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EC number: 237-048-9 | CAS number: 13597-46-1
Essentiality of selenium
Human health risk assessments conventionally focus primarily on the effects of high doses of chemicals, which ultimately may induce toxicity. However, in the case of essential trace elements, harmful effects may also occur at low intakes due to deficiency. This has implications for risk assessment when the aim of minimising exposure as far as possible may result in recommendations that lead to harm from deficiency.
It is well established that selenium is an essential element for humans, and animals,that is found ubiquitously in the environment, being released from both natural and anthropogenic sources.“Exposure of the general population to selenium is primarily by ingestion of its organic and inorganic forms, both of which occur naturally in the diet.Other exposure pathways for selenium, which are of lesser importance, are water and air. […] As an essential trace element in humans and animals, selenium is a biologically active part of a number of important proteins, particularly enzymes involved in antioxidant defence mechanisms (e.g., glutathione peroxidases), thyroid hormone metabolism (e.g., deiodinase enzymes), and redox control of intracellular reactions (e.g., thioredoxin reductase).“(ATSDR, 2003). Without selenium, organisms cannot function and will show signs of deficiency.
As for many essential nutrients, recommendations are issued by different organisations in various countries on lower and adequate intake levels, and minimum dietary requirements of selenium. “The current RDA[Recommended Dietary Allowance; ed.]for selenium, established by the Food and Nutrition Board of the National Research Council (National Academy of Sciences), is 55 μg/day for male and female adults (approximately 0.8 μg/kg/day)”(ATSDR, 2003). RDA of selenium in European countries varies between 30 and 75 µg [EC Scientific Committee on Food: Opinion of the Scientific Committee on Food on the revision of reference values for nutrition labelling (2003)].“The current NAS [National Academy of Science; ed.] Tolerable Upper Intake Level (UL) for selenium is 400 μg/day for adults (approximately 5.7 μg/kg/day)”.The recommended nutrient intakes (RNI) of selenium, recommended by the WHO, 2001: Human Vitamin and Mineral Requirements are 25 – 26 µg/d for adult females and 33 – 34 µg/d for adult males. During pregnancy and lactation the estimated requirements are up to 42 µg/d.
Comparison of toxicity of the zinc component and the selenite component in zinc selenite
Based on a comparison between toxicity reference values for zinc substances and selenium compounds, it can safely be assumed that the selenium/selenite moiety of zinc selenite is generally of higher toxicological relevance than the zinc cations. This is based on the following comparison of oral NOAELs for “zinc” substances (source: EU RAR zinc and zinc substances, ECB) with those of NOAELs for “selenite”, which indicate significantly higher toxicity of the selenite moiety. This comparison is restricted to systemic toxicity in view of the lack of any local effects of zinc selenite:
NOAELs for “zinc” from zinc metal EU RAR:
- human oral NOAEL of 50 mg Zn2+/day (0.83 mg/kg bw/day)
NOAELs for “selenite”:
- lowest oral NOAEL (rat, 2 months):0.12 mg Se/kg bw/d(administered as sodium selenite)
However, because of the very low water solubility and the thus anticipated poor oral absorption of zinc selenite (~1 %), the toxicity of zinc selenite may reasonably be anticipated to be much lower than that of the soluble selenite substances. Nevertheless, in lack of substance-specific data, the dossier on zinc selenite is based on read-across from selenites or selenates, with the bioavailability correction described in detail below.
Very little toxicological data exist with the test substance zinc selenite itself. However, for any kind of systemic toxicity, a substance first needs to be taken up systemically. In the case of an inorganic salt like zinc selenite, such an uptake requires dissolution of the substance, i.e. dissociation into ions. Zinc selenite initially dissociates into zinc cations (Zn2+) and selenite anions (SeO32-). Since toxicological test data are available for sodium selenite (Na2SeO3) and selenous acid (H2SeO3), the first level of read-across considers extrapolation from these substances to zinc selenite.
a) In vivo toxicokinetic data or in vitro bioaccessibility data for a comparative assessment of relative bioavailability of various selenite substances are not available. Thus, water solubility is adopted as a surrogate of bioavailability:
Sodium selenite and selenous acid are readily soluble, with water solubilities of 800 – 900 g/L and 1670 g/L at 20 °C, respectively. Zinc selenite is a salt which is only poorly soluble in water at a concentration of 16 mg/L at 20 °C. Based on that, an intrinsically very conservative read-across from the highly soluble selenite substances to the poorly soluble zinc selenite is proposed since zinc selenite may reasonably be assumed to have a lower bioavailability than sodium selenite or selenous acid.
b) Sodium selenite, selenous acid and zinc selenite all liberate the selenite anion upon dissolution. Assuming that (i) sodium selenite, and zinc selenite both dissociate in water to SeO32-and the cationic counter-ions, and (ii) the potential effects are caused by SeO32-and not by the cations, the results from the available studies with sodium selenite can be used for read across to zinc selenite. The selenite anions are formed under most physiologically relevant conditions (i.e., neutral pH), thus facilitating unrestricted read-across between these species. In slightly acid condition, the hydrogenselenite ion, HSeO3-, is formed; in more acidic conditions selenous acid, H2SeO3, exists.
H2SeO3<=> H++ HSeO3- (pKa= 2.62)
HSeO3- <=> H++ SeO32- (pKa= 8.32)
Based on these equilibrium conditions, read-across between the groups of selenites, hydrogenselenites and selenous acid is possible.
c)Considering the poor water solubility of zinc selenite (16 mg/L), the extrapolation of the above values obtained with highly soluble selenite substances is likely to constitute an intrinsic overestimate of bioavailability. However, due to the lack of information on substance-specific in-vivo toxicokinetic or in-vitro bioaccessibility data related to zinc selenite, read-across from the absorption data of other selenites should be performed. However, since the water solubility is about a factor of > 10 000 lower for zinc selenite compared to sodium selenite,it appears appropriate to introduce a default oral absorption factor of 1 %, although the differences in solubility are much higher.
The following summary was extracted from an evaluation of toxicokinetic information performed by a renowned scientific body (ATSDR, 2003).According to ATSDR (2003), selenites are generally readily absorbed after oral administration. Absorption rates of selenites in humans and animals after ingestion often exceed 80 % of the administered dose. In human studies, absorption rates of 90–95 % have been observed(Thomson 1974, Thomson et al. 1977). Absorption in rats after oral administration of sodium selenite was examined to be between 80–100 %(Furchner et al. 1975; Thomson and Stewart 1973). However, in a recent publication,Frankenberger & Benson (1994) described a lower absorption rate for sodium selenite administered to humans as food fortificant: „The selenite is a white, water-soluble compound, from which absorption is about 50 %”.However,overall it may be assumed that oral absorption of selenites is more or less complete (>> 80 %).
Considering the very low water solubility of zinc selenite (16 mg/L), the extrapolation of the above values obtained with highly soluble selenite substances is likely to constitute an intrinsic overestimate of bioavailability.However, due to the lack of informationon substance-specific in-vivo toxicokinetic or in-vitro bioaccessibility datarelated to zinc selenite, read-across from the absorption data of other selenites could in principle be performed. However, since the water solubility is about a factor >10 000 lower for zinc selenite compared to sodium selenite, it appears appropriate to introduce a default oral absorption factor of 1 %, although the differences in solubility are much higher.
In the absence of measured data on dermal absorption, current guidance suggests the assignment of either 10% or 100% default dermal absorption rates. In contrast, the currently available scientific evidence on dermal absorption of metals (predominantly based on the experience from previous EU risk assessments) yields substantially lower figures, which can be summarised briefly as follows:
Measured dermal absorption values for metals or metal compounds in studies corresponding to the most recent OECD test guidelines are typically 1 % or even less. Therefore, the use of a 10 % default absorption factor is not scientifically supported for metals. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn), which have derived dermal absorption rates of 2 % or far less (but with considerable methodical deviations from existing OECD methods) fromliquidmedia.
However, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the in the EU RA on zinc. A reasoning for this is described in detail elsewhere (Cherrie and Robertson, 1995), based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than it’s mass.
Consistent with the methodology proposed in HERAG guidance for metals (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metal cations and inorganic metal substances; EBRC Consulting GmbH / Hannover /Germany; August 2007), the following default dermal absorption factors for metal cations have therefore been proposed (reflective of full-shift exposure, i.e. 8 hours):
From exposure to liquid/wet media: 1.0 %
From dry (dust) exposure: 0.1 %
Given that the primary cause between the lack of percutaneous transfer is considered to be the ionic nature, it is proposed to assume similar behaviour forseleniumanions as for metal cations, and toadopt the above stated dermal absorption factors for zinc selenite.
No data on inhalation absorption are available for zinc selenite, and little reliable information is available in ATSDR (2003) on absorption and distribution of other selenium compounds after inhalation. According to ATSDR (2003) “Occupational studies indicate that humans absorb elemental selenium dusts and other selenium compounds, but quantitative inhalation toxicokinetic studies in humans have not been done”.A study by Glover (1970) “indicates that[although; ed.]selenium was absorbed from the lungs of the workers, the nonspecific exposure levels and lack of compound identification precluded an estimate of the extent and rate of absorption from the lungs.[...]Studies using dogs and rats indicate that absorption of selenium following inhalation exposure is extensive, although the rate of absorption depends on the chemical form of selenium. In rats(Medinsky et al. 1981a)and dogs(Weissman et al. 1983),the absorption of selenium following inhalation exposure to selenious acid aerosol is approximately twice as rapid as the absorption of selenium following inhalation exposure to elemental selenium aerosol.”
Nevertheless, after completion of a testing programme on dustiness testing and particle size analysis of the airborne fraction on zinc selenite, the collected information can be used to estimate inhalation absorption factors based on a prediction of deposition patterns in the respiratory tract (MPPD model), in accordance with guidance developed under HERAG.
The available particle size data can be summarised as follows: Zinc selenite is produced as a solid powder, with a physical particle size D50 of 17.4 µm; the total dustiness of this material was determined at 151.82 mg/g – in other words, approximately 15 % of the material has the tendency to become airborne (for details see IUCLID section 4.5).
Based on the above particle size data of zinc selenite, inhalation absorption factors can be derived according to the following scheme:
The systemic availability of zinc selenite via the inhalation route can be expected as a function of regional deposition in the respiratory tract, which in turn depends foremost on the particle size distribution of the inhaled dust. However, product-specific physical particle size distributions do not necessarily reflect the particle size of aerosols that may be formed under practically relevant workplace conditions, for example during manual operations such as filling and emptying of bags, or under mechanical agitation as in mixing and weighing operations.
During the dustiness testing (Parr, 2010), the sample was introduced into a rotating drum apparatus according to DIN 55992 Part 1, to simulate mechanical agitation. In this modified rotating drum method, a fraction of the material becomes airborne and is carried out of the drum by a constant air stream into a cascade impactor. From the mass fractions deposited on the impactor stages, the mass median aerodynamic diameter (MMAD) of the airborne material has been determined together with the geometric standard deviation (GSD) of the MMAD (Grewe, 2010).
In the absence of actual measurements of the distribution of dust particles in the workplace air, the above determined MMAD and GSD can therefore be used as surrogate parameters of the associated particle size distribution. It takes into account potential particle agglomeration under mechanical agitation and the fact that larger/heavier particles show less tendency to become airborne (and are therefore not likely to be available via inhalation of workplace air).
The relative densities of the samples were determined according to European Commission Regulation (EC) No. 440/2008 method A.3. and OECD-Guideline 109. Data on particle size, relative density and calculated MMAD and associated GSD are presented in Table 1:
Table1:Data on particle size, dustiness and relative density of zinc selenite
MMAD of airborne particles#(mm)
Geometric standard deviation of MMAD (mm)
4.69 at 20°C
13.13 (23.4 %)
26.17 (76.6 %)
*d50 = median physical particle size
#MMAD = mass median aerodynamic diameter, for the observed bimodal distribution
In order to estimate the deposition of particles in the respiratory tract (head, tracheobronchial and pulmonary region), the Multiple Path Particle Deposition (MPPD) model (CIIT, 2002-2006) was used with the following input data: The human–five lobular lung model, a polydisperse particle distribution, oronasal (normal augmenter) mode, a full shift breathing volume of- corresponding to a tidal volume of 1042 ml and a breathing frequency of 20 breaths * min-1, and an aerosol concentration of 5,000 µg/m3.
Table 2:Calculated deposited fractions of zinc selenite
The fate and uptake of deposited particles depends on the clearance mechanisms present in the different parts of the airway. In the head region, most material will be cleared rapidly, either by expulsion or by translocation to the gastrointestinal tract. A small fraction will be subjected to more prolonged retention, which can result in direct local absorption. More or less the same is true for the tracheobronchial region, where the largest part of the deposited material will be cleared to the pharynx (mainly by mucociliary clearance) followed by clearance to the gastrointestinal tract, and only a small fraction will be retained (ICRP, 1994). Once translocated to the gastrointestinal tract, the uptake will be in accordance with oral uptake kinetics.
In consequence, the material deposited in the head and tracheobronchial regions would be translocated to the gastrointestinal tract, where it would be subject to gastrointestinal uptake at a ratio of 1% (see discussion oral absorption). The material that is deposited in the pulmonary region may be assumed by default to be absorbed to 100%. This absorption value is chosen in the absence of relevant scientific data regarding alveolar absorption although knowing that this is a conservative choice. Thus, a predicted inhalation absorption factor of 1.4 % (rounded value) can be derived for zinc selenite.
“Selenium accumulates in many organ systems in the body; in general, the highest concentrations are found in the liver and kidney. […] Selenium concentrations in tissues do not seem to be correlated with effects. […] Blood, hair, and nails also contain selenium, and selenium has been found in human milk. […] In addition, selenium is subject to placental transfer.”(ATSDR, 2003).
“In summary, inorganic selenium is reduced stepwise to the assumed key intermediate hydrogen selenide, and it (or a closely related species) is either incorporated into selenoproteins after being transformed to selenophosphate and selenocysteinyl tRNA according to the UGA codon encoding selenocysteinyl residue, or excreted into urine after being transformed into methylated metabolites of selenide. […] Consequently, selenium is mainly present in the mammalian body in forms of covalent carbon-selenium bonds, particularly selenoprotein P (the principal selenoprotein in plasma), selenoenzymes such as glutathione peroxidases (enzymes that catalyze the reduction of peroxidases and thereby protect cells from oxidative damage), type 1-iodothyronine deiodinase (which catalyzes the deiodination of thyroxine to triiodothyronine), and thioredoxin reductase (which may trigger cell signaling in response to oxidative stress) […] As a component of glutathione peroxidase and the iodothyronine 5'-deiodinases, selenium is an essential micronutrient for humans. Its role in the deiodinase enzymes may be one reason that growing children require more selenium than adults. Selenium is also a component of the enzyme thioredoxin reductase, which catalyses the NADPH-dependent reduction of the redox protein thioredoxin. Other selenium containing proteins of unknown functions, including selenoprotein P found in the plasma, have also been identified. Excess selenium administered as selenite and selenate can be metabolized to methylated compounds and excreted.”(ATSDR, 2003).
„Selenium is primarily eliminated in the urine and faeces in both humans and laboratory animals. The distribution of selenium between the two routes seems to vary with the level of exposure and time after exposure. The form of selenium excreted is dependent on the form of selenium that was ingested. [...] Sweat is a minor pathway of selenium excretion in humans. […] In cases of acute exposure to toxic concentrations of selenium or selenium compounds, significant amounts of selenium can be eliminated in the breath, causing the characteristic ‚garlic breath‘. [...] Thomson and Stewart (1974) found that <6% of a trace dose (0.01 mg selenium) of orally administered sodium selenite was excreted in the urine within 24 hours of administration, whereas 64–73% of a 1-mg dose of selenium was excreted in the first 24 hours. […] Thus, when higher amounts of selenium are administered, a higher proportion of the selenium is excreted in the urine during the first 24 hours following exposure. […] Decreasing urinary or faecal excretion appears to be the homeostatic mechanism by which the body retains greater amounts of selenium“(ATSDR, 2003).
-CIIT, (2006). Multiple-path Particle Deposition Model. Chemical Industry Institute of Toxicology, National Institute of Public Health and the Environment (RIVM), the Netherlands, and The Ministry of Housing, Spatial Planning and the Environment, the Netherlands 2002-2006
- Cherrie and Robertson (1995): Biologically relevant assessment of dermal exposure. Ann. Occup. Hyg. 39, 387-392
-Frankenberger, W.T.; Benson, S. (1994). Selenium in the environment. New York, N.Y: Marcel Dekker, p. 133
-Furchner JE, London JE, Wilson JS. (1975). Comparative metabolism of radionuclides in mammals. IX. Retention of 75Se in the mouse, rat, monkey and dog. Health Phys 29:641-648.
-Glover, J.R. (1970). Selenium and its industrial toxicology. Indust Med 39(1):50-53.
-Grewe (2010). Final Report – Dustiness and particle size testing: zinc selenite. EBRC Consulting GmbH, Hannover, Germany, 5th August 2010.
- HERAG (2007): HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal substances; EBRC Consulting GmbH / Hannover /Germany; August 2007
-ICRP (1994). Human Respiratory Tract Model for Radiological Protection. Pergamon Press, Elsevier Science Ltd UK, ISBN 0 08 041154 1; 66
-Medinsky, M.A.; et al. (1981a). A simulation model describing the metabolism of inhaled and ingested selenium compounds. Toxicol Appl Pharmacol 59:54-63.
-Parr (2010): Final-Report on the determination of the dust generation tendency („dustiness“) of Zinkselenit, Report No. GS3-00007-10, DMT GmbH & Co.KG, Essen, Germany, 03/03/2010.
-Thomson, C.D. (1974). Recovery of large doses of selenium given as sodium selenite with or without vitamin E. N Z Med J 80:163-168
-Thomson, C.D. (1977). Selenium in human health and disease: A review. Trace elements in human and animal health and disease in New Zealand. Hamilton, New Zealand: Waikato University Press, 72-83.
-Thomson, C.D.; Stewart, R.D.H. (1973). Metabolic studies of [75Se]selenomethionine and [75Se]selenite in the rat. Br J Nutr 30:139-147.
- Thomson, C.D.; Stewart, R.D.H. (1974). The metabolism of [75Se]selenite in young women. Br J Nutr 32:47-57.
-Weissman, S.H.; Cuddihy, R.G.; Medinsky, M.A. (1983). Absorption, distribution, and retention of inhaled selenious acid and selenium metal aerosols in beagle dogs. Toxicol Appl Pharmacol 67:331-337.
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