Update of the risk assessment of inorganic arsenic in food.

The European Commission asked EFSA to update its 2009 risk assessment on arsenic in food carrying out a hazard assessment of inorganic arsenic (iAs) and using the revised exposure assessment issued by EFSA in 2021. Epidemiological studies show that the chronic intake of iAs via diet and/or drinking water is associated with increased risk of several adverse outcomes including cancers of the skin, bladder and lung. The CONTAM Panel used the benchmark dose lower confidence limit based on a benchmark response (BMR) of 5% (relative increase of the background incidence after adjustment for confounders, BMDL05) of 0.06 µg iAs/kg bw per day obtained from a study on skin cancer as a Reference Point (RP). Inorganic As is a genotoxic carcinogen with additional epigenetic effects and the CONTAM Panel applied a margin of exposure (MOE) approach for the risk characterisation. In adults, the MOEs are low (range between 2 and 0.4 for mean consumers and between 0.9 and 0.2 at the 95th percentile exposure, respectively) and as such raise a health concern despite the uncertainties.

Update of the risk assessment of mineral oil hydrocarbons in food.

Mineral oil hydrocarbons (MOH) are composed of saturated hydrocarbons (MOSH) and aromatic hydrocarbons (MOAH). Due to the complexity of the MOH composition, their complete chemical characterisation is not possible. MOSH accumulation is observed in various tissues, with species-specific differences. Formation of liver epithelioid lipogranulomas and inflammation, as well as increased liver and spleen weights, are observed in Fischer 344 (F344) rats, but not in Sprague-Dawley (SD) rats. These effects are related to specific accumulation of wax components in the liver of F344 rats, which is not observed in SD rats or humans. The CONTAM Panel concluded that F344 rats are not an appropriate model for effects of MOSH with wax components. A NOAEL of 236 mg/kg body weight (bw) per day, corresponding to the highest tested dose in F344 rats of a white mineral oil product virtually free of wax components, was selected as relevant reference point (RP). The highest dietary exposure to MOSH was estimated for the young population, with lower bound-upper bound (LB-UB) means and 95th percentiles of 0.085-0.126 and 0.157-0.212 mg/kg bw per day, respectively. Considering a margin of exposure approach, the Panel concluded that the present dietary exposure to MOSH does not raise concern for human health for all age classes. Genotoxicity and carcinogenicity are associated with MOAH with three or more aromatic rings. For this subfraction, a surrogate RP of 0.49 mg/kg bw per day, calculated from data on eight polycyclic aromatic hydrocarbons, was considered. The highest dietary exposure to MOAH was also in the young population, with LB-UB mean and 95th percentile estimations of 0.003-0.031 and 0.011-0.059 mg/kg bw per day, respectively. Based on two scenarios on three or more ring MOAH contents in the diet and lacking toxicological information on effects of 1 and 2 ring MOAH, a possible concern for human health was raised.

Risk assessment of N-nitrosamines in food.

EFSA was asked for a scientific opinion on the risks to public health related to the presence of N-nitrosamines (N-NAs) in food. The risk assessment was confined to those 10 carcinogenic N-NAs occurring in food (TCNAs), i.e. NDMA, NMEA, NDEA, NDPA, NDBA, NMA, NSAR, NMOR, NPIP and NPYR. N-NAs are genotoxic and induce liver tumours in rodents. The in vivo data available to derive potency factors are limited, and therefore, equal potency of TCNAs was assumed. The lower confidence limit of the benchmark dose at 10% (BMDL10) was 10 µg/kg body weight (bw) per day, derived from the incidence of rat liver tumours (benign and malignant) induced by NDEA and used in a margin of exposure (MOE) approach. Analytical results on the occurrence of N-NAs were extracted from the EFSA occurrence database (n = 2,817) and the literature (n = 4,003). Occurrence data were available for five food categories across TCNAs. Dietary exposure was assessed for two scenarios, excluding (scenario 1) and including (scenario 2) cooked unprocessed meat and fish. TCNAs exposure ranged from 0 to 208.9 ng/kg bw per day across surveys, age groups and scenarios. 'Meat and meat products' is the main food category contributing to TCNA exposure. MOEs ranged from 3,337 to 48 at the P95 exposure excluding some infant surveys with P95 exposure equal to zero. Two major uncertainties were (i) the high number of left censored data and (ii) the lack of data on important food categories. The CONTAM Panel concluded that the MOE for TCNAs at the P95 exposure is highly likely (98-100% certain) to be less than 10,000 for all age groups, which raises a health concern.

Decontamination process for dioxins and dioxin-like PCBs from fish oil and vegetable oils and fats by a physical process with activated carbon.

Following a request from the European Commission, the EFSA Panel on Contaminants in the Food Chain (CONTAM) assessed a decontamination process of fish oils and vegetable oils and fats to reduce the concentrations of dioxins (polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans, abbreviated together as PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) by adsorption to activated carbon. All feed decontamination processes must comply with the acceptability criteria specified in the Commission Regulation (EU) 2015/786. Data provided by the feed food business operator (FBO) were assessed for the efficacy of the process and to demonstrate that the process did not adversely affect the characteristics and properties of the product. The limited information provided, in particular on the analysis of the samples before and after decontamination, did not allow the CONTAM Panel to conclude whether or not the proposed decontamination process is effective in reducing PCDD/Fs and DL-PCBs in the fish- and vegetable oils and fats. Although there is no evidence from the data provided that the decontamination process leads to detrimental changes in the nutritional composition of the fish- and vegetable oils, it is possible that the process could deplete some beneficial constituents (e.g. vitamins). Taken together, it was not possible for the CONTAM Panel to conclude that the decontamination process as proposed by the FBO is compliant with the acceptability criteria provided for in Commission Regulation (EU) 2015/786 of 19 May 2015.

Treatment of radiological contamination: a review.

After nuclear accidents, people can be contaminated internally via ingestion, inhalation and via intact skin or wounds. The assessment of absorbed, committed doses after internal exposure is based on activity measurement byin vivoorin vitrobioassay. Estimation of dose following internal contamination is dependent on understanding the nature and form of the radionuclide. Direct counting methods that directly measureγ-rays coming from within the body or bioassay methods that measure the amount of radioactive materials in urine or feces are used to estimate the intake, which is required for calculating internal exposure doses. The interpretation of these data in terms of intake and the lifetime committed dose requires knowledge or making assumptions about a number of parameters (time, type of exposure, route of the exposure, physical, biological and chemical characteristics) and their biokinetics inside the body. Radioactive materials incorporated into the body emit radiation within the body. Accumulation in some specific organs may occur depending on the types of radioactive materials. Decorporation therapy is that acceleration of the natural rate of elimination of the contaminant will reduce the amount of radioactivity retained in the body. This article presents an overview of treatment of radiological contamination after internal contamination.

Refinement of health-based guidance values for cadmium in the French population based on modelling.

In France, part of the population is overexposed to cadmium by the diet. In our work, we first revised the tolerable daily intake (TDI) of 0.36 µg Cd.kg bw.d.-1 proposed by the European Food Safety Authority (EFSA), derived from effects on kidneys and based on the critical urinary Cd concentration of 1.0 µg Cd.g-1 creatinine for humans. After reviewing the epidemiological data on Cd toxicity published after 2011, bone effects were selected as the critical effects. Body burden data of 0.5 µg.g-1 creatinine was chosen for the critical threshold for human urinary cadmium concentrations. To be used for the derivation of the new oral toxicological reference value, we used a modified physiologically based pharmacokinetic model (PBPK). The reverse calculation on the PBPK model gave a TDI of 0.35 µg Cd.kg bw-1.day-1. This TDI is compatible with a urinary Cd concentrations not exceeding 0.5 µg Cd.g-1 creatinine, in a 60 year-old adult, assuming that ingestion is the only source of exposure to Cd at 60 years. After implementing the PBPK model with French physiological data, Cd biological reference values as a function of age were modelled so as to remain below the revised health-based guidance values.

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

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 BMDL 10 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.

Risk assessment of aflatoxins in food.

EFSA was asked to deliver a scientific opinion on the risks to public health related to the presence of aflatoxins in food. The risk assessment was confined to aflatoxin B1 (AFB1), AFB2, AFG1, AFG2 and AFM1. More than 200,000 analytical results on the occurrence of aflatoxins were used in the evaluation. Grains and grain-based products made the largest contribution to the mean chronic dietary exposure to AFB1 in all age classes, while 'liquid milk' and 'fermented milk products' were the main contributors to the AFM1 mean exposure. Aflatoxins are genotoxic and AFB1 can cause hepatocellular carcinomas (HCCs) in humans. The CONTAM Panel selected a benchmark dose lower confidence limit (BMDL) for a benchmark response of 10% of 0.4 µg/kg body weight (bw) per day for the incidence of HCC in male rats following AFB1 exposure to be used in a margin of exposure (MOE) approach. The calculation of a BMDL from the human data was not appropriate; instead, the cancer potencies estimated by the Joint FAO/WHO Expert Committee on Food Additives in 2016 were used. For AFM1, a potency factor of 0.1 relative to AFB1 was used. For AFG1, AFB2 and AFG2, the in vivo data are not sufficient to derive potency factors and equal potency to AFB1 was assumed as in previous assessments. MOE values for AFB1 exposure ranged from 5,000 to 29 and for AFM1 from 100,000 to 508. The calculated MOEs are below 10,000 for AFB1 and also for AFM1 where some surveys, particularly for the younger age groups, have an MOE below 10,000. This raises a health concern. The estimated cancer risks in humans following exposure to AFB1 and AFM1 are in-line with the conclusion drawn from the MOEs. The conclusions also apply to the combined exposure to all five aflatoxins.

Risk assessment of ochratoxin A in food.

The European Commission asked EFSA to update their 2006 opinion on ochratoxin A (OTA) in food. OTA is produced by fungi of the genus Aspergillus and Penicillium and found as a contaminant in various foods. OTA causes kidney toxicity in different animal species and kidney tumours in rodents. OTA is genotoxic both in vitro and in vivo; however, the mechanisms of genotoxicity are unclear. Direct and indirect genotoxic and non-genotoxic modes of action might each contribute to tumour formation. Since recent studies have raised uncertainty regarding the mode of action for kidney carcinogenicity, it is inappropriate to establish a health-based guidance value (HBGV) and a margin of exposure (MOE) approach was applied. For the characterisation of non-neoplastic effects, a BMDL 10 of 4.73 µg/kg body weight (bw) per day was calculated from kidney lesions observed in pigs. For characterisation of neoplastic effects, a BMDL 10 of 14.5 µg/kg bw per day was calculated from kidney tumours seen in rats. The estimation of chronic dietary exposure resulted in mean and 95th percentile levels ranging from 0.6 to 17.8 and from 2.4 to 51.7 ng/kg bw per day, respectively. Median OTA exposures in breastfed infants ranged from 1.7 to 2.6 ng/kg bw per day, 95th percentile exposures from 5.6 to 8.5 ng/kg bw per day in average/high breast milk consuming infants, respectively. Comparison of exposures with the BMDL 10 based on the non-neoplastic endpoint resulted in MOEs of more than 200 in most consumer groups, indicating a low health concern with the exception of MOEs for high consumers in the younger age groups, indicating a possible health concern. When compared with the BMDL 10 based on the neoplastic endpoint, MOEs were lower than 10,000 for almost all exposure scenarios, including breastfed infants. This would indicate a possible health concern if genotoxicity is direct. Uncertainty in this assessment is high and risk may be overestimated.

PBPK and population modelling to interpret urine cadmium concentrations of the French population.

As cadmium accumulates mainly in kidney, urinary concentrations are considered as relevant data to assess the risk related to cadmium. The French Nutrition and Health Survey (ENNS) recorded the concentration of cadmium in the urine of the French population. However, as with all biomonitoring data, it needs to be linked to external exposure for it to be interpreted in term of sources of exposure and for risk management purposes. The objective of this work is thus to interpret the cadmium biomonitoring data of the French population in terms of dietary and cigarette smoke exposures. Dietary and smoking habits recorded in the ENNS study were combined with contamination levels in food and cigarettes to assess individual exposures. A PBPK model was used in a Bayesian population model to link this external exposure with the measured urinary concentrations. In this model, the level of the past exposure was corrected thanks to a scaling function which account for a trend in the French dietary exposure. It resulted in a modelling which was able to explain the current urinary concentrations measured in the French population through current and past exposure levels. Risk related to cadmium exposure in the general French population was then assessed from external and internal critical values corresponding to kidney effects. The model was also applied to predict the possible urinary concentrations of the French population in 2030 assuming there will be no more changes in the exposures levels. This scenario leads to significantly lower concentrations and consequently lower related risk.

Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC1) genotypes as determinants of acenocoumarol sensitivity.

The aim of the study is to explore the contribution of genetic factors related either to drug metabolism (cytochrome P450 2C9) or to drug target (vitamin K epoxide reductase) to variability in the response to acenocoumarol among 222 healthy volunteers after a single oral dose. Associations between a pharmacodynamic index (reduction in factor VII activity and international normalized ratio [INR] change) and several genetic polymorphisms (VKORC1: -4931T>C, -4451C>A, -2659G>C, -1877A>G, -1639G>A, 497C>G, 1173C>T, and CYP2C9*3) were investigated using haplotype and univariate analyses. VKORC1 haplotypes were associated with the pharmacologic response, and this association can be explained only by the effect of the -1639G>A polymorphism (or alternatively by 1173C>T, which is in complete association with it). Indeed, it explains about one third of the variability of the pharmacologic response (37% of factor VII decrease and 30% of INR change). Moreover, the previously observed effect of the CYP2C9*3 allele is independent of the VKORC1 gene effect. These 2 polymorphisms account for up to 50% of the interindividual variability. The simple genotyping of 2 single-nucleotide polymorphisms (SNPs), VKORC1 -1639G>A or 1173C>T and the CYP2C9*3 polymorphisms, could thus predict a high risk of overdose before initiation of anticoagulation with acenocoumarol, and provide a safer and more individualized anticoagulant therapy.