Update of the risk assessment of nickel in food and drinking water

EFSA JournalVolume 18, Issue 11 e06268 Scientific OpinionOpen Access Update of the risk assessment of nickel in food and drinking water EFSA Panel on Contaminants in the Food Chain (CONTAM), Corresponding Author contam@efsa.europa.eu Correspondence:contam@efsa.europa.euSearch for more papers by this authorDieter Schrenk, Search for more papers by this authorMargherita Bignami, Search for more papers by this authorLaurent Bodin, Search for more papers by this authorJames Kevin Chipman, Search for more papers by this authorJesús del Mazo, Search for more papers by this authorBettina Grasl-Kraupp, Search for more papers by this authorChrister Hogstrand, Search for more papers by this authorLaurentius (Ron) Hoogenboom, Search for more papers by this authorJean-Charles Leblanc, Search for more papers by this authorCarlo Stefano Nebbia, Search for more papers by this authorEvangelia Ntzani, Search for more papers by this authorAnnette Petersen, Search for more papers by this authorSalomon Sand, Search for more papers by this authorTanja Schwerdtle, Search for more papers by this authorChristiane Vleminckx, Search for more papers by this authorHeather Wallace, Search for more papers by this authorThierry Guérin, Search for more papers by this authorPeter Massanyi, Search for more papers by this authorHenk Van Loveren, Search for more papers by this authorKatleen Baert, Search for more papers by this authorPetra Gergelova, Search for more papers by this authorElsa Nielsen, Search for more papers by this author EFSA Panel on Contaminants in the Food Chain (CONTAM), Corresponding Author contam@efsa.europa.eu Correspondence:contam@efsa.europa.euSearch for more papers by this authorDieter Schrenk, Search for more papers by this authorMargherita Bignami, Search for more papers by this authorLaurent Bodin, Search for more papers by this authorJames Kevin Chipman, Search for more papers by this authorJesús del Mazo, Search for more papers by this authorBettina Grasl-Kraupp, Search for more papers by this authorChrister Hogstrand, Search for more papers by this authorLaurentius (Ron) Hoogenboom, Search for more papers by this authorJean-Charles Leblanc, Search for more papers by this authorCarlo Stefano Nebbia, Search for more papers by this authorEvangelia Ntzani, Search for more papers by this authorAnnette Petersen, Search for more papers by this authorSalomon Sand, Search for more papers by this authorTanja Schwerdtle, Search for more papers by this authorChristiane Vleminckx, Search for more papers by this authorHeather Wallace, Search for more papers by this authorThierry Guérin, Search for more papers by this authorPeter Massanyi, Search for more papers by this authorHenk Van Loveren, Search for more papers by this authorKatleen Baert, Search for more papers by this authorPetra Gergelova, Search for more papers by this authorElsa Nielsen, Search for more papers by this author First published: 05 November 2020 https://doi.org/10.2903/j.efsa.2020.6268 Requestor: European Commission Question number: EFSA-Q-2019-00214 Panel members: Margherita Bignami, Laurent Bodin, James Kevin Chipman, Jesús del Mazo, Bettina Grasl-Kraupp, Christer Hogstrand, Laurentius (Ron) Hoogenboom, Jean-Charles Leblanc, Carlo Stefano Nebbia, Elsa Nielsen, Evangelia Ntzani, Annette Petersen, Salomon Sand, Dieter Schrenk, Tanja Schwerdtle, Christiane Vleminckx and Heather Wallace Acknowledgements: The Panel wishes to thank the following for the support provided to this scientific output: Elena Rovesti. The Panel wishes to acknowledge all European competent institutions, Member State bodies and other organisations that provided data for this scientific output. Adopted: 24 September 2020 This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2020.EN-1940/full AboutSectionsPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat Abstract The European Commission asked EFSA to update its previous Opinion on nickel in food and drinking water, taking into account new occurrence data, the updated benchmark dose (BMD) Guidance and newly available scientific information. More than 47,000 analytical results on the occurrence of nickel were used for calculating chronic and acute dietary exposure. An increased incidence of post-implantation loss in rats was identified as the critical effect for the risk characterisation of chronic oral exposure and a BMDL10 of 1.3 mg Ni/kg body weight (bw) per day was selected as the reference point for the establishment of a tolerable daily intake (TDI) of 13 μg/kg bw. Eczematous flare-up reactions in the skin elicited in nickel-sensitised humans, a condition known as systemic contact dermatitis, was identified as the critical effect for the risk characterisation of acute oral exposure. A BMDL could not be derived, and therefore, the lowest-observed-adverse-effect-level of 4.3 μg Ni/kg bw was selected as the reference point. The margin of exposure (MOE) approach was applied and an MOE of 30 or higher was considered as being indicative of a low health concern. The mean lower bound (LB)/upper bound (UB) chronic dietary exposure was below or at the level of the TDI. The 95th percentile LB/UB chronic dietary exposure was below the TDI in adolescents and in all adult age groups, but generally exceeded the TDI in toddlers and in other children, as well as in infants in some surveys. This may raise a health concern in these young age groups. The MOE values for the mean UB acute dietary exposure and for the 95th percentile UB raises a health concern for nickel-sensitised individuals. The MOE values for an acute scenario regarding consumption of a glass of water on an empty stomach do not raise a health concern. Summary The European Commission asked the European Food Safety Authority (EFSA) to update the previous EFSA Scientific Opinion on the risks to public health related to the presence of nickel in food and drinking water (EFSA CONTAM Panel, 2015), taking into account the new occurrence data, the updated benchmark dose (BMD) Guidance and any newly available scientific information. The CONTAM Panel developed the draft scientific Opinion which underwent a public consultation from 4 June until 15 July 2020. The comments received and how they were taken into account when finalising the scientific Opinion were published in an EFSA Technical Report (EFSA, 2020). Nickel is a widespread component of Earth's crust and is ubiquitous in the biosphere. Its presence in food and drinking water can arise from both natural and anthropogenic sources. Nickel occurs in different oxidation states. In food and drinking water, nickel generally occurs in the divalent form, which is the most stable oxidation state. Nickel is usually measured in food as total nickel and there are only few studies of nickel speciation in food. It is generally assumed that nickel occurs in food in the form of complex bound organic nickel, which has different physico-chemical and possibly also different biological properties than inorganic nickel. Hazard identification and characterisation Nickel absorption from the gastrointestinal tract is dependent on the chemical form and thus, the solubility of the nickel compound. Absorption may be decreased by binding or chelating substances, competitive inhibitors or redox reagents. On the other hand, absorption is often enhanced by substances that increase pH, solubility or oxidation, or by chelating agents that are actively absorbed. In humans, the bioavailability of nickel following ingestion also depends on the solubility of the administered nickel compound, the dosing vehicle and the fasting state of the subject. A low absorption (0.7–2.5%) was reported when nickel was ingested in the presence of food or under a non-fasted state, whereas a higher absorption (25–27%) was reported when nickel was ingested via drinking water in the absence of food, or under a fasted state. The number of individuals examined in the relevant human studies was low. There was also a considerable inter-individual variability in these studies. Thus, a precise estimate of the oral bioavailability of nickel in humans under different conditions cannot be established for the acute risk characterisation. A study in rats showed an absorption of around 10% when soluble nickel compounds were administered in a 5% starch saline solution as a vehicle. Such a condition is considered as being representative for dietary exposure via food and beverages for the chronic risk characterisation. After absorption, nickel is widely distributed in the organism. Nickel was shown to cross the placenta in mice. Nickel can also be transported across the blood–brain barrier. Absorbed nickel is excreted mainly via the urine. During lactation, nickel can also be excreted in the breast milk. An elimination half-life of 28 ± 9 h was estimated in human volunteers. The divalent metal transporter 1 (DMT1) mediates the transport of nickel and other divalent metal ions such as iron from the lumen of the intestine into the enterocyte and also mediates apical uptake of divalent cations in the kidney. DMT1 is known to be involved in the transport of divalent iron into the cytosol of endosomal cells prior to transport across the blood–brain barrier by ferroportin. Since nickel is also a substrate for DMT1, this transporter is likely to also be involved in nickel uptake into the brain. The major effects observed in the short-term repeated dose toxicity studies in rodents and dogs following oral administration were decreased body weight and effects in the liver and kidney (changes in organ weights and histopathological changes). Effects on bone and on gut microbiota have also been reported in a few recent studies. A few studies indicate that nickel can disturb neurobehavioural functions in mice and rats as indicated by impaired spatial memory performance and effects on locomotor activity. Neurodegeneration in adult rats has also been reported. In mice, different reproductive effects such as decreased male sex organ weights and histopathological changes in these organs, disturbed spermatogenesis, decreased sperm motility and sperm damage have been reported after oral exposure to soluble nickel compounds. The reproductive effects were responsible for a decreased fertility in mice. A recent short-term toxicity study (28 days) with limited reporting suggested that nickel may also cause testicular degeneration in rats. Mice appear to be more sensitive than rats regarding reproductive effects. There is consistent evidence of developmental toxicity in rats in the form of increased pup mortality (stillbirth or post implantation loss/perinatal lethality) and decreased pup weight after oral exposure to soluble nickel compounds. Developmental toxicity was also observed in mice (decreased fetal weight, malformations) but at higher doses than for rats suggesting that rats appear to be more sensitive than mice regarding developmental toxicity. Based on the available data, the CONTAM Panel considers that the increased incidence of post-implantation loss in rats is the critical effect for the risk characterisation of chronic oral exposure to nickel. This is in agreement with the previous Opinion. Nickel compounds are inactive in almost all bacterial mutagenicity tests and are weakly mutagenic in cultured mammalian cells. Nickel ions may be co-mutagenic, which is likely due to interference with DNA repair processes. Nickel compounds can induce sister chromatid exchanges, chromosomal aberrations and micronuclei at high (mM), cytotoxic levels in different mammalian cell systems; these effects are likely due to aneugenic as well as clastogenic actions. Nickel compounds have been shown to induce DNA single-strand breaks (SSBs), DNA–protein cross-links and oxidative DNA damage in mammalian test systems in vitro. Induction of chromosomal aberrations and micronuclei in rodents treated with different nickel compounds is not consistent across studies and both positive and negative results have been reported after oral administration, and intraperitoneal or subcutaneous injection. Nickel compounds give rise to both DNA SSBs and DNA–protein cross-links in vivo after oral administration or subcutaneous injection. No tumours have been observed in the carcinogenicity studies in experimental animals after oral administration of soluble nickel compounds. Nickel has different types of effects on the immune system. It is a sensitiser; hence exposure may lead to adverse hypersensitivity reactions. Oral exposure studies to investigate sensitisation to nickel by the oral route are scant. Oral exposure to nickel is not known to cause sensitisation, but nickel may elicit eczematous flare-up reactions in the skin of nickel-sensitised individuals that suffer from a condition known as systemic contact dermatitis (SCD). The CONTAM Panel concludes that SCD elicited by oral intake of nickel in humans already sensitive to nickel is the critical effect for the risk assessment of acute effects of nickel. However, there are uncertainties associated with information regarding adverse reactions in humans after ingestion of nickel. The evaluation is based on 3 individual studies, all with a limited number of nickel-sensitised individuals. The degree of sensitivity of these individuals is not known. The outcomes of these studies were expressed in different ways, i.e. as flare-up reactions of already eczematous skin lesions, or as flare-up reactions in addition to new skin reactions, which makes comparison of these studies difficult. Individuals were fasted before oral exposure to nickel and subsequent monitoring of the effects, which may not represent all types of nickel intake. Nevertheless, the CONTAM Panel considers, in agreement with the previous Opinion, that SCD is the critical effect for the risk characterisation of acute oral exposure to nickel. In the previous Opinion, the CONTAM Panel concluded that the data from the available epidemiological studies do not support an association between oral exposure to nickel and reproductive and developmental effects in humans. From the small number of studies published since the previous opinion, a few suggest that there may be an association between nickel exposure and adverse reproductive and developmental outcomes. No studies on neurotoxicity in humans were identified in the previous Opinion. In the few studies published since then, no clear signs of neurotoxicity were reported. No data linking cancer in humans with oral exposure to nickel are available. It is evident that oxidative stress and an elevation of reactive oxygen species (ROS) are involved in the toxicity of nickel. A contribution of oxidative stress is evident in relation to reproductive toxicity, genotoxicity, immunotoxicity and neurotoxicity. It has also been postulated that nickel might exert some of its effects via perturbation of iron homeostasis since divalent nickel competes with the transport of divalent iron into cells via DMT1 and possibly could also compete with iron sites on enzymes like the prolyl hydroxylases that modify hypoxia inducible factor-1α (HIF-1α). Nickel has been demonstrated to disturb regulation of mammalian reproductive function at several levels. Mice appear more sensitive than rats and this was associated with a higher level of oxidative stress in mouse testes compared to testes of rats. A part of this higher sensitivity of mice appears to be due to the formation of a complex between nickel and protamine 2 in sperm chromatin, which further elevates ROS production. Oxidative stress and nickel complexation with protamine 2 may both contribute to infertility. Rats have very low levels of protamine 2 in contrast to mice and humans, which have much higher levels of this protein. The fact that protamine 2 is expressed in humans might suggest that the mouse is a better model than the rat in predicting the ability of nickel to induce human male infertility. However, the relative level of the antioxidant status of human testes will be an important determinant of susceptibility based on the role of ROS. The genotoxicity of nickel is likely due to indirect effects including inhibition of DNA repair and ROS production. In addition, chromatin changes may occur following dysregulation of signalling pathways and alteration of the epigenetic landscape. The ability of nickel to bind to proteins is responsible for the induction of specific immune responses, leading to allergic reactions. These may be evident in the skin but can also occur elsewhere in the body. Nickel has also a non-specific activity on the immune system, such as the induction of inflammatory reactions through toll like receptors and nucleic factor kappa B signalling pathways that may be involved in the adverse reactions, including the allergic reactions. Even though predominant reactions to nickel occur after skin exposure, oral exposure to nickel may potentially induce these effects as well, and especially may elicit flare-up reactions in already sensitised individuals suffering from systemic contact dermatitis. In addition, nickel may also interfere with immunity through causing apoptosis of monocytes as observed in vitro, and thus may have an impact on host resistance. Nickel causes deficits in neurobehavioural performance in rodents and neuronal cell toxicity in vivo and in vitro. These effects are associated with oxidative stress and disturbance of mitochondrial aerobic metabolism evidently involving HIF-1α. Nickel is classified as a human carcinogen via inhalation. No data linking cancer in humans with oral exposure to nickel are available. No tumours have been observed in the carcinogenicity studies in experimental animals after oral administration of soluble nickel compounds. Therefore, the CONTAM Panel considers it unlikely that dietary exposure to nickel results in cancer in humans. For chronic oral exposure to nickel, the critical effect is the increased incidence of post-implantation loss in rats observed in the one- and two-generation studies. The CONTAM Panel noted that other toxic effects, including neurotoxic effects reported in the experimental animal studies were observed at higher dose levels than those resulting in developmental toxicity, i.e. post-implantation loss. From the BMD analysis, the BMDL10 of 1.3 mg Ni/kg body weight (bw) per day was selected as the reference point for the establishment of the tolerable daily intake (TDI). A TDI of 13 μg/kg bw was established by applying the default uncertainty factor of 100 to account for intra- and interspecies differences. For acute oral exposure to nickel, the critical effect is eczematous flare-up reactions in the skin (SCD) elicited in nickel-sensitised humans. The dose–response modelling showed that a BMDL could not be derived from the available data by applying the current BMD guidance. Therefore, the reference point was based on the no-observed-adverse-effect-level (NOAEL)/lowest-observed-adverse-effect-level (LOAEL) approach. In the absence of a NOAEL, a LOAEL of 4.3 μg Ni/kg bw was identified. In accordance with the previous Opinion, the data were considered insufficient to derive an acute reference dose (ARfD) and an margin of exposure (MOE) approach was applied for the acute risk assessment. The CONTAM Panel considered that an MOE of 30 or higher would indicate a low health concern. Occurrence/exposure for the EU population More than 47,000 analytical results on the occurrence of nickel in food and drinking water were used for the chronic and acute dietary exposure assessment. The highest mean nickel concentrations were measured for the food category 'Legumes, nuts and oilseeds' and for the food category 'Products for special nutritional use'. The mean lower bound (LB)/upper bound (UB) chronic dietary exposure to nickel across the different dietary surveys and age classes ranged from 1.57/1.89 μg/kg bw per day in elderly to 12.5/14.6 μg/kg bw per day in toddlers. The 95th percentile LB/UB chronic dietary exposure to nickel ranged from 3.35/3.93 μg/kg bw per day in very elderly to 28.1/29.9 μg/kg bw per day in infants. The food category, 'grains and grain-based products' was the most important contributor to the mean LB chronic dietary exposure to nickel in all age classes. The mean UB acute exposure ranged from 1.89 μg/kg bw per day in the elderly to 14.6 μg/kg bw per day in toddlers. The 95th percentile UB acute exposure ranged from 5.35 μg/kg bw per day in the elderly to 40.8 μg/kg bw per day in toddlers. The most relevant food categories for the 95th percentile UB acute dietary exposure varied between age classes and surveys. Beans, coffee, ready-to-eat soups, chocolate and breakfast cereals were the most relevant food categories in most of the surveys. The acute dietary exposure to nickel from consumption of a small bottle of water (500 mL) containing a high concentration of nickel was estimated to be 0.04 μg/kg bw from tap water and 0.08 μg/kg from bottled water. Risk characterisation The mean LB and UB chronic dietary exposure was below the TDI and thus, does not indicate a concern. However, for one survey in toddlers, the mean chronic dietary exposure was at the level of the TDI (LB/UB: 12.5/14.6 μg/kg bw per day) and this may indicate a health concern. The 95th percentile LB chronic dietary exposure exceeded the TDI in toddlers in 10 out of 14 dietary surveys and in other children in 11 out of 19 dietary surveys. Also in infants, an exceedance of the TDI was observed in some surveys. The 95th percentile LB chronic dietary exposure was below the TDI in adolescents and in all adult age groups. Thus, the 95th percentile chronic dietary exposure to nickel may raise a health concern for infants, toddlers and other children. The CONTAM Panel noted that the risk characterisation for chronic dietary exposure is conservative and thus will overestimate the risk, as the critical effect for the TDI, post-implantation loss, is not a relevant effect for young age groups. The TDI is also protective for effects that might occur in these age groups as no effects of relevance for young age groups have been reported at the reference point identified for the derivation of the TDI. Comparison of the estimated mean UB acute dietary exposure with the acute reference point of 4.3 μg Ni/kg bw resulted in MOE values ranging from 0.3 to 2.3, across dietary surveys and age classes. The MOE values when using the 95th percentile UB acute dietary exposure ranged from 0.1 to 0.8 across dietary surveys and age classes. Thus, these MOE values raise a health concern for nickel-sensitised individuals. For the scenario regarding consumption of a small bottle of drinking water, the MOE values of 120 and 55 for tap water and bottled water, respectively do not raise a health concern. Uncertainty analysis The CONTAM Panel concluded that the uncertainties in the risk assessment of acute exposure to nickel in food and drinking water are larger than for the chronic exposure. The CONTAM Panel considered that the use of fasting condition in the pivotal study is a major source of uncertainty and therefore the assessment is more likely to overestimate than to underestimate the risk. Recommendations In order to improve the risk assessment and reduce the uncertainties, the CONTAM Panel recommends the generation of more information on oral bioavailability of nickel in humans under different dosing regimens (i.e. vehicle, fasting/non-fasting condition). In addition, it is recommended to perform new studies with larger numbers of nickel-sensitised individuals and different dosing regimens and dose levels included to allow a better characterisation of the dose–response and facilitate a BMD approach. Such studies would form the basis for a more precise risk assessment of skin and systemic reactions to nickel exposure via food and drinking water in nickel-sensitised individuals. Information on the potential presence of nickel nanoparticles in food and drinking water is also needed. 1 Introduction 1.1 Background and terms of reference as provided by the requestor Background On 22 January 2015, EFSA's Scientific Panel on Contaminants in the Food Chain (CONTAM) adopted a Scientific Opinion on the risks to public health related to the presence of nickel in food and drinking water, in which it established a tolerable daily intake (TDI) of 2.8 μg/kg Ni/kg body weight (bw) per day and concluded that on the basis of the available occurrence data the current chronic dietary exposure raises health concerns for all age groups and that the acute exposure is of concern for nickel-sensitised individuals. The CONTAM Panel noted the need for mechanistic studies to assess the human relevance of the effects on reproduction and development that had been observed in experimental animals and for additional studies on human absorption of nickel from food; for example, in combination with duplicate diet studies. In its Opinion, EFSA considered occurrence data on nickel in food and drinking water, which were collected in 15 different European countries. However, as 80% of the total collected data were collected in just one Member State, a geographically more widespread data set would be needed to verify the occurrence of nickel in food throughout the EU. Furthermore, for certain food groups, considered as main contributors to dietary exposure in the EFSA Scientific Opinion, only limited occurrence data were available. In order to discuss possible future risk management measures, a better view of the nickel content in food commodities belonging to these food groups was needed. Therefore, by means of Recommendation (EU) 2016/111111 Commission Recommendation (EU) 2016/1111 of 6 July 2016 on the monitoring of nickel in food. C/2016/3858. OJ L 183, 8.7.2016, p. 70–71., Member States were asked to collect additional occurrence data for several foodstuffs in 2016, 2017 and 2018. On 17 November 2016, EFSA adopted its updated guidance on the use of the benchmark dose (BMD) approach in risk assessment, which might impact on the previously established TDI for nickel. It is therefore appropriate to request EFSA to update the EFSA Scientific Opinion on the risks to public health related to the presence of nickel in food and drinking water, taking into account the new occurrence data, the updated BMD Guidance and any newly available scientific information. Terms of reference In accordance with Art 29 (1) of Regulation (EC) No 178/200222 Regulation (EC) No 178/2002 of the European Parliament and of the Council of 28 January 2002 laying down the general principles and requirements of food law, establishing the European Food Safety Authority and laying down procedures in matters of food safety. OJ L 31, 1.2.2002, p. 1–24., the European Commission asks the European Food Safety Authority for an updated Scientific Opinion on the risks to public health related to the presence of nickel in food and drinking water, taking into account the new occurrence data, the updated BMD Guidance and any newly available scientific information. 1.2 Interpretation of the terms of reference The CONTAM Panel concluded that this Opinion should comprise: an evaluation of the toxicity of nickel for humans, considering all relevant toxicological endpoints; an estimation of the dietary exposure of the EU population to nickel from food and drinking water, including the consumption patterns of specific groups of the population; and an assessment of the human health risks to the EU population, including specific (vulnerable) groups of the population, as a consequence of the estimated dietary exposure. In the context of human exposure to nickel via the diet and drinking water, water-soluble nickel compounds are the most relevant. This Scientific Opinion is therefore confined to water-soluble nickel compounds (i.e. nickel (II), nickel chloride, nickel sulfate, nickel dinitrate and nickel acetate). Non- or low-soluble nickel compounds such as nickel sulfide, nickel oxide and nickel carbonate are not considered in the current assessment. Nickel can also be present in the environment as nickel nanoparticles. In the absence of evidence that nickel nanoparticles occur in food and/or drinking water, studies on the toxicity of nickel nanoparticles were not considered in the present assessment. As outlined in the terms of reference, the current risk assessment is an update of the previous Opinion, published in 2015. The literature search for the latter was conducted in 2013. Therefore, papers published since 2013 were taken into account for the current risk assessment when not yet included in the previous Opinion. 1.3 Supporting information for the assessment This section is an adapted and amended version of the corresponding sections in the previous Opinion on nickel in food and drinking water (EFSA CONTAM Panel, 2015). 1.3.1 Chemistry The chemistry of nickel (CAS registry No. 7440-02-0) and nickel compounds is described in many general scientific references (e.g. IARC, 1990, 2012; Health Canada, 1994; ATSDR, 2005, EU RAR 2008; Nielsen and Larsen, 2013). Only the main relevant information is presented here. Nickel is a silver-white metal with typical metallic properties and has an atomic number of 28 and atomic weight of 58.71. It has five naturally occurring stable isotopes, with mass numbers 58 (68.07%), 60 (26.23%), 61 (1.14%), 62