Health risk assessment of environmental selenium: Emerging evidence and challenges (Review)
- Authors:
- Published online on: March 24, 2017 https://doi.org/10.3892/mmr.2017.6377
- Pages: 3323-3335
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Copyright: © Vinceti et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
The health risk assessment of environmental selenium, concerning both abnormally low and high intakes, and the related regulatory guidelines are generally based on ‘old’ evidence, since they have generally been unable to take into consideration the most recent epidemiologic and biochemical evidence, and particularly the recent results of large and well-designed randomized controlled trials (RCTs) (1–3). The results of these trials, in connection with biochemical and toxicological studies, have shed new light on this relevant public health issue. This has happened with reference to both the upper and the lower limits of selenium intake, which have been so far based in all the assessment on observational studies carried out in seleniferous Chinese areas during the 1980s (4,5). The availability of the experimental studies (the trials) is of particular importance, since they allowed to rule out the key issue of (unmeasured) confounding, typically affecting most of observational studies with the possible only exception of the so called ‘natural experiments’ (6). In addition, the recent observational and experimental studies made it possible to investigate different populations with reference to age, genetic background and life-style factors, also allowing to test the health effect of selective exposure to specific selenium compounds, such as inorganic haxavalent selenium (selenate) and an organic form, selenomethionine. This is particularly important since there is growing evidence of the key importance of the specific selenium forms in influencing the biological activity of this element, with reference to both its toxicological and nutritional effects (7–11).
The epidemiologic evidence
A very large number of epidemiologic studies assessed the relation between chronic exposure to environmental selenium and human health. The studies on this issue frequently investigated the effect on human health of unusually low or high environmental exposures to selenium, due to an abnormal selenium content in soil, locally produced foods and drinking water, or following combustion of coal with high selenium content (5,12,13). In addition, the scientific literature encompasses a large number of nutritional epidemiology studies on the long-term health effects of selenium carried out in populations living in non-seleniferous regions and countries. These studies include experimental investigations (randomized controlled trials) and observational studies, the latter characterized by case-control, cohort, cross-sectional and ecologic design and being characterized by a far weaker ability compared with trials in addressing the selenium and health relation (1,14,15). While the entire review of this huge literature goes beyond the possibility of this report, we aim at briefly updating the evidence generated by the most recent environmental and nutritional studies on the human health effects of selenium, the biological plausibility of this relation, an overview of the challenges that these studies and their interpretation pose, and finally their implications on the adequacy of current environmental selenium standards. Our update of this issue starts from the comprehensive assessments of selenium exposure carried out by the US Institute of Medicine in 2000 (4) and by a World Health Organization (WHO) working group in 2004 (16).
Studies in populations living in unusually high and low selenium environments
A large number of environmental studies which investigated the health effects of unusually high or low selenium areas have been published, as summarized in Table I. These studies have also substantially contributed to the PubMed-indexed papers on the epidemiology of selenium and human health in addition to the previous papers (Fig. 1), adding relevant data to our understanding of the health effects of selenium in humans. Some of these studies have been published after the 2000 Institute of Medicine selenium assessment (4), considerably extending the limited evidence previously available on the basis of a few ‘old’ Chinese studies. This literature includes the investigation of health effects of high-selenium environment in South and North America, India, China, and Italy. The high content of selenium in these areas, in most cases of geological origin, has induced unusually high levels of selenium in locally grown foodstuffs and occasionally in outdoor air and in drinking water, thus increasing human exposure to the element. However, systematic investigations of the health effects of such exposures are unfortunately limited, and in most cases they came from cross-sectional studies, and very rarely from studies with a more adequate design, such as case-control and particularly cohort studies. In addition, the observational design of these studies induces in most cases a major concern, the potential bias arising from unmeasured (dietary and life-style) confounding, in addition to the potential issue of exposure misclassification. Moreover, health endpoints were generally different in these studies, thus not allowing their systematic analysis (and meta-analysis) in the different populations. Finally, in several cases the small number of exposed subjects made it impossible to compute statistically stable estimates, and this lack of precision hampered the detection of potential health effects of such abnormally low and high exposures to environmental selenium.
Overall, these studies have yielded an indication that the extremely low selenium intake, in the order of <10-15 µg/day, may increase the risk of a severe cardiomyopathy named ‘Keshan disease’ (17–20), while high selenium intake may have unfavorable effects on the endocrine system and particularly on the thyroid status (21), and increase the risk of type 2 diabetes (3,22,23), some specific cancers such as melanoma and lymphoid cancers (24–26), and nervous system disturbances including alterations in visual evoked potentials (27) and excess risk of amyotrophic lateral sclerosis (26,28).
Studies in populations with ‘intermediate’ selenium status. Several studies have investigated the effects on human health of even limited changes in exposure to environmental selenium, which occurs through different environmental sources (primarily diet, but also air pollution, occupational environment, smoking and drinking water), in populations characterized by exposure levels not considered a priori to be unusually ‘low’ or ‘high’ (14). These studies, generally carried out in Western populations, have investigated a broad number of health outcomes, but in the majority of cases they focused on cancer risk (14,15). However, most of these studies had an observational design, thus suffering from the potential severe bias due to unmeasured confounding and exposure misclassification even in prospective cohort studies, in addition to the other biases typically effecting studies with case-control, cross-sectional and clearly ecologic design (1,14,29). In addition, their results have frequently been conflicting even for the same cancer type, as shown for instance for liver cancer (30,31), lung cancer (32–34) or breast cancer (35–38), though in most cases they supported the occurrence of an inverse relation between selenium status and cancer risk (1). Luckily and rather unexpectedly for a nutrient with also was known to exert a powerful toxicity, the nutritional interest in this metalloid as well as the extremely ‘attractive’ preliminary results of the first selenium trial carried out in Western countries, the Nutrition Prevention of Cancer (NPC) trial (39), a large number of randomized controlled trials have been conducted during the last two decades. The aim of these studies has been to investigate the effects on cancer risk of an increased intake of this element (1,40).
In Table II, we report the main features and results of these human studies with experimental design, including an assessment of the possible or established bias of this study based on our evaluation and the criteria developed within the Cochrane Collaboration network (41). In this overview, ‘old’ selenium trials carried out in China are also reported, but their scientific interest is very limited, if any, due to their very high risk of bias, as reported in detail in a previous assessment (1). Fortunately, these RCTs have generated a clear and consistent pattern of evidence about the effect of selenium on cancer risk, though partially unexpected given the underlying hypothesis which generated the trials, i.e. a beneficial effect of selenium on cancer risk (15). This is even more particularly with reference to the cancer type originally suggested by NPC to be most strongly associated with a beneficial effect of selenium, prostate cancer (39). In addition, these studies contributed in elucidating the relation between selenium and cardiovascular risk, another major issue of interest (42). Moreover, these trials have been fundamental in our understanding of the adverse effects of environmental selenium, rather unexpectedly since they encompassed supplementation of selenium doses considered a priori to be entirely safe (1,15). Therefore, and differently from other elements of comparable toxicity and of less nutritional interest, the risk assessment of environmental selenium has benefitted from the implementation of experimental studies originally designed for a setting of potential selenium deficiency, but later found to be able to show and identify the early signs and symptoms related to the toxicity of this element.
 | Table II.Overview and main details of the randomized controlled trials with selenium supplementation in cancer prevention. |
Overall, all the recent trials have consistently shown that selenium does not modify risk of overall cancer, prostate cancer and other specific cancers (2,3,23,43–45), while it may even increase risk of cancers such as advanced (46,47) or overall prostate cancer (48), non-melanoma skin cancer (49,50) and possibly breast cancer in high-risk women (51). These results strongly and unexpectedly differ from the results reported in the earliest trial, the NPC (49,52), which however was small and more importantly was later found to be affected by a detection bias (53). As previously mentioned, these trials have also been of fundamental (and unforeseen) importance in identifying the early signs, symptoms and diseases associated with chronic or subchronic selenium toxicity. In fact, they have shown that already at amount of selenium exposure (baseline dietary intake plus supplementation) of around 250–300 µg/day there is an increased risk of type-2 diabetes. Such excess diabetes risk linked to selenium overexposure was first discovered in trial carried out in a population with a ‘low’ baseline selenium status (15,22) and later confirmed in large trials (3,23). Finally, the largest of the selenium RCTs, SELECT (23), whose overall selenium intake in the supplemented group averaged 300 µg/day (15), has shown that such amount of exposure induces ‘minor’ adverse effects such as dermatitis and alopecia [a long-recognized sign of selenium toxicity (12)]. These effects indicate that the selenium lower-observed-adverse-effect-level (LOAEL) is much lower than previously considered by regulatory agencies (5,54), which could base their assessment on the scarce data yielded by a few old Chinese environmental studies (55), calling for an update of the risk assessment of this element (5,15,56,57).
Adequacy of environmental standards
An issue therefore arises about the adequacy of current standards for environmental risk assessment of selenium in the human, for both abnormally low and high exposures. These standards have been defined by a number of agencies since 2000 to 2014, and as summarized in Fig. 2 they encompass minimal recommended values ranging from 30 to 70 µg/day, and upper doses ranging from 300 to 400 µg/day (in adults) for overall selenium exposure (4,16,58–61). On the contrary, specific guidelines for single selenium species have not been unfortunately set, despite the clear evidence that the various chemical forms of selenium have different biological properties, i.e. nutritional and toxicological activities (7,9,10,62).
So far, the adequacy of the selenium standards has been mainly based on biochemical endpoints (for the lowest recommended intake) and on the occurrence of adverse health outcomes (for the upper level), as identified in old studies carried out in seleniferous areas from China. However, the newly available data from the clinical trials indicate the need of a substantial reassessment of the dose of selenium toxicity, though they unfortunately do not allow to clearly identify a NOAEL and probably also a reliable LOAEL, since only one supplemental dose (200 µg/selenium/day) have been used in these trials and dose-response data are lacking. However, using an uncertainty factor as little as 3, i.e. lower that the uncertainty factors usually adopted in risk assessment (10 or more) also in light of the peculiar nature of this element and its nutritional relevance, selenium intake should not exceed 90 µg/day taking into account the signs of toxicity yielded by the NPC trial (an excess diabetes and skin cancer risk) and by the SELECT trial (an excess incidence of diabetes, advanced prostate cancer, dermatitis and alopecia) (1), as shown in Fig. 2. However, this estimate may be still inadequate to protect human health from chronic selenium toxicity, and in addition it appears to apply only to organic selenium, and to selenomethionine in particular [whose toxicity has bene recently much better elucidated (63–65)].
For inorganic selenium, typically selenate such as those found in underground and drinking waters, the epidemiologic evidence points to a much higher toxicity compared with organic selenium and exactly as expected on the basis of experimental studies (10), therefore suggesting much lower acceptable environmental standards (57), tentatively 1 µg/l for drinking water (5). New standards should also be considered for occupational exposure to selenium, given the limited data available and the potential for toxicity of this source of exposure (12,13,66,67). Finally, air selenium might represent a so far overlooked risk factor for chronic diseases, taking into account that its outdoor air concentrations have been positively associated with cardiovascular mortality (68) and with childhood leukemia risk (69), though more evidence is clearly required to confirm such possible associations mainly due to the inherent risk of unmeasured confounding in these observational studies.
The lowest acceptable amount of selenium exposure is instead much more controversial and uncertain. Two approaches have been used to define such lowest safe level of exposure: the proteomic change induced by the trace element, and the avoidance of adverse health effects. Concerning the latter point (health issues), still limited and inconclusive evidence is available on the large number of diseases tentatively ascribed to a deficiency of environmental selenium (4,70), such as the chronic degenerative osteoarthropathy with unclear etiology named ‘Kashin-Beck’ disease (71,72) and an increased susceptibility to viral infections (73,74).
In addition, the hypothesis of an effect of ‘low’ environmental selenium exposure in increasing cancer risk may now be ruled out, thanks to the consistent evidence yielded by the recent large and well-conducted randomized trials, which ruled out any preventive effect of selenium on cancer risk. On the converse, evidence exists on the involvement of selenium deficiency on the etiology of a rare but severe cardiomyopathy named Keshan disease and endemic in some Chinese areas (17,18,20,75–77), and this observation has played a key role in the identification of the minimal amount of selenium which appears to be required in humans (4,78). Such involvement has been suggested mainly on the basis of observational evidence, i.e. a lower selenium status in the populations more affected by this disease, and following the beneficial effects of a selenium supplementation trial on disease incidence.
However, some epidemiologic features of the disease have since the discovery of the disease suggested alternative etiologic hypotheses (79), particularly a cardiotropic infectious agent such as a Coxsackie virus, selenium deficiency possibly being a cofactor in disease etiology or simply an innocent bystander (19,20,54,77). Under this perspective, the beneficial effect of selenium supplementation in a Chinese trial might be interpreted as an indication of antiviral effects of the selenium compound used (inorganic tetravalent selenium, i.e. selenite), as suggested by laboratory studies (40,80). In any case, while still investigating the cause of Keshan disease and the possible involvement of selenium status, it is prudent to avoid a too low intake of selenium under the hypothesis of a role in Keshan disease etiology, and therefore average population intake must be higher than that shown to be required to avoid disease incidence, i.e. 13.3 µg/day in females and 19.1 in males (16). Finally, recent evidence has suggested adverse health effects of mutations affecting Sec insertion sequence-binding protein 2 or the selenoprotein N1 gene (81–83), though such abnormalities might not be strictly related to a ‘selenium deficiency’ neither were they corrected by its supplementation (84), thus being of limited interest in the setting of minimal dietary selenium requirements.
Alternatively, to the use of health endpoints, and considerably more frequently, the amount of the selenium needed to induce the maximization of selenoprotein synthesis (particularly glutathione-peroxidase and plasma selenoprotein P) has been proposed to set the minimal requirement of selenium in the human. This approach has been based on the assumption that achievement of this biochemical endpoint, i.e. upregulation (frequently defined as ‘optimization’) of selenoprotein synthesis indicates the achievement of an adequate supply of this trace element to the human (40,85). This would point to adequate dietary intake (considering this as only source of selenium exposure) of amount in the order of 70 µg/day (85), thus reaching or even exceeding the upper limit definable on the basis of the SELECT trial results using an uncertainty factor of 3 and clearly even more, of course, when using an uncertainty factor of 10 (Fig. 2). In addition, this ‘biochemical’ approach does not take into account that selenoprotein maximization which follows selenium species administration may derive not just from the ‘correction’ of a nutritional deficiency of the trace element, but as a compensatory response of these proteins (all characterized by antioxidant properties) to the pro-oxidant activity of selenium species (40,54,86–94).
There is also little evidence showing that selenoprotein activity, and particularly its maximization, are beneficial to human health, and therefore (as more generally levels for antioxidant enzymes) this should not be regarded as an objective unless more evidence in humans are provided (40,54). This approach is further strengthened when taking into account that these enzymes are physiologically induced and inducible by oxidative stress (for selenoproteins, even in the absence of any change in selenium supply) (40,54), as long recognized since the discovery of the selenium-containing antioxidant enzyme glutathione-peroxidase (95–97). Overall, it seems therefore prudent to avoid a maximal expression of selenoproteins (54,98), setting as standard a lower amount of their activity, such as proposed by WHO when suggesting a ‘nutritionally adequate’ target (‘recommended nutrient intake’) the achievement of two thirds of the maximal selenoprotein activity, corresponding to a daily selenium intake of 25–34 µg in adults (Fig. 2). However, more research is clearly required to set reliable lower and upper safe selenium levels, though the current standards need to be quickly updated with reference to the upper levels taking into account the above-mentioned recent results of the epidemiologic studies, i.e. the high-quality RCTs and the environmental studies, and also considering the opportunity to set species-specific standards for this element.
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