key: cord-0893748-cbsjhsd8 authors: Doulgeridou, Aik; Amlund, H.; Sloth, J. J.; Hansen, M. title: Review of Potentially Toxic Rare Earth Elements, Thallium and Tellurium in Plant‐based Foods date: 2020-11-26 journal: EFSA J DOI: 10.2903/j.efsa.2020.e181101 sha: 23ba3bb7683492c51e6d59444880443ef8c49312 doc_id: 893748 cord_uid: cbsjhsd8 In the last decades, there is an increasing inclusion of various trace metals and metalloids such as thallium, tellurium and rare earth elements (REEs; lanthanides, scandium, and yttrium) in the composition and production of alloys, in agricultural and medicinal applications, as well as in the manufacturing of hi‐tech products. All these activities have led to an accumulation of the aforementioned elements both in soil and water bodies and consequently in the food chain, through discharges from mining and mineral processing, liquid industrial waste or disposal of urban and industrial products. It has been demonstrated that chronic exposure to some of these elements, even at low doses, might lead to a wide range of adverse health effects, even from the early stages of life, such as neurotoxicity, neurodevelopmental toxicity and hepatic alterations. Particularly in children, there have been studies suggesting that some of these elements might negatively affect the children's spatial learning and memory ability indirectly. Such effects are triggered by processes like the production of reactive oxygen species (ROS), lipid peroxidation and modulation of antioxidant activities. Nevertheless, the limited data from toxicological studies and their so‐far naturally low occurrence levels in the environment acted as a deterrent in measuring their concentrations during routine analyses of metals in foodstuff. Thus, it is important to collect information on their occurrence data both in adults and in children's daily diet. This review sumrises the current knowledge on the concentration of these elements, in plant‐based food products to identify whether a potential health risk occurs. As side projects, this Fellowship provided hands‐on training on the evaluation of new biocides application and participation in the given advice to the Danish Food and Veterinary Administration, Danish Environmental Protection Agency, the Danish Medical Agency and the European Chemicals Agency. 1. The history of human kind has been closely connected with metals and metalloids. Most attention has so far been paid to heavy metals and their toxicity to humans, through the food consumption. Nevertheless, in the last decades, the use of various trace metals and metalloids has increased in medicinal, industrial and agricultural applications (Du and Graedel, 2011) . As a result, there has been an elevation in their accumulation in the ecosystem (atmosphere, water, soil), resulting in potential human contamination via food, through discharges from mining and mineral processing, liquid industrial waste or disposal of urban and industrial products (Cheng et al., 2015) . In the current review, we focus on the rare earth elements, thallium, and tellurium. It has been documented that they can pass through the gastrointestinal tract and accumulate in the human body causing short-or long-term structural or functional alterations that can eventually lead to a toxic effect. The REEs are 17 f-block inner transition elements of the periodic table, consisting of the 15 lanthanides: lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb), and lutetium (Lu), and scandium (Sc) and yttrium (Y) (Connelly and Damhus, 2005) . They have similar physicochemical properties and are classified into light (Ce, La, Pr and Nd), medium (Sm, Eu and Gd) and heavy (Tb, Dy, Ho, Er, Tm, Yb, Lu and Y) REEs, according to their ionic radii, which for the trivalent REEs is similar to the one of calcium (Ca). Despite their name, most of the REEs are abundant in Earth's crust, with Ce being more plentiful than copper (Cu). Due to their geochemical properties though, they are dispersed and not found highly concentrated in minerals (Haxel et al., 2020) . The REEs and alloys containing them are used in many technological devices, like cell phones, computers and rechargeable batteries for phones, cameras, electric and hybrid vehicles . REEs are distributed to and accumulated at elevated concentrations in the liver, eyes, bone, spleen, lungs, kidneys, testis, brain, heart and adipose tissue (Fei et al., 2011; Kawagoe et al., 2005) . The distribution ratio in the organs is higher for the heavier REEs (Nakamura et al., 1997) . More specifically, it has been proved that the lighter lanthanides, as well as Eu, accumulate in the microsomal fraction of the liver, in the spleen and other organs rich in reticuloendothelial cells (Ohnishi et al., 2011; Magnusson, 1963; Haley, 1965; Durbin et al., 1956) . Yb has been shown to accumulate in the brain, liver and femur, while Tb has been found in liver, lung and spleen, with a very slow elimination rate (Feng et al., 2007; Shinohara et al., 1997) . Seven out of the seventeen REEs (Y, La, Ce, Nd, Gd, Tb and Yb) have been reported to have oxidative stress-related negative impacts. The most analysed endpoints were the lipid peroxidation, reactive oxygen species (ROS) production and formation of antioxidant activities, such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) (Marubashi et al., 1998; Tseng et al., 2012; Huang et al., 2011; Wu et al., 2013; Zhao et al., 2011b; Xia et al., 2011; Kumari et al., 2014b) . Furthermore, exposure to elements like Ce and La can lead to a decrease in body weight, accumulate in the liver and brain, and lead to alterations in the histopathology and organ function (Aalapati et al., 2014; Hong et al., 2014; Kumari et al., 2014a; Peng et al., 2014; Sang et al., 2013; Zhao et al., 2011b) . La has been shown to affect the spatial learning ability and memory of rats, potentially because of the inhibition of the signalling pathway in the hippocampus . Another study on La administration, during and after the pregnancy in mice resulted in smaller brain size and indication that this element is a potentially behavioural teratogen (Briner et al., 2000) . The REEs have already been found in edible plant-based foodstuff, like fresh edible fungi, vegetables (leafy, fruiting, legume, root, brassica, and bulb), and cereals (corn, rice and wheat flour) (Jiang et al., 2012; Zhuang et al., 2017; Howe et al., 2005) . Thallium (Tl) is an element belonging to the same family as aluminium, gallium and indium. It has been used as a pesticide for rodents and insects. Nowadays, it is used in the manufacturing of optic lenses and glass, in pharmaceuticals, medicine, alloys and electronics (International Programme on Chemical Safety, 1996; NLM, 1998; EPA, 1991b ; Agency for toxic substances and disease registry, 1992). While, naturally, it is found in small concentrations, thallium accumulation in soil has been increased because of human activity, like copper mining, during the smelting of ores (lead, copper, zinc) and petroleum-refining processes (Nriagu, 1998; Queirolo et al., 2009; Kazantzis, 2000) . It is considered a highly toxic element and once it enters the body, it is absorbed via gastrointestinal and respiratory tracts and widely distributed. It accumulates in the bone, liver, heart, muscle, lung, central nervous system and renal medulla (L eonard and Gerber, 1997; John Peter and Viraraghavan, 2005; Galvan et al., 2000) . Several mechanisms and modes of action have been proposed to explain the toxicity of Tl. Its chemical properties are similar to those of potassium (K). Thus, Tl can replace K and modify enzymatic activation of the Na+/ K+ ATPases, pyruvate kinase and other proteins, to move via the membrane system and accumulate in the cell (Britten and Blank, 1968; Kayne, 1971) . Another mechanism proposes that Tl inactivates sulfhydryl groups, responsible for increasing the permeability of mitochondria, leading to water influx and swelling (Spencer et al., 1973; Maya-L opez et al., 2018) . Exposure to Tl during pregnancy has been linked to decreased mitochondrial DNA in neonates (Wu et al., 2019) . Tl concentrations have been detected in grain and cereal, leafy vegetable (cabbage, lettuce, and kale), oilseed rape, bean and potato samples (Asami et al., 1996; Małuszy nski, 2009; Liu et al., 2019; Xiao et al., 2014 ). Tellurium (Te) is a metalloid included in the same group as oxygen, sulfur, selenium and polonium. It has been used as catalyst and pigment for ceramics, in metallurgy as an additive to other metals, in glass optical fibres for telecommunications, as well as in magnetic disk and solar panel manufacturing. Its alloys with other metals are used for nanomaterials, such as quantum dots (Fairhill, 1969; Kominkova et al., 2017; Nishii et al., 1992) . Te is distributed to the kidneys, liver, bone, brain and testes (MEDITEXT, 1997) . It has been reported that plants that accumulate selenium, can accumulate also Te. Therefore, there is a risk of Te exposure, after consuming a contaminated edible plant (onions, garlic) (Cowgill, 1988) . Furthermore, Te's chloride accumulates in brain cells, called astrocytes, and causes cytotoxicity (Roy and Hardej, 2011) . In addition to onions and garlic, Te has been found in baby food samples, citrus fruits, cereals, vegetables, legumes and potatoes (Filippini et al., 2019; Ruiz-de-Cenzano et al., 2017) . Description of work programme The main aim of the present work programme was to provide an overview of an area, still not completely explored. More specifically, this report reviews the current literature of the REEs, thallium and tellurium, regarding their potential toxicity after short-or long-term exposure, along with their concentrations in plant-based food including baby food. Moreover, the current work programme allowed the fellow to become familiar with how to conduct assessments in response to a request (public authorities, stakeholders) in compliance with ethical standards to prevent conflicts of interest. The project is comprised of a literature review of relevant publications (scientific papers and reports) published since 1956 on numerous trace metals and metalloids. The search was based on two factors: 1) Their potential toxicity on humans, mainly after oral administration. 2) Their occurrence in the human diet, and more specifically in edible plants. The initial plan was to perform chemical analysis and retrieve occurrence data of the aforementioned elements in plant-based food. Due to the COVID-19 crisis, there was a lockdown at the university and the performance of chemical analysis in the risk assessment of a specific scenario was not feasible. Therefore, a more theoretical approach, for the final part of the project, had to be adapted. Besides, the hosting institution encouraged the fellow to participate in the postgraduate course 'Risk Analysis in Food Safety', divided in microbiological and chemical risk assessment. The chemical risk assessment module included a group case study, with a final report and poster presentation, elaborating on the risk assessment on a chemical hazard. The fellow was part of the evaluation of applications and requests, related to biocides' products that meant to be used mainly as disinfectants. Furthermore, the fellow was taking part, monthly, in recommending and consulting the Danish Food and Veterinary Administration, the Danish Environmental Protection Agency, and the Danish Medical Agency regarding residues in food. During the fellowship programme the fellow participated in numerous secondary activities, provided by EFSA and DTU (Appendix B). The widespread application of the aforementioned elements in numerous industries and agriculture is increasing, by possibly leading to an increase of their concentrations into the environment and consequently our food. Therefore, the fact that these potentially toxic elements have been already detected in several plant-based foodstuff is of concern (Appendix A). For some of these elements, we have acquired knowledge regarding their adverse effects in human health. However, most of the animal studies up to now are limited to few REE (mostly Ce and La), and short-/medium-term tests (Pagano et al., 2015a; Pagano et al., 2015b) . The little research regarding their potential on humans toxicity combined with their high request in the technological applications has led to an apparent need to extend the research on this field, including hazard evaluation and risk assessment. The same argument applies for Tl and Te, as studies of long-term exposures and life-long observations are yet lacking, while their occurrence in human's diet is evident. The present study constitutes just the first step of all the steps needed to establish a chemical risk assessment regarding the potential risks posed by REEs, Tl and Te present in plant-based foodstuff, including baby-food. Nevertheless, this is a key step to estimate the size of this risk, according to the current knowledge. The next step would be to evaluate their content in foods that are consumed by the general population and to estimate their actual dietary intake. From a broader perspective, the EU-FORA programme provided the means to a fast and extensive first-hand knowledge and experience of food risk assessment. During the modules and hands-on training, the EU-FORA fellowship programme offered a unique opportunity of networking and enhancing the cooperation among the food safety agencies. In a multicultural atmosphere, the colleagues of the National Food Institute, DTU provided the expertise and mentoring, and creating the ideal environment for knowledge exchange on food safety. Therefore, National Food Institute makes a suitable host site for future EU-FORA fellows. Potatoes, skimmed milk, monkfish (10%), tomato, onion, butter, celery Te: 2.58 lg/kg (fw) Survey in Italian population (Filippini et al., 2019) Toxicity and bio accumulation of inhaled cerium oxide nanoparticles in CD1 mice Agency for toxic substances and disease registry, 1992. Toxicological profile for thallium Determination of thallium in soils by flame atomic absorption spectrometry Neurodevelopmental effects of lanthanum in mice The thallium activation of the (Na+-K+)activated ATPase of rabbit kidney Rare Earth Element Transfer from Soil to Navel Orange Pulp (Citrus sinensis Osbeck cv. Newhall) and the Effects on Internal Fruit Quality Nomenclature of Inorganic Chemistry: IUPAC Recommendations The tellurium content of vegetation Uncovering the global life cycles of the rare earth elements Metabolism of the lanthanons in the rat Available from the National Technical Information Service The mechanism of liver injury in mice caused by lanthanoids Ytterbium and trace element distribution in brain and organic tissues of offspring rats after prenatal and postnatal exposure to ytterbium Dietary estimated intake of trace elements: risk assessment in an Italian Population. 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Thallium in environment Thallium-induced toxicity in rat brain crude synaptosomal/mitochondrial fractions is sensitive to antiexcitatory and antioxidant agents Differences in behavior among the chlorides of seven rare earth elements administered intravenously to rats Recent advances and trends in chalcogenide glass fiber technology: a review Thallium. In HSDB (Hazardous Substances Data Bank) Tallium in the environment Health effects and toxicity mechanisms of rare earth elements: Knowledge gaps and research prospects Human exposures to rare earth elements: state of art and research priorities Comparative pulmonary toxicity of two ceria nanoparticles with the same primary size Thallium levels and bioaccumulation in environmental samples of norhern Chile: human health risks Tellurium tetrachloride and diphenyl ditelluride cause cytotoxicity in rathippocampal astrocytes Evaluation of the content of antimony, arsenic, bismuth, selenium, tellurium and their inorganic forms in commercially baby foods Kidney injury and alterations of inflammatory cytokine expressions in mice following long-term exposure to cerium chloride Distribution of terbium and increase of calcium concentration in the organs of mice i.v.-administered with terbium chloride Effects of thallium salts on neuronal mitochondria in organotypic cord-ganglia-muscle combination cultures Alteration of hepatic structure and oxidative stress induced by intravenous nanoceria Health risks of thallium in contaminated arable soils and food crops irrigated with wastewater from a sulfuric acid plant in western Guangdong province Lanthanum induced primary neuronal apoptosis through mitochondrial dysfunction modulated by Ca2+ and Bcl-2 family Prenatal exposure to thallium is associated with decreased mitochondrial DNA copy number in newborns: evidence from a birth cohort study Gadolinium-induced oxidative stress triggers endoplasmic reticulum stress in rat cortical neurons Environmental concerns related to high thallium levels in soils and thallium uptake by plants in southwest Guizhou Oxidative injury in the brain of mice caused by lanthanid Global potential of rare earth resources and rare earth demand from clean technologies. Minerals Health risk assessment of rare earth elements in cereals from mining area in Shandong Puree of fruits (100 g/100 g), (peach, banana and grape juice from concentrate), corn starch and vitamin C Te: 2 lg/kg (fw) potatoes (27%), onion, milk cream (3%) Te: 2.94 lg/kg (fw) Skimmed milk (32%), water, beans (14%), peas (10%), onion (5%), pasta (4%) Acknowledgements: This report is funded by EFSA as part of the EU-FORA programme.