EFSA received a request from the Hellenic Food Authority (EFET) for a scientific opinion on the risk to human health from the presence of nickel (Ni) in food, particularly in vegetables. The EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) decided to extend the risk assessment also to drinking water. The reproductive and developmental toxicity in experimental animals was selected as the critical effect for the assessment of chronic effects of Ni. A tolerable daily intake of 2.8 µg Ni/kg body weight (b.w.) per day was derived from a lower 95 % confidence limit for a benchmark dose at 10 % extra risk (BMDL10) of 0.28 mg/kg b.w. for post-implantation fetal loss in rats. The current dietary exposure to Ni raises concern when considering the mean and 95th percentile chronic exposure levels for all different age groups. The systemic contact dermatitis (SCD) elicited in Ni-sensitive humans after oral exposure to Ni was selected as the critical effect suitable for the assessment of acute effects of Ni. A lowest BMDL10 of 1.1 µg Ni/kg b.w. was derived for the incidence of SCD following oral exposure to Ni of human volunteers. The CONTAM Panel applied a margin of exposure (MOE) approach and considered an MOE of 10 to be indicative of a low health concern. The MOEs calculated considering the estimated mean and the 95th percentile acute exposure levels were considerably below 10 for all age groups. Overall, the CONTAM Panel concluded that, at the current levels of acute dietary exposure to Ni, there is a concern that Ni-sensitized individuals may develop eczematous flare-up skin reactions. The CONTAM Panel noted the need for mechanistic studies to assess the human relevance of the effects on reproduction and development observed in experimental animals and for additional studies on human absorption of nickel from food, for example in combination with duplicate diet studies.
In March 2012, the European Food Safety Authority (EFSA) received a request from the Hellenic Food Authority (EFET) for a scientific opinion on the risk to human health for the presence of nickel (Ni) in food addressing particularly the presence of Ni in vegetables. The EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) decided to extend the risk assessment to Ni in water intended for human consumption and natural mineral waters, to assess their contribution to the dietary exposure to nickel.
Ni is a widespread component of Earth’s surface. Its presence in food and drinking water is determined by both natural and anthropogenic factors, the latter generically identifiable with industrial and technological sources. In food and drinking water Ni generally occurs in the divalent form – Ni2+ or Ni(II) – its most stable oxidation state.
There are no maximum levels (MLs) for Ni in food. For drinking water, a parametric value of 20 μg Ni/L in water intended for human consumption, and a ML of 20 μg Ni/L in natural mineral waters are laid down in Council Directive 98/83/EC and in Commission Directive 2003/40/EC, respectively. These maximum limits are well within the guideline value of 70 µg/L set by the World Health Organization (WHO, 2005).
Following a call for data on Ni levels in food and drinking water (water intended for human consumption and mineral waters), a total of 18 885 food samples and 25 700 drinking water samples were available in the final dataset to estimate dietary exposure to nickel. No speciation data were provided. Samples were collected between 2003 and 2012 in 15 different European countries, with almost 80 % of the total collected in one Member State. The most reported analytical methods were inductively coupled plasma-mass spectrometry (ICP-MS) and atomic absorption spectrometry (AAS), that represented 54 % and 42 % of the methods reported, respectively. The highest sensitivity was reported for the analysis of drinking water with a limit of quantification (LOQ) of 0.001 µg/L (for both ICP-MS and AAS). In food, ICP-MS showed the lowest LOQ for the analysis of ‘Alcoholic beverages’ (0.002 µg/kg) while the lowest LOQ reported with AAS was 1 µg/kg for samples of ‘Fish and seafood’ and ‘Sugar and confectionery’. In the final dataset, left-censored data represented 66 % of the analytical results, with 35 % in food samples and 89 % in drinking water samples.
At FoodEx level 1, all food groups were well represented, with a maximum of 25 700 samples of ‘Drinking water’ and 4 291 and 3 738 samples in the food groups ‘Grain and grain-based products’ and ‘Vegetables and vegetable products (including fungi)’, respectively. High mean levels of Ni were reported for ‘Legumes, nuts and oilseeds’ (~ 2 mg/kg), certain types of chocolate (cocoa) products (3.8 mg/kg), and ‘Cocoa beans and cocoa products’ (9.5 mg/kg).
The potential leaching of Ni into food from food contact material is not covered by the occurrence dataset used to estimate dietary exposure.
Chronic dietary exposure to Ni was estimated combining food mean occurrence data with food consumption data at the individual level. Mean chronic dietary exposure to nickel, across the different dietary surveys and age classes, ranged from 2.0 (minimum lower bound (LB), ‘Elderly’) to 13.1 μg/kg body weight (b.w.) per day (maximum upper bound (UB), ‘Toddlers’). The 95th percentile dietary exposure ranged from 3.6 (minimum LB, ‘Elderly’) to 20.1 μg/kg b.w. per day (maximum UB, ‘Toddlers’). Among the different age classes, ‘Toddlers’ and ‘Other children’ showed the highest chronic dietary exposure to nickel. Overall, the main contributors to the dietary exposure to nickel across the different dietary surveys and age classes were ‘Grain and grain-based products’, ‘Non-alcoholic beverages (except milk-based beverages)’, ‘Sugar and confectionery’, ‘Legumes, nuts and oilseeds’, and ‘Vegetables and vegetable products (including fungi)’. ‘Milk and dairy products’ were also important contributors to the dietary exposure to nickel in the young population, in particular in toddlers. In the age classes ‘Other children’ and ‘Adolescents’ the relatively high consumption of chocolate and chocolate-based products made ‘Sugar and confectionery’ one of the main contributors. The important role of ‘Non-alcoholic beverages (except milk-based beverages)’ in the dietary exposure to nickel is explained by the consumption of cocoa beverages and coffee in the young and adult population, respectively.
The contribution of ‘Drinking water’ to the total exposure to nickel was very small across dietary surveys and age classes (0.0005 %–1.7 %, LB-UB).
Highest levels for acute dietary exposure were observed in ‘Toddlers’ and ‘Other children’. Mean dietary acute exposure in the young population (‘Infants’, ‘Toddlers’, ‘Other children’ and ‘Adolescents’) ranged from 3.4 (95 % confidence interval (CI) = 3.1–3.7) μg/kg b.w. in one survey for ’Adolescents’ to 14.3 (95 % CI = 13.2–15.5) μg/kg b.w. in one survey for ’Toddlers’. The 95th percentile ranged from 8.6 (95 % CI = 8.0–9.1) μg/kg b.w. in one survey for ‘Adolescents’ to 35.0 (95 % CI = 26.8–47.2) μg/kg b.w. in one survey for ‘Toddlers’. Mean dietary acute exposure in the adult population (‘Adults’, ‘Elderly’ and ‘Very elderly’) ranged from 2.5 (95 % CI = 2.2–2.9) μg/kg b.w. in one survey for ‘Elderly’ to 4.9 (95 % CI = 4.6–5.5) μg/kg b.w. in one survey for ‘Adults’. The 95th percentile ranged from 5.5 (95 % CI = 5.1–6.0) μg/kg b.w. in one survey for ‘Elderly’ to 11.8 (95 % CI = 10.6–13.8) μg/kg b.w. in one survey for ‘Adults’.
The CONTAM Panel concluded that the exposure via the diet likely represents the most important contribution to the overall exposure to Ni in the general population. Both for smokers and non-smokers not occupationally exposed to Ni, exposure by inhalation may be expected in general to represent a negligible or minor addition to the daily exposure via the diet.
Ni and Ni compounds have been classified by IARC (2012) as human carcinogens causing cancers of the lung, nasal cavity and paranasal sinuses after inhalation. There is currently no consistency in the epidemiological data to suggest that nickel compounds cause cancer at additional sites or by additional routes. Moreover, no tumours have been found in the oral carcinogenicity studies in experimental animals. Therefore, the CONTAM Panel considered it unlikely that dietary exposure to Ni results in cancer in humans.
In humans, non-carcinogenic health effects of oral exposure to Ni include effects on the gastrointestinal, haematological, neurological and immune system. Gastrointestinal and neurological symptoms were the most reported effects after acute exposure. Exposure through skin or by inhalation may lead to Ni sensitization. Whereas oral exposure to Ni is not known to lead to sensitization, oral absorption of Ni is able to elicit eczematous flare-up reactions in the skin in Ni-sensitized individuals.
In experimental animals, oral ingestion of soluble Ni salts has resulted in a wide range of adverse effects including nephrotoxicity/hepatotoxicity and metabolic effects. Ni is able to cross the placental barrier and exerts its primary toxic effects in experimental animals by affecting directly the developing embryo or fetus. Pre- and perinatal mortality were reported to be increased in the offspring of female rats ingesting Ni salts. These adverse effects occur at the lowest doses. Therefore, the CONTAM Panel identified reproductive and developmental toxicity as the critical effect for the risk characterization of chronic oral exposure to Ni. Benchmark dose (BMD) modelling was performed on a dose range finding 1-generation study, on a subsequent full 2-generation (2-GEN) study and on the combination of the data from the two studies. The CONTAM Panel noted that the use of combined data from the dose range finding and 2-GEN studies provided the most robust results and decided to use the results from this dataset for the selection of the reference point (RP). The Panel derived a tolerable daily intake (TDI) of 2.8 µg Ni/kg b.w. from a lower 95 % confidence limit for a benchmark dose at 10 % extra risk (BMDL10) of 0.28 mg Ni /kg b.w. as calculated from the dose response analysis of the incidence of litters with post-implantation loss in rats, applying the default uncertainty factor of 100 to account for interspecies differences and human variability.
The mean chronic dietary exposure to Ni, across the different dietary surveys and age classes, ranging from 2.0 (minimum LB, ‘Elderly’) to 13.1 µg Ni/kg b.w. per day (maximum UB, ‘Toddlers’) is close to the TDI or above it particularly when considering the young age groups (‘Infants’, ‘Other children’, ‘Toddlers’ and ‘Adolescents’). The 95th percentile dietary exposure ranging from 3.6 (minimum LB, ‘Elderly’) to 20.1 µg Ni/kg b.w. per day (maximum UB, ’Toddlers’) is above the TDI for all age groups. Therefore, the CONTAM Panel concluded that the current chronic dietary exposure to Ni is of concern for the general population.
Although based on limited consumption data, the dietary exposure to Ni of the vegetarian population seems to be slightly higher than that estimated for the general population, with a highest estimated 95th percentile exposure of 7.1 µg Ni/kg b.w. per day. Therefore, the level of concern for dietary exposure to Ni for the general population can be extended to the vegetarian population.
It has been reported that individuals sensitised to nickel through dermal contact and who have allergic contact dermatitis (estimated prevalence in the general population to be up to 15 %, but frequently remaining undiagnosed) may develop eczematous flare-up reactions in the skin (systemic contact dermatitis, SCD) from oral exposure to nickel salts. The TDI of 2.8 µg Ni/kg b.w. per day may therefore not be sufficiently protective of individuals sensitized to nickel. Three studies analysing SCD elicited in Ni-sensitive humans after acute oral exposure to Ni were identified as suitable for dose-response analysis using the BMD approach. The Panel selected a lowest BMDL10 of 1.1 µg Ni/kg b.w. from the dose-response analysis of these studies as an acute RP and adopted a margin of exposure (MOE) approach for risk characterization.
This selected RP is calculated on data obtained in a highly sensitive study group of fasted individuals given Ni sulphate in lactose capsules. Under these conditions, absorption is assumed to be considerably higher than from food. These considerations suggest that the selected RP could be conservative for the characterisation of the acute risks. On the other hand, the CONTAM Panel took into account the large inter-individual variability in the immune response that might not be covered by the limited number of individuals examined in the selected studies, and therefore decided that an MOE of 10 or higher would be indicative of a low health concern.
The MOEs calculated considering the estimated mean and the 95th percentile acute exposure levels were considerably below 10 for all age groups. Due to the approach followed for the derivation of the acute RP, it cannot be predicted whether all sensitized individuals will actually develop adverse reactions, nor what percentage eventually will develop such reactions at the estimated levels of Ni intake.
Overall, the CONTAM Panel concluded that, at the current levels of acute dietary exposure to Ni, there is a concern that Ni-sensitized individuals may develop eczematous flare-up skin reactions. The CONTAM Panel noted the need for mechanistic studies to assess the human relevance of the effects on reproduction and development observed in experimental animals and for additional studies on human absorption of Ni from food, for example in combination with duplicate diet studies.
Fuente: European Food Safety Autority (EFSA)
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