Selenium | Cam-Cancer

Selenium

Abstract and key points

The trace element selenium is a nutrient essential to human health and occurs naturally in a variety of foods. Inorganic forms (e.g. sodium selenite or selenate) and organic forms (e.g., selenomethionine) are both used in large numbers of selenium-containing medications, nutritional supplements or dietary aids that are promoted for medical or health purposes. These may contain either selenium alone (mono-supplements) or selenium in combination with other trace minerals as well as vitamins. Supplemental selenium has been advocated for the treatment of cancer, prevention of cancer, and for the treatment of cancer-related symptoms and adverse effects of cancer therapy.

Antitumour therapy

Four RCTs carried out an assessment of survival in cancer patients receiving selenium supplements:

  • There is insufficient evidence to support the use of selenium for treating cancer.

Supportive cancer care

Five systematic reviews of varying quality and eleven reports of nine small trials focused on the use of selenium for managing adverse effects or improving quality of life during cancer treatment.

  • Convincing evidence in lymphoedema is not available; promising preliminary results require further confirmation.
  • There is insufficient evidence to confirm an effect on mucositis or xerostomia.
  • Beneficial effects have been reported of selenium supplements for deficiency in cancer patients receiving radiotherapy but further confirmation is required
  • Low certainty evidence suggests that selenium has little or no effect on radiation-induced diarrhoea, and no evidence was found on other gastrointestinal adverse effects of radiotherapy.
  • Some low-quality evidence is available of an effect on reduction of chemotherapy toxicity but effects have not been replicated.
  • No convincing evidence of an effect on quality of life is available.

Cancer prevention

Four systematic reviews have investigated the effects of selenium mono-supplements on cancer prevention including a Cochrane review of 11 RCTs (27,232 participants) and 70 observational studies (over 2,360,000 participants); three subsequent reports included one long term follow up study. Overall, there is no evidence of a beneficial effect with selenium supplements on reducing cancer risk:

  • Good evidence exists of a lack of effect on prostate cancer.
  • Good evidence exists of a lack of effect on colorectal cancer.
  • Good evidence exists of a lack of effect on lung cancer.
  • Moderate evidence exists of a lack of effect on breast cancer.
  • Moderate evidence exists of a lack of effect on skin cancer.
  • Good evidence exists of a lack of effect on bladder cancer.
  • Evidence on other cancers is not conclusive.

Selenium occurs naturally in a variety of foods and is generally safe at the recommended daily intake levels while deficiency may require correction using supplements. Although a number of health problems have been linked to selenium deficiency, selenium is also toxic in large doses. The safety of long-term intake of nutritional doses is a controversial issue, which continues to be discussed. Long-term supplementation has caused symptoms of chronic overexposure and has also been linked to increased risks of developing type 2 diabetes mellitus in two randomised clinical trials. Increased risk of prostate cancer and of melanoma have also been reported.

Document history

Fully revised and updated in July 2020 by Karen Pilkington. The previous versions “selenium – prevention” and “selenium during cancer treatment” were merged.
Revised and updated in October 2013 by Gabriele Dennert
Summary first published in November 2010, authored by Gabriele Dennert.

Citation

Karen Pilkington, Gabriele Dennert, CAM Cancer Consortium. Selenium – during cancer treatment [online document], http://cam-cancer.org/en/selenium. August 18, 2020.

What is it?

Description and background

The trace element selenium (Se) is nutritionally essential for human health and is naturally present in various food groups including grains, pulses, meat and fish. Although a number of health problems have been linked to selenium deficiency, selenium is also toxic in large doses. Selenium occurs naturally in a number of inorganic forms (e.g. selenite, selenate, selenide) and is also found in organic compounds (e.g. selenomethionine, selenocysteine) (Rayman et al. 2008).

Humans usually ingest selenium in crop-grown or animal products. One slice of whole-wheat bread or a half-cup of boiled rice contains approximately 10microgram (mcg) selenium; one egg includes approximately 15 mcg selenium, and 100 g of meat or fish generally contains between 20 mcg and 40 mcg of selenium (NIH ODS, 2020). However, the selenium content of foods may vary significantly depending on plant and animal metabolism, growing conditions and animal nutrition, or even the geographic region from which the food originates (FAO/WHO, 2001).

The bioavailability of ingested organic and inorganic selenium – as a function of absorption, metabolism and excretion – is reported to be between 50% and 90%, depending on the form of selenium and type of preparation, as well as on age, physiological status and polymorphisms in selenium transport protein genes (NCI, 2017).

Subclinical selenium deficiency is sometimes defined as being a serum selenium level of below 75 mcg/l (0.95microM) (Arnaud et al. 2006; Burri et al. 2008). According to this definition, subclinical selenium deficiency is rare in middle and northern European countries (e.g. studies with volunteers have found prevalence rates below 2% in Switzerland and France) (Arnaud et al. 2006; Burri et al. 2008), but prevalence of subclinical selenium deficiency may be higher in Eastern and Southern European countries (Kvieala et al. 1996; Klapcinska et al. 2005) and in populations with chronic diseases and cancer (Vinceti et al. 2000). However, there is no consensus for using the serum selenium level as a marker of selenium status, and no universal normal reference values have as yet been established. Representative figures for the use of selenium supplements among people living with cancer are unavailable. Surveys from Germany suggest that between 4% and 10% of people with cancer use selenium supplements (Nagel et al. 2004; Bruns et al. 2006;    Sehouli et al. 2000). A systematic review of international studies on the use of complementary and alternative medicine in prostate cancer patients identified 11 studies, which reported 4–27% used selenium supplements (Bishop et al. 2011).

The author is not aware of any studies investigating the prevalence of supplemental selenium use for cancer prevention in general populations.

Ingredients

Licensed preparations for the treatment of selenium deficiency contain sodium selenite and can be obtained as liquid solutions for oral intake or intravenous administration. In addition, a large number of selenium-containing nutritional supplements or dietary aids are marketed for medical or health purposes. These contain either selenium alone (in inorganic or organic forms) or selenium in combination with other trace minerals as well as vitamins. Fermentation of yeast in a medium that is rich in inorganic selenium yields selenised yeast which contains 80-90% organic forms such as selenomethione, Se-methylselenocysteine and γ-glutamyl-Se-methylselenocysteine (Rayman, 2004).

Alleged indications

Selenium supplements have been claimed to protect against several types of cancer, in particular those of the prostate and the digestive tract (primary prevention of cancer).

Selenium supplementation has been promoted for several distinct purposes in relation to cancer:

  • Increasing the efficacy of conventional radio- and chemotherapy during cancer treatment.
  • Prevention of relapse or metastases in people with a complete remission of cancer.
  • Prevention and treatment of the adverse effects of conventional cancer therapy.

Application and dosage

Selenium supplements are available as tablets, capsules, pellets and liquid solutions for oral intake. Mono-selenium preparations usually contain 50–300 mcg of selenium per single dose, while multi-component supplements usually contain 30–50 mcg.

Sodium selenite is available as liquid solutions for oral intake or intravenous administration for the treatment of selenium deficiency.

Recommended daily intake of selenium differs between regulatory agencies. The US Institute of Medicine (2006) recommends a daily selenium intake of 55 mcg selenium for adult women and men, which is higher than some regulatory agencies while the UK recommendations are 75 mcg/day for men and 60 mcg/day for women (Public Health England, 2016). The World Health Organization (WHO) recommends a daily selenium intake range of 30–40 mcg/day for adults, depending on body weight (WHO/FAO, 2004). The average dietary intake of selenium in European populations appears to meet the WHO recommendations (FAO/WHO 2001), with mean values of between 40 mcg and 93 mcg/day in men and women, respectively. However, estimation of individual daily selenium intake is difficult and the optimal amount of selenium intake for a person’s health is unknown.

A maximum intake of 300 mcg per day for adults was recommended in 2000 by the European Commission Scientific Committee on Food (SCF), to include selenium intake from all sources of food, including supplements (SCF, 2000). For the treatment of selenium deficiency in adults, organisations have recommended a dose of between 100 to 500 mcg per day of supplemental selenium (BNF, 2020).  The doses used in cancer prevention trials have ranged from 200–400 mcg/day of selenised yeast to 500 mcg/day of sodium selenite. For the prevention and treatment of adverse effects of chemo- or radiotherapy, higher doses have been used on days of treatment with lower doses on the interim days. For example, one trial used 500mcg during treatment and 300mcg on interim days (Muecke et al. 2014)

Mechanisms of action

Selenium is bound to selenoproteins in the human body after intestinal absorption and incorporated into proteins either specifically, in catalytically active selenoenzymes, or non-specifically in tissue proteins (Reilly, 2006). More than 25 selenium-containing enzymes have been identified to date. There are at least two functional groups of selenoproteins. The first is involved in redox processes in the tissues (glutathione peroxidases, thioredoxin reductase), the second in thyroid hormone metabolism (iodothyronine deiodinases). Furthermore, several selenoproteins have been linked to a variety of health problems (Rayman, 2012).

The bioavailability of ingested organic and inorganic selenium – as a function of absorption, metabolism and excretion – is reported to be between 50% and 90%, depending on the form of selenium and type of preparation (Reilly, 2006).

Selenium has an antioxidant role in the body (Tapiero et al. 2003). An antioxidant is an agent that is able to lower the level of unstable and reactive molecules (free radicals, or reactive oxygen species; ROS) in the tissues, and in turn protect tissues against ROS-induced damage, which putatively contributes to cancer development and induces or aggravates the adverse effects of cancer therapy (NCI, 2017). Purported mechanisms of action against cancer include, amongst others, the modulation of immune function, regulation of the cell cycle and apoptosis, alteration of DNA damage/repair (Fairweather-Tait et al. 2011)( p1355, Figure 9). In-vitro studies showed that selenium affects Akt enzymatic activity (Lee et al. 2008) and p53 expression (Li et al. 2010). The understanding of selenium biology, however, is still incomplete.

Legal issues

Most, but not all, forms of selenium are freely marketable for human use within the EU (selenised yeast, for example, is not). Licensed drugs for the treatment of selenium deficiency are available over the counter in most European countries (a prescription is required for example in Germany for preparations containing more than 50 mcg selenium) (Bundesinstitut für Arzneimittel und Medizinprodukte, 2020).

Costs and expenditures

The price of 100 mcg of inorganic selenium, via Internet pharmacies, is about €0.50 (€0.15–1.60); this amounts to approximately €15 a month.

Expenditures are higher for prescription drugs than for over-the-counter nutritional supplements, but may be reimbursable in some countries if the individual has a clinical diagnosis of selenium deficiency.

Does it work?

Antitumour therapy

No systematic reviews were located that assessed selenium as antitumour therapy. Four RCTs carried out an assessment of survival in cancer patients receiving selenium supplements (Asfour et al. 2007; Karp et al. 2013; Muecke et al. 2014; Mix et al. 2015).

  • There is insufficient evidence to support the use of selenium for treating cancer.

Description of studies

Survival

Asfour et al. (2007) investigated the use of high doses of sodium selenite in the treatment of non-Hodgkin lymphoma. Fifty participants with aggressive lymphoma were randomised into the intervention group receiving CHOP-28 plus selenium and a control group, which received CHOP-28 alone (CHOP: cyclophosphamide, vincristine, adriamycin; cycle length: 28 days). Sodium selenite (200 mcg/kg/day = about 14 mg/day for a 70 kg adult) was administered orally on each day of the first course of chemotherapy. More participants in the selenium group reached complete remission compared to the control group (60% vs. 40%; statistical significance not reported). The overall survival rate after two years was 72% in the control group and 80% in the selenium group (no statistically significant difference). Generalisability of these results to other patients is limited as the report lacks information about the histological type of the lymphomas and the distribution of risk factors (for example, the International Prognostic Index) between both groups. Both parameters strongly predict the response to CHOP chemotherapy. Also, it should be mentioned that CHOP-28 is not the standard therapy for aggressive lymphoma in high-income countries.

Karp et al. (2013) conducted a double-blind, placebo-controlled randomised trial for the prevention of second primary tumours (SPT) in persons with resected stage I non-small-cell lung cancer. The verum group took 200 mcg of selenium yeast daily. The trial was terminated early after an interim analysis of 1522 patients showed no benefit of selenium over placebo with regard to the incidence of SPT and five-year progression-free survival. At the five-year mark, 28% in the selenium group and 22% in the placebo group had experienced cancer progression.

Muecke et al (2014) carried out a trial in 81 selenium-deficient cervical and uterine cancer patients while Mix and colleagues (2015) recruited 18 patients with Stage III or IV head and neck squamous cell cancer. Both trials assessed survival. In both trials, the selenium was given in conjunction with radiotherapy. The Muecke trial used 500 mcg Se orally on days of radiotherapy with 300 mcg Se on non-treatment days until the last day of radiotherapy. A 6 year follow up found no difference between receiving the supplement or not. The dose in the Mix trial was 3600 mcg/m2 twice daily for 7 days prior to and once daily during radiotherapy, and daily for the following 3 weeks. This interim analysis from a trial of selenium against placebo also found no difference and was terminated early. Neither trial appeared to be sufficiently powered to detect differences between groups.

Supportive cancer care

Five systematic reviews were located that focused on use of selenium in managing adverse effects or improving quality of life during cancer treatment (Dennert  and Horneber, 2006; Tabassum et al. 2010; Fritz et al. 2011; Lee 2015; Lawrie et al. 2018). The review by Tabassum et al. (2010) did not, however, report systematic methods and a review by Fritz et al (2011)included a range of study types and was primarily descriptive. Of the remaining 3 reviews, one addressed a range of treatment-related adverse effects (Dennert and Horneber 2006), one investigated effects on gastrointestinal problems (Lawrie et al. 2018) and one focused specifically on mucositis (Lee et al. 2015).

  • Lymphoedema: Convincing evidence of an effect is not available and promising preliminary results require further investigation and confirmation.
  • Mucositis and xerostomia: There is currently insufficient evidence to confirm whether there is an effect on mucositis or xerostomia.
  • Selenium deficiency during radiotherapy: Beneficial effects have been reported of selenium supplements for deficiency in cancer patients receiving radiotherapy but further confirmation is required
  • Gastrointestinal: Low certainty evidence suggest that selenium has little or no effect on acute diarrhoea. No evidence was found on other gastrointestinal adverse effects of radiotherapy.
  • Chemotherapy toxicity: Little convincing evidence is available of an effect on reduction of chemotherapy toxicity.
  • Quality of life: No convincing evidence of an effect on quality of life is available.

Description of studies: alleviating the adverse effects of conventional therapy

Lymphoedema/erisipelas

A Cochrane review which was originally published in 2006 and updated in 2009 (Dennert and Horneber 2006) located two randomised clinical trials. These used sodium selenite for the treatment of lymphedoema and the prevention of erysipelas after surgery in breast cancer and head and neck cancer respectively (Kasseroller 1998; Zimmerman et al. 2005). Both trials were considered to be at high risk of bias, and the authors of the review concluded that it was unclear whether the reported results in these trials reflected a clinically relevant reduction in postoperative lymphoedema or erysipelas infection in the selenium group. Generalisation to other cancer patients was also considered questionable.

A more recent systematic review reported that several studies have found positive outcomes resulting from treatment with sodium selenite, dose range 200–500 mcg/day for up to 10 weeks. (Fritz et al. 2011) One of the trials cited (Zimmerman et al. 2005) in postoperative lymphedema after oral tumor surgery had been assessed as high risk of bias in the Cochrane review above. The remaining reports appear to relate to 36 cancer patients with head and neck lymphoedema all of whom were treated with selenium (no control group).  Further details of the study methods and risk of bias were not, however, provided.

Subsequently, one small RCT in 26 participants with clinical stage II to III breast cancer-related lymphoedema compared selenium injections with saline (Han et al. 2019). Apparently large differences in lymphoma improvement were reported. Lack of details of randomisation and allocation and omission of discontinued patients from the analysis indicate that these results must be taken with caution.

Mucositis/stomatitis/xerostomia

One systematic review included a single RCT assessing the effects of selenium on mucositis and xerostomia (Fritz et al. 2011). Beneficial effects were reported but details of the trial design are not reported and it appeared to be a pilot study only.

A systematic review of trials of various mineral derivatives for mucositis (Lee et al. 2015) included 2 RCTs (Jahangard-Rafsanjani et al. 2013; Büntzel et al. 2010b) with a total 116 participants assessing selenium. Selenium was given twice daily in one trial and an hour before radiotherapy sessions in the other trial. While the rate of stomatitis in one RCT was higher in the selenium group (intervention vs. no intervention group: 36.4% vs. 23.5%.), participants that received selenium complained less about loss of taste (22.7% vs. 47.1%), and dysphagia (22.7% vs. 35.3%) and with an almost identical frequency about dry mouth (22.7% vs. 23.5%); none of these differences were statistically significant (Büntzel et al. 2010b). Selenium was favoured in the decision analysis on choice of mineral derivative based on a reduction in mucositis severity but both RCTs were assessed as high risk of bias

An RCT in 2015 in 18 patients with Stage III or IV head and neck squamous cell cancer (HNSCC) compared selenium with placebo (Mix et al. 2015). The supplement was well-tolerated. No differences were found between the groups but the trial was too small for conclusive results.

Radiotherapy-induced selenium deficiency

One systematic review reported that several clinical trials had shown the selenium supplementation (sodium selenite 500 mcg/day) corrected the deficiency caused by radiotherapy (Fritz et al. 2011). Few further details were reported but this appears to be based on early results from the trials described below.

Two randomised trials have investigated the efficacy of sodium selenite for the treatment of selenium deficiency in cancer patients receiving radiotherapy. All study participants had subclinical selenium deficiency (i.e., whole-blood concentration below 85 mcg/l) and received radiotherapy for gynaecological cancers (n=81) (Mücke et al 2010) or head and neck cancers (n=39) with or without concomitant selenium supplementation (Buentzel et al. 2009; Büntzel et al 2010a). Both trials also reported on radiotherapy-associated side effects as secondary outcomes. A pooled analysis of both trials found that blood selenium levels were normalised by selenium supplementation (Büntzel et al 2010b. The first trial (Mücke et al 2010) was assessed as at unclear risk of bias in a subsequent Cochrane review (Lawrie et al. 2018) due to lack of details of randomisation and blinding, a similar issue with the second study by the same group. Monitoring of outcomes was also carried out by the sponsor so that other authors have assessed the trial as high risk of bias (Lee et al. 2015).

Gastro-intestinal adverse effects of radiotherapy

A Cochrane review of various interventions for reducing adverse effects of radiotherapy for primary pelvic cancers located a single RCT on selenium (Lawrie et al. 2018). In the trial (Mücke et al 2010) 81 participants with gynaecological cancers were randomised to oral selenium supplements (500 mcg on the days of radiotherapy and 300 mcg on the rest days or no intervention. Participants were followed up for six weeks after radiotherapy. The risk of bias was assessed as unclear so that the review concluded that there was low‐certainty evidence that oral selenium may have little or no effect on acute diarrhoea (grade 2+) during RT (RR 0.40, 95% CI 0.12 to 1.41). No evidence was found on other adverse gastrointestinal effects of radiotherapy.

This appears to contradict an earlier previous systematic review by Fritz (2011) but this review had simply reported the original study results.

Reduction in chemotherapy toxicity

The systematic review by Fritz (2011) reported results of 3 studies of selenium supplementation in conjunction with chemotherapy. Varying outcomes were described including: reduced nephrotoxicity and leukopenia (described under clinical trials below) (Hu et al. 1997); improved response to chemotherapy and immune function (Asfour et al. 2007); and lack of effect on irinotecan pharmacokinetics (Fakih et al. 2008). All 3 trials were excluded from the Cochrane review for reasons including lack of data for assessment (Dennert and Horneber 2008). While the beneficial effects reported require further investigation, none of the studies reported deleterious interactions between selenium and chemotherapy.

Hu et al. (1997) measured biomarkers of cisplatin toxicity using a randomised crossover design with 41 participants. A dose of 4000 mcg/day seleno-kappacarrageenan was administered orally over eight days in the intervention groups (organic selenium compound: carrageenan is a polysaccharide). Investigators reported a higher white blood count (WBC) at day 14 after chemotherapy and lower levels of cisplatin toxicity biomarkers in urine with selenium, suggesting reduced cisplatin-associated bone marrow suppression and nephrotoxicity. Red blood and platelet count did not differ, but fewer blood transfusions and doses of G-CSF (growth factor for leucocytes) were administered during chemotherapy cycles with selenium. Although the results of this study are interesting, the clinical relevance of the results is disputable. For WBC, means were compared in the presence of concomitant G-CSF application. G-CSF can lead to an excessively high WBC and the comparison of means is sensitive towards extreme values. Differences in urine biomarkers were found 24 hours and 48 hours after cisplatin application, but not 72 hours after application, and blood biomarkers and the laboratory reference limits were not reported. Cisplatin nephrotoxicity has an acute phase (beginning after two to three days) and a delayed phase (two weeks after application) and it seems questionable whether the reported biomarker adequately reflects the occurrence of this adverse effect. This study was excluded from the Cochrane review due to data not being presented according to toxicity scale (Dennert and Horneber 2008).

Another study included in Fritz’ review but excluded from the Cochrane review was Asfour (see Outcome 1 survival). The third excluded study was by Fakih (2008) who investigated whether selenium supplementation allowed the escalation of the dose of irinotecan above the maximum tolerated dose (125 mg/m2 in weekly application). The primary dose-limiting adverse effect of irinotecan is diarrhoea. This phase-1-dose escalation trial found that selenomethionine (2,200 mcg/day (2.2mg/day)) did not allow a safe dose-escalation of irinotecan; 3 of 4 evaluable participants who received the escalated dose suffered from dose-limiting diarrhoea.

Ghorbani (2013) assessed the use of selenium in prevention of cisplatin- induced renal injury.  121 cancer patients were randomised to 400 mcg selenium tablet or placebo the day before chemotherapy. No cases of acute renal failure were observed in the selenium group with 7 patients in the placebo group (p =0.013). 11 (8%) of patients discontinued the study, however, and intention-to-treat analysis was not carried out.

Description of studies: Improving quality of life

Quality of life

The Cochrane review in 2009 included no RCTs studying the effect of selenium supplementation on quality of life/performance status in cancer patients and concluded that there is insufficient evidence that selenium supplementation improves quality of life in cancer patients (Dennert and Horneber 2006).

A subsequent RCT in 18 patients with Stage III or IV head and neck squamous cell cancer comparing selenium with placebo did not demonstrate an improvement in quality of life (Ghorani et al. 2013). The trial was, however, very small and may have been underpowered to detect a difference

Other outcomes

Selenium (200 mcg twice daily from the first day of high dose chemotherapy to 14 days after hematopoietic stem cell transplantation (HSCT)) had no effect on pro-inflammatory cytokines levels in an RCT in 77 AML and ALL patients undergoing HSCT (Daeian et al. 2014). The trial may have been underpowered.

Cancer prevention

Four systematic reviews including one Cochrane review have investigated the effects of selenium mono-supplements on cancer prevention (Vinceti et al. 2018; Kuria et al. 2020; Talebi et al. 2018;  de Oliveira Maia et al. 2019). One Cochrane investigated the effects of various interventions on prevention of lung cancer but the only RCT on selenium was also included in the Cochrane review on cancer prevention in general. (Table 1)

The Cochrane review published in 2018 included 11 RCTs and 70 observational studies (Vinceti et al. 2018). Meta-analyses was conducted when two or more RCTs or five or more observational studies were available for a specific outcome. RCTs involved 27,232 participants allocated to either selenium supplements or placebo. The observational studies included over 2,360,000 participants.

The Cochrane review concluded that there was high certainty evidence based on high quality RCTs of no beneficial effect of selenium supplements in reducing cancer risk (based on low risk of bias RCTs: 1.01 (95% CI 0.93 to 1.10). Concerns were raised about a higher incidence of high-grade prostate cancer, type 2 diabetes and skin abnormalities in participants with selenium supplementation reported in some RCTs. No clear evidence of an influence of baseline participant selenium status was found. While observational longitudinal studies have shown an inverse association between selenium exposure and risk of some cancer types, conflicting findings are also reported and limitations in the study design suggest these findings should be taken with caution. Based on these considerations, the overall conclusions were of no evidence to suggest that increasing selenium intake through diet or supplementation prevents cancer in humans.

A more recent systematic review included 37 studies but it is unclear how many were RCTs (Kuria et al. 2020). Selenium at recommended daily allowance levels of at least 55 mcg/day was reported to decrease the risk of cancer (RR 0.94, 95% CI 0.90–0.98) while supplements were described as protective at levels of at least 55 mcg/day (RR 0.89, 95% CI: 0.82–0.97). Effects may vary with different cancers. The Newcastle-Ottawa scale (NOS) used to assess studies but these assessments were not referred to when reporting the results and the first figure above does not appear to match those in the table and text which is reported as 0.96 (0.92–0.99).  Meta-analysis of intervention and observational studies are reported separately for all doses, highest doses, doses of at least 55 mcg/day and doses of less than 55 mcg/day. The only significant result is for intervention studies using doses of at least 55 mcg/day (0.92 (0.86–0.99)).

Three further studies were located: one case control is described under ”Prostate cancer” and the other under ”Other cancers” below. The remaining study, an RCT with a long term follow-up (5 years treatment Selenium 300 mcg/d) reported an increase in all-cause mortality 10 years later (Rayman et al. 2018). The authors of the study which was conducted in Denmark suggest that total selenium intake over 300 mcg/d and high-dose selenium supplements should be avoided.

  • Good evidence exists of a lack of effect on prostate cancer. An increased risk has been reported but this is not fully confirmed.
  • Good evidence exists of a lack of effect on colorectal cancer.
  • Good evidence exists of a lack of effect on lung cancer.
  • Moderate evidence exists of a lack of effect on breast cancer.
  • Moderate evidence exists of a lack of effect on skin cancer. An increased melanoma risk has been reported.
  • Good evidence exists of a lack of effect on bladder cancer. Evidence on other cancers is not conclusive.

Description of studies

Prostate cancer

Based on the Cochrane review in 2018, prostate cancer was unaffected by selenium (RR 1.01, 95% CI 0.90 to 1.14; 4 studies, 18,942 participants) (Vinceti et al. 2018). Certainty of the evidence was high.  Concerns were raised about a higher incidence of high-grade prostate cancer in participants with selenium supplementation reported in some RCTs.

The systematic review by Kuria et al. (2020) also found no effects on incidence (0.99 (0.96–1.01)).

A 17 year case control follow up of one of the studies included in the Cochrane review concluded that serum selenium was not associated with PCa risk (continuous OR: 0.66; 0.32-1.37) (Chatterjee et al. 2019).

Colorectal cancer

Based on the Cochrane review in 2018, two RCTs with 19,009 participants indicated that colorectal cancer was unaffected by selenium administration (RR 0.99, 95% CI 0.69 to 1.43) (Vinceti et al. 2018). Certainty of the evidence was high. 

The systematic review by Kuria et al. (2020) also found no effects of selenium intake (1.04 (0.94–1.16)).

Lung cancer

Based on the Cochrane review in 2018, lung cancer was unaffected by selenium administration (RR 1.16, 95% CI 0.89 to 1.50; 2 studies, 19,009 participants) (Vinceti et al. 2018). Certainty of the evidence was high.

The systematic review by Kuria 2020 also found no effects of selenium intake 1.08 (0.89–1.31) (Kuria et al. 2020).

One systematic review claimed that the results indicated a preventive role of increased selenium levels in the incidence of lung cancer (Talebi et al. 2018). This claim was based solely on observational studies (13 case-control and 2 cohort) and the reliability of the conclusions is unclear.

Breast cancer

Based on the Cochrane review in 2018, breast cancer was unaffected by selenium administration (RR 2.04, 95% CI 0.44 to 9.55; 1 study, 802 participants) (Vinceti et al. 2018). Certainty of the evidence was moderate owing to imprecision.

The systematic review by Kuria et al. (2020) also found no effects of selenium intake 1.27 (0.99–1.62).

Skin cancer

Based on the Cochrane review in 2018, non-melanoma skin cancer was unaffected by selenium administration (RR 1.16, 95% CI 0.30 to 4.42; 2 studies, 2027 participants) (Vinceti et al. 2018). Certainty of the evidence was moderate owing to high heterogeneity. RCTs with low risk of bias suggested increased melanoma risk.

The systematic review by Kuria et al. (2020) found an increased risk of skin cancer 1.11 (1.03–1.19).

Other cancers

Based on the Cochrane review in 2018, bladder cancer was unaffected by selenium administration (RR 1.07, 95% CI 0.76 to 1.52; 2 studies, 19,009 participants) (Vinceti et al. 2018). Certainty of the evidence was high.

The systematic review by Kuria et al. (2002) found no difference in incidence of bladder, oesophageal, stomach or haematological cancer but a reduced risk of liver (RR 0.78 (0.68–0.90)) and pancreatic (0.76 (0.65–0.89)) cancer.

One further systematic review assessed the evidence on prevention of thyroid cancer (de Oliveira Maia et al. 2019). Only 5 cross-sectional studies were identified and the evidence assessed as inconclusive.

One recent study assessing risk of ovarian cancer in African American women found a protective effect of supplementary but no effect of dietary selenium (Terry et al. 2017). This was a case control study and the findings require further confirmation.

Is it safe?

Adverse events

Selenium is a nutrient essential to human health that occurs naturally in a variety of foods and is generally safe at the recommended daily intake levels (although these vary according to the regulatory agency - see Application and Dosage). Chronic selenium poisoning (selenosis) has, however, been seen in seleniferous areas of North America and China, but has also been attributed to commercially available selenium supplements (Sutter et al. 2008). Symptoms of selenosis include hair loss, thickened nails, nausea, vomiting, fatigue and paresthesia and paralysis. The EU Scientific Committee on Food considers an upper selenium limit (for adults) of 300 mcg/day (including supplements) to be acceptable for the avoidance of selenosis (SCF 2000; SCF 2006) US Food and Nutrition Board, Institute of Medicine, set the tolerable upper level of selenium intake to 400 mcg/day (US Institute of Medicine, 2006), a recommendation currently used by the National Institutes of Health Office of Dietary Supplements (NIH ODS 2020). Other authorities suggest lower maximum intakes: the European Commission Scientific Committee on Food recommends a maximum of 300 mcg/day, to include selenium intake from all sources of food, including supplements (SCF 2000). Adverse effects have also been reported with levels of intake as low as around 260 µg/day for organic selenium and around 16 µg/day for inorganic selenium (Vinceti et al. 2017b).

In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which used 200 mcg/day selenomethionine for 7–12 years, the rate of alopecia (overall incidence: 3% of participants) and mild dermatitis (7% of participants) was higher than in the placebo group (relative risk increase: +28% and +17%, respectively) (Lippman et al. 2009). No differences were seen in halitosis, nail changes, fatigue, and nausea. Early signs of selenium toxicity (garlic breath, hair and nail changes, upset stomach) were observed in participants of a clinical trial who received 1600 mcg or 3200 mcg selenised yeast/day for up to 24 months(Reid et al. 2008). Neither trial reported more severe adverse effects or signs of chronic toxicity.

However, there are concerns that long-term selenium supplementation may increase the risk of developing type 2 diabetes mellitus in selenium-replete populations. The relative risk for male selenium users in the SELECT trial was 1.07 (95% confidence interval (CI) 0.94–1.22), when compared to the placebo group, a non-statistically significant increased risk (Lippman et al. 2009). In the Nutritional Prevention of Cancer Trial (NPCT), the risk of developing diabetes mellitus in the selenium group was 1.55 (95% CI: 1.03–2.33); this meant that there were four additional cases of diabetes in 1000 selenium users per year (Stranges et al. 2007).

Lethal and non-lethal acute poisoning related to the use of selenium has been reported in a number of cases (Sutter et al. 2008; See et al. 2006). The lethal selenium dose for humans is unknown, but is estimated to be between 0.12g and 1g (120–1000mg)(Sutter et al. 2008). Acute poisoning is characterised by vomiting, garlic breath, abdominal pain, hypersalivation, cardiac arrhythmia, haemolysis, necrosis of the liver, cerebral and pulmonary oedema, coma and death (SCF, 2000).

A small RCT compared the safety, tolerability and pharmacokinetic profiles of 3 different selenium compounds reported that all three were well-tolerated and non-genotoxic (Evans et al. 2019). This trial was likely to be underpowered as only 24 patients were recruited.

Contraindications

Chronic overexposure to selenium (selenosis).

According to the NPCT, selenium may increase the risk of non-melanoma cancer recurrence. Selenium supplementation may therefore be problematic, especially for light-skinned people (Stranges et al. 2007).

No controlled data are available on the effects of selenium supplements in non-selenium-deficient women during pregnancy or lactation.

Interactions

One potential major (highly clinically significant) interaction is listed on the Drugs.com database, between selenium and dimercaprol which can bind to form a nephrotoxic compound (Drugs.com, 2020)

A number of moderate risk (moderately clinically significant) interactions is listed on the Drugs.com database. These include interactions with bisphosphonates and quinolone antibiotics amongst others.

The manufacturer of Eltrombopag advises that it should be taken 2 hours before or 4 hours after selenium which may decrease the absorption of eltrombopag (BNF, 2020)

Cisplatin can reduce selenium levels in hair and serum but the clinical significance of this is unknown (NIH ODS, 2020).

Vitamin C is reported to lower the intestinal absorption of selenium (Sandström 2001).

Other problems or complications

Severe complications have been reported because not only consumers, but also healthcare professionals, have confused the measurements ‘milligram’ (mg) and ‘microgram’ (µg). Also, a number of websites mistakenly recommend ‘milligrams’ of selenium instead of ‘micrograms’, the ingestion of which may result in a thousand-fold overdose.

References

Arnaud J, Bertrais S, Roussel AM, Arnault N, Ruffieux D, Favier A, Berthelin S, Estaquio C, Galan P, Czernichow S, et al. Serum selenium determinants in French adults: the SU.VI.M.AX study. Br J Nutr 2006; 95(2): 313-20.

Asfour IA, Fayek M, Raouf S, et al. The impact of high-dose sodium selenite therapy on Bcl-2 expression in adult non-Hodgkin's lymphoma patients: correlation with response and survival. Biol Trace Elem Res. 2007;120(1-3):1-10. doi:10.1007/s12011-007-0029-5

Bishop FL, Rea A, Lewith H, Chan YK, Saville J, Prescott P, von Elm E, Lewith GT: Complementary medicine use by men with prostate cancer: a systematic review of prevalence studies. Prostate Cancer and Prostatic Diseases 2011:14, 1–13.

BNF (British National Formulary). Selenium. Available at: https://bnf.nice.org.uk/drug/selenium.html. Accessed 01/07/20.

Bruns F, Glatzel M, Schönekaes K, Riesenbeck D, Mücke R, Büntzel J, Micke P, Schäfer U, Kisters K, Micke O. Complementary and alternative medicine experience in radiation oncology patients: first results of a multi-center approach. Trace Elements & Electrolytes 2006; 23(4): 318-26.

Buentzel J, Micke O, Glatzel M, Bruns F, Kisters K, Muecke R. Evaluation of the effect of selenium on radiation-induced toxicities in head neck cancer patients. Journal of clinical oncology. 2009;27(15, suppl 1):e20698.

Bundesinstitut für Arzneimittel und Medizinprodukte. https://www.bfarm.de/SharedDocs/Downloads/DE/Arzneimittel/Pharmakovigilanz/Gremien/Verschreibungspflicht/77Sitzung/protokoll.pdf?__blob=publicationFile&v=1 (last access 07/07/2020).

Büntzel 2010a Büntzel J, Micke O, Kisters K, Bruns F, Glatzel M, Schönekaes K, Kundt G, Schäfer U, Mücke R. Selenium substitution during radiotherapy of solid tumours - laboratory data from two observation studies in gynaecological and head and neck cancer patients. Anticancer Res. 2010 May;30(5):1783-6 (Buntzel 2010a)

Büntzel J, Riesenbeck D, Glatzel M, Berndt-Skorka R, Riedel T, Mücke R, Kisters K, Schönekaes KG, Schäfer U, Bruns F, Micke O. Limited effects of selenium substitution in the prevention of radiation-associated toxicities. results of a randomized study in head and neck cancer patients. Anticancer Res. 2010 May;30(5):1829-32. (Buntzel 2010b)

Burri J, Haldimann M, Dudler V. Selenium status of the Swiss population: Assessment and change over a decade. J Trace Elem Med Biol 2008; 22(2): 112-9.

Chatterjee S, Combs GF, Jr., Chattopadhyay A, Stolzenberg-Solomon R. Serum selenium and pancreatic cancer: a prospective study in the Prostate, Lung, Colorectal and Ovarian Cancer Trial cohort. Cancer causes & control : CCC. 2019;30(5):457-64.

Daeian N, Radfar M, Jahangard-Rafsanjani Z, Hadjibabaie M, Ghavamzadeh A. Selenium supplementation in patients undergoing hematopoietic stem cell transplantation: effects on pro-inflammatory cytokines levels. Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences. 2014;22:51.

de Oliveira Maia M, Batista BAM, Sousa MP, de Souza LM, Maia CSC. Selenium and thyroid cancer: a systematic review. Nutrition and cancer. 2019:1-9.

Dennert G, Horneber M. Selenium for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients. Cochrane Database Syst Rev. 2006;2006(3):CD005037. Published 2006 Jul 19. doi:10.1002/14651858.CD005037.pub2

Evans SO, Jacobson GM, Goodman HJB, Bird S, Jameson MB. Comparative Safety and Pharmacokinetic Evaluation of Three Oral Selenium Compounds in Cancer Patients. Biol Trace Elem Res. 2019;189(2):395-404. doi:10.1007/s12011-018-1501-0

Fairweather-Tait SJ, Bao Y, Broadley MR, Collings R, Ford D, Hesketh JE, Hurst R: Selenium in Human Health and Disease. Antioxidants & Redox Signaling 2011; 14: 1337-1383

Fakih MG, Pendyala L, Brady W, et al. A Phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors. Cancer Chemother Pharmacol. 2008;62(3):499-508. doi:10.1007/s00280-007-0631-4

FAO/WHO 2001. Chapter 15 Selenium. In: FAO & WHO: Human vitamin and mineral requirements. Report of a joint FAO/WHO expert consultation, Bangkok, Thailand. 2002. (last accessed 01/07/2020).

Fritz H, Kennedy D, Fergusson D, et al. Selenium and lung cancer: a systematic review and meta analysis. PLoS One. 2011;6(11):e26259. doi:10.1371/journal.pone.0026259

Ghorbani A, Omidvar B, Parsi A. Protective effect of selenium on cisplatin induced nephrotoxicity: A double-blind controlled randomized clinical trial. Journal of nephropathology. 2013;2(2):129-34.Lee 2015

Han HW, Yang EJ, Lee SM. Sodium Selenite Alleviates Breast Cancer-Related Lymphedema Independent of Antioxidant Defense System. Nutrients. 2019;11(5).

Hu YJ, Chen Y, Zhang YQ, et al. The protective role of selenium on the toxicity of cisplatin-contained chemotherapy regimen in cancer patients. Biol Trace Elem Res. 1997;56(3):331-341. doi:10.1007/BF02785304

Jahangard-Rafsanjani Z, Gholami K, Hadjibabaie M, Shamshiri AR, Alimoghadam K, Sarayani A, et al. The efficacy of selenium in prevention of oral mucositis in patients undergoing hematopoietic SCT: a randomized clinical trial. Bone marrow transplantation. 2013;48(6):832-6.

Karp DD, Lee SJ, Keller SM, et al. Randomized, double-blind, placebo-controlled, phase III chemoprevention trial of selenium supplementation in patients with resected stage I non-small-cell lung cancer: ECOG 5597. J Clin Oncol. 2013;31(33):4179-4187. doi:10.1200/JCO.2013.49.2173

Kasseroller R. Sodium selenite as prophylaxis against erysipelas in secondary lymphedema. Anticancer Res. 1998;18(3C):2227-2230.

Klapcinska B, Poprzecki S, Danch A, Sobczak A, Kempa K. Selenium levels in blood of upper silesian population: evidence of suboptimal selenium status in a significant percentage of the population. Biol Trace Elem Res 2005; 108(1-3): 1-16.

Kuria A, Fang X, Li M, et al. Does dietary intake of selenium protect against cancer? A systematic review and meta-analysis of population-based prospective studies. Crit Rev Food Sci Nutr. 2020;60(4):684-694. doi:10.1080/10408398.2018.1548427

Kvieala J, Zamrazil V, Jiranek V. Selenium Deficient Status of Inhabitants of south Moravia. In: Kumpulainen JT, Salonen JT (Ed.). Natural Antioxidants and Food Quality in Atherosclerosis and Cancer Prevention. Cambridge: The Royal Society of Chemistry; 1996. 177-87.

Lawrie TA, Green JT, Beresford M, et al. Interventions to reduce acute and late adverse gastrointestinal effects of pelvic radiotherapy for primary pelvic cancers. Cochrane Database Syst Rev. 2018;1(1):CD012529. Published 2018 Jan 23. doi:10.1002/14651858.CD012529.pub2

Lee JH, Shin SH, Kang S, Lee YS, Bae S: A novel activation-induced suicidal degradation mechanism for Akt by selenium. Int J Mol Med. 2008; 21: 91–97.

Lee S. Mineral derivatives in alleviating oral mucositis during cancer therapy: a systematic review. PeerJ. 2015;3:e765. 2015. doi:10.7717/peerj.765

Li Z, Shi K, Guan L, Cao T, Jiang Q, Yang Y, Xu C: ROS leads to MnSOD upregulation through ERK2 translocation and p53 activation in selenite-induced apoptosis of NB4 cells. FEBS Lett. 2010; 584(11): 2291-7.

Lippman SM, Klein EA, Goodman PJ, 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

Mix M, Singh AK, Tills M, Dibaj S, Groman A, Jaggernauth W, et al. Randomized phase II trial of selenomethionine as a modulator of efficacy and toxicity of chemoradiation in squamous cell carcinoma of the head and neck. World journal of clinical oncology. 2015;6(5):166-73.

Muecke R, Micke O, Schomburg L, Glatzel M, Reichl B, Kisters K, Schaefer U, Huebner J, Eich HT, Fakhrian K, Adamietz IA, Buentzel J; German Working Group Trace Elements and Electrolytes in Oncology-AKTE. Multicenter, phase III trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization. Integr Cancer Ther. 2014 Nov;13(6):463-7.

Muecke R, Micke O, Schomburg L, Glatzel M, Reichl B, Kisters K, Schaefer U, Huebner J, Eich HT, Fakhrian K, Adamietz IA, Buentzel J; German Working Group Trace Elements and Electrolytes in Oncology-AKTE. Multicenter, phase III trial comparing selenium supplementation with observation in gynecologic radiation oncology: follow-up analysis of the survival data 6 years after cessation of randomization. Integr Cancer Ther. 2014 Nov;13(6):463-7.

Muecke* R, Schomburg L, Glatzel M, Berndt‐Skorka R, Baaske D, Reichl B, et al. Multicenter, phase 3 trial comparing selenium supplementation with observation in gynecologic radiation oncology. International Journal of Radiation Oncology, Biology, Physics 2010;78(3):828‐35 (*also cited as Mücke)

Nagel G, Hoyer H, Katenkamp D. Use of complementary and alternative medicine by patients with breast cancer: observations from a health-care survey. Support Care Cancer 2004; 12(11): 789-96.

NCI (National Cancer Institute): Antioxidants and Cancer Prevention: Fact Sheet. Reviewed: February 6, 2017  (last access 01/07/2020).

NIH ODS. Selenium: Fact Sheet for Health Professionals. Dietary supplement fact sheet: Selenium. Updated 11th March 2020 (last accessed 01/07/2020).

Public Health England. Government Dietary Recommendations:  Government recommendations for energy and nutrients for males and females aged 1 – 18 years and 19+ years.2016. Available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/618167/government_dietary_recommendations.pdf. Accessed 01/07/20.

Rayman MP, Infante HG, Sargent M. Food-chain selenium and human health: spotlight on speciation. Br J Nutr 2008; 100: 238-53.

Rayman MP, Winther KH, Pastor-Barriuso R, Cold F, Thvilum M, Stranges S, et al. Effect of long-term selenium supplementation on mortality: Results from a multiple-dose, randomised controlled trial. Free radical biology & medicine. 2018;127:46-54.

Rayman MP. The use of high-selenium yeast to raise selenium status: how does it measure up? Br J Nutr 2004; 92(4): 557-73.

Rayman, MP: Selenium and human health. Lancet 2012; 379: 1256–68.

Reid ME, Duffield-Lillico AJ, Slate E, Natarajan N, Turnbull B, Jacobs E, Combs GF, Jr., Alberts DS, Clark LC, Marshall JR. The nutritional prevention of cancer: 400 mcg per day selenium treatment. Nutr Cancer 2008; 60(2): 155-63.

Reilly C. Selenium in food and health. 2nd Edition. New York: Springer 2006. here: pp. 46ff.

Sandström B: Micronutrient interactions: effects on absorption and bioavailability. Br J Nutr 2001; 85: S181-S185.

SCF (Scientific Committee on Food): opinion of the scientific Committee on Food on the Tolerable Upper Intake Level of Selenium. 2000. (last access 01/07/20).

SCF (Scientific Committee on Food): Tolerable upper intake levels for vitamins and minerals . European Food Safety Authority 2006. Available at: https://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf. Accessed 1st July 2020.

See KA, Lavercombe PS, Dillon J, Ginsberg R. Accidental death from acute selenium poisoning. Med J Aust 2006; 185(7): 388-9.

Sehouli J, David M, Kaufmann B, Lichtenegger W. Unkonventionelle Methoden in der Krebsmedizin - Postoperative Nutzung durch Patientinnen mit gynäkologischen Malignomen [Use of alternative treatments by patients after surgery for gynecologic malignancies]. Geburtsh Frauenheilk 2000; 60: 147-54.

Stranges S, Marshall JR, Natarajan R, Donahue RP, Trevisan M, Combs GF, Cappuccio FP, Ceriello A, Reid ME: Effects of Long-Term Selenium Supplementation on the Incidence of Type 2 Diabetes: A Randomized Trial. Ann Intern Med 2007; 147:217-223.

Sutter ME, Thomas JD, Brown J, Morgan B. Selenium toxicity: a case of selenosis caused by a nutritional supplement. Ann Intern Med 2008;148(12): 970-1.

Tabassum A, Bristow RG, Venkateswaran V. Ingestion of selenium and other antioxidants during prostate cancer radiotherapy: a good thing?. Cancer Treat Rev. 2010;36(3):230-234. doi:10.1016/j.ctrv.2009.12.008

Talebi SS, Badfar G, Shohani M, Soleymani A, Azami M. The Relationship between Selenium and Lung Cancer: An Updated Systematic Review and Meta-Analysis. International Journal of Cancer Management . Jun 2018; 11(6): 1-10.

Tapiero H, Townsend DM, Tew KD. The antioxidant role of selenium and seleno-compounds. Biomed Pharmacother. 2003;57(3-4):134-144. doi:10.1016/s0753-3322(03)00035-0

Terry PD, Qin B, Camacho F, Moorman PG, Alberg AJ, Barnholtz-Sloan JS, et al. Supplemental Selenium May Decrease Ovarian Cancer Risk in African-American Women. The Journal of nutrition. 2017;147(4):621-7.

US Institute of Medicine, Summary Report of the Dietary Reference Intakes. 2006 https://www.nationalacademies.org/our-work/summary-report-of-the-dietary-reference-intakes. Accessed 01/07/20.

Vieira ML, Fonseca FL, Costa LG, Beltrame RL, Chaves CM, Cartum J, et al. Supplementation with selenium can influence nausea, fatigue, physical, renal, and liver function of children and adolescents with cancer. Journal of medicinal food. 2015;18(1):109-17.

Vinceti M, Filippini T, Del Giovane C, et al. Selenium for preventing cancer. Cochrane Database Syst Rev. 2018;1(1):CD005195. Published 2018 Jan 29. doi:10.1002/14651858.CD005195.pub4

Vinceti M, Rovesti S, Bergomi M, Vivoli G. The epidemiology of selenium and human cancer. Tumori 2000; 86(2):105-18.

WHO/FAO 2004: Joint FAO/WHO Expert Consultation on Human Vitamin and Mineral Requirements (1998): Bangkok T. Vitamin and mineral requirements in human nutrition : report of a joint FAO/WHO expert consultation, Bangkok, Thailand, 21-30 September 1998. Accessed 01/07/20.

Zimmermann T, Leonhardt H, Kersting S, Albrecht S, Range U, Eckelt U. Reduction of postoperative lymphedema after oral tumor surgery with sodium selenite. Biol Trace Elem Res. 2005;106(3):193-203. doi:10.1385/BTER:106:3:193

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