 1 Highest versus lowest selenium exposure, outcome: 1.7 Prostate cancer risk.

Randomised controlled trials

An overview of the risk of bias in the included randomised controlled trials is presented in Table 3.

Table 3
Risk of bias: randomised controlled trials

Primary liver cancer

All three trials on liver cancer risk (Li 2000; Yu 1991; Yu 1997) were considered to have an unclear risk of bias. In these trials, the generation of allocation sequence and the allocation concealment were not reported. One study mentioned that the drop-out rate was similar in the intervention and control group, the remaining two studies did not report the completeness of outcome data. Blinding was judged as adequate in all three studies as the use of placebo supplements was reported. We inferred from this procedure that at least the study participants and the physicians directly involved were blinded towards treatment status.

We would like to point out that we are not entirely convinced that Li 2000 is a randomised controlled trial. The study investigators used the term ’randomization based on the residence area’ and did not describe the randomisation procedure any further. As participants were recruited from 17 villages, the villages and not the individual participants (stratified by village) could have been randomly assigned to the intervention and control group. However, we could not make contact with the study investigators and clarify these questions. A randomisation of villages instead of individuals would have introduced bias to the study results as the incidence of liver cancer is known to differ between areas as a result of environmental factors.

Studies with inadequate or unclear allocation concealment have been found to overestimate the benefit of interventions in RCTs, especially in trials with subjective outcomes (Pildal 2007; Wood 2008). In all three liver cancer RCTs, follow-up and case-detection procedures were not reported, so the influence of subjective factors on case detection, such as interpretation of bodily symptoms as trigger of further diagnostic tests, is unknown. Although we judged blinding as ’adequate’ in all three liver cancer trials, we do not know whether it was successful in practice for patients, healthcare providers and outcome assessors.

These uncertainties about study methods seriously weaken our confidence in the reported RCT results on liver cancer risk.

Non-melanoma skin cancer

Both included RCTs on non-melanoma skin cancer (NPCT 1996; Reid 2008) were considered to have a low risk of bias with adequate generation of allocation sequence, allocation concealment, blinding and completeness of outcome data. Reid 2008 was a sub-study of NPCT 1996.

Both studies also reported data for several secondary outcomes that were introduced post-hoc, such as lung, prostate, colorectal cancer and total cancer incidence. Placebo and selenium groups were similar regarding the distribution of the risk factors smoking, age, gender and PSA levels at randomisation. New cases were identified in the biannual participants’ interviews and by documenting cancer screening and diagnostic procedures from their medical files. Detection bias might have been introduced by a different use of diagnostic procedures in both groups: Men in the placebo group were, despite similar PSA levels, more likely to have undergone prostate biopsy (NPCT 1996) than men in the selenium group (Duffield-Lillico 2003b see NPCT 1996) which might have led to an underestimation of prostate cancer incidence in the selenium group and an overestimation of the treatment effect. As the background of this difference is unclear, it cannot be ruled out that differential health behaviours and diagnostic activities in both study groups might have affected the detection of lung and colorectal cancer as well, at least in the 75% male participants.

Prostate cancer

SELECT 2009 was considered to have a low risk of bias with adequate generation of allocation sequence, allocation concealment, blinding and completeness of outcome data.

Placebo and selenium groups were similar regarding the distribution of age, education, smoking status, PSA levels and race/ethnicity at baseline. No inter-group differences were found in the utilisation of PSA tests, prostate biopsies or digital rectal examinations during the course of the study.

Ethical criteria

Informed consent and ethics board approval was fulfilled by NPCT 1996, Reid 2008 and SELECT 2009, but not mentioned in Li 2000, Yu 1997, and Yu 1991.

Effects of interventions

1. Observational studies

When comparing the risk of cancer in higher and lower levels of selenium exposure, a summary risk estimate of 1 suggests that there is no association between selenium exposure and cancer, a summary risk estimate below 1 suggests a possible protective effect of higher selenium exposure and a summary risk estimate above 1 suggests a possible harmful effect of higher selenium exposure.

1.1. Aetiological association: Results from meta-analyses

1.1.1. Any cancer

Results of 13 prospective observational studies on total cancer risk including data of more than 143,000 participants were meta-analysed. The cohorts of Salonen 1984 and Salonen 1985 overlapped. Hence, only data from Salonen 1985 were included in the meta-analysis. Fex 1987 had to be omitted as the CI value was not reported and could not be calculated from the available data.

In participants in the highest category of pre-diagnostic selenium exposure, the summary risk estimate was OR 0.69 (95% CI 0.53 to 0.91) for cancer incidence and OR 0.55 (95% CI 0.36 to 0.83) for cancer mortality in both genders (Analysis 1.17) when compared with participants in the lowest exposure category. Statistically significant heterogeneity was observed both among studies on incidence (I2 = 49%) and mortality (I2 = 58%).

Analyses by gender found the risk to be lower in men (incidence: OR 0.66 (95% CI 0.42 to 1.05), mortality 0.56 (95% CI 0.38 to 0.81)) (Analysis 1.20) than in women (incidence: OR 0.90 (95% CI 0.45 to 1.77), mortality: OR 0.92 (95% CI 0.79 to 1.07) (Analysis 1.19).

All studies used either serum or serum and plasma biomarker levels for the assessment of selenium status. Analysis 1.18 shows the results in ascending order of baseline exposure of those studies that reported their category borders. The graph does not reveal a clear pattern of a relationship between baseline biomarker level and cancer risk.

1.1.2. Female breast cancer

Seven studies were included in the meta-analysis. No association was seen between baseline selenium levels and incidence of breast cancer with an overall risk estimate of OR 1.00 (95% CI 0.78 to 1.29) (Analysis 1.1). The heterogeneity of trial results (I2 = 5.4%) was low and not statistically significant.

1.1.3. Bladder cancer

Meta-analysis of bladder cancer incidence in five observational studies found an inverse association with an overall risk estimate of 0.67 (95% CI 0.46 to 0.97) suggesting a protective effect of higher selenium levels against bladder cancer (Analysis 1.2) (overall heterogeneity: I2 = 30%).

Gender-disaggregated data were only available from Michaud 2005 indicating a protective effect in women, but not in men in this study. However, two studies (Michaud 2002; Nomura 1987) had only male participants and both found a non-significantly reduced bladder cancer risk for higher selenium exposure (Analysis 1.2). Heterogeneity was not reduced by gender stratification (I2 = 40% in study results for men).

1.1.4. Lung cancer

Eleven studies were included in this meta-analysis. Data from Menkes 1986 and Knekt 1990 were not meta-analysed as the study population of the former overlapped with another meta-analysed study (Comstock 1997) and results of the latter were presented in insufficient detail.

The summary risk estimate for lung cancer incidence in both genders was 0.75 (95% CI 0.54 to 1.03) (Analysis 1.3). Statistically significant moderate heterogeneity was seen between study results (I2 = 54%).

In the meta-analysis according to gender using gender-stratified study results (Analysis 1.4), the summary risk estimate for women was OR 0.83 (95% CI 0.43 to 1.61)) and for men OR 0.88 (95% CI 0.61 to 1.28)). Heterogeneity among study results was not reduced by stratification. However, we expected the results for gender-combined data to be more or less a combination of the separate results for women and men. This was not the case here with ’gender-neutral’ data suggesting a larger protective effect than gender-stratified data. This discrepancy might relate to differences in study designs or populations.

In Knekt 1998, 95% of the lung cancer cases occurred in men. We repeated the meta-analysis of gender-disaggregated data categorising Knekt 1998 as ’men-only’ study and found a slightly changed summary risk estimate for men (OR 0.81 (95% CI 0.56 to 1.18)). The only study using nutritional intake assessment for exposure classification (Kromhout 1987) found no association with lung cancer risk (Analysis 1.6). Two studies measured selenium content in toenails with inconsistent results: Participants of the (all women) Nurses’ Health Study (Garland 1995) showed an increased lung cancer risk with higher selenium toenail levels, while an inverse association was observed in the Netherlands’ Cohort Study (vd Brandt 1993). The remaining eight studies used serum or plasma selenium levels. The summary OR was 0.84 (95% CI 0.66 to 1.06) with low heterogeneity (I2 = 3.5).

We plotted the studies using serum/plasma in ascending order of baseline exposure level (Analysis 1.5). No clear pattern of a relationship between baseline exposure levels and lung cancer risk could be seen in this graph. The two studies, which suggested the largest protective effect of higher selenium levels, were Knekt 1998 and Kabuto 1994. However, two other studies with quite similar biomarker levels found discrepant results (Nomura 1987; Ratnasinghe 2000).

1.1.5. Prostate cancer

Fourteen epidemiological studies on prostate cancer incidence were included in the meta-analysis. The summary risk estimate for higher selenium exposure was OR 0.78 (95% CI 0.66 to 0.92) (heterogeneity: I2 = 37%) (Analysis 1.7).

Stratification by the method of selenium assessment showed a reduction in prostate cancer risk for higher baseline biochemical markers (OR 0.74 (95% CI 0.61 to 0.88)), but not for higher estimated selenium intake (OR 1.00 (95% CI 0.73 to 1.36)) (Analysis 1.8). The inverse association between selenium biomarkers and prostate cancer incidence was stronger for toenail levels (OR 0.53 (95% CI 0.35 to 0.81)) than for blood levels (OR 0.81 (95% CI 0.68 to 0.97)) (Analysis 1.9). Heterogeneity among study results was slightly reduced with these stratifications.

Stratification by country and continent found the risk reduction more pronounced in the US than in Europe (Analysis 1.10; Analysis 1.11).

Overall, the strongest inverse associations were seen in studies from the US published before 2001. These findings cannot be explained by differences in baseline selenium levels alone. Analysis 1.12 shows the results for studies using serum or plasma measurements in ascending order of selenium levels. For quite similar categories of selenium concentration, studies indicated different effects (Goodman 2001 versus Clark 1985; Nomura 2000 versus Peters 2007 and Gill 2009 see Epplein 2009).

1.1.6. Stomach cancer

Five observational studies were included in the meta-analysis of gastric cancer incidence. The summary risk estimate for both genders was OR 0.66 (95% CI 0.43 to 1.01) in the highest exposure category when compared with the lowest (I2 = 50.8%) (Analysis 1.13). However, in this meta-analysis one cohort (Mark 2000 in: Wei 2004) is included twice because the results were reported stratified according to cardia and non-cardia gastric cancer.

We repeated the meta-analyses including alternately the results of Mark 2000 (see Wei 2004) for cardia and non-cardia gastric cancer. The summary OR was 0.75 (95% CI 0.47 to 1.21) when data for non-cardia cancer were included and OR 0.59 (95% CI 0.38 to 0.93) when data for cardia cancer were included.

Using the available gender-stratified results for meta-analysis, the risk estimate for men was OR 0.43 (95% CI 0.14 to 1.32) (I2 = 56.1%) and for women OR 0.73 (95% CI 0.12 to 4.35) (I2 = 62.3%) (Analysis 1.14).

1.1.7. Colon/colorectal cancer

Five observational studies reported data on colon or colorectal cancer incidence. The summary risk estimate was OR 0.89 (95% CI 0.65 to 1.23) for both genders (I2 = 3.8%) (Analysis 1.15), OR 0.69 (95% CI 0.42 to 1.12) for men and OR 1.06 (95% CI 0.57 to 2.00) for women (Analysis 1.16).

1.2. Aetiological association: other results

Results of the observational studies, which were not included in meta-analyses, are reported in Table 4.

Table 4
Results of observational studies not included in meta-analysis

2. Randomised controlled trials

2.1. Preventive efficacy: main outcomes

2.1.1. Primary liver cancer

Three RCTs investigated the efficacy of selenium supplementation for liver cancer prevention. All RCTs were conducted in China and with participants of different high-risk groups in the Qidong province.

Yu 1997 investigated a 4-year supplementation period with 200 μg selenium yeast/day in 226 male and female hepatitis B-surface antigen (HBs-Ag) carriers. Eleven cases (person-time incidence rate: 1573.03/100,000) were detected in the placebo group and four cases in the selenium group (RR 0.36 (95% CI 0.12 to 1.11)) during the 8-year follow-up period. The mean blood selenium level was 152 ng/ml in the intervention group and 107 ng/ml in the control group (during the intervention period).

Yu 1991 reported on a trial with 2474 male and female first-degree relatives of liver cancer patients who also received 200 μg selenium yeast/day. During the study period of two years, 10 cases in the selenium and 13 cases in the placebo group were observed (RR 0.55 (95% CI 0.24 to 1.25)).

Li 2000 randomised 2065 male HBs-Ag carriers receiving 0.5 mg sodium selenite daily for 3 years. Thirty four cases of liver cancer occurred in the 1112 subjects receiving selenium and 57 cases in the 953 placebo subjects (RR 0.51 (95% CI 0.34 to 0.77)).

2.1.2. Non-melanoma skin cancer

2.1.2.1. Total non-melanoma skin cancer

A higher risk for non-melanoma skin cancer was seen in the 200 μg/day selenium supplementation group of the NPCT (RR 1.27 (95% CI 1.11 to 1.45)) (Duffield-Lillico 2003 see NPCT 1996). The increase remained statistically significant after multivariate adjustment (HR 1.17 (95% CI 1.02 to 1.34)). No variation in this effect by age, gender or smoking status was statistically significant. Mean selenium plasma concentration of the participants was 114 ng/ml at the time of randomisation. An increased risk for total non-melanoma skin cancer was seen in all tertiles of baseline plasma levels (Reid 2008 see NPCT 1996). The increased risk could be observed more pronouncedly at one study centre (Macon, Georgia) than at the other study sites. The percentage of female participants was higher in Macon, but distribution of other factors, in particular baseline selenium levels, was similar to the other sites and the reason for the different effect, if not due to chance alone, remained unclear.

In the sub-study with 400 μg/day selenium supplementation (Reid 2008), no alteration of non-melanoma skin cancer risk was seen (HR 0.91 (95% CI 0.69 to 1.20)). Gender-stratified analyses found a decreased risk in women (RR 0.40 (95% CI 0.20 to 0.80)) and a non-statistically significant increased risk in men (exact data not reported). Distribution of baseline plasma selenium levels was similar in this sub-study to the participants of the NPCT main study and we found no evidence for an effect modification according to baseline selenium exposure.

Neither the intervention with 200 μg/day nor with 400 μg/day found evidence that supported a preventive efficacy of selenium yeast supplementation against non-melanoma skin cancer in these populations. The results of the NPCT raised concerns about harmful effects of selenium yeast supplementation.

The comparison of the results of both investigations did not show a dose-response relationship between the amount of supplemental selenium intake and outcome: While a harmful effect on non-melanoma skin cancer risk was seen with the 200 μg/day supplement, the 400 μg/day supplement showed a decreased risk in women and no effect in men. This might indicate differential biological mechanisms and health effects of selenium at different levels of supplemental intake by gender. The 400 μg/day supplemental intake led to a mean selenium level of approximately 250 ng/ml while 200 μg/day supplemental intake increased plasma levels to approximately 200 ng/ml.

2.1.2.2. Basal cell carcinoma

At the end of the total blinded treatment period in the NPCT, the RR 1.17 (95% CI 1.02 to 1.35) for basal cell carcinoma (BCC) was increased in the 200 μg/day selenium group. Multivariate adjustment attenuated the effect to a HR of 1.09 (95% CI 0.94 to 1.26). Eliminating the cases that occurred within the first two years of supplementation had no further effect on the RR. We found no statistically significant variations in effects according to age, gender or smoking status.

Reid 2008 found an adjusted HR of 0.95 (95% CI 0.69 to 1.29) in the 400 μg/day selenium sub-study.

2.1.2.3. Squamous cell carcinoma

In the NPCT, selenium supplementation increased both the (unadjusted) risk for squamous cell carcinoma (SCC) (RR 1.32 (95% CI 1.09 to 1.60)) and the multivariate-adjusted HR 1.25 (95% CI 1.03 to 1.51). After exclusion of the cases that occurred within the first two years, a slight decline in the effect of selenium supplementation was seen (leading to statistical non-significance). We found no statistically significant variations in effects according to age, gender or smoking status. The adverse effect of selenium supplementation on SCC risk seemed to increase with increasing plasma selenium levels at baseline. A higher risk of non-melanoma skin cancer incidence was seen only in participants with baseline plasma levels in the highest two tertiles of baseline exposure (greater or equal to 105.6 ng/ml), which suggested a possible interaction between supplementation and baseline exposure.

In the 400 μg/day selenium sub-study (Reid 2008), we found no alteration of SCC risk by selenium supplementation (HR 1.05 (95% CI 0.71 to 1.56)).

2.1.3. Prostate cancer

In the SELECT trial, we found no evidence of benefit of L-selenomethionine supplementation (compared to placebo) for a median of 5.5 years on prostate cancer incidence (HR 1.04, (95% CI 0.90 to 1.18), (99% CI 0.87 to 1.24)) (SELECT 2009). The adjusted HR for prostate cancer in the selenium plus vitamin E group compared to placebo was HR 1.05 ((95% CI 0.91 to 1.20), (99% CI 0.88 to 1.25)).

SELECT was terminated early in 2008 following the recommendation of the data and safety monitoring committee. The committee had some concern over a statistically non-significant increase in prostate cancer in the vitamin E-alone group (HR 1.13, (95% CI 0.99 to 1.29), (99% CI 0.95 to 1.35)).

SELECT failed to replicate the findings of the NPCT, which observed a reduction in prostate cancer incidence in the selenium yeast group (adjusted HR 0.48 (95% CI 0.28 to 0.80)), and found no evidence for a statistically significant cancer preventive efficacy of selenium supplements. NPCT investigators argued that as randomisation worked, bias seemed unlikely to explain the positive findings for some cancers including prostate cancer in their trial. Regarding prostate cancer, however, a differential participation of men with elevated PSA levels in prostate biopsies was observed in the selenium and placebo group (35% versus 14%; Duffield-Lillico 2003 see NPCT 1996). This may have occurred by chance and could have contributed to an overestimation of the effect of selenium supplementation in the NPCT.

2.2. Preventive efficacy: secondary and other outcomes

The NPCT (NPCT 1996) reported on a number of secondary outcomes identified post-hoc and other cancers, which had occurred in the trial population.

The total cancer incidence was reduced in the selenium group (adjusted HR 0.75 (95% CI 0.58 to 0.97)) after a mean follow-up of 7.4 years (Duffield-Lillico 2002 see NPCT 1996). Cancer mortality was also reduced (adjusted HR 0.59 (95% CI 0.39 to 0.87)). A gender-stratified analysis revealed that any possibly protective effect on total cancer incidence in the NPCT was confined to men (adjusted HR 0.67 (95% CI 0.50 to 0.89)). The adjusted HR for women was 1.20 (95% CI 0.66 to 2.2). Because of the predominance of male participants, these gender-differential effects added up to a net benefit for the total study population.

The observed risk of specific cancers in the selenium group was lower than in the placebo group for lung cancer (adjusted HR 0.74 (95% CI 0.44 to 1.24)), colorectal cancer (adjusted HR 0.46 (95% CI 0.21 to 1.02)), oesophageal cancer (adjusted HR 0.40 (95% CI 0.08 to 2.07)) and prostate cancer, as mentioned above. On the contrary, it was higher in the selenium group than in the placebo group for melanoma (adjusted HR 1.18 (95% CI 0.49 to 2.85)), bladder cancer (adjusted HR 1.28 (95% CI 0.50 to 3.25)), breast cancer (adjusted HR 1.89 (95% CI 0.69 to 5.14)), head and neck cancer (adjusted HR 1.27 (95% CI 0.47 to 3.42)) and lymphoma/leukaemia (adjusted HR 1.25 (95% CI 0.43 to 3.61)). Reid 2008 found no evidence that selenium supplementation altered total cancer incidence (RR 1.10 (95% CI 0.57 to 2.17)).

2.3. Adverse effects

NPCT 1996 and SELECT 2009 reported on adverse effects of selenium supplements.

In the NPCT, 35 participants had withdrawn from the study because of adverse effects, mainly gastrointestinal upset. The RR for adverse events in the selenium group was 1.51 (95% CI 0.74 to 3.11) (own calculation, based on the number of all randomised participants).

In SELECT, men in the selenium group had an increased risk of alopecia (RR 1.28 (99% CI 1.10 to 1.62)) and dermatitis (grade 1 to 2) (RR 1.17 (99% CI 1.00 to 1.35)), but not of halitosis, nail changes, fatigue, nausea or dermatitis (grade 3 to 4). A statistically non-significant increase in diabetes mellitus type II in the selenium-alone group (HR 1.07 (99% CI 0.94: 1.22)) was seen.

An increased risk for diabetes mellitus type II was also observed in the NPCT (Stranges 2007 in: NPCT 1996). A secondary analysis of participants who did not have diabetes at the start of the study revealed an excess risk in the selenium group (adjusted HR 1.55 (95% CI 1.03 to 2.33)). We found no statistically significant interactions with age, gender, smoking status and BMI. The RR for developing type II diabetes mellitus was higher in participants in the upper two tertiles of plasma selenium levels, indicating a possible interaction with baseline exposure status.

Both the SELECT and the NPCT results suggest that long-term supplementation with selenium may adversely affect glucose metabolism and increase the risk for diabetes mellitus type II.

The three trials on liver cancer and Reid 2008 did not mention the occurrence of adverse effects. One paper stated that no case of selenosis had been observed during the trial.

DISCUSSION

Summary of main results

The aims of this review were to examine the efficacy of selenium supplements in preventing cancer and possible associations between selenium exposure and the risk of cancer incidence and mortality.

Observational studies and aetiological association

From our meta-analyses of 13 prospective observational studies on total cancer risk, we found a reduced cancer incidence and mortality with higher selenium exposure. The risk of cancer disease was 31% (95% CI 9% to 47%) lower in the highest category of selenium exposure than in the lowest, the risk of death from cancer was 45% (95% CI 17% to 64%) lower. Subgroup analyses by gender suggested that a beneficial effect of higher selenium exposure, if existent, could be higher in men than in women.

The risk of developing bladder cancer was reduced by 33% (95% CI 3% to 54%) and that of prostate cancer by 22% (95% CI 8% to 44%). The risk of lung, gastric or colorectal cancers were also found to be reduced with higher selenium exposure; however the confidence intervals of the summary risk estimates overlapped the 1.

No association was seen between selenium and the risk of breast cancer.

For all other types of cancer, data were only available from less than five epidemiological studies; thus results were narratively summarised. None of the study results supported an association between selenium exposure and gynaecological cancer risk, while results for cancers of the gastrointestinal, respiratory or urological tract were inconsistent. For respiratory and urological cancers (other than bladder, prostate or lung cancer), studies reported either no associations or increased risks for participants with a higher selenium exposure. For gastrointestinal cancers, studies found either no associations or reduced risks with a higher selenium exposure.

As is the case with all meta-analyses of epidemiological data, our findings have potential limitations resulting from study design as well as quality and heterogeneity of the data. These limitations can complicate the interpretation of the summary statistics.

RCTs and preventive efficacy

We identified six randomised controlled trials, which investigated mono-selenium supplements in the prevention of non-melanoma skin cancer, liver cancer and prostate cancer. There was no convincing evidence that selenium supplementation can prevent non-melanoma skin cancer or liver cancer in women or men or prostate cancer. The results of the Nutritional Prevention of Cancer Trial (NPCT) raised concerns about possible harmful effects of selenium supplements.

The NPCT was considered to have a low risk of bias and found a statistically significant increase in the incidence of squamous cell carcinoma as well as a trend towards an increased basal cell carcinoma incidence with selenium yeast supplementation. The RR increase was 17% for total non-melanoma skin cancer and 25% for squamous cell carcinoma in both genders after a mean follow-up of 7.4 years. The number needed to harm in the study population was 19 (95% CI 10 to 143) after a duration of five years selenium supplementation. A sub-study of the NPCT, which used supplements with a higher selenium content, found no differences in non-melanoma skin cancer risk between the active and the control group in both genders combined (HR 0.91, 95% CI 0.69 to 1.20), but an indication of a possible modification of effect by sex or gender, which was not seen in the main part of the NPCT.

Secondary outcomes of the NPCT indicated a lower total cancer incidence and mortality in the selenium group in men, but not in women. Analyses stratified according to cancer type found a statistically significantly reduced risk for prostate cancer. These results were not seen in the sub-study of the NPCT and could not be replicated in the SELECT trial, although it should be noted that this trial used a different intervention.

The SELECT trial was a large prostate cancer prevention trial in the general population of North America. It was considered to have a low risk of bias and found no alteration of prostate cancer incidence by L-selenomethionine supplements after a median follow-up of 5.5 years (HR 1.04, 95% CI 0.90 to 1.18).

One out of three liver cancer prevention trials reported a statistically significantly reduced risk of liver cancer (RR 0.51 (95% CI 0.34 to 0.77)) for male carriers of the hepatitis B surface antigen taking inorganic selenium supplements (sodium selenite) for three years. This was in contrast to the other two studies reporting no statistically significant effect of organic selenium supplements (selenium yeast) for the same cancer site. Due to several methodological concerns relating to randomisation and completeness of outcome data, the risk of bias was unclear for all three RCTs. Therefore, we cannot conclude that there is strong support for selenium supplements as agents for the prevention of liver cancer.

Overall completeness and applicability of evidence

Observational studies and aetiological association

We reviewed data from prospective observational studies, where selenium exposure was measured in populations without evidence of cancer, and which were then followed-up for a specified period of time. This approach minimised the risk of reverse causality if an association between selenium exposure and cancer was observed in the study.

The included studies differed in terms of selenium exposure measurement, types of outcomes, study designs and study populations. The low number of studies for most of the meta-analysed types of cancers prevented a thorough investigation of the sources of heterogeneity between study results. In particular, we could not explore the influence of specific sources of bias or the methodological quality of epidemiological studies on heterogeneity.

The investigations included over 1,078,000 individuals from diverse study populations predominantly from Europe and the USA and to a lesser extent, Asia and Australia) (also see: Dennert 2008). No prospective observational study on selenium and cancer risk could be identified from Africa or South America. This regional distribution reflects the under-representation of non-Western and resource-poor countries in epidemiological research (Pearce 2004). Differential regional representation in epidemiological studies is of special interest for this review, as selenium levels in humans vary significantly around the world. The selenium levels measured in the included cohorts reflect a broad range of naturally occurring selenium exposure as measured in cross-sectional studies worldwide. However, some of the lowest as well as the highest selenium levels in humans were reported in literature from South American populations (Jaffé 1992), a region which was not investigated in any of the reviewed observational studies.

More than half of the studies included mixed gender populations, but the majority of them did not report gender-disaggregated data. In the available gender-specific results, men are over-represented, which inhibits the further understanding of a possible gender-specific association between selenium exposure and cancer risk in epidemiological data. This also limits the generalisability of the review results that evidence for a clinically relevant sex or gender-differential effect exists.

RCTs and preventive efficacy

This review investigated a diverse range of cancers, but cancer is not a uniform condition and malignant neoplasms show great differences in tumour biology. Only non-melanoma skin cancer, liver cancer and prostate cancer were investigated in the included prevention trials as primary outcomes. The results cannot be generalised to other types of cancers.

Regarding the three main outcomes, specific characteristics of the study populations may also limit the generalisability of the results to non-participants. Participants of the included RCTs on skin and liver cancer belonged to populations with a high risk for the outcome under investigation. The participants of the NPCT were mostly older and white, predominantly male inhabitants of the US Mean plasma selenium concentration was in the lower range of U.S. levels, but still well above the average selenium level of Europeans. A possible interaction with baseline selenium levels was found resulting in an increased risk for developing squamous cell cancer and diabetes mellitus type II in participants receiving the selenium supplement who had higher baseline levels. An indication of interaction and modification of effect was also found for gender regarding some of the study results. When applying the study results to other populations, characteristics of the population regarding gender and selenium exposure should be considered.

Apparently healthy men over 50 years of age from the general population of North America participated in the SELECT trial on prostate cancer prevention. The large sample size and the inclusion of non-white participants from different socio-economic backgrounds supported the generalisability of study findings to other adequately nourished populations.

Selenium supplements contain either organic or inorganic species of selenium or a mixture of both, e.g. in the form of selenised yeast. The different species of selenium may exhibit differential effects on human health. Four included RCTs used selenised yeast supplements and found either a harmful or no effect of supplementation on the main study outcome. The SELECT trial used L-selenomethionine supplements, which is the major component of selenium yeast, and also found no preventive efficacy. The only RCT investigating sodium selenite supplements found a protective effect against liver cancer, but was considered to have an unclear risk of bias. It is also unclear how applicable these results are in other settings and populations with a different nutritional status.

Interpretation of the results of clinical trials using selenium supplements should consider the different biological forms as well as their potential differential health effects when supplemented.

Quality of the evidence

Observational studies and aetiological association

The 49 observational studies were heterogenous, not only regarding methodology, but also in the quality and level of detail of reporting. The publications included ranged from a congress abstract to a full-text dissertation.

Bias and confounding

Selenium measurement and categorical exposure classification

Five observational studies measured nutritional or supplemental selenium intake using questionnaires or interviews. Most studies, however, relied on selenium biomarkers such as toenail, serum or plasma selenium levels. Percentile borders, for example quartiles or quintiles, were usually applied as cut-off points for exposure categories. Our analyses were based on the comparison of highest versus lowest baseline exposure category. In our meta-analyses, different methods of selenium measurement and different numbers of exposure categories covering different absolute selenium levels were combined.

Assessment of total selenium intake with food-frequency questionnaires (FFQ) or interviews has proven difficult in other investigations because of the lack of food composition data which adequately reflects regional and seasonal variations in selenium concentration. The Duffield 1999 trial compared duplicate diet collections, dietary logs, FFQ and biomarkers as measurements for selenium intake and status in New Zealand men and women. The FFQ overestimated the mean selenium intake in study participants when compared with laboratory analyses of duplicate meals. The ranking in quartiles according to intake for both dietary logs and FFQ differed from the results from duplicate meals. Correlation between all three dietary measurements and selenium biomarkers (whole blood and plasma) were modest (r = 0.1 to 0.4) at the best. Also Karita 2003 found only a modest correlation between selenium intake as estimated from FFQ and from a 7-day dietary log in Japanese men and women. In the same study, a correlation between both estimates of dietary intake and serum selenium levels could not be seen.

Validity problems, possibly leading to exposure misclassification, have also been reported when questionnaires are used to assess supplement use (Murphy 2002).

Regarding biomarkers for selenium measurement, Ashton 2009 showed in a systematic review that plasma and whole-blood selenium concentrations increased with higher selenium intake in supplementation studies. Plasma, whole-blood and presumably serum selenium levels, although Ashton 2009 could not identify serum studies for their systematic review, were therefore considered by the authors to adequately reflect a short-term increase in supplemental selenium intake in healthy adults. However, authors also found significant, unexplained heterogeneity in the reaction of participants’ plasma selenium levels to selenium supplementation.

Concerning the estimation of long-term nutritional intake with biomarkers, Longnecker 1996 demonstrated a high correlation between long-term selenium intake as estimated from duplicate food portions and single measurements from whole blood, serum and toenail specimens.

These findings support the concern that the ranking of selenium exposure differs according to the instruments used to assess intake and also between intake assessment and biomarkers. Exposure misclassification may have biased the results of individual studies and a meta-analysis of observational data is likely to reflect these biases. Non-differential exposure misclassification might have occurred in all included studies due to measurement errors or as a result of the gap between the theoretical definition of selenium exposure and the measurement thereof, which served as a proxy. Non-differential misclassification might lead to an under- as well as over-estimation of an effect in the presence of more than two exposure categories. Our approach of a meta-analysis covering different methods of selenium assessment might have introduced additional heterogeneity to review results.

A concern, which we cannot clarify to date, is that biomarkers do not adequately reflect intake of both organic and inorganic selenium species. Animal studies indicate that selenium from inorganic sources is not retained so well in the body as organic selenium. Selenium from organic sources led to higher blood selenium levels and a higher activity of glutathione peroxidase than equal doses of inorganic supplements in veterinary studies (Slavik 2008; Steen 2008). However, symptoms of acute toxicity were observed in animals with a lower intake of inorganic than organic selenium species (Kim 2001; Tiwary 2006). Hall 2008 found an increased genotoxic effect in human cell lines by sodium selenite in comparison to organic selenium. When considering the possibly differential effects of selenium species on human health, an adequate interpretation of the biomarkers representing selenium exposure would require knowledge of the selenium sources of the individual.

The observation in our review that cancer risks only show an association with biomarker levels, but not with nutritional intake might therefore be a consequence of an invalid measurement of nutritional intake, which biased the results towards the null. Alternatively, it might likewise reflect that there truly is no association and that the findings from the biomarker studies were the result of chance and measurements of nutritional intake may provide better estimates of the exposure situation than do biomarkers, which may misclassify the exposure to inorganic selenium sources.

Furthermore, the comparison of risks between the highest and the lowest exposure category is most suitable to identify an effect when there is a consistent decrease or increase across absolute exposure levels. Other associations (e.g. threshold effects or U-shaped relationships) may be missed by this method of meta-analyses or the true effect might be diminished.

Comparability of cases and controls and detection of cancer

All included studies recruited participants pre-diagnostically and cases and control subjects stemmed from the same population. This approach decreased potential differences between both groups, which could have influenced cancer disease or death due to factors other than selenium exposure. We included the results from each study in meta-analyses which were adjusted for the highest number of additional variables.

Any cancer

All studies on total cancer risk identified cases by using registry links or a combination of several methods and losses to follow-up were low. Two studies on cancer incidence and two studies on cancer mortality analysed less than 80% of all identified cases (incidence: Persson 2000: 76%; Coates 1988: 79%; mortality: Kok 1987: 71%; Kornitzer 2004: 57%). The main reason for this was samples missing for selenium measurement. Not all studies that assessed mortality as a measure of cancer risk excluded participants with cancer disease at study inception. This might have led to an overestimation of a protective effect when selenium levels were lowered by the presence of cancer.

We therefore consider the results for cancer incidence to provide the more valid estimation for the relationship between selenium exposure and cancer risk than the mortality data.

Prostate cancer

All but two of the studies on prostate cancer risk identified cases by using links to cancer registries or a combination of personal follow-up interviews with PSA screening. Two studies with health professionals used self-reporting for case identification, followed by confirmation through medical records. The number of people lost to follow-up was low in all studies included. Two studies, however, included less than 80% of all identified cases in their analyses (Brooks 2001: 39%; van den Brandt 2003 in: vd Brandt 1993: 77%) because samples were not available for selenium measurement or diagnosis was not confirmed. In Brooks 2001, bias might have been introduced to the results to some extent, as the demographic variables differed between the identified and analysed cases.

Bladder cancer

Losses to follow-up were low in three studies (Michaud 2002; Nomura 1987; Zeegers 2002 in: vd Brandt 1993) and unclear in two on bladder cancer risk (Helzlsouer 1986 in: Menkes 1986; Michaud 2005). Endpoints were ascertained in elaborate ways in four studies including linkages to registries and regional and national databases; one study relied on the self-reporting of study participants (Michaud 2005). The latter investigation compared bladder cancer in the Nurses’ Health Study (women) and the Health Professionals Follow-Up Study (men) and was the only one to report gender disaggregated data. A gender-differential association between selenium exposure and bladder cancer risk was found, but the role of potential biases due to possible different self-reporting behaviour in these two distinct cohorts remained unclear.

The second study which found a statistically inverse association between selenium exposure and bladder cancer risk was Zeegers 2002, which could only analyse 70% of the identified bladder cancer cases as specimens for selenium measurement were not available for the remainder.

Residual confounding and effect modification

Most of the studies included controls for smoking and age, either by matching or by using multivariate techniques. However, only a few considered the potential effect of other factors. Possible confounding factors could be another food nutrient or a certain behaviour, which exhibits cancer protective effects and is associated with higher intake of selenium-rich foods. Furthermore, intake of heavy metals and other dietary factors may modify selenium health effects or the relationship between selenium exposure and biomarker concentration (overview in: Vinceti 2000). Metabolic interactions, for example, are known for arsenic (Zeng 2005).

Even in studies that considered the influence of a specific factor, validity of the assessment of the potential confounder can be challenging and is not commonly reported in study publications. For example, control for smoke exposure as a known risk factor for several types of cancer seems a crucial issue in epidemiologic studies on cancer risk. Cigarette smokers, for example, tend to have lower selenium biomarker levels, though cigarette smoking is a source of selenium exposure itself. Therefore an inverse association between selenium and lung cancer risk might also be the result of residual confounding and effect modification by smoking. Exposure to environmental and household smoking, which has been shown to be associated with increased risks of cancer (Gorlova 2006; Nishino 2001), might also be associated with selenium status due to differential nutritional behaviours or other mechanisms. We are not aware of any study that investigated this issue. Unknown factors may influence an observed selenium - cancer association and thus pose a challenge as to causal inferences.

Some of these factors cluster in population groups according to socio-economic position (SEP). Only a few studies attempted to control for indicators of adult SEP as potential confounders, e.g. education, occupation or income. None used a composite index of indicators or considered childhood SEP. Some studies restricted their cohorts to certain subgroups of a population, such as occupational groups, and were likely only to include people of a similar adult socio-economic background.

It has been claimed that associations between vitamins and diseases are the result of confounding by social and behavioural factors acting over the course of a lifetime (Lawlor 2004). Lawlor 2004 argued that the divergent results from epidemiological and randomised controlled studies on the prevention of cardiovascular diseases can be explained by unmeasured confounding due to SEP. Risk of most cancers is - like cardiovascular morbidity - known to decrease with higher SEP. Research also indicated a positive association between higher SEP and selenium biomarkers (Barany 2002; Niskar 2003). However, other investigations did not confirm these findings: Kant 2007, for example, did not find an association between a measure of household poverty and selenium status.

The hypothesis of possible confounding due to SEP leading to an indirect association between selenium and cancer in epidemiological research would be consistent with the results for all types of cancers in this review - including the null association with breast cancer - with the exception of prostate cancer findings. Prostate cancer has been found to be more often diagnosed in men of a higher SEP (Dalton 2008) while we saw a protective association with higher selenium exposure. However, it remains unclear whether the more frequent diagnoses of prostate cancer in men with higher SEP reflects an excess of prostate cancer incidence in this population. It might also result from differential health and screening behaviours leading to a detection of otherwise symptom-free cases while men with a lower SEP tend to be overrepresented in diagnoses of advanced stages of the disease (Rapiti 2009). More information on screening and diagnostic behaviour of the male cohort participants would be necessary to further elucidate these findings.

For prostate cancer, studies published before 2000 and especially those from the US found a larger protective effect with higher selenium levels than did later studies. We consistently observed this in the studies on lung cancer.

This might be attributable to differences in study design or populations (with the later studies being the larger studies including the general population) or changing health and screening behaviours over time in the case of prostate cancer studies. It could also reflect publication bias in earlier years favouring positive results.

An alternative explanation could be a ’threshold’ effect for a possible protective effect of selenium against prostate cancer around a certain level, which has been diminishing due to the increasing use of selenium supplements in the US. Brooks 2001 reportedly observed results consistent with a threshold effect at a level of 108 μg/l serum selenium. Conversely, a threshold effect was not seen in another study with almost the same percentile limits (Goodman 2001) in a population of asbestos workers, who may have had other sources of selenium exposure than the participants of Brooks 2001 from the general population. It has been frequently suggested that an increase in selenium intake might be beneficial only for men with lower selenium levels as glutathione peroxidase activity reaches a plateau above approximately 95 (range 89 to 114) μg/l (Rayman 2000).

We found no clear indication of a threshold effect in either lung or prostate cancer in the overview of study results. Heterogeneity between studies might therefore not reflect a consistent biological threshold effect of baseline selenium exposure levels, but a cluster of known and unknown influences of factors related to study design, population and potential biases.

The role of chance

Large epidemiological studies are not designed to test for a specific aetiological hypothesis, but enable research to investigate a large number of possible associations. Given the multiplicity of possible comparisons, associations between selenium exposure and cancer endpoints may have resulted from chance alone.

Summary

Factors which seemed to account partially for the inter-study heterogeneity were type of outcome measure (incidence or mortality), assessment of exposure and gender.

Considering the possible influences of bias, residual confounding and modifying factors on the selenium-cancer relationship, the summary estimates from meta-analyses should be interpreted with caution. Meta-analyses of spurious findings in observational studies increase the precision of a summary risk estimate, which does not itself get nearer to the true value and may suggest an nonexistent association (Egger 1998).

RCTs and preventive efficacy

The NPCT, its sub-study and the SELECT trial were considered to have a low risk of bias with adequate sequence generation, allocation concealment, blinding and reporting of findings.

In the three trials on liver cancer prevention, quality of reporting was an issue and they were considered to have an unknown risk of bias. The individual trials were - in some cases discrepantly - reported in several papers and essential questions regarding sequence generation, allocation concealment, handling of drop-outs and withdrawals and detection of outcomes remained unanswered. This might be due to inadequate reporting, but might also hint to flaws in trial design and implementation. We were uncertain that the only trial which found positive results for selenium supplements in liver cancer prevention randomised participants individually. A cluster randomisation of participants who lived in the same area/village, which may have been the procedure in this investigation, might have introduced additional bias to the study results, e.g. due to different environmental factors contributing to liver cancer development or detection, and might have led to an overestimation of the protective efficacy of selenium. A duplication of results with a rigorous study design would be necessary to assess the effect of sodium selenite on liver cancer incidence.

Potential biases in the review process

RCTs and preventive efficacy & observational studies and aetiological association

The literature search included the major international databases in the English and German language and we applied a broad search strategy supplemented by hand searching for references. We assume that we identified all randomised controlled studies and prospective observational studies relevant to our review questions. As we did not search databases in other languages, e.g. Chinese or Russian, we cannot rule out that we missed smaller studies which were not published in international journals. There is also a chance that we might have missed observational studies whose results on selenium exposure and cancer were reported in the body of a paper but not mentioned in the paper’s title or abstract, even if the paper is indexed in the searched databases.

Although we tried to contact all investigators for missing or additional data on their studies, we were unable to retrieve answers to questions we had regarding methodology or outcomes in some studies. This applied particularly to earlier epidemiological studies where primary investigators may have relocated, died, or where data were not available in a current electronic format. Similarly, we could not make contact with the primary investigators of the Chinese RCTs.

The risk of bias assessment was based on the included publications. The risk of bias of studies that did not adequately describe the study design in the included publication but gave a reference to another paper, might therefore have been overestimated in this review.

Another concern, especially with the epidemiological studies, is publication bias. Cohort and nested case-control studies are not exclusively designed to test for a specific exposure-outcome association, but enable researchers to investigate a range of questions. It is conceivable that unfavourable results were less likely to be published.

We decided a priori to conduct meta-analyses only when five or more studies were available for a study outcome. As a result of this cut-off, we did not conduct meta-analyses for a number of observational study outcomes with two to four studies available (see: Table 1). Our primary intention was to facilitate the investigation of heterogeneity between studies that were included in meta-analyses, in order to avoid producing more precise, but still unexplainably biased results. However, results of this review revealed that the cut-off at five studies did not guarantee this possibility and could therefore be reconsidered in future updates.

Regarding the question of the efficacy of selenium for cancer prevention, the cut-off point led to the situation that no meta-analytic procedures were conducted for RCTs. Looking out our results, however, only liver cancer results would have pooled without the cut-off. Results for this meta-analysis of liver cancer have already been published in another systematic review (Bjelakovic 2008) and were included in the discussion here. Replicating the meta-analysis of liver cancer trials would not have changed the results of this systematic review.

The authors of this review came from different disciplines and have different focuses, e.g. epidemiology, clinical medicine and nutrition. We consider this internal variety of expertise to be a strength of this review and made use of it by applying double-checking procedures during the entire review process whenever possible.

Agreements and disagreements with other studies or reviews

The idea of selenium supplementation for cancer prevention received broad support following the NPCT and the publication of several large epidemiological studies which supported the hypothesis of an aetiological relationship between low selenium status and cancer development. Combs 2005 stated that “the hypothesis that Se (selenium) can affect cancer risk is supported by a remarkably consistent body of scientific evidence” (Combs 2005, p346). These ideas stimulated the largest ever cancer prevention trial SELECT, which failed to provide support for this hypothesis. Disagreement between the results of this systematic review and other publications may partly be explained by the differentiation between aetiology and efficacy in the research questions of this review.

Observational studies and aetiological association

A number of systematic reviews with and without meta-analyses have been conducted on selenium and the risk of different types of cancer. Overall, our combined risk estimates are consistent with their results and slight discrepancies in numbers are attributable to different inclusion criteria. However, some of the previous publications arrived at more favourable conclusions regarding a possible protective association of higher selenium exposure against cancer. Our meta-analyses of epidemiological studies suggested an inverse association between selenium exposure and risk of several cancers in men, which was reflected in a reduced overall cancer incidence and mortality. Associations with toenail selenium levels tended to be larger than with serum or plasma levels and in general no associations were seen with selenium intake. These findings were consistent with the secondary outcomes of the NPCT, which suggested a preventive efficacy of selenium supplements against several types of cancers in men, the strongest of which was prostate cancer. However, the large-scale SELECT trial failed to confirm any beneficial effects of supplemental selenium intake on prostate cancer risk. An earlier ecological analysis of a nationwide program to increase selenium intake with fortification in Finland also found no evidence of any protective effect against prostate cancer (Vinceti 2000).

Overall, there is little evidence for an association between selenium exposure and cancer risk in women and, if existent, it is likely to be small. Our meta-analyses do not support a protective association between higher selenium exposure and breast or colorectal cancer in women. These findings are consistent with the results of the NPCT trial, where all protective effects of selenium yeast supplementation were confined to men.

It has been argued that gender-related outcomes may reflect different exposure levels at baseline possibly related to gender-specific nutritional behaviour, which might be true for comparisons of distinct women-only and men-only cohorts (Michaud 2005). However, comparisons by gender within studies also pointed to a differential effect at similar exposure levels. We cannot rule out that sex or gender differences are observed by chance only, but laboratory and animal research have suggested sex differences in selenium metabolism and biology. Also sex-specific tumour biology and the predominance of specific cancer types may contribute to differential health outcomes in women and men. However, we cannot estimate the magnitude sex or gender differences possibly contribute to the observed differential health outcomes in men and women.

These considerations are of special interest as selenium supplements are aggressively marketed especially to women with regard to breast cancer prevention and treatment, which is not supported by data from observational or clinical investigations.

Heterogeneity between studies was not largely reduced by gender stratification in our meta-analyses. Furthermore, we expected that non-gender stratified data from observational studies would more or less reflect a combination of gender-stratified results for a specific tumour type, which was not always the case. In lung cancer meta-analysis, for example, the risk reduction by higher selenium levels seems to be larger in data for both genders combined than it was in data for women and men separately. This underlines the influence of other sources of heterogeneity on study outcomes. Reporting of gender-stratified results in mixed-gender cohort studies, which has become increasingly common over the years, might therefore reflect other factors related to study design, such as a better evaluation of possible confounders in more recently published studies. Socioeconomic position could be one such possible confounder, leading to an overestimation of a protective effect of selenium. Several studies have found selenium levels to be positively associated with adult socioeconomic position in both men and women (Gundacker 2006; Niskar 2003).

Doubts seem therefore justified that the observed associations point to a causal relationship between selenium biomarker levels and cancer risk.

RCTs and preventive efficacy

Non-melanoma skin cancer

The risk increase in non-melanoma skin cancer by selenium supplements in the NPCT raises concerns about the safety of selenium yeast supplementation in both men and women.

The overall lack of a protective effect of selenium yeast against non-melanoma skin cancer is consistent with the results of the French SU.VI.M.AX trial. However, an increased risk (non-statistically significant) of non-melanoma skin cancer was only seen in women in the SU.VI.M.AX trial, not in men. These discrepancies between the results of both trials might relate to differences in intervention and characteristics of the study populations. Increased risk of non-melanoma skin cancer could be more pronounced in or restricted to high-risk populations or observable only at certain selenium levels.

Liver and other gastrointestinal cancers

Bjelakovic 2008 conducted a systematic review of antioxidant supplements for the prevention of gastrointestinal (GIT) cancers. They meta-analysed RCT data for liver cancer prevention with selenium-containing supplements and reported a protective effect in both genders (RR 0.56 (95% CI (95% CI 0.42 to 0.76)). Three of the four trials in their meta-analysis were also included in this systematic review (Li 2000; Yu 1991; Yu 1997). The remaining RCT (Li 2004b) used a combination of selenium with allitridum, a synthetic garlic extract, in the intervention and therefore did not meet our inclusion criteria. Li 2004b found a preventive efficacy of high-dose allitridum/100 μg sodium selenite supplementation on total and gastric cancer incidence in men, but not in women. No effect on liver cancer was seen in either gender. Allitridum was considered the main intervention by Li and colleagues in their paper and the contribution of selenium to the overall effect remained unclear. The more recent RCT by Qu 2007 found no effect of 50 μg selenium yeast in combination with beta-carotene and alpha-tocopherol on liver cancer mortality.

We did not calculate a summary risk estimate for the included RCTs on liver cancer in this review. The minimum number of studies required for meta-analyses was set a priori to five in the protocol because we expected large heterogeneity between interventions and study populations and a high risk of bias in studies using selenium supplements. Considering the methodological constraints of the studies, the summary risk estimate of Bjelakovic 2008 may have overestimated the preventive efficacy of selenium against liver cancer.

We could not identify RCTs that investigated other GIT cancers as primary outcomes. The NPCT reported a (statistically non-significant) reduced risk of colorectal and oesophageal cancer as a secondary outcome in the selenium group. Other studies using multi-component selenium-containing supplements found divergent results, which also indicated potential sex or gender differences (Blot 1993; Hercberg 2004; see Background)

We consider that a replication of study results in adequately conducted randomised controlled trials is necessary before the preventive efficacy of selenium supplements against liver or other gastrointestinal cancers can be further evaluated or any recommendation made regarding supplements for GIT cancer prevention. However, the indication that nutritional supplements may prevent GIT cancers in borderline nutrient-deficient populations of developing countries should not be ignored in future research. Special consideration should be given to sex or gender-specific effects, selenium specification and possible interactions with other nutrients and the presence of risk factors for gastrointestinal cancers.

Prostate cancer

The SELECT trial failed to provide evidence for the preventive efficacy of oral L-selenomethionine and alpha-tocopherol either alone or in combination against prostate cancer.

The SELECT results contrasted with findings of the NPCT on prostate cancer. This might have occurred because of an overestimation of the real effect in the NPCT, where prostate cancer was not the primary outcome. It has also been argued that selenomethionine was the wrong supplement to replicate the NPCT results (Goossens 2009; El-Bayoumy 2009) and future trials should investigate selenium yeast as the active intervention.

SELECT participants had a higher selenium level at randomisation than men in the NPCT. While the mean plasma selenium concentration was 113 to 114 μg/l in the NPCT, median serum concentration was 135 to 138 μg/l in the different study arms in SELECT. Lower prostate cancer incidence in the NPCT trial was confined to men with baseline selenium levels in the lower two thirds (below 121 μg/l). Subgroup analyses of the SELECT trial are underway to investigate a possible modification by pre-intervention selenium levels.

The SU.VI.M.AX trial, which used a multivitamin and mineral supplement containing 100 μg selenised yeast, found a reduction in the rate of prostate cancers only in men with normal PSA levels at baseline (HR 0.52 (95% CI 0.29 to 0.92)), but an increased risk in men with elevated PSA (> 3 ng/ml) (HR 1.54 (95% CI 0.87 to 2.72) (Meyer 2005). There was no interaction with serum selenium levels at baseline in this study and authors hypothesised that their multi component supplement might be beneficial in healthy men, but might promote prostate cancer development in men at higher risk. However, an interaction with baseline PSA levels was not seen in the NPCT. In SELECT, only men with normal PSA levels (less than 4 ng/ml) were eligible for participation.

Other cancers and diseases

Data for a variety of other cancers were reported in the NPCT trial. Notably, the results for the primary outcome of the NPCT, i.e. the incidence of non-melanoma skin cancer, received less attention in the public debate than those for secondary outcomes, especially those in favour of selenium supplementation. As they were based on a post-hoc analysis, the question of confounding and bias arose. Also the role of chance was unclear because of the uncontrolled procedures for detection of secondary outcomes. Under-representation of women in the NPCT decreased the power to detect sex-/gender-specific effects (Duffield-Lillico 2002, in: NPCT 1996) and is a concern as the highest hazard ratio for a single cancer type in the selenium group was seen for breast cancer (HR 1.89 (95% CI 0.69 to 5.14), non-statistically significant). All possible beneficial effects on cancer incidence were confined to men in this study.

In the SU.VI.M.AX trial, the selenium yeast-containing supplement did not alter breast cancer risk in female participants (Hercberg 2004). Overall, the SU.VI.M.AX trial detected no effect on total cancer incidence by its multivitamin/nutrient supplement in both genders combined (RR 0.90 (95% CI 0.76 to 1.06). Gender-stratified analyses showed a protective efficacy in men (RR 0.60 (95% CI 0.53 to 0.91), but not in women (RR 1.04 (95% CI 0.85 to 1.29)), with a reduction of cases mainly seen in gastrointestinal and respiratory cancers in men. Women had the higher baseline levels of antioxidants and study authors hypothesised that differences in outcomes between men and women may be attributable to gender differences in nutritional behaviour and consequent antioxidant status.

Also the Linxian General Population Trial (Blot 1993) found no statistically significant protective effect of the selenium containing supplement on total cancer incidence in either gender(RR 0.93 (95% CI 0.83 to 1.03); gender stratified results were not reported). Cancer deaths were marginally significantly reduced (RR 0.87 (95% CI 0.75 to 1.00)) in participants receiving the selenium/beta-carotene/vitamin E supplement.

For lung cancer, the Linxian trial found no alteration in mortality by selenium-containing study supplements (RR 0.98 (95% CI 0.71 to 1.35); Kamangar 2006).

One study currently in progress investigates the efficacy of selenium for the recurrence of early stage non-small cell lung cancer after initial surgery (RCT ECOG 2002).

The SELECT trial reported a slightly elevated risk (statistically non-significant) for diabetes mellitus type II in the selenium group (RR 1.07 99% CI (95% CI 0.94 to 1.22)). Secondary analysis of the NPCT also indicated that long-term selenium supplementation may increase the risk for developing type II diabetes mellitus (Stranges 2007).

AUTHORS’ CONCLUSIONS

Implications for practice

For women, there is little evidence for lower or higher nutritional intake of selenium exhibiting a major impact on cancer risk. The only RCT results that have a low risk of bias support concerns of an increased risk of non-melanoma skin cancer by selenium yeast supplements in women who had already suffered from this disease.

For men, there is evidence for an inverse association between higher selenium biomarker levels and cancer risk. However, we cannot exclude that this effect may well be the result of other factors related to higher selenium biomarker levels than caused by selenium exposure itself. Results from two randomised controlled trials (NPCT and SELECT) have failed to provide evidence that non-melanoma skin cancer or prostate cancer can be prevented by selenium supplementation in men.

Additionally, concerns have been raised about possible toxicities from long-term intake of supplemental selenium.

Currently, regular intake of selenium supplements for cancer prevention cannot be recommended to either the selenium-replete or deficient populations.

Implications for research

Selenium may have different effects on specific types of cancer. The results from randomised controlled trials for the prevention of liver cancer need to be replicated in studies with a rigorous design.

Potential differential effects of sex or gender and the use of selenium supplements in populations with a high burden of specific types of cancer diseases and differing selenium exposure levels, e.g. known low nutritional selenium intake, require further examination.

Future prospective epidemiological studies as well as intervention trials should be adequately designed to detect sex or gender differences on specific types of cancer. Results of gender-stratified analyses should be reported even when statistically significant differences cannot be found.

Further research should aim to clarify why biomarkers of selenium exposure failed to reliably predict the results of RCTs with low risk of bias.

Acknowledgments

We thank Connie Hui and Mina Nishimori very much for the translation of the Chinese and Japanese papers.

We would like to thank Christine Fink and Birgit Kraus for their valuable help with data and literature management.

SOURCES OF SUPPORT

Internal sources

  • No sources of support supplied

External sources

  • Dr. Ernst und Anita Bauer Foundation, Germany.
  • This work was partially funded by the Dr. Ernst and Anita Bauer Foundation. The funding source had no role in designing, conducting or writing this systematic review. The contents of this systematic review are solely the responsibility of the authors and do not necessarily represent the official views of the Dr. Ernst and Anita Bauer Foundation.
  • EU (European Union) Project: Concerted action for complementary and alternative medicine in the cancer field (EU CAM-Cancer) (Contract no.: QLG4-CT-2002-00786), Not specified.
    This work was partially funded by the EU CAM-Cancer Project. The funding source had no role in designing, conducting or writing this systematic review. The contents of this systematic review are solely the responsibility of the authors and do not necessarily represent the official views of the EU CAM-Cancer Project.
  • Deutsche Krebshilfe (German Cancer Aid), Germany.
    This work was partially funded by the German Cancer Aid. The funding source had no role in designing, conducting or writing this systematic review. The contents of this systematic review are solely the responsibility of the authors and do not necessarily represent the official views of the German Cancer Aid.
  • NCCAM, USA.
    This work was partially funded by Grant Number R24 AT001293 from the National Center for Complementary and Alternative Medicine (NCCAM). The contents of this systematic review are solely the responsibility of the authors and do not necessarily represent the official views of the NCCAM or the National Institutes of Health.

APPENDICES

Appendix 1. Electronic search strategies

DatabaseDate of most recent literature searchSearch strategyComment
www.cancer.gov4 Feb 2011medication: selenium
indication: prevention
CancerlitOct 2004
  1. selen* OR organoselen* OR natriumselen*
  2. random* OR placebo* OR clinical trial* OR controlled trial* OR controlled clinical trial* OR double blind* OR single blind*
  3. epidemiologic stud* OR cohort OR case-control stud* OR nested case-control* OR case-control design* OR prospectiv*
  4. 2 OR 3
  5. 1 AND 4
now included in Medline database
Clinical Contents in Medicine (CCMed)4 Feb 2011selen* OR organoselen* OR natriumselen*
CENTRALIssue 1 2011selen*
Cochrane LibraryIssue 1 2011selen*
metaRegister of Controlled Trials (mRCT, www.controlled-trials.com)4 Feb 2011selen AND cancer
EMBASE2010 week 50
  1. selenium/or selen$.mp.
  2. exp Clinical Study/
  3. exp NEOPLASM/
  4. 1 and 2 and 3
  5. Selenium 75/
  6. 4 not 5
  7. limit 6 to human (707)
  8. exp Selenium Derivative/(765)
  9. methylseleninic acid/or methylselenium.mp.
  10. exp Organoselenium Derivative/
  11. 1 or 8 or 9 or 10
  12. 12 11 and 2 and 3
  13. 13 12 not 5
  14. 15 limit 13 to human
German Cancer Study Register: www.studien.de4 Feb 2011selen
Medline (via Pubmed)4 Feb 2011
  • #1
    Search selen* OR seleno* OR selenium[mesh] OR selenium compounds[mesh] OR organoselenium compounds[mesh]
  • #2
    Search randomized-controlled-trial[pt] Or controlled-clinical-trial[pt] OR clinical-trial[pt]
  • #3
    Search randomized-controlled-trials OR random-allocation OR double-blind-method OR single-blind-method OR placebos OR research-design OR follow-up-studies OR prospective-studies
  • #4
    Search epidemiologic study characteristics[mesh]
  • #5
    Search clinic*[tiab] NEAR trial*[tiab]
  • #6
    Search placebo*[tiab] OR random*[tiab]
  • #7
    Search clinical trial[tiab]
  • #8
    Search (singl*[tiab] OR doubl*[tiab] OR trebl*[tiab] OR tripl*[tiab]) NEAR (blind*[tiab] OR mask*[tiab])
  • #9
    Search control*[tiab] OR prospect*[tiab] OR volunteer*[tiab]
  • #10
    Search #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9
  • #11
    Search neoplasms[mesh]
  • #12
    Search cancer* OR cancers* OR cancero* OR carcino* OR carcinom* OR carcinog* OR malignan* OR neoplasm* OR tumor* OR tumori* Or tumors OR tumour*
  • #13
    Search melanoma* OR sarcoma* OR adenoma* OR adenosarcoma* OR adenocarcinoma* OR carcinosarcoma* OR chondrosarcoma* OR fibrosarcoma* OR dermatofibrosarcoma* OR neurofibrosarcoma* OR hemangiosarcoma* OR leiomyosarcoma* OR liposarcoma* OR myosarcoma* OR rhabdomyosarcoma* OR myxosarcoma* OR osteosarcoma* OR lymphoma*
  • #14
    Search #11 OR #12 OR # 13
  • #15
    Search animals[mh] NOT human[mh]
  • #16
    Search #1 AND #10 AND #14
  • #17
    Search #16 NOT #15
SIGLEOct 2004?selen?database discontinued in 2005

Appendix 2. Newcastle-Ottawa-Scale for Cohort Studies

((*) means that a ’star’ was assigned to the study for the corresponding item)

1) SELECTION

1.1)
representativeness of the exposed cohorttruly representative of the average………………(target population) in the community (*)somewhat representative of the average………………(target population) in the community (*)selected group of users, e.g. volunteers/nursesno description of the derivation of the cohort
1.2)
selection of the non-exposed cohortdrawn from the same community as the exposed cohort (*)drawn from a different sourceno description
1.3)
ascertainment of selenium exposuresecure record (biochemical records) (*)structured interview (*)written self report or medical record onlyno description
1.4)
demonstration that outcome of interest was not present at start of studyno history of disease or exclusion of cases that occurred in the first 12 months (*)not stated

2) COMPARABILITY

2.1)
comparability of cohorts on the basis of the design or analysisstudy controls for AGE (*)study controls for SMOKING (*)

3) OUTCOME

3.1)
assessment of outcomeindependent blind validation (> 1 person/record/time/process to extract information or reference to primary source such as X-rays/hospital records) (*)record linkage (e.g. ICD codes in databases) (*)self reportno description
3.2)
Was follow-up long enough for outcomes to occur?yes (> 3 years)no
3.3)
adequacy of follow up of cohortscomplete follow-up of all subjects (*)ORsubjects lost to follow-up unlikely to introduce bias (< 5% lost to follow-up or description provided of lost people) (*)follow-up-rate < 95% and no description of those lostno statement

Appendix 3. Additional Newcastle-Ottawa-Scale for Nested Case-Control Studies

((*) means that a ’star’ was assigned to the study for the corresponding item)

1) SELECTION

1.1)
case definitionindependent validation (> 1 person/record/time/process to extract information or reference to primary source such as X-rays/hospital records) (*)record linkage (e.g. ICD codes in databases) or self-report with no reference to primary recordno description
1.2)
representativeness of cases:all eligible cases with outcome of interest over a defined period, cases in a defined catchment area/hospital etc. or an appropriate/random sample of those cases (*)not satisfying requirements in part (a) or not stated
1.3)
selection of controls:community controls (same community and would be cases if had outcome) (*)hospital controls (within the same population e.g. city as cases)no description
1.4)
definition of controlscases had no history of outcome controls had no history of outcome OR case had new (not necessarily first) occurrence of outcome controls with previous occurrence of outcome should not be excluded (*)no mention of history of outcome

2) COMPARABILITY

(validated in cohort assessment in question 2 - number of stars was copied)

3) EXPOSURE

3.1)
ascertainment of selenium exposure:(validated in cohort assessment in question 1.3 - number of stars was copied)
3.2)
Same method of ascertainment for cases and controlsyes (*)no
3.3)
non-response ratesame rate for both groups (*)non-respondents describedrate different and no designation

DATA AND ANALYSES

Comparison 1. Highest versus lowest selenium exposure

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Breast cancer risk (women)7Odds Ratio (Random, 95% CI)1.00 [0.77, 1.29]
 1.1 Breast cancer (all)6Odds Ratio (Random, 95% CI)1.01 [0.74, 1.36]
 1.2 Breast cancer (premenopausal)1Odds Ratio (Random, 95% CI)1.10 [0.46, 2.65]
2 Bladder cancer risk5Odds Ratio (Random, 95% CI)0.67 [0.46, 0.97]
 2.1 all (male + female)2Odds Ratio (Random, 95% CI)0.65 [0.46, 0.92]
 2.2 male3Odds Ratio (Random, 95% CI)0.82 [0.41, 1.62]
 2.3 female1Odds Ratio (Random, 95% CI)0.36 [0.14, 0.92]
3 Lung cancer risk (gender-aggregated data)11Odds Ratio (Random, 95% CI)0.76 [0.57, 1.03]
 3.1 incidence10Odds Ratio (Random, 95% CI)0.75 [0.54, 1.03]
 3.2 mortality1Odds Ratio (Random, 95% CI)0.98 [0.41, 2.35]
4 Lung cancer risk (gender-disaggregated data)11Odds Ratio (Random, 95% CI)0.77 [0.60, 0.98]
 4.1 all (female + male)4Odds Ratio (Random, 95% CI)0.58 [0.39, 0.86]
 4.2 female4Odds Ratio (Random, 95% CI)0.83 [0.43, 1.61]
 4.3 male6Odds Ratio (Random, 95% CI)0.88 [0.61, 1.28]
5 Lung cancer risk (ascending order of selenium levels)71756Odds Ratio (Random, 95% CI)0.90 [0.69, 1.16]
6 Lung cancer risk11Odds Ratio (Random, 95% CI)0.76 [0.57, 1.03]
 6.1 intake1Odds Ratio (Random, 95% CI)0.98 [0.41, 2.35]
 6.2 serum or plasma8Odds Ratio (Random, 95% CI)0.84 [0.66, 1.06]
 6.3 toenail2Odds Ratio (Random, 95% CI)1.05 [0.11, 10.36]
7 Prostate cancer risk14Odds Ratio (Random, 95% CI)0.78 [0.66, 0.92]
8 Prostate cancer risk (by selenium measurement)14Odds Ratio (Random, 95% CI)0.78 [0.66, 0.92]
 8.1 biochemical selenium level12Odds Ratio (Random, 95% CI)0.74 [0.61, 0.88]
 8.2 estimated selenium intake2Odds Ratio (Random, 95% CI)1.00 [0.73, 1.36]
9 Prostate cancer risk (by exposure assessment)14Odds Ratio (Random, 95% CI)0.78 [0.66, 0.92]
 9.1 intake2Odds Ratio (Random, 95% CI)1.00 [0.73, 1.36]
 9.2 serum or plasma9Odds Ratio (Random, 95% CI)0.81 [0.68, 0.97]
 9.3 toenail3Odds Ratio (Random, 95% CI)0.53 [0.35, 0.81]
10 Prostate cancer risk (by continent)14Odds Ratio (Random, 95% CI)0.78 [0.66, 0.92]
 10.1 Europe4Odds Ratio (Random, 95% CI)0.91 [0.70, 1.17]
 10.2 North America10Odds Ratio (Random, 95% CI)0.71 [0.58, 0.88]
11 Prostate cancer risk (by country)14Odds Ratio (Random, 95% CI)0.78 [0.66, 0.92]
 11.1 Several European countries1Odds Ratio (Random, 95% CI)0.96 [0.70, 1.31]
 11.2 Finland2Odds Ratio (Random, 95% CI)1.24 [0.75, 2.05]
 11.3 The Netherlands1Odds Ratio (Random, 95% CI)0.69 [0.48, 0.99]
 11.4 U.S.A.10Odds Ratio (Random, 95% CI)0.71 [0.58, 0.88]
12 Prostate cancer risk (ascending order of selenium levels)92112Odds Ratio (Random, 95% CI)0.81 [0.68, 0.97]
13 Stomach cancer risk5Odds Ratio (Random, 95% CI)0.66 [0.43, 1.01]
 13.1 stomach4Odds Ratio (Random, 95% CI)0.65 [0.35, 1.19]
 13.2 stomach: cardia cancer1Odds Ratio (Random, 95% CI)0.47 [0.33, 0.66]
 13.3 stomach: non-cardia cancer1Odds Ratio (Random, 95% CI)1.07 [0.55, 2.08]
14 Stomach cancer risk (by gender)5Odds Ratio (Random, 95% CI)0.66 [0.42, 1.04]
 14.1 all (female + male)2Odds Ratio (Random, 95% CI)0.75 [0.41, 1.36]
 14.2 female2Odds Ratio (Random, 95% CI)0.73 [0.12, 4.35]
 14.3 male3Odds Ratio (Random, 95% CI)0.43 [0.14, 1.32]
15 Colorectal cancer risk5Odds Ratio (Random, 95% CI)0.89 [0.65, 1.23]
 15.1 colon and rectal cancer2Odds Ratio (Random, 95% CI)1.11 [0.50, 2.46]
 15.2 colon cancer3Odds Ratio (Random, 95% CI)0.80 [0.56, 1.15]
16 Colorectal cancer risk (by gender)5Odds Ratio (Random, 95% CI)0.89 [0.65, 1.23]
 16.1 all (female + male)1Odds Ratio (Random, 95% CI)1.22 [0.52, 2.86]
 16.2 female3Odds Ratio (Random, 95% CI)1.06 [0.57, 2.00]
 16.3 male3Odds Ratio (Random, 95% CI)0.69 [0.42, 1.12]
17 Total cancer incidence and mortality13Odds Ratio (Random, 95% CI)Subtotals only
 17.1 incidence8Odds Ratio (Random, 95% CI)0.69 [0.53, 0.91]
 17.2 mortality5Odds Ratio (Random, 95% CI)0.55 [0.36, 0.83]
18 Total cancer incidence and mortality (ascending order of selenium levels)11Odds Ratio (Random, 95% CI)Subtotals only
 18.1 incidence61297Odds Ratio (Random, 95% CI)0.69 [0.52, 0.91]
 18.2 mortality51032Odds Ratio (Random, 95% CI)0.55 [0.36, 0.83]
19 Total cancer incidence and mortality (women)5Odds Ratio (Random, 95% CI)Subtotals only
 19.1 incidence2Odds Ratio (Random, 95% CI)0.90 [0.45, 1.77]
 19.2 mortality3Odds Ratio (Random, 95% CI)0.92 [0.79, 1.07]
20 Total cancer incidence and mortality (men)8Odds Ratio (Random, 95% CI)Subtotals only
 20.1 incidence5Odds Ratio (Random, 95% CI)0.66 [0.42, 1.05]
 20.2 mortality3Odds Ratio (Random, 95% CI)0.56 [0.38, 0.81]

Analysis 1.1

An external file that holds a picture, illustration, etc.
Object name is nihms472378f6.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 1 Breast cancer risk (women).

Analysis 1.2

An external file that holds a picture, illustration, etc.
Object name is nihms472378f7.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 2 Bladder cancer risk.

Analysis 1.3

An external file that holds a picture, illustration, etc.
Object name is nihms472378f8.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 3 Lung cancer risk (gender-aggregated data).

Analysis 1.4

An external file that holds a picture, illustration, etc.
Object name is nihms472378f9.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 4 Lung cancer risk (gender-disaggregated data).

Analysis 1.5

An external file that holds a picture, illustration, etc.
Object name is nihms472378f10.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 5 Lung cancer risk (ascending order of selenium levels).

Analysis 1.6

An external file that holds a picture, illustration, etc.
Object name is nihms472378f11.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 6 Lung cancer risk.

Analysis 1.7

An external file that holds a picture, illustration, etc.
Object name is nihms472378f12.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 7 Prostate cancer risk.

Analysis 1.8

An external file that holds a picture, illustration, etc.
Object name is nihms472378f13.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 8 Prostate cancer risk (by selenium measurement).

Analysis 1.9

An external file that holds a picture, illustration, etc.
Object name is nihms472378f14.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 9 Prostate cancer risk (by exposure assessment).

Analysis 1.10

An external file that holds a picture, illustration, etc.
Object name is nihms472378f15.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 10 Prostate cancer risk (by continent).

Analysis 1.11

An external file that holds a picture, illustration, etc.
Object name is nihms472378f16a.jpg
An external file that holds a picture, illustration, etc.
Object name is nihms472378f16b.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 11 Prostate cancer risk (by country).

Analysis 1.12

An external file that holds a picture, illustration, etc.
Object name is nihms472378f17.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 12 Prostate cancer risk (ascending order of selenium levels).

Analysis 1.13

An external file that holds a picture, illustration, etc.
Object name is nihms472378f18.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 13 Stomach cancer risk.

Analysis 1.14

An external file that holds a picture, illustration, etc.
Object name is nihms472378f19.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 14 Stomach cancer risk (by gender).

Analysis 1.15

An external file that holds a picture, illustration, etc.
Object name is nihms472378f20.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 15 Colorectal cancer risk.

Analysis 1.16

An external file that holds a picture, illustration, etc.
Object name is nihms472378f21.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 16 Colorectal cancer risk (by gender).

Analysis 1.17

An external file that holds a picture, illustration, etc.
Object name is nihms472378f22.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 17 Total cancer incidence and mortality.

Analysis 1.18

An external file that holds a picture, illustration, etc.
Object name is nihms472378f23.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 18 Total cancer incidence and mortality (ascending order of selenium levels).

Analysis 1.19

An external file that holds a picture, illustration, etc.
Object name is nihms472378f24.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 19 Total cancer incidence and mortality (women).

Analysis 1.20

An external file that holds a picture, illustration, etc.
Object name is nihms472378f25.jpg

Comparison 1 Highest versus lowest selenium exposure, Outcome 20 Total cancer incidence and mortality (men).

Footnotes

DECLARATIONS OF INTEREST

GD: None known

MZw: None known

MB: None known

MV: None known

MZe: Maurice Zeegers is the first investigator of one included observational study and one ongoing randomised controlled trial. He is second author of another included observational study.

MH: None known

CONTRIBUTIONS OF AUTHORS

GD is the primary author and co-ordinator of the authors’ group and was involved in all steps of realising the protocol and the review.

MZw commented on the protocol, extracted data from papers, conducted the data analyses in STATA and commented on the review and provided a methodological perspective.

MB commented on the protocol, assisted by checking the original literature search and inclusion criteria, providing a brief and early background on urological cancer and provided feedback at various stages of the review.

MV commented on the protocol, screened search results, extracted data from papers, provided an early version of the background and feedback on the review text at various stages of the review.

MZe commented on the protocol, screened search results, extracted data from papers and provided feedback on the review text

MH commented on the protocol, screened search results, extracted data from papers, designed the Access database for data management, provided support for securing funding for the review, supported data management and commented on the review text at various stages of the review.

References

* Indicates the major publication for the study

References to studies included in this review

Akbaraly 2005 {published data only} Akbaraly NT, Arnaud J, Hininger-Favier I, Gourlet V, Roussel AM, Berr C. Selenium and mortality in the elderly: results from the EVA study. Clinical Chemistry. 2005;51(11):2117–23. [PubMed]
Allen 2008 {published data only} Allen NE. Reply to B bekaert and MP rayman. American Journal of Clinical Nutrition. 2009;89(4):1277. [PubMed]Allen NE, Appleby PN, Roddam AW, Tjonneland A, Johnsen NF, Overvad K, et al. Plasma selenium concentration and prostate cancer risk: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) American Journal of Clinical Nutrition. 2008;88(6):1567–75. [PubMed]
Bleys 2008 {published data only} Bleys J, Navas-Acien A, Guallar E. Serum selenium levels and all-cause, cancer, and cardiovascular mortality among US adults. Archive of Internal Medicine. 2008;168(4):404–10. [PubMed]
Brooks 2001 {published data only} Brooks JD, Metter EJ, Chan DW, Sokoll LJ, Landis P, Nelson WG, et al. Plasma selenium level before diagnosis and the risk of prostate cancer development. The Journal of Urology. 2001;166(6):2034–8. [PubMed]
Clark 1985 {published data only} Clark L, Graham G, Bray J. Nonmelanoma skin cancer and plasma selenium: a prospective cohort study. American Journal of Epidemiology [Abstracts of papers presented at the eighteenth annual meeting of the Society For Epidemiologic Research; Chapel Hill, North Carolina. June 19–21, 1985; 1985. p. 528.
Coates 1988 {published data only} Coates RJ. Cancer risk in relation to serum levels of selenium, retinol, and copper. Dissertation Abstract International (Sci) 1987;47(12):4836.*. Coates RJ, Weiss NS, Daling JR, Morris JS, Labbe RF. Serum levels of selenium and retinol and the subsequent risk of cancer. American Journal of Epidemiology. 1988;128(3):515–23. [PubMed]
Combs 1993 {published data only} Combs GF, Jr, Clark LC, Turnbull BW, Graham GF, Smith CL, Sanders B, Jr, et al. Low plasma selenium (Se) predicts the 24 month incidence of squamous cell carcinoma of the skin in a cancer prevention trial. FASEB J. 1993;7(3):A 278.
Comstock 1997 {published data only} Comstock GW, Alberg AJ, Huang HY, Wu K, Burke AE, Hoffman SC, et al. The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acid, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity. Cancer Epidemiology, Biomarkers & Prevention. 1997;6(11):907–16. [PubMed]
Dong 2008 {published data only} Dong LM, Kristal AR, Peters U, Schenk JM, Sanchez CA, Rabinovitch PS, et al. Dietary supplement use and risk of neoplastic progression in esophageal adenocarcinoma: a prospective study. Nutrition and Cancer. 2008;60(1):39–48. [PMC free article] [PubMed]
Dorgan 1998 {published data only} Dorgan JF, Sowell A, Swanson CA, Potischman N, Miller R, Schussler N, et al. Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States) Cancer Causes and Control. 1998;9(1):89–97. [PubMed]
Epplein 2009 {published data only} *. Epplein M, Franke AA, Cooney RV, Morris JS, Wilkens LR, Goodman MT, et al. Association of plasma micronutrient levels and urinary isoprostane with risk of lung cancer: the multiethnic cohort study. Cancer Epidemiology, Biomarkers & Prevention. 2009;18(7):1962–70. [PMC free article] [PubMed]Gill JK, Franke AA, Steven MJ, Cooney RV, Wilkens LR, Le ML, et al. Association of selenium, tocopherols, carotenoids, retinol, and 15-isoprostane F(2t) in serum or urine with prostate cancer risk: the multiethnic cohort. Cancer Causes Control. 2009;20(7):1161–71. [PubMed]Kolonel LN. [accessed 6 April 2011];5P01CA033619-20. Epidemiologic studies of diet and cancer in Hawaii. http://cancercontrol.cancer.gov/grants/abstract.asp?ApplID=6805844.
Fex 1987 {published data only} Fex G, Pettersson B, Akesson B. Low plasma selenium as a risk factor for cancer death in middle-aged men. Nutrition and Cancer. 1987;10(4):221–9. [PubMed]
Garland 1995 {published data only} *. Garland M, Morris JS, Stampfer MJ, Colditz GA, Spate VL, Baskett CK, et al. Prospective study of toenail selenium levels and cancer among women. Journal of the National Cancer Institute. 1995;87(7):497–505. [PubMed]Hunter DJ, Morris JS, Stampfer MJ, Colditz GA, Speizer FE, Willett WC. A prospective study of selenium status and breast cancer risk. JAMA. 1990;264(9):1128–31. [PubMed]
Glattre 1989 {published data only} Glattre E, Thomassen Y, Thoresen SO, Haldorsen T, Lund-Larsen PG, Theodorsen L, et al. Prediagnostic serum selenium in a case-control study of thyroid cancer. International Journal of Epidemiology. 1989;18(1):45–9. [PubMed]
Goodman 2001 {published data only} Goodman GE, Schaffer S, Bankson DD, Hughes MP, Omenn GS. The CaroteneRetinol Efficacy Trial (CARET) Co-Investigators. Predictors of serum selenium in cigarette smokers and the lack of association with lung and prostate cancer risk. Cancer Epidemiology, Biomarkers & Prevention. 2001;10(10):1069–76. [PubMed]
Hartman 1998 {published data only} Hartman TJ, Albanes D, Pietinen P, Hartman AM, Rautalahti M, Tangrea JA, et al. The association between baseline vitamin E, selenium, and prostate cancer in the alpha-tocopherol, beta-carotene cancer prevention study. Cancer Epidemiology, Biomarkers & Prevention. 1998;7(4):335–40. [PubMed]
Helzlsouer 2000 {published data only} Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. Journal of the National Cancer Institute. 2000;92(24):2018–23. [PubMed]
Kabuto 1994 {published data only} Kabuto M, Imai H, Yonezawa C, Neriishi K, Akiba S, Kato H, et al. Prediagnostic serum selenium and zinc levels and subsequent risk of lung and stomach cancer in Japan. Cancer Epidemiology, Biomarkers & Prevention. 1994;3(6):465–9. [PubMed]
Karagas 1997 {published data only} Karagas MR, Greenberg ER, Nierenberg D, Stukel TA, Morris JS, Stevens MM, et al. Risk of squamous cell carcinoma of the skin in relation to plasma selenium, alpha-tocopherol, beta-carotene, and retinol: a nested case-control study. Cancer Epidemiology, Biomarkers & Prevention. 1997;6(1):25–9. [PubMed]
Knekt 1990 {published data only} Hakama M, Aaran RK, Alfthan G, Aromaa A, Hakulinen T, Knekt P, et al. New York: Wiley-Liss; 1990. Linkage of serum sample bank and cancer registry in epidemiological studies. Progress in clinical and biological research, v. 346; pp. 169–78. [PubMed]Knekt P, Aromaa A, Alfthan G, Maatela J, Hakama M, Hakulinen T, et al. Re: Prospective study of serum micronutrients and ovarian cancer. Journal of the National Cancer Institute. 1996;88(19):1408. [PubMed]*. Knekt P, Aromaa A, Maatela J, Alfthan G, Aaran RK, Hakama M, et al. Serum selenium and subsequent risk of cancer among Finnish men and women. Journal of the National Cancer Institute. 1990;82(10):864–8. [PubMed]Knekt P, Aromaa A, Maatela J, Alfthan G, Aaran RK, Teppo L, et al. Serum vitamin E, serum selenium and the risk of gastrointestinal cancer. International Journal of Cancer. 1988;42(6):846–50. [PubMed]Knekt P, Jarvinen R, Seppanen R, Rissanen A, Aromaa A, Heinonen OP, et al. Dietary antioxidants and the risk of lung cancer. American Journal of Epidemiology. 1991;134(5):471–9. [PubMed]
Knekt 1998 {published data only} Knekt P, Marniemi J, Teppo L, Heliovaara M, Aromaa A. Is low selenium status a risk factor for lung cancer? American Journal of Epidemiology. 1998;148(10):975–82. [PubMed]
Kok 1987 {published data only} Kok FJ, De Bruijn AM, Hofman A, Valkenburg HA. Selenium status and chronic disease mortality: Dutch epidemiological findings. International Journal of Epidemiology. 1987a;16(2):329–32. [PubMed]*. Kok FJ, De Bruijn AM, Hofman A, Vermeeren R, Valkenburg HA. Is serum selenium a risk factor for cancer in men only? American Journal of Epidemiology. 1987b;125(1):12–6. [PubMed]
Kornitzer 2004 {published data only} Kornitzer M, Valente F, De Bacquer D, Neve J, De Backer G. Serum selenium and cancer mortality: A nested case-control study within an age- and sex-stratified sample of the Belgian adult population. European Journal of Clinical Nutrition. 2004;58(1):98–104. [PubMed]
Kromhout 1987 {published data only} Kromhout D. Essential micronutrients in relation to carcinogenesis. American Journal of Clinical Nutrition. 1987;45(5 Suppl):1361–7. [PubMed]
Li 2000 {published data only} Li W, Zhu Y, Yan X, Zhang Q, Li X, Ni Z, et al. [The prevention of primary liver cancer by selenium in high risk populations]. Zhonghua Yu Fang Yi Xue.Za Zhi [Chinese Journal of Preventive Medicine] 2000;34(6):336–8. [PubMed]
Li 2004a {published data only} Li H, Kantoff PW, Giovannucci E, Leitzmann MF, Gaziano JM, Stampfer MJ, et al. Manganese superoxide dismutase polymorphism, prediagnostic antioxidant status, and risk of clinical significant prostate cancer. Cancer Research. 2005a;65(6):2498–504. [PubMed]*. Li H, Stampfer MJ, Giovannucci EL, Morris JS, Willett WC, Gaziano JM, et al. A prospective study of plasma selenium levels and prostate cancer risk. Journal of the National Cancer Institute. 2004;96(9):696–703. [PubMed]Li H, Stampfer MJ, Giovannucci EL, Morris JS, Willett WC, Gaziano MJ, et al. Plasma selenium levels associated with subsequent risk of prostate cancer. American Journal of Urology Review. 2005b;3(1):28–34.
McNaughton 2005 {published data only} Heinen MM, Hughes MC, Ibiebele TI, Marks GC, Green AC, van der Pols JC. Intake of antioxidant nutrients and the risk of skin cancer. European Journal of Cancer. 2007;43(18):2707–16. [PubMed]*. McNaughton SA, Marks GC, Gaffney P, Williams G, Green AC. Antioxidants and basal cell carcinoma of the skin: a nested case-control study. Cancer Causes and Control. 2005;16(5):609–18. [PubMed]van der Pols JC, Heinen MM, Hughes MC, Ibiebele TI, Marks GC, Green AC. Serum antioxidants and skin cancer risk: an 8-year community-based follow-up study. Cancer Epidemiol Biomarkers Prev. 2009;18(4):1167–73. [PubMed]
Menkes 1986 {published data only} Batieha AM, Armenian HK, Norkus EP, Morris JS, Spate VE, Comstock GW. Serum micronutrients and the subsequent risk of cervical cancer in a population-based nested case-control study. Cancer Epidemiology, Biomarkers & Prevention. 1993;2(4):335–9. [PubMed]Breslow RA, Alberg AJ, Helzlsouer KJ, Bush TL, Norkus EP, Morris JS, et al. Serological precursors of cancer: malignant melanoma, basal and squamous cell skin cancer, and prediagnostic levels of retinol, beta-carotene, lycopene, alpha-tocopherol, and selenium. Cancer Epidemiology, Biomarkers & Prevention. 1995;4(8):837–42. [PubMed]Burney PG, Comstock GW, Morris JS. Serologic precursors of cancer: Serum micronutrients and the subsequent risk of pancreatic cancer. American Journal of Clinical Nutrition. 1989;49(5):895–900. [PubMed]Helzlsouer KJ, Alberg AJ, Norkus EP, Morris JS, Hoffman SC, Comstock GW. Prospective study of serum micronutrients and ovarian cancer. Journal of the National Cancer Institute. 1996;88(1):32–7. [PubMed]Helzlsouer KJ, Comstock GW, Morris JS. Selenium, lycopene, alpha-tocopherol, beta-carotene, retinol, and subsequent bladder cancer. Cancer Research. 1989;49(21):6144–8. [PubMed]Ko W. The associations of serologic precursors and the anatomicsite specific incidence of colon cancer. Baltimore, MD: John Hopkins University; 1994. Menkes MJ. Vitamins A, E, selenium and risk of lung cancer. Dissertation Abstract International (Sci) 1986a;46(11):3807.*. Menkes MS, Comstock GW, Vuilleumier JP, Helsing KJ, Rider AA, Brookmeyer R. Serum beta-carotene, vitamins A and E, selenium, and the risk of lung cancer. New England Journal of Medicine. 1986b;315(20):1250–14. [PubMed]Schober SE. Vitamin A, vitamin E, selenium, and colon cancer risk. Dissertation Abstract International (Sci) 1986;46(11):3808.Schober SE, Comstock GW, Helsing KJ, Salkeld RM, Morris JS, Rider AA, et al. Serologic precursors of cancer. I. Prediagnostic serum nutrients and colon cancer risk. American Journal of Epidemiology. 1987;126(6):1033–41. [PubMed]Zheng W, Blot WJ, Diamond EL, Norkus EP, Spate V, Morris JS, et al. Serum micronutrients and the subsequent risk of oral and pharyngeal cancer. Cancer Research. 1993;53(4):795–8. [PubMed]
Michaud 2002 {published data only} Michaud DS, Hartman TJ, Taylor PR, Pietinen P, Alfthan G, Virtamo J, et al. No association between toenail selenium levels and bladder cancer risk. Cancer Epidemiology, Biomarkers & Prevention. 2002;11(11):1505–6. [PubMed]
Michaud 2005 {published data only} Michaud DS, De Vivo I, Morris JS, Giovannucci E. Toenail selenium concentrations and bladder cancer risk in women and men. British Journal of Cancer. 2005;93(7):804–6. [PMC free article] [PubMed]
Nomura 1987 {published data only} Nomura A, Heilbrun LK, Morris JS, Stemmermann GN. Serum selenium and the risk of cancer, by specific sites: case-control analysis of prospective data. Journal of the National Cancer Institute. 1987;79(1):103–8. [PubMed]
Nomura 2000 {published data only} Nomura AMY, Lee J, Stemmermann GN, Combs GF., Jr Serum selenium and subsequent risk of prostate cancer. Cancer Epidemiology, Biomarkers & Prevention. 2000;9(9):883–7. [PubMed]
NPCT 1996 {published data only} Clark L, Krongrad A, Dalkin B, Witherington R, Herlong H, Carpenter D. Decreased incidence of prostate cancer with selenium supplementation: 1983–96 results of a double-blind cancer prevention trial. European Journal of Cancer Prevention. 1997;6(issue 5):497–8.*. Clark LC, Combs GF, Turnbull BW, Slate EH, Chalker DK, Chow J, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. JAMA. 1996;276(24):1957–63. [PubMed]Clark LC, Combs GF, Jr, Turnbull BW, Slate EH, Chalker DK, Chow J. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: A randomized clinical trial. JAMA. 1996;276:1957–63. [PubMed]Clark LC, Dalkin B, Krongrad A, Combs GF, Turnbull BW, Slate EH, et al. Decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial. British Journal of Urology. 1998;81(5):730–4. [PubMed]Clark LC. UARIZ-CA49764 NCI-P89-0003. Double-blind, randomized trial of selenium-enriched brewer’s yeast vs brewer’s yeast placebo for the prevention of skin cancer in patients with a history of squamous or basal cell skin cancer (Summary Last Modified 05/91) National Cancer Institute; [accessed 1 March 2004]. http://www.cancer.gov.Combs GF, Clark LC, Turnbull BW. Reduction of cancer mortality and incidence by selenium supplementation. Medizinische Klinik. 1997;92(Suppl 3):42–5. [PubMed]Combs GF, Jr, Clark LC, Turnbull BW. Reduction of cancer risk with an oral supplement of selenium. Biomedical and Environmental Sciences. 1997;10(2–3):227–34. [PubMed]Duffield-Lillico AJ, Dalkin BL, Reid ME, Turnbull BW, Slate EH, Jacobs ET, et al. Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial. BJU International. 2003b;91(7):608–12. [PubMed]Duffield-Lillico AJ, Reid ME, Turnbull BW, Combs GF, Jr, Slate EH, Fischbach LA, et al. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Cancer Epidemiology, Biomarkers & Prevention. 2002;11(7):630–9. [PubMed]Duffield-Lillico AJ, Slate EH, Reid ME, Turnbull BW, Wilkins PA, Combs GF, Jr, et al. Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial. Journal of the National Cancer Institute Cancer Spectrum. 2003a;95(19):1477–81. [PubMed]Marshall JR. [accessed 1 March 2004];5R01CA049764-15. Nutritional Prevention of Cancer. http://crisp.cit.nih.gov.Reid ME, Duffield-Lillico AJ, Garland L, Turnbull BW, Clark LC, Marshall JR. Selenium supplementation and lung cancer incidence: An update of the Nutritional Prevention of Cancer Trial. Cancer Epidemiology, Biomarkers & Prevention. 2002;11(11):1285–91. [PubMed]Reid ME, Duffield-Lillico AJ, Slate E, Natarajan N, Turnbull B, Jacobs E, et al. The nutritional prevention of cancer: 400 mcg per day selenium treatment. Nutrition and Cancer. 2008;60(2):155–63. [PubMed]Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M, Combs GF, et al. Effects of Long-Term Selenium Supplementation on the Incidence of Type 2 Diabetes: A Randomized Trial. Annals of Internal Medicine. 2007;147:217–23. [PubMed]
Overvad 1991 {published data only} Overvad K, Wang DY, Olsen J, Allen DS, Thorling EB, Bulbrook RD, et al. Selenium in human mammary carcinogenesis: a case-cohort study. European Journal of Cancer. 1991;27(7):900–2. [PubMed]
Peleg 1985 {published data only} Peleg I, Morris S, Hames CG. Is serum selenium a risk factor for cancer? Medical Oncology and Tumor Pharmacotherapy. 1985;2(3):157–63. [PubMed]
Persson 2000 {published data only} Persson-Moschos ME, Stavenow L, Akesson B, Lindgarde F. Selenoprotein P in plasma in relation to cancer morbidity in middle-aged Swedish men. Nutrition and Cancer. 2000;36(1):19–26. [PubMed]
Peters 2007 {published data only} Peters U, Foster CB, Chatterjee N, Schatzkin A, Reding D, Andriole GL, et al. Serum selenium and risk of prostate cancer - a nested case-control study. American Journal of Clinical Nutrition. 2007;85(1):209–17. [PMC free article] [PubMed]
Peters 2008 {published data only} Asgari MM, Maruti SS, Kushi LH, White E. Antioxidant supplementation and risk of incident melanomas: results of a large prospective cohort study. Archives of Dermatology. 2009;145(8):879–82. [PubMed]Peters U, Littman AJ, Kristal AR, Patterson RE, Potter JD, White E. Vitamin E and selenium supplementation and risk of prostate cancer in the Vitamins and lifestyle (VITAL) study cohort. Cancer Causes Control. 2008;19(1):75–87. [PubMed]
Ratnasinghe 2000 {published data only} Ratnasinghe D, Tangrea JA, Forman MR, Hartman T, Gunter EW, Qiao YL, et al. Serum tocopherols, selenium and lung cancer risk among tin miners in China. Cancer Causes and Control. 2000;11(2):129–35. [PubMed]
Reid 2008 {published data only} Reid ME, Duffield-Lillico AJ, Slate E, Natarajan N, Turnbull B, Jacobs E, et al. The nutritional prevention of cancer: 400 mcg per day selenium treatment. Nutrition and Cancer. 2008;60(2):155–63. [PubMed]
Ringstad 1988 {published data only} Ringstad J, Jacobsen BK, Tretli S, Thomassen Y. Serum selenium concentration associated with risk of cancer. Journal of Clinical Pathology. 1988;41(4):454–7. [PMC free article] [PubMed]
Sakoda 2005 {published data only} Sakoda LC, Graubard BI, Evans AA, London WT, Lin WY, Shen FM, et al. Toenail selenium and risk of hepatocellular carcinoma mortality in Haimen City, China. International Journal of Cancer. 2005;115(4):618–24. [PubMed]
Salonen 1984 {published data only} Salonen JT, Alfthan G, Huttunen JK, Puska P. Association between serum selenium and the risk of cancer. American Journal of Epidemiology. 1984;120(3):342–9. [PubMed]
Salonen 1985 {published data only} Salonen JT, Salonen R, Lappetelainen R, Maenpaa PH, Alfthan G, Puska P. Risk of cancer in relation to serum concentrations of selenium and vitamins A and E: matched case-control analysis of prospective data. British Medical Journal (Clinical Research Edition) 1985;290(6466):417–20. [PMC free article] [PubMed]
SELECT 2009 {published data only} Cook ED. Selenium and Vitamin E Cancer Prevention Trial - this one’s for us. Journal of the National Medical Association. 2002;94(9):856–8. [PubMed]Cook ED, Moody-Thomas S, Anderson KB, Campbell R, Hamilton SJ, Harrington JM, et al. Minority recruitment to the Selenium and Vitamin E Cancer Prevention Trial (SELECT) Clinical Trials. 2005;2(5):436–42. [PubMed]DeFrancesco L. Prostate cancer prevention trial launched. Nature Medicine. 2001;7(10):1076. [PubMed]Dunn BK, Ryan A, Ford LG. Selenium and Vitamin E Cancer Prevention Trial: a nutrient approach to prostate cancer prevention. Recent Results in Cancer Research. 2009;181:183–93. [PubMed]FDA. Largest-ever prostate cancer prevention trial. FDA Consumer. 2001;35(5):8. [PubMed]Ford LG, Minasian LM, McCaskill-Stevens W, Pisano ED, Sullivan D, Smith RA. Prevention and early detection clinical trials: opportunities for primary care providers and their patients. CA: A cancer journal for clinicians. 2003;53(2):82–101. [PubMed]Hoque A, Albanes D, Lippman SM, Spitz MR, Taylor PR, Klein EA, et al. Molecular epidemiologic studies within the Selenium and Vitamin E Cancer Prevention Trial (SELECT) Cancer Causes and Control. 2001;12(7):627–33. [PubMed]Kardinal C, Brooks J. Ochsner Cancer Institute studies vitamin E and selenium as prostate cancer prevention agents. Ochsner Journal. 2003;5(2):51. [PMC free article] [PubMed]Klein E, Atkins MB, Walther P, Klotz L. [accessed 12 January 2004];SWOG-S000. Phase III randomized study of selenium and vitamin E for the prevention of prostate cancer (SELECT trial) http://clinicaltrials.gov/Klein EA. Clinical models for testing chemopreventative agents in prostate cancer and overview of SELECT: the Selenium and vitamin E cancer prevention trial. Recent Results in Cancer Research. 2003;163:212–25. [PubMed]Klein EA. Selenium and vitamin E cancer prevention trial. Annals of the New York Academy of Sciences. 2004;1031:234–41. [PubMed]Klein EA, Lippman SM, Thompson IM, Goodman PJ, Albanes D, Taylor PR, et al. The selenium and vitamin E cancer prevention trial. World Journal of Urology. 2003;21(1):21–7. [PubMed]Klein EA, Thompson IM, Lippman SM, Goodman PJ, Albanes D, Taylor PR, et al. SELECT: the next prostate cancer prevention trial. Selenium and vitamin E cancer prevention trial. Journal of Urology. 2001;166(4):1311–5. [PubMed]Klein EA, Thompson IM, Lippman SM, Goodman PJ, Albanes D, Taylor PR, et al. SELECT: the selenium and vitamin E cancer prevention trial. Urologic Oncology. 2003;21(1):59–65. [PubMed]Klein EA, Thompson IM, Lippman SM, Goodman PJ, Albanes D, Taylor PR, et al. SELECT: the Selenium and Vitamin E Cancer Prevention Trial: rationale and design. Prostate Cancer and Prostatic Diseases. 2000;3(3):145–51. [PubMed]Lippman SM, Goodman PJ, Klein EA, Parnes HL, Thompson IM, Jr, Kristal AR, et al. Designing the Selenium and Vitamin E Cancer Prevention Trial (SELECT) Journal of the National Cancer Institute. 2005;97(2):94–102. [PubMed]*. Lippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT) JAMA. 2009;301(1):39–51. [PubMed]Miller M. Enrollment begins for largest-ever prostate cancer prevention trial. Journal of the National Cancer Institute. 2001;93(15):1132. [PubMed]Pak RW, Lanteri VJ, Scheuch JR, Sawczuk IS. Review of vitamin E and selenium in the prevention of prostate cancer: implications of the selenium and vitamin E chemoprevention trial. Integrative Cancer Therapies. 2002;1(4):338–44. [PubMed]South West Oncology Group. [accessed 16 April 2004];Selenium and Vitamin E Cancer Prevention Trial (SELECT) http://www.controlled-trials.com/mrct/trial/SELENIUM/1059/42795.html.South West Oncology Group. Selenium and vitamin E in preventing prostate cancer. Southwest Oncology Group; [accessed 16 April 2004]. http://www.controlled-trials.com/mrct/trial/SELENIUM/1059/32859.html.Tangen CM, Goodman PJ, Crowley JJ, Thompson IM. Statistical design issues and other practical considerations for conducting phase III prostate cancer prevention trials. Journal of Urology. 2004;171(2 Pt 2):S64–7. [PubMed]Tom J. SELECT (opportunity for prostate cancer prevention) Hawaii Medical Journal. 2002;61(6):126–9. [PubMed]
Thomson 2008 {published data only} Thomson CA, Neuhouser ML, Shikany JM, Caan BJ, Monk BJ, Mossavar-Rahmani Y, et al. The role of antioxidants and vitamin A in ovarian cancer: results from the Women’s Health Initiative. Nutrition and Cancer. 2008;60(6):710–9. [PubMed]
van Noord 1987 {published data only} van Noord PAH, Collette HJA, Maas MJ, de Waard F. Selenium levels in nails of premenopausal breast cancer patients assessed prediagnostically in a cohort-nested case-referent study among women screened in the DOM project. International Journal of Epidemiology. 1987;16(2):318–22. [PubMed]
vd Brandt 1993 {published data only} van den Brandt PA, Goldbohm RA, van’t Veer P, Bode P, Dorant E, Hermus RJJ, et al. A prospective cohort study on selenium status and the risk of lung cancer. Cancer Research. 1993a;53(20):4860–5. [PubMed]*. van den Brandt PA, Goldbohm RA, van’t Veer P, Bode P, Dorant E, Hermus RJJ, et al. A prospective cohort study on toenail selenium levels and risk of gastrointestinal cancer. Journal of the National Cancer Institute. 1993b;85(3):224–9. [PubMed]van den Brandt PA, Goldbohm RA, van’t Veer P, Bode P, Dorant E, Hermus RJJ, et al. Toenail selenium levels and the risk of breast cancer. American Journal of Epidemiology. 1994;140(1):20–6. [PubMed]van den Brandt PA, Zeegers MPA, Bode P, Goldbohm RA. Toenail selenium levels and the subsequent risk of prostate cancer: A prospective cohort study. Cancer Epidemiology, Biomarkers & Prevention. 2003;12(9):866–71. [PubMed]Zeegers MPA, Goldbohm RA, Bode P, van den Brandt PA. Prediagnostic toenail selenium and risk of bladder cancer. Cancer Epidemiology, Biomarkers & Prevention. 2002;11(11):1292–7. [PubMed]
Virtamo 1987 {published data only} Virtamo J, Valkeila E, Alfthan G, Punsar S, Huttunen JK, Karvonen MJ. Serum selenium and risk of cancer. A prospective follow-up of nine years. Cancer. 1987;60(2):145–8. [PubMed]
Wei 2004 {published data only} Mark SD, Qiao YL, Dawsey SM, Wu YP, Katki H, Gunter EW, et al. Prospective study of serum selenium levels and incident esophageal and gastric cancers. Journal of the National Cancer Institute. 2000;92(21):1753–63. [PubMed]*. Wei WQ, Abnet CC, Qiao YL, Dawsey SM, Dong ZW, Sun XD, et al. Prospective study of serum selenium concentrations and esophageal and gastric cardia cancer, heart disease, stroke, and total death. American Journal of Clinical Nutrition. 2004;79(1):80–5. [PubMed]
Willett 1983 {published data only} Willett WC, Polk BF, Morris JS, Stampfer MJ, Pressel S, Rosner B, et al. Prediagnostic serum selenium and risk of cancer. Lancet. 1983;2(8342):130–4. [PubMed]
Yoshizawa 1998 {published data only} Yoshizawa K, Willett WC, Morris SJ, Stampfer MJ, Spiegelman D, Rimm EB, et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. Journal of the National Cancer Institute. 1998;90(16):1219–24. [PubMed]
Yu 1991 {published data only} Li WG. [Preliminary observations on effect of selenium yeast on high risk populations with primary liver cancer]. Zhonghua Yu Fang Yi Xue.Za Zhi [Chinese Journal of Preventive Medicine] 1992;26(5):268–71. [PubMed]Yu S, Li W, Zhu Y. Chemoprevention of Liver Cancer. CCPC-93: Second International Cancer Chemo Prevention Conference; April 28–30, 1993; Berlin. 1993. (Meeting Abstract)*. Yu SY, Zhu YJ, Li WG, Huang QS, Huang CZ, Zhang QN, et al. A preliminary report on the intervention trials of primary liver cancer in high-risk populations with nutritional supplementation of selenium in China. Biological Trace Element Research. 1991;29(3):289–94. [PubMed]
Yu 1997 {published data only} Li WG. [Preliminary observations on effect of selenium yeast on high risk populations with primary liver cancer]. Zhonghua Yu Fang Yi Xue.Za Zhi [Chinese Journal of Preventive Medicine] 1992;26(5):268–71. [PubMed]*. Yu SY, Zhu YJ, Li WG. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biological Trace Element Research. 1997;56(1):117–24. [MEDLINE: 15873] [PubMed]Yu SY, Zhu YJ, Li WG, Huang QS, Huang CZ, Zhang QN, et al. A preliminary report on the intervention trials of primary liver cancer in high-risk populations with nutritional supplementation of selenium in China. Biological Trace Element Research. 1991;29(3):289–94. [PubMed]
Yu 1999 {published data only} Yu MW, Horng IS, Hsu KH, Chiang YC, Liaw YF, Chen CJ. Plasma selenium levels and risk of hepatocellular carcinoma among men with chronic hepatitis virus infection. American Journal of Epidemiology. 1999;150(4):367–74. [PubMed]

References to studies excluded from this review

Bostick 1993 {published data only} Bostick RM, Potter JD, McKenzie DR, Sellers TA, Kushi LH, Steinmetz KA, et al. Reduced risk of colon cancer with high intake of vitamin E: the Iowa Women’s Health Study. Cancer Research. 1993;53(18):4230–7. [PubMed]
Brock 1991 {published data only} Brock KE, Gridley G, Morris JS, Willett WC. Serum selenium level in relation to in situ cervical cancer in Australia. Journal of the National Cancer Institute. 1991;83(4):292–3. [PubMed]
Chen 1988 {published data only} Chen Q. [Protective effects of selenium, zinc and copper on lung cancer]. Zhonghua Yu Fang Yi Xue Za Zhi [Chinese Journal of Preventive Medicine] 1988;22(4):221–4. [PubMed]
Chen 2003 {published data only} Chen K, Qiu JL, Sui LM, Yu WP, Wang JY, Zhang LJ. Nutrient intake and gastric cancer in residents of Zhoushan Islands, China. Digestive and Liver Disease. 2003;35(12):912–3. [PubMed]
Connelly-Frost 2009 {published data only} Connelly-Frost A, Poole C, Satia JA, Kupper LL, Millikan RC, Sandler RS. Selenium, folate, and colon cancer. Nutrition and Cancer. 2009;61(2):165–78. [PMC free article] [PubMed]
Costello 2001 {published data only} Costello AJ. A randomized, controlled chemoprevention trial of selenium in familial prostate cancer: rationale, recruitment, and design issues. Urology. 2001;57(4 Suppl 1):182–84. [PubMed]
Criqui 1991 {published data only} Criqui MH, Bangdiwala S, Goodman DS, Blaner WS, Morris JS, Kritchevsky S, et al. Selenium, retinol, retinol-binding protein, and uric acid. Associations with cancer mortality in a population-based prospective case-control study. Annals of Epidemiology. 1991;1(5):385–93. [PubMed]
Cui 2007 {published data only} Cui Y, Vogt S, Olson N, Glass AG, Rohan TE. Levels of zinc, selenium, calcium, and iron in benign breast tissue and risk of subsequent breast cancer. Cancer Epidemiology, Biomarkers & Prevention. 2007;16(8):1682–5. [PubMed]
Davies 2002 {published data only} Davies TW, Treasure FP, Welch AA, Day NE. Diet and basal cell skin cancer: Results from the EPIC-Norfolk cohort. British Journal of Dermatology. 2002;146(6):1017–22. [PubMed]
Fleshner 2003 {published data only} Fleshner N. CAN-CNIC-PRP1. Phase II randomized study of vitamin E, selenium, and soy protein isolate in patients with high-grade prostatic intraepithelial neoplasia. [accessed 1 April 2004]; http://www.cancer.gov.
Hagmar 1992 {published data only} Hagmar L, Linden K, Nilsson A, Norrving B, Akesson B, Schutz A, et al. Cancer incidence and mortality among Swedish Baltic Sea fishermen. Scandinavian Journal of Work, Environment and Health. 1992;18(4):217–24. [PubMed]
Hartman 2002 {published data only} Hartman TJ, Taylor PR, Alfthan G, Fagerstrom R, Virtamo J, Mark SD, et al. Toenail selenium concentration and lung cancer in male smokers (Finland) Cancer Causes & Control. 2002;13(10):923–8. [PubMed]
Huzarski 2006 {published data only} Huzarski T, Byrski T, Gronwald J, Kowalska E, Zajaczek S, Gorski B, et al. A lowering of breast and ovarian cancer risk in women with a BRCA1 mutation by selenium supplementation of diet. Hereditary Cancer in Clinical Practice. 2006;4(1):58. [PMC free article] [PubMed]
Joniau 2007 {published data only} Joniau S, Goeman L, Roskams T, Lerut E, Oyen R, Van PH. Effect of nutritional supplement challenge in patients with isolated high-grade prostatic intraepithelial neoplasia. Urology. 2007;69(6):1102–6. [PubMed]
Kellen 2008 {published data only} Kellen E, Zeegers MP, Bruckers L, Buntinx F. The investigation of a geographical cluster of bladder cancer. Acta Clinica Belgica. 2008;63(5):313–20. [PubMed]
Kilander 2001 {published data only} Kilander L, Berglund L, Boberg M, Vessby B, Lithell H. Education, lifestyle factors and mortality from cardiovascular disease and cancer. A 25-year follow-up of Swedish 50-year-old men. International Journal of Epidemiology. 2001;30(5):1119–26. [PubMed]
Knekt 1988a {published data only} Knekt P, Reunanen A, Aromaa A, Heliovaara M, Hakulinen T, Hakama M. Serum cholesterol and risk of cancer in a cohort of 39, 000 men and women. Journal of Clinical Epidemiology. 1988;41(6):519–30. [PubMed]
Knekt 1988c {published data only} Knekt P, Aromaa A, Maatela J, Aaran RK, Nikkari T, Hakama M, et al. Serum vitamin E and risk of cancer among Finnish men during a 10-year follow-up. American Journal of Epidemiology. 1988;127(1):28–41. [PubMed]
Knekt 1991b {published data only} Knekt P, Aromaa A, Maatela J, Alfthan G, Aaran RK, Nikkari T, et al. Serum micronutrients and risk of cancers of low incidence in Finland. American Journal of Epidemiology. 1991;134(4):356–61. [PubMed]
Kok 1987c {published data only} Kok FJ, van Duijn CM, Hofman A, Vermeeren R, De Bruijn AM, Valkenburg HA. Micronutrients and the risk of lung cancer (letter) New England Journal of Medicine. 1987c;316:1416. [PubMed]
Kune 2006 {published data only} Kune G, Watson L. Colorectal cancer protective effects and the dietary micronutrients folate, methionine, vitamins B6, B12, C, E, selenium, and lycopene. Nutrition and Cancer. 2006;56(1):11–21. [PubMed]
Kuroda 1988 {published data only} Kuroda M, Imura T, Morikawa K, Hasegawa T. Decreased serum levels of selenium and glutathione peroxidase activity associated with aging, malignancy and chronic hemodialysis. Trace Elements in Medicine. 1988;5(3):97–103.
Lawson 2007 {published data only} Lawson KA, Wright ME, Subar A, Mouw T, Hollenbeck A, Schatzkin A, et al. Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study. Journal of the National Cancer Institute. 2007;99(10):754–64. [PubMed]
Le Marchand 2006 {published data only} Le Marchand L, Saltzman BS, Hankin JH, Wilkens LR, Franke AA, Morris SJ, et al. Sun exposure, diet, and melanoma in Hawaii Caucasians. American Journal of Epidemiology. 2006;164(3):232–45. [PubMed]
Li 2004b {published data only} Li H, Li HQ, Wang Y, Xu HX, Fan WT, Wang ML, et al. An intervention study to prevent gastric cancer by micro-selenium and large dose of allitridum. Chinese Medical Journal. 2004;117(8):1155–60. [PubMed]
Limburg 2005 {published data only} Limburg PJ, Wei W, Ahnen DJ, Qiao Y, Hawk ET, Wang G, et al. Randomized, placebo-controlled, esophageal squamous cell cancer chemoprevention trial of selenomethionine and celecoxib. Gastroenterology. 2005;129(3):863–73. [PubMed]
Linxian Pilot 2000 {published data only} NCI-OH95-C-N026NCI-P00-0157. Pilot randomized chemoprevention study of selenium and celecoxib, alone or in combination, in patients with esophageal squamous dysplasia who are residing in Linxian. People’s Republic of China; [accessed: 25/02/2009]. http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=67930&version=HealthProfessional&protocolsearchid=5845119.
Neuhouser 2009 {published data only} Neuhouser ML, Wassertheil-Smoller S, Tomson C, Aragaki A, Anderson GL, Manson JE, et al. Multivitamin use and risk of cancer and cardiovascular disease in the women’s health initiative cohorts. Archives of Internal Medicine. 2009;169(3):294–304. [PMC free article] [PubMed]
Ray 2006 {published data only} Ray AL, Semba RD, Walston J, Ferrucci L, Cappola AR, Ricks MO, et al. Low serum selenium and total carotenoids predict mortality among older women living in the community: the women’s health and aging studies. Journal of Nutrition. 2006;136(1):172–6. [PubMed]
Rayman 2001 {published data only} Larsen EH. [accessed 6 April 2011];Prevention of cancer by intervention with Selenium (pilot) - PRECISE-PILOT. http://www.food.dtu.dk/Default.aspx?ID=20782.MRC Clinical Trials Unit. [accessed 6 April 2011];ISRCTN64336220. A randomised double-blind placebo-controlled cancer prevention trial with an estimated duration of 5 years with 52,000 subjects recruited from the general populations of the UK, Denmark, Sweden, Finland and the United States. http://www.controlled-trials.com/ISRCTN64336220.Rayman M. [accessed 6 April 2011];ISRCTN25193534. UK prevention of cancer by intervention with selenium. http://www.controlled-trials.com/ISRCTN25193534/Rayman M. NCT00022165. Selenium in the Prevention of Cancer. England, W12 ONN, United Kingdom: Hammersmith Hospital London; [accessed 6 April 2011]. http://clinicaltrials.gov/ct2/show/NCT00022165.
Rendon {published data only} Rendon RA, Fleshner N. [accessed 6 April 2011];Vitamin E, selenium and soy protein in preventing cancer in patients with high-grade prostate neoplasia. http://clinicaltrials.gov/ct2/show/NCT00064194. www.clinicaltrials.gov.
Thompson 2009 {published data only} Thompson CA, Habermann TM, Wang AH, Vierkant RA, Folsom AR, Ross JA, et al. Antioxidant intake from fruits, vegetables and other sources and risk of non-hodgkin lymphoma: The Iowa women’s health study. International Journal of Cancer. 2009 doi: 10.1002/ijc.24830. (epub ahead of print) [PMC free article] [PubMed] [Cross Ref]
Tsugane 1996 {published data only} Tsugane S, Hamada GS, Karita K, Tsubono Y, Laurenti R. Cancer patterns and lifestyle among Japanese immigrants and their descendants in the city of Sao Paulo, Brazil. Gann Monographs on Cancer Research. 1996;44:43–50.
Ujiie 2002 {published data only} Ujiie S, Kikuchi H. The relation between serum selenium value and cancer in Miyagi, Japan: 5-year follow up study. Tohoku Journal of Experimental Medicine. 2002;196(3):99–109. [PubMed]
van Noord 1992 {published data only} van Noord PAH, van der Tweel I, Kaaks R, de Waard F. Selenium levels and subsequent colorectal cancers: the efficiency gain of a sequential test to a cohort-nested study with a 1:4 matching ratio. In: van Noord PAH, editor. Selenium and human cancer risk: Nail keratin as a tool in metabolic epidemiology. Amsterdam: Thesis Publishers; 1992. pp. 139–53.
van Noord 1993 {published data only} van Noord PAH, Maas MJ, van der Tweel I, Collette C. Selenium and the risk of postmenopausal breast cancer in the DOM cohort. Breast Cancer Research and Treatment. 1993;25(1):11–9. [PubMed]
van’t Veer 1996 {published data only} van’t Veer P, Strain JJ, Fernandez-Crehuet J, Martin BC, Thamm M, Kardinaal AF, et al. Tissue antioxidants and postmenopausal breast cancer: the European Community Multicentre Study on Antioxidants, Myocardial Infarction, and Cancer of the Breast (EURAMIC) Cancer Epidemiology, Biomarkers & Prevention. 1996;5(6):441–7. [PubMed]
Wallace 2009 {published data only} Wallace K, Kelsey KT, Schned A, Morris JS, Andrew AS, Karagas MR. Selenium and risk of bladder cancer: a population-based case-control study. Cancer Prevention Research (Phila Pa) 2009;2(1):70–3. [PMC free article] [PubMed]
Watters 2009 {published data only} Watters JL, Park Y, Hollenbeck A, Schatzkin A, Albanes D. Cigarette smoking and prostate cancer in a prospective US cohort study. Cancer Epidemiology, Biomarkers & Prevention. 2009;18(9):2427–35. [PMC free article] [PubMed]
Wright 2004 {published data only} Wright ME, Mayne ST, Stolzenberg-Solomon RZ, Li Z, Pietinen P, Taylor PR, et al. Development of a comprehensive dietary antioxidant index and application to lung cancer risk in a cohort of male smokers. American Journal of Epidemiology. 2004;160(1):68–76. [PubMed]
You 2005 {published data only} You WC, Li JY, Zhang L, Jin ML, Chang YS, Ma JL, et al. Etiology and prevention of gastric cancer: a population study in a high risk area of China. Chinese Journal of Digestive Diseases. 2005;6(4):149–54. [PubMed]
Yuan 2006 {published data only} Yuan JM, Gao YT, Ong CN, Ross RK, Yu MC. Prediagnostic level of serum retinol in relation to reduced risk of hepatocellular carcinoma. JNCI Cancer Spectrum. 2006;98(7):482–90. [PubMed]
Zeegers 2009 {published data only} Zeegers MP, Bryan RT, Langford C, Billingham L, Murray P, Deshmukh NS, et al. The West Midlands Bladder Cancer Prognosis Programme: rationale and design. BJU International. 2009 doi: 10.1111/j.1464-410X.2009.08849.x. (epub ahead of print) [PubMed] [Cross Ref]

References to ongoing studies

Epi Nomura 2002 {published data only} Nomura AM. [accessed 12 January 2004];5R01CA033644-19. Cancer sero epidemiology among the Japanese in Hawaii. http://crisp.cit.nih.gov/
RCT Cheng 2003 {published data only} Cheng KK. [accessed 16 April 2004];ISRCTN38534743. Selenium supplementation for the prevention of hepatocellular carcinomas in HBsAg positive patients (pilot study) http://www.controlled-trials.com/isrctn/trialprint-friendly.asp?ISRCTN=38534743.
RCT Cheng 2006 {published data only} Cheng KK. [accessed 18 February 2009];ISRCTN13889738. Bladder Cancer Prognosis Programme (incorporating SELENIB trial) http://www.controlled-trials.com/mrct/trial/232573/selenib.
RCT ECOG 2002 {published data only} Eastern Cooperative Oncology Group. [accessed 6 April 2011];Selenium in preventing tumor growth in patients with previously resected stage I non-small cell lung cancer. http://clinicaltrials.gov/ct2/show/NCT00008385.Eastern Cooperative Oncology Group. ECOG-5597. Phase III randomized chemoprevention study of selenium in participants with previously resected stage I non-small cell lung cancer. Eastern Cooperative Oncology Group; [accessed 6 April 2011]. http://www.cancer.gov/clinicaltrials/featured/trials/ecog-5598.Karp DD. Phase III chemoprevention trial of selenium supplementation in persons with resected stage I non-small-cell lung cancer. Clinical Advances in Hematology and Oncology. 2005;3(4):313–5.
RCT HGPIN Marshall 2006 {published data only} Clark LC, Marshall JR. Randomized, controlled chemoprevention trials in populations at very high risk for prostate cancer: elevated prostate-specific antigen and high-grade prostatic intraepithelial neoplasia. Urology. 2001;57(4 Suppl 1):185–7. [PubMed]Coltman CA. [accessed 12 January 2004];5U01CA077178-06. Selenium based chemoprevention. http://crisp.cit.nih.gov/Marshall J, Jarrard D, Lee WR. [accessed 16 April 2004];SWOG-S9917. Phase III randomized study of selenium as chemoprevention of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia. http://clinicaltrials.gov/Marshall JR. Larry Clark’s legacy: randomized controlled, selenium-based prostate cancer chemoprevention trials. Nutrition and Cancer. 2001;40(1):74–7. [PubMed]Marshall JR, Sakr W, Wood D, Berry D, Tangen C, Parker F, et al. Design and progress of a trial of selenium to prevent prostate cancer among men with high-grade prostatic intraepithelial neoplasia. Cancer Epidemiology, Biomarkers & Prevention. 2006;15(8):1479–84. [PubMed]Nelson MA, Reid M, Duffield-Lillico AJ, Marshall JR. Prostate cancer and selenium. The Urologic clinics of North America. 2002;29(1):67–70. [PubMed]South West Oncology Group. [accessed 16 April 2004];NCT00030901. Selenium in preventing cancer in patients with neoplasia of the prostate. http://clinicaltrials.gov/
RCT NBT Stratton 2003 {published data only} Ahmann F. [accessed 20 October 2009];Phase III Randomized Study of Selenium for Prostate Cancer Prevention. http://www.cancer.gov./search/ViewClinicalTrials.aspx?cdrid=654651.Ahmann FR. [accessed 12 January 2004];5R01CA077789-05. Phase III Trial of Selenium for Prostate Cancer. http://crisp.cit.nih.gov/Clark LC, Marshall JR. Randomized, controlled chemoprevention trials in populations at very high risk for prostate cancer: Elevated prostate-specific antigen and high-grade prostatic intraepithelial neoplasia. Urology. 2001;57(4 Suppl 1):185–7. [PubMed]Marshall JR. Larry Clark’s legacy: randomized controlled, selenium-based prostate cancer chemoprevention trials. Nutrition and Cancer. 2001;40(1):74–7. [PubMed]Nelson MA, Reid M, Duffield-Lillico AJ, Marshall JR. Prostate cancer and selenium. The Urologic clinics of North America. 2002;29(1):67–70. [PubMed]Stratton MS, Reid ME, Schwartzberg G, Minter FE, Monroe BK, Alberts DS, et al. Selenium and prevention of prostate cancer in high-risk men: the negative biopsy study. Anticancer Drugs. 2003;14(8):589–94. [PubMed]

Additional references

Alfthan 1996. Alfthan G, Neve J. Selenium intakes and plasma selenium levels in various populations. In: Kumpulainen JT, Salonen JT, editors. Natural antioxidants and food quality in atherosclerosis and cancer prevention. Cambridge: The Royal Society of Chemistry; 1996. pp. 161–7.
Arnaud 2007. Arnaud J, Arnault N, Roussel AM, Bertrais S, Ruffieux D, Galan P, et al. Relationships between selenium, lipids, iron status and hormonal therapy in women of the SU.VI.M.AX cohort. Journal of Trace Elements in Medicine and Biology. 2007;21(Suppl 1):66–9. [PubMed]
Ashton 2009. Ashton K, Hooper L, Harvey LJ, Hurst R, Casgrain A, Fairweather-Tait SJ. Methods of assessment of selenium status in humans: a systematic review. American Journal of Clinical Nutrition. 2009;89(6):2025S–39S. [PubMed]
Barany 2002. Barany E, Bergdahl IA, Bratteby LE, Lundh T, Samuelson G, Schutz A, et al. Trace elements in blood and serum of Swedish adolescents: relation to gender, age, residential area, and socioeconomic status. Environmental Research. 2002;89(1):72–84. [PubMed]
Bjelakovic 2006. Bjelakovic G, Nagorni A, Nikolova D, Simonetti RG, Bjelakovic M, Gluud C. Meta-analysis: antioxidant supplements for primary and secondary prevention of colorectal adenoma. Alimentary Pharmacology & Therapeutics. 2006;24(2):281–91. [PubMed]
Bjelakovic 2008. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Database of Systematic Reviews. 2008;(3) doi: 10.1002/14651858.CD004183.pub3]. [PubMed] [Cross Ref]
Blot 1993. Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. Journal of the National Cancer Institute. 1993;85(18):1483–92. [PubMed]
Brinkman 2006. Brinkman M, Reulen RC, Kellen E, Buntinx F, Zeegers MP. Are men with low selenium levels at increased risk of prostate cancer? European Journal of Cancer. 2006;42(15):2463–71. [PubMed]
Burri 2008. Burri J, Haldimann M, Dudler V. Selenium status of the Swiss population: Assessment and change over a decade. Journal of Trace Elements in Medicine and Biology. 2008;22(2):112–9. [PubMed]
Combs 2005. Combs GF., Jr Current evidence and research needs to support a health claim for selenium and cancer prevention. Journal of Nutrition. 2005;135(2):343–7. [PubMed]
Dalton 2008. Dalton SO, Schuz J, Engholm G, Johansen C, Kjaer SK, Steding-Jessen M, et al. Social inequality in incidence of and survival from cancer in a population-based study in Denmark, 1994–2003: Summary of findings. European Journal of Cancer. 2008;44(14):2074–85. [PubMed]
Dawsey 1994. Dawsey SM, Wang GQ, Taylor PR, Li JY, Blot WJ, Li B, et al. Effects of vitamin/mineral supplementation on the prevalence of histological dysplasia and early cancer of the esophagus and stomach: results from the Dysplasia Trial in Linxian, China. Cancer Epidemiology, Biomarkers & Prev. 1994;3(2):167–72. [PubMed]
Dennert 2008. Dennert G, Brinkman M, Vinceti M, Zeegers M, Zwahlen M, Horneber M. [P18–179] How global is our knowledge? Population diversity in observational studies on selenium and cancer risk; 16th Cochrane Colloquium; Freiburg. 3–7 October 2008; http://www.cochrane.org/colloquium/2008/virtualposters/?poster=168. (Poster)
Drake 2006. Drake EN. Cancer chemoprevention: Selenium as a prooxidant, not an antioxidant. Medical Hypotheses. 2006;67(2):318–22. [PubMed]
Duffield 1999. Duffield AJ, Thomson CD. A comparison of methods of assessment of dietary selenium intakes in Otago, New Zealand. British Journal of Nutrition. 1999;82(2):131–8. [PubMed]
Egger 1998. Egger M, Schneider M, Davey Smith G. Spurious precision? Meta-analysis of observational studies. BMJ. 1998;316(7125):140–4. [PMC free article] [PubMed]
El-Bayoumy 2009. El-Bayoumy K. The negative results of the SELECT study do not necessarily discredit the selenium-cancer prevention hypothesis. Nutrition and Cancer. 2009;61(3):285–6. [PubMed]
Goossens 2009. Goossens ME, Buntinx F, Zeegers MP. Re: Selenium and vitamin E: interesting biology and dashed hope. Journal of the National Cancer Institute. 2009;101(19):1363–4. [PubMed]
Gorlova 2006. Gorlova OY, Zhang Y, Schabath MB, Lei L, Zhang Q, Amos CI, et al. Never smokers and lung cancer risk: a case-control study of epidemiological factors. International Journal of Cancer. 2006;118(7):1798–804. [PubMed]
Gundacker 2006. Gundacker C, Komarnicki G, Zodl B, Forster C, Schuster E, Wittmann K. Whole blood mercury and selenium concentrations in a selected Austrian population: Does gender matter? The Science of the Total Environment. 2006;8:1–11. [PubMed]
Hall 2008. Hall C. Univ Diss. Berlin, Germany: Technische Universität Berlin; 2008.
Hatfield 2001. Hatfield DL. In: Selenium. Its molecular biology and role in human health. Hatfield DL, editor. Boston: Kluwer Academic Publishers; 2001.
Hercberg 2004. Hercberg S, Galan P, Preziosi P, Bertrais S, Mennen L, Malvy D, et al. The SU.VI.M.AX Study: A Randomized, Placebo-Controlled Trial of the Health Effects of Antioxidant Vitamins and Minerals. Archives of Internal Medicine. 2004;164(21):2335–42. [PubMed]
Higgins 2003. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. British Medical Journal. 2003;327(7414):557–60. [PMC free article] [PubMed]
Higgins 2009a. Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions 5.0.2 [updated September 2009] The Cochrane Collaboration. 2009 Available from www.cochrane-handbook.org.
Higgins 2009b. Higgins JPT, Thompson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. Journal of the Royal Statistical Society Series A (Statistics in Society) 2009;172:137–59. [PMC free article] [PubMed]
Institute of Medicine 2009. Institute of Medicine. [accessed 18 May 2009];Dietary Reference Intakes: Elements. http://www.iom.edu/Object.File/Master/54/395/DRIs.Elements.pdf.
Jaffé 1992. Jaffé W. Selenio, un elemento esencial y toxico. Datos de Latinoamerica. Archivos latinoamericanos de nutrición. 1992;42(2):90–3. [PubMed]
Kafai 2003. Kafai MR, Ganji V. Sex, age, geographical location, smoking, and alcohol consumption influence serum selenium concentrations in the USA: third National Health and Nutrition Examination Survey, 1988–1994. Journal of Trace Elements in Medicine and Biology. 2003;17(1):13–8. [PubMed]
Kamangar 2006. Kamangar F, Qiao YL, Yu B, Sun XD, Abnet CC, Fan JH, et al. Lung cancer chemoprevention: a randomized, double-blind trial in Linxian, China. Cancer Epidemiology, Biomarkers and Prevention. 2006;15(8):1562–4. [PubMed]
Kandas 2009. Kandas NO, Randolph C, Bosland MC. Differential effects of selenium on benign and malignant prostate epithelial cells: stimulation of LNCaP cell growth by noncytotoxic, low selenite concentrations. Nutrition and Cancer. 2009;61(2):251–64. [PMC free article] [PubMed]
Kant 2007. Kant AK, Graubard BI. Ethnicity is an independent correlate of biomarkers of micronutrient intake and status in american adults. Journal of Nutrition. 2007;137(11):2456–63. [PubMed]
Karita 2003. Karita K, Sasaki S, Ishihara J, Tsugane S. Validity of a self-administered food frequency questionnaire used in the 5-year follow-up survey of the JPHC Study to assess selenium intake: comparison with dietary records and blood levels. Journal of Epidemiology. 2003;13(1 Suppl):S92–7. [PubMed]
Kim 2001. Kim YY, Mahan DC. Comparative effects of high dietary levels of organic and inorganic selenium on selenium toxicity of growing-finishing pigs. Journal of Animal Science. 2001;79(4):942–8. [PubMed]
Lawlor 2004. Lawlor DA, Davey SG, Kundu D, Bruckdorfer KR, Ebrahim S. Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence? Lancet. 2004;363(9422):1724–7. [PubMed]
Longnecker 1996. Longnecker MP, Stram DO, Taylor PR, Levander OA, Howe M, Veillon C, et al. Use of selenium concentration in whole blood, serum, toenails, or urine as a surrogate measure of selenium intake. Epidemiology. 1996;7(4):384–90. [PubMed]
McNaughton 2005b. McNaughton SA, Marks GC, Green AC. Role of dietary factors in the development of basal cell cancer and squamous cell cancer of the skin. Cancer Epidemiology, Biomarkers & Prevention. 2005;14(7):1596–607. [PubMed]
Meyer 2005. Meyer F, Galan P, Douville P, Bairati I, Kegle P, Bertrais S, et al. Antioxidant vitamin and mineral supplementation and prostate cancer prevention in the SU.VI.M.AX trial. International Journal of Cancer. 2005;116(2):182–6. [PubMed]
Murphy 2002. Murphy SP, Wilkens LR, Hankin JH, Foote JA, Monroe KR, Henderson BE, et al. Comparison of two instruments for quantifying intake of vitamin and mineral supplements: a brief questionnaire versus three 24-hour recalls. American Journal of Epidemiology. 2002;156(7):669–75. [PubMed]
Navarro Silvera 2007. Navarro Silvera SA, Rohan TE. Trace elements and cancer risk: a review of the epidemiologic evidence. Cancer Causes and Control. 2007;18(1):7–27. [PubMed]
Nishino 2001. Nishino Y, Tsubono Y, Tsuji I, Komatsu S, Kanemura S, Nakatsuka H, et al. Passive smoking at home and cancer risk: a population-based prospective study in Japanese nonsmoking women. Cancer Causes and Control. 2001;12(9):797–802. [PubMed]
Niskar 2003. Niskar AS, Paschal DC, Kieszak SM, Flegal KM, Bowman B, Gunter EW, et al. Serum selenium levels in the US population: Third National Health and Nutrition Examination Survey, 1988–1994. Biological Trace Element Research. 2003;91(1):1–10. [PubMed]
Novoselov 2005. Novoselov SV, Calvisi DF, Labunskyy VM, Factor VM, Carlson BA, Fomenko DE, et al. Selenoprotein deficiency and high levels of selenium compounds can effectively inhibit hepatocarcinogenesis in transgenic mice. Oncogene. 2005;24(54):8003–11. [PubMed]
Office of Dietary Supplements 2009. Office of Dietary Supplements, NIH Clinical Centers, National Institutes of Health. [accessed 18 May 2009];Dietary Supplement Fact Sheet: Selenium. http://ods.od.nih.gov/factsheets/selenium.asp.
Patterson 1998. Patterson RE, Kristal AR, Levy L, McLerran D, White E. Validity of methods used to assess vitamin and mineral supplement use. American Journal of Epidemiology. 1998;148(7):643–9. [PubMed]
Pearce 2004. Pearce N. The globalization of epidemiology: introductory remarks. International Journal of Epidemiology. 2004;33(5):1127–31. [PubMed]
Pildal 2007. Pildal J, Hrobjartsson A, Jorgensen KJ, Hilden J, Altman DG, Gotzsche PC. Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials. International Journal of Epidemiology. 2007;36(4):847–57. [PubMed]
Qu 2007. Qu CX, Kamangar F, Fan JH, Yu B, Sun XD, Taylor PR, et al. Chemoprevention of primary liver cancer: a randomized, double-blind trial in Linxian, China. Journal of the National Cancer Institute. 2007;99(16):1240–7. [PubMed]
Rapiti 2009. Rapiti E, Fioretta G, Schaffar R, Neyroud-Caspar I, Verkooijen HM, Schmidlin F, et al. Impact of socioeconomic status on prostate cancer diagnosis, treatment, and prognosis. Cancer. 2009;115(23):5556–65. [PubMed]
Rayman 2000. Rayman MP. The importance of selenium to human health. Lancet. 2000;356(9225):233–41. [PubMed]
Rayman 2004. Rayman MP. The use of high-selenium yeast to raise selenium status: how does it measure up? British Journal of Nutrition. 2004;92(4):557–73. [PubMed]
Rayman 2008a. Rayman MP, Infante HG, Sargent M. Food-chain selenium and human health: spotlight on speciation. British Journal of Nutrition. 2008;100(2):238–53. [PubMed]
Rayman 2008b. Rayman MP. Food-chain selenium and human health: emphasis on intake. British Journal of Nutrition. 2008;100(2):254–68. [PubMed]
Rodriguez 1995. Rodriguez Rodriguez EM, Sanz Alaejos MT, Diaz Romero C. Urinary selenium status of healthy people. European Journal of Clinical Chemistry and Clinical Biochemistry : Journal of the Forum of European Clinical Chemistry Societies. 1995;33:127–33. [PubMed]
Sarada 2008. Sarada SK, Himadri P, Ruma D, Sharma SK, Pauline T, Mrinalini Selenium protects the hypoxia induced apoptosis in neuroblastoma cells through upregulation of Bcl-2. Brain Research. 2008;1209:29–39. [PubMed]
Schrauzer 1977. Schrauzer GN, White DA, Schneider CJ. Cancer mortality correlation studies - III: Statistical associations with dietary selenium intakes. Biological Chemistry. 1977;7:23–31. [PubMed]
Shamberger 1969. Shamberger RJ, Frost DV. Possible protective effect of selenium against human cancer (letter) Canadian Medical Association Journal. 1969;100:682. [PMC free article] [PubMed]
Slavik 2008. Slavik P, Illek J, Brix M, Hlavicova J, Rajmon R, Jilek F. Influence of organic versus inorganic dietary selenium supplementation on the concentration of selenium in colostrum, milk and blood of beef cows. Acta Veterinaria Scandinavica. 2008;50:43. [PMC free article] [PubMed]
Smith 2000. Smith AM, Chang MP, Medeiros LC. Generational differences in selenium status of women. Biological Trace Element Research. 2000;75(1–3):157–65. [PubMed]
Steen 2008. Steen A, Strom T, Bernhoft A. Organic selenium supplementation increased selenium concentrations in ewe and newborn lamb blood and in slaughter lamb meat compared to inorganic selenium supplementation. Acta Veterinaria Scandinavica. 2008;50:7. [PMC free article] [PubMed]
Stranges 2007. Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M, Combs GF, et al. Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Annals of Internal Medicine. 2007;147:217–23. [PubMed]
Su 2005. Su YP, Tang JM, Tang Y, Gao HY. Histological and ultrastructural changes induced by selenium in early experimental gastric carcinogenesis. World Journal of Gastroenterology. 2005;11(29):4457–60. [PubMed]
Tiwary 2006. Tiwary AK, Stegelmeier BL, Panter KE, James LF, Hall JO. Comparative toxicosis of sodium selenite and selenomethionine in lambs. Journal of Veterinary Diagnostic Investigation. 2006;18(1):61–70. [PubMed]
Vinceti 1998. Vinceti M, Rothman KJ, Bergomi M, Borciani N, Serra L, Vivoli G. Excess melanoma incidence in a cohort exposed to high levels of environmental selenium. Cancer Epidemiology, Biomarkers & Prevention. 1998;7(10):853–6. [PubMed]
Vinceti 2000. Vinceti M, Rovesti S, Bergomi M, Vivoli G. The epidemiology of selenium and human cancer. Tumori. 2000;86(2):105–18. [PubMed]
Vinceti 2000a. Vinceti M, Nacci G, Rocchi E, Cassinadri T, Vivoli R, Marchesi C, et al. Mortality in a population with long-term exposure to inorganic selenium via drinking water. Journal of Clinical Epidemiology. 2000;53(10):1062–8. [PubMed]
Vinceti 2001. Vinceti M, Wei ET, Malagoli C, Bergomi M, Vivoli G. Adverse health effects of selenium in humans. Reviews on Environmental Health. 2001;16(4):233–51. [PubMed]
Vinceti 2009. Vinceti M, Maraldi T, Bergomi M, Malagoli C. Risk of chronic low-dose selenium overexposure in humans: insights from epidemiology and biochemistry. Reviews on Environmental Health. 2009;24(3):231–48. [PubMed]
Wang 1994. Wang GQ, Dawsey SM, Li JY, Taylor PR, Li B, Blot WJ, et al. Effects of vitamin/mineral supplementation on the prevalence of histological dysplasia and early cancer of the esophagus and stomach: results from the General Population Trial in Linxian, China. Cancer Epidemiology, Biomarkers & Prevention. 1994;3(2):161–6. [PubMed]
Waters 2004. Waters DJ, Chiang EC, Cooley DM, Morris JS. Making sense of sex and supplements: differences in the anticarcinogenic effects of selenium in men and women. Mutation Research. 2004;551(1–2):91–107. [PubMed]
Wells 2004. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. Ottawa: [accessed 1 April 2004]. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. http://www.ohri.ca/programs/clinicalepidemiology/oxford.htm.
Whanger 2004. Whanger PD. Selenium and its relationship to cancer: an update. British Journal of Nutrition. 2004;91(1):11–28. [PubMed]
WHO 2004. Joint FAO/WHO Expert Consultation on Human Vitamin, Mineral Requirements. World Health Organization (WHO); 2004. (1998; Bangkok T. Vitamin and mineral requirements in human nutrition : report of a joint FAO/WHO expert consultation, Bangkok, Thailand, 21–30 September 1998) http://whqlibdoc.who.int/publications/2004/9241546123.pdf.
WHO 2008. WHO. [accessed 9 September 2008];Are the number of cancer cases increasing or decreasing in the world? http://www.who.int/features/qa/15/en/index.html.
Wood 2008. Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. British Medical Journal. 2008;336(7644):601–5. [PMC free article] [PubMed]
Zeng 2005. Zeng H, Uthus EO, Combs GF., Jr Mechanistic aspects of the interaction between selenium and arsenic. Journal of Inorganic Biochemistry. 2005;99(6):1269–74. [PubMed]
Zhuo 2004. Zhuo H, Smith AH, Steinmaus C. Selenium and lung cancer: a quantitative analysis of heterogeneity in the current epidemiological literature. Cancer Epidemiology, Biomarkers & Prevention. 2004;13(5):771–8. [PubMed]