Human serum albumin-bound selenium (Se-HSA) in serum and its correlation with other selenium species.

INTRODUCTION: Selenium (Se) is a trace element with different toxicological and nutritional properties according to its chemical forms. Among the wide range of selenium species, human serum albumin-bound selenium (Se-HSA) has still uncertain composition in terms of organic or inorganic selenium species. This study aimed at investigating the relation between Se-HSA levels with total selenium and the specific organic and inorganic selenium species. METHODS: We determined levels of total selenium and selenium species in serum of participants enrolled in two populations of the Emilia-Romagna region, in Northern Italy. Anion exchange chromatography coupled with inductively coupled plasma dynamic reaction cell mass spectrometry was used as quantification method. Correlations between Se-HSA and the other selenium compounds were analyzed using linear regression and restricted cubic spline regression models, adjusted for potential confounders. RESULTS: The first cohort comprised 50 participants (men/women: 26/24) with median (interquartile range, IQR) age 50 (55-62) years, while the second was composed of 104 participants (M/W: 50/54), median (IQR) age 48 (44-53) years. Median (IQR) levels of total selenium were 118.5 (109-136) µg/L and 116.5 (106-128) µg/L, respectively, while Se-HSA was 25.5 µg/L (16.2-51.5) and 1.1 (0.03-3.1) µg/L, respectively. In both populations, Se-HSA was positively associated with inorganic selenium species. Conversely, Se-HSA was inversely associated with organic selenium, especially with selenoprotein P-bound-Se (Se-SELENOP) and less strongly with selenomethionine-bound-Se (Se-Met), while the relation was null or even positive with other organic species. Evaluation of non-linear trends showed a substantially positive association with inorganic selenium, particularly selenite, until a concentration of 30 µg/L, above which a plateau was reached. The association with Se-SELENOP was inverse and strong until 100 µg/L, while it was almost null at higher levels. CONCLUSIONS: Our findings seem to indicate that Se-HSA incorporates more selenium when circulating levels of inorganic compounds are higher, thus supporting its mainly inorganic nature, particularly at high circulating levels of selenite.

Clinical and Lifestyle Factors and Risk of Amyotrophic Lateral Sclerosis: A Population-Based Case-Control Study.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease of the motor neurons. The etiology of ALS remains largely unknown, particularly with reference to the potential environmental determinants. Methods: We performed a population-based case-control study in four provinces from both Northern and Southern Italy in order to assess non-genetic ALS risk factors by collecting through tailored questionnaires information about clinical and lifestyle factors. We estimated ALS risk by calculating odds ratio (OR) with its 95% confidence interval (CI) using unconditional logistic regression models adjusted for sex, age and educational attainment. Results: We recruited 230 participants (95 cases and 135 controls). We found a possible positive association of ALS risk with trauma, particularly head trauma (OR = 2.61, 95% CI 1.19-5.72), electric shock (OR = 2.09, 95% CI 0.62-7.06), and some sports, although at a competitive level only. In addition, our results suggest an increased risk for subjects reporting use of private wells for drinking water (OR = 1.38, 95% CI 0.73-2.27) and for use of herbicides during gardening (OR = 1.95, 95% CI 0.88-2.27). Conversely, there was a suggestion of an inverse association with overall fish consumption (OR = 0.27, 95% CI 0.12-0.60), but with no dose-response relation. Consumption of some dietary supplements, namely those containing amino acids and, in the Southern Italy population, vitamins and minerals such as selenium, seemed associated with a statistically imprecise increased risk. Conclusions: Our results suggest a potential etiologic role a number of clinical and lifestyle factors with ALS risk. However, caution is needed due to some study limitations. These include the small sample size and the low number of exposed subjects, which affect statistical precision of risk estimates, the potential for exposure misclassification, and the uncertainties about mechanisms underpinning the possible association between these factors and disease risk.

Amyotrophic lateral sclerosis incidence following exposure to inorganic selenium in drinking water: A long-term follow-up.

Some studies have reported an association between overexposure to selenium and risk of amyotrophic lateral sclerosis (ALS), a rare degenerative disease of motor neurons. From 1986 through 2015, we followed a cohort in Northern Italy that had been inadvertently consuming tap water with unusually high concentrations of inorganic hexavalent selenium from 1974 to 1985. We had previously documented an excess incidence of ALS in this cohort during 1986-1994. Here, we report extended follow-up of the cohort for an additional 21 years, encompassing 50,100 person-years of the exposed cohort and 2,233,963 person-years of the unexposed municipal cohort. We identified 7 and 112 incident ALS cases in the exposed and unexposed cohorts, respectively, yielding crude incidence rates of 14 and 5 cases per 100,000 person-years. A Poisson regression analysis, adjusting for age, sex and calendar year, produced an overall incidence rate ratio (IRR) for ALS of 2.8 (95% confidence interval (CI) 1.3, 6), with a substantially stronger IRR in 1986-1994 (8.2, 95% CI 2.7, 24.7) than in 1995-2015 (1.5, 95% CI 0.5, 4.7), and among women (5.1, 95% CI 1.8, 14.3) than men (1.7, 95% CI 0.5, 5.4). Overall, these results indicate an association between high exposure to inorganic selenium, a recognized neurotoxicant, and ALS incidence, with declining rates after cessation of exposure and stronger effects among women.

Selenium and selenium species in the etiology of Alzheimer's dementia: The potential for bias of the case-control study design.

Several human studies imply that the trace element selenium and its species may influence the onset of neurological disease, including Alzheimer's dementia (AD). Nevertheless, the literature is conflicting, with reported associations between exposure and risk in opposite direction, possibly due to biases in exposure assessment. After conducting a cohort study that detected an excess AD risk associated with higher levels of inorganic-hexavalent selenium in subjects with mild cognitive impairment (MCI), we investigated the relation between selenium and AD using a case-control study design. We determined cerebrospinal fluid levels of selenium species in 56 MCI participants already included in the cohort study, considered as referents, and in 33 patients with established AD. AD risk was inversely correlated with inorganic selenium species and with the organic form bound to selenoprotein P. Selenium bound to other organo-selenium species was positively correlated with AD risk, suggesting compensatory selenoprotein upregulation following increased oxidative stress. The finding of an increased AD risk associated with inorganic-hexavalent selenium from the cohort study was not replicated. This case-control study yielded entirely different results than those generated by a cohort study with a partially overlapping participant population, suggesting that case-control design does not allow to reliably assess the role of selenium exposure in AD etiology. This inability appears to be due to exposure misclassification, falsely indicating an etiologic role of selenium deficiency likely due to reverse causation, and involving most selenium species. The case-control design may instead lend insights into the pathologic process underlying disease progression.

Cancer incidence following long-term consumption of drinking water with high inorganic selenium content.

Selenium, a trace element to which humans are exposed mainly through diet, has been involved in the etiology of human cancer. We investigated the long-term effects of selenium exposure on cancer incidence using data from a natural experiment in Northern Italy. During the 1970s-1980s, in a part of the Italian municipality of Reggio Emilia, residents were inadvertently exposed to unusually high levels of inorganic hexavalent selenium (selenate) through drinking water. We followed the exposed residents for 28years, generating data on incidence (when available) and mortality rates for selected cancer sites; the remaining municipal residents comprised the unexposed (reference) group. We observed no substantial difference in overall cancer incidence comparing exposed and unexposed cohorts. We detected, however, a higher incidence of cancer at some sites, and for a few of them, namely cancers of the buccal cavity and pharynx, melanoma, urinary tract and lymphoid tissue, the excess incidence was particularly evident in the first period of follow-up but decreased over time. Overall, these results suggest that consumption of water with levels of selenium in its inorganic hexavalent form close to the European standard, 10µg/L, may have unfavourable effects on cancer incidence.

Diet composition and serum levels of selenium species: A cross-sectional study.

Selenium is a trace element of both nutritional and toxicological interest, depending on its dose and chemical form. Diet is the primary source of exposure for most individuals. We sought to investigate the influence of food intake on serum levels of selenium species. Among fifty subjects randomly selected from a Northern Italian population, we assessed dietary habits using a validated semi-quantitative food frequency questionnaire. We also measured circulating levels of selenium species in serum using high pressure liquid chromatography associated with inductively-coupled plasma dynamic reaction cell mass spectrometer. Circulating levels of inorganic selenium, the most toxic selenium species, were positively associated with intake of fish, legumes and dry fruits, and inversely associated with intake of dairy products and mushrooms. Concerning the organic selenium species, selenoproteinP-bound selenium was inversely associated with intake of fish, fresh fruits, vegetables, and legumes, while selenocysteine-bound selenium positively associated with intake of fresh fruit, potato, legume and mushroom. In the present study, intakes of different foods were correlated with different types of selenium species. These results have important public health implications when assessing the nutritional and toxicological potential of diet composition with reference to selenium exposure.

Dietary intake of cadmium, chromium, copper, manganese, selenium and zinc in a Northern Italy community.

This study provides the dietary intakes of six trace elements (cadmium, chromium, copper, manganese, selenium and zinc), generally characterized by both nutritional and toxicological features depending on their exposure. Being diet the most relevant source of exposure to trace elements in non-professionally exposed subjects, we measured content of these trace elements in foods composing the typical Italian diet using inductively coupled plasma-mass spectrometry, and assessing dietary habits using a validated semi-quantitative food frequency questionnaire we eventually estimated dietary daily intake of trace elements in a Northern Italian community. In the 890 analyzed food samples, the main contributors to cadmium intake are cereals, vegetables and sweets, while cereals, beverages and vegetable are to primary source of manganese. The primary contributors for copper are cereals, fresh fruits and vegetables, while for chromium are beverages, cereals and meat. The main source of selenium intake are cereals and meat, followed by fish, seafood and milk and dairy products, while of zinc intake are meat, cereals, milk and dairy products. In our Italian population sample, the estimated median (interquartile range) dietary daily intakes are 5.00 (3.17-7.65), 56.70 (36.08-86.70) and 66.53 (40.04-101.32) µg/day for cadmium, chromium and selenium, and corresponding figures are 0.98 (0.61-1.49), 2.34 (1.46-3.52) and 8.50 (5.21-12.48) mg/day for copper, manganese and zinc. The estimated intakes are generally within the average intake reported in other European populations, and in such cases well above the daily dietary intakes recommended by national international agencies, avoiding the risk of excess or deficiency. The present estimated intake data can be used to examine a specific trace element of interest and would afford enhanced health protection from those trace elements characterized by both nutritional and toxicological effects.

A selenium species in cerebrospinal fluid predicts conversion to Alzheimer's dementia in persons with mild cognitive impairment.

BACKGROUND: Little is known about factors influencing progression from mild cognitive impairment to Alzheimer's dementia. A potential role of environmental chemicals and specifically of selenium, a trace element of nutritional and toxicological relevance, has been suggested. Epidemiologic studies of selenium are lacking, however, with the exception of a recent randomized trial based on an organic selenium form. METHODS: We determined concentrations of selenium species in cerebrospinal fluid sampled at diagnosis in 56 participants with mild cognitive impairment of nonvascular origin. We then investigated the relation of these concentrations to subsequent conversion from mild cognitive impairment to Alzheimer's dementia. RESULTS: Twenty-one out of the 56 subjects developed Alzheimer's dementia during a median follow-up of 42 months; four subjects developed frontotemporal dementia and two patients Lewy body dementia. In a Cox proportional hazards model adjusting for age, sex, duration of sample storage, and education, an inorganic selenium form, selenate, showed a strong association with Alzheimer's dementia risk, with an adjusted hazard ratio of 3.1 (95% confidence interval 1.0-9.5) in subjects having a cerebrospinal fluid content above the median level, compared with those with lower concentration. The hazard ratio of Alzheimer's dementia showed little departure from unity for all other inorganic and organic selenium species. These associations were similar in analyses that measured exposure on a continuous scale, and also after excluding individuals who converted to Alzheimer's dementia at the beginning of the follow-up. CONCLUSIONS: These results indicate that higher amounts of a potentially toxic inorganic selenium form in cerebrospinal fluid may predict conversion from mild cognitive impairment to Alzheimer's dementia.

Determinants of serum manganese levels in an Italian population.

Manganese (Mn) is both essential and toxic for humans, mainly depending on the total levels and its species. Main sources of exposure include food and air pollution, particularly motorized traffic. We sought to determine the potential influence of these sources on serum total levels of Mn and Mn species. We selected a random sample of municipality residents from an Italian urban municipality, from whom we collected detailed personal information, dietary habits and a blood sample for serum Mn determination. We also assessed outdoor air Mn exposure, by modeling levels of particulate matter ≤10 µm (PM10) from motorized traffic at the residence of geocoded subjects. Serum Mn species generally showed higher levels in males and positive correlation with age, while no such differences were found according to smoking habits or use of dietary supplements. Among nutrients, only iron intake showed a relation with Mn [an inverse correlation with Mn­ferritin (Mn­Fer) and a direct one with inorganic­Mn (Inorg­Mn)]. Meat consumption directly correlated and fish and seafood inversely correlated with total Mn, Mn­transferrin (Mn­Tf) and Mn-citrate (Mn-Cit). Fruits and vegetables, including legumes and nuts, generally showed a positive correlation with all Mn species, especially Mn­Cit, and an inverse one with Inorg­Mn. Odds ratios (ORs) of having serum Mn levels above median value increased with increasing PM10 tertiles, with an OR for highest­to­lowest tertile of 7.40 (1.36­40.25) in multivariate analysis. Analyses for Mn species did not highlight a clear comparable pattern. In conclusion, our results seem to demonstrate that PM10 exposure positively influences total Mn serum levels, while single Mn species show conflicting results.

Toenail selenium as an indicator of environmental exposure: A cross-sectional study.

The relation between toxicity and essentiality of selenium (Se) is of growing interest in human health, as the effects may widely differ depending of its different chemical species and the exposure levels. Toenail Se has been proposed as a reliable biomarker of long-term Se exposure, but few studies investigated the correlation between its toenail content and environmental determinants (i.e., dietary food intake). We aimed to determine the relation of toenail Se levels with serum Se species as well as food items. We recruited a random sample of Modena (Northern Italy) municipal residents, from whom we collected detailed personal information, dietary habits, toenail specimen for Se determination and a blood sample for serum Se speciation analysis. Toenail Se mean value was 0.96 µg/g (range, 0.47­1.60), with slightly higher levels in females, in non-obese subjects and in Se supplements users, while it was lower in current smokers. Toenail Se positively correlated with organic Se forms, mainly selenoprotein P and selenocysteine, and inversely with the inorganic forms (selenite and selenate). Toenail Se was not associated with meat, cereals and dairy products consumption, positively correlated with fruit and slightly with vegetable intake, and negatively with fish and seafood consumption. Finally, no clear association emerged with estimated air Se exposure.

Long-term mortality patterns in a residential cohort exposed to inorganic selenium in drinking water.

Selenium (Se) is a metalloid of considerable nutritional and toxicological importance in humans. To date, limited epidemiologic evidence exists about the health effects of exposure to this trace element in drinking water. We investigated the relationship between Se levels in water and mortality in the municipality of Reggio Emilia, Italy, where high levels of Se were previously observed in drinking water. From 1974 to 1985, 2065 residents consumed drinking water with Se levels close to the European standard of 10µg/l, in its inorganic hexavalent form (selenate). Follow-up was conducted for the years 1986-2012 in Reggio Emilia and a lesser exposed comparison group of around 100,000 municipal residents, with comparable socio-demographic characteristics. Overall mortality from all causes, cardiovascular disease and cancer showed little evidence of differences. However, excess rate ratios were seen for some site specific cancers such as neoplasms of buccal cavity and pharynx, urinary tract, lymphohematopoietic tissue, melanoma, and two neurodegenerative diseases, Parkinson's disease and amyotrophic lateral sclerosis. Excess mortality in the exposed cohort for specific outcomes was concentrated in the first period of follow-up (1986-1997), and waned starting 10 years after the high exposure ended. We also found lower mortality from breast cancer in females during the first period of follow-up. When we extended the analysis to include residents who had been consuming the high-selenium drinking water for a shorter period, mortality rate ratios were also increased, but to a lesser extent. Overall, we found that the mortality patterns related to long-term exposure to inorganic hexavalent selenium through drinking water were elevated for several site-specific cancers and neurodegenerative disease.

Selenium speciation in human serum and its implications for epidemiologic research: a cross-sectional study.

Observational studies addressing the relation between selenium and human health, particularly cancer risk, yielded inconsistent results, while most recent randomized trials showed a fairly consistent pattern suggesting null or adverse effects of the metalloid. One of the most plausible explanations for such inconsistencies is inadequate exposure assessment in observational studies, commonly carried out by measuring total Se content without taking into account the specific exposure to the individual chemical forms of the metalloid, whose toxic and nutritional properties may vary greatly. Data on the distribution of these species in human blood and their correlation with overall selenium levels are very limited. The concentrations of organic and inorganic selenium species were analyzed in serum of fifty subjects sampled from the general population of the municipality of Modena, northern Italy, aged from 35 to 70 years. Samples were collected during a 30-month period, and determinations of selenium species were carried out using high pressure liquid chromatography coupled with inductively coupled plasma dynamic reaction cell mass spectrometry. The majority of selenium was found to be present as organic species, but the inorganic forms showed higher levels than expected. These species showed limited correlations with age, sex and body mass index, while the organic forms increased in subjects consuming selenium-containing dietary supplements and decreased in smokers. The length of the sample storage period strongly influenced the distribution of selenium compounds, with a clear tendency towards higher inorganic and lower organic selenium levels over time. In multivariate analysis adjusting for potential confounders, total serum selenium correlated with human serum albumin-bound selenium and, in males, with two organic species of the metalloid (selenocysteine and glutathione peroxidase-bound selenium), while little association existed with the other organic forms and the inorganic ones. These findings highlight the potential for exposure misclassification of observational epidemiologic investigations based on overall selenium content in blood and possibly other tissues, and the critical role of the storage conditions for speciation analysis.

Toenail selenium and risk of type 2 diabetes: the ORDET cohort study.

Epidemiologic studies, particularly randomized controlled trials, have shown a direct relation between dietary and environmental exposure to the metalloid selenium and risk of type 2 diabetes. We investigated the association between baseline toenail selenium levels and diabetes occurrence in a case-control study nested in ORDET, a population-based female cohort in Northern Italy. After a median follow-up of 16 years, we identified 226 cases of type 2 diabetes cases and 395 age-matched control women with available toenail samples at baseline. The multivariate odds ratios of diabetes in increasing a priori defined categories of toenail selenium exposure were 1.09 (95% confidence interval 0.61, 1.96), 0.71 (0.38, 1.34) and 1.14 (0.46, 2.80) compared with the lowest category. The results were not substantially altered when quartile distribution of toenail selenium in controls was used to define exposure categories. Spline regression analysis did not show homogeneous risk trends. Overall, we did not find an association between toenail selenium and subsequent development of diabetes. Since the diabetogenic activity of selenium is strongly supported by experimental studies and some observational investigations, our null results might be explained by the limitations of overall selenium toenail content to assess environmental exposure to selenium species of etiologic relevance in the study population.

Friend or foe? The current epidemiologic evidence on selenium and human cancer risk.

Scientific opinion on the relationship between selenium and the risk of cancer has undergone radical change over the years, with selenium first viewed as a possible carcinogen in the 1940s then as a possible cancer preventive agent in the 1960s-2000s. More recently, randomized controlled trials have found no effect on cancer risk but suggest possible low-dose dermatologic and endocrine toxicity, and animal studies indicate both carcinogenic and cancer-preventive effects. A growing body of evidence from human and laboratory studies indicates dramatically different biological effects of the various inorganic and organic chemical forms of selenium, which may explain apparent inconsistencies across studies. These chemical form-specific effects also have important implications for exposure and health risk assessment. Overall, available epidemiologic evidence suggests no cancer preventive effect of increased selenium intake in healthy individuals and possible increased risk of other diseases and disorders.

The need for a reassessment of the safe upper limit of selenium in drinking water.

Results of recent epidemiologic studies suggest the need to reassess the safe upper limit in drinking water of selenium, a metalloid with both toxicological and nutritional properties. Observational and experimental human studies on health effects of organic selenium compounds consumed through diet or supplements, and of inorganic selenium consumed through drinking water, have shown that human toxicity may occur at much lower levels than previously surmised. Evidence indicates that the chemical form of selenium strongly influences its toxicity, and that its biological activity may differ in different species, emphasizing the importance of the few human studies on health effects of the specific selenium compounds found in drinking water. Epidemiologic studies that investigated the effects of selenate, an inorganic selenium species commonly found in drinking water, together with evidence of toxicity of inorganic selenium at low levels in from in vitro and animal studies, indicate that health risks may occur at exposures below the current European Union and World Health Organization upper limit and guideline of 10 and 40 µg/l, respectively, and suggest reduction to 1 µg/l in order to adequately protect human health. Although few drinking waters are currently known to have selenium concentrations exceeding this level, the public health importance of this issue should not be overlooked, and further epidemiologic research is critically needed in this area.

Possible involvement of overexposure to environmental selenium in the etiology of amyotrophic lateral sclerosis: a short review.

Excess exposure to the metalloid selenium (Se), a trace element with both toxicological and nutritional properties, has been implicated in the etiology of a human motor neuron disease of unknown origin and extremely severe prognosis, sporadic amyotrophic lateral sclerosis (ALS). This relation has been suggested on the basis of two epidemiologic investigations which found an increased risk of ALS associated with residence in a seleniferous area or with consumption of drinking water with unusually high levels of inorganic hexavalent Se, in South Dakota and in northern Italy respectively. Biological plausibility to a Se-ALS relation is provided by veterinary medicine observations and toxicological studies, showing that Se, particularly the inorganic forms, has a selective toxicity to motor neurons in swine and in cattle. Neurotoxic effects of Se species have also been demonstrated in laboratory studies and, for the inorganic forms, even at very low concentrations. Selenium has also been shown to affect muscle function in experimental animal models. Overall, these findings from the epidemiologic and the toxicological literature indicate that environmental Se, particularly in its inorganic forms and at unexpectedly low levels of exposure, might be a risk factor for ALS, suggesting the opportunity to further investigate this issue.

Risk of chronic low-dose selenium overexposure in humans: insights from epidemiology and biochemistry.

The latest developments of epidemiologic and biochemical research suggest that current upper limits of intake for dietary selenium and for overall selenium exposure may be inadequate to protect human health. In particular, recent experimental and observational prospective studies indicate a diabetogenic effect of selenium at unexpectedly low levels of intake. Experimental evidence from laboratory studies and veterinary medicine appears to confirm previous epidemiologic observations that selenium overexposure is associated with an increased risk of amyotrophic lateral sclerosis, and a recent large trial indicated no beneficial effect in preventing prostate cancer. Moreover, the pro-oxidant properties of selenium species and the observation that the selenium-containing enzymes glutathione peroxidases are induced by oxidative stress imply that the increase in enzymatic activity induced by this metalloid may represent at least in part a compensatory response. Taken together, the data indicate that the upper safe limit of organic and inorganic selenium intake in humans may be lower than has been thought and that low-dose chronic overexposure to selenium may be considerably more widespread than supposed.