Michael Dinovi

Survey of furan in heat processed foods by headspace gas chromatography/mass spectrometry and estimated adult exposure

Furan is a suspected human carcinogen that is formed in some processed foods at low ng per g levels. Recent improvements in analytical methodology and scientific instrumentation have made it possible to accurately measure the amount of furan in a wide variety of foods. Results from analysis of more than 300 processed foods are presented. Furan was found at levels ranging from non-detectable (LOD, 0.2–0.9 ng g−1) to over 100 ng g−1. Exposure estimates for several adult food types were calculated, with brewed coffee being the major source of furan in the adult diet (0.15 µg kg−1 body weight day−1). Estimates of mean exposure to furan for different subpopulations were calculated. For consumers 2 years and older, the intake is estimated to be about 0.2 µg kg−1 body weight day−1.

Application of the margin-of-exposure (MoE) approach to substances in food that are genotoxic and carcinogenic e.g.: Benzo[a]pyrene and polycyclic aromatic hydrocarbons

Benzo[a]pyrene (BaP) and a number of other polycyclic aromatic hydrocarbons (PAH) are mutagenic and are also carcinogenic in rodent bioassays. Oral carcinogenicity data are not available for individual PAH other than BaP, and so BaP has been used as a marker of the carcinogenicity of, and exposure to, PAHs. Carcinogenicity studies of coal tar mixtures, considered to be representative of the genotoxic and carcinogenic PAH in food, have been used for dose-response modelling. Modelling the number of tumour-bearing mice resulted in a BMDL(10) of 0.122 mg BaP/kg-bw/day, which was lower than that for any of the individual tumours and was considered to be most appropriate since the different PAH may have different mechanisms of carcinogenicity. An average dietary exposure estimates of 0.008 microg BaP/kg-bw/day was identified from the range of national estimates. The calculated MoE was 15,000.

Risks for human health related to the presence of pyrrolizidine alkaloids in honey, tea, herbal infusions and food supplements

Abstract EFSA was asked by the European Commission to deliver a scientific opinion on the risks for human health related to the presence of pyrrolizidine alkaloids (PAs) in honey, tea, herbal infusions and food supplements and to identify the PAs of relevance in the aforementioned food commodities and in other feed and food. PAs are a large group of toxins produced by different plant species. In 2011, the EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) assessed the risks related to the presence of PAs in food and feed. Based on occurrence data limited to honey, the CONTAM Panel concluded that there was a possible health concern for those toddlers and children who are high consumers of honey. A new exposure assessment including new occurrence data was published by EFSA in 2016 and was used to update the risk characterisation. The CONTAM Panel established a new Reference Point of 237 μg/kg body weight per day to assess the carcinogenic risks of PAs, and concluded that there is a possible concern for human health related to the exposure to PAs, in particular for frequent and high consumers of tea and herbal infusions. The Panel noted that consumption of food supplements based on PA‐producing plants could result in exposure levels too close (i.e. less than 100 times lower) to the range of doses known to cause severe acute/short term toxicity. From the analysis of the available occurrence data, the CONTAM Panel identified a list of 17 PAs of relevance for monitoring in food and feed. The Panel recommended continuing the efforts to monitor the presence of PAs in food and feed, including the development of more sensitive and specific analytical methods. A recommendation was also issued on the generation of data to identify the toxic and carcinogenic potency of the PAs commonly found in food.

Application of the Margin of Exposure (MOE) approach to substances in food that are genotoxic and carcinogenic: Example: CAS No: 105650-23-5 PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine)

PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is a heterocyclic amine and genotoxic carcinogen contaminant that occurs during the grilling and frying of meat and fish, through an interaction between sugars and creatine via the Maillard reaction. PhIP causes cancers of the prostate, mammary gland and colon in rodents. Dose-response modelling of the data for these three tumour types gives BMDL10 values of 0.48 mg/kg/day for the prostate tumours, 0.74 mg/kg/day for mammary tumours and 2.71 mg/kg/day for colon tumours. The lowest MOEs for prostate, mammary and colon tumours were 20,000, 40,000 and 150,000, respectively.

Application of the margin of exposure (MoE) approach to substances in food that are genotoxic and carcinogenic Example: Ethyl carbamate (CAS 51-79-6)

Ethyl carbamate is mutagenic and produces DNA-adducts in vivo, and is carcinogenic in rodent bioassays. Dose-response modelling of the data for alveolar and bronchiolar adenoma or carcinoma in male and female mice combined gave a BMDL(10) of 0.25 mg/kg-bw/day. The dietary exposure from consumption of foods and non-alcoholic beverage was estimated to be 1 microg/person/day (15 ng/kg-bw/day), while the exposure of a high-percentile consumer of alcoholic beverages was estimated to be 5 microg/person per day (80 ng/kg-bw/day). The corresponding calculated MOEs were 16600 and 3125, respectively.

Risks for public health related to the presence of tetrodotoxin (TTX) and TTX analogues in marine bivalves and gastropods

Abstract Tetrodotoxin (TTX) and its analogues are produced by marine bacteria and have been detected in marine bivalves and gastropods from European waters. The European Commission asked EFSA for a scientific opinion on the risks to public health related to the presence of TTX and TTX analogues in marine bivalves and gastropods. The Panel on Contaminants in the Food Chain reviewed the available literature but did not find support for the minimum lethal dose for humans of 2 mg, mentioned in various reviews. Some human case reports describe serious effects at a dose of 0.2 mg, corresponding to 4 μg/kg body weight (bw). However, the uncertainties on the actual exposure in the studies preclude their use for derivation of an acute reference dose (ARfD). Instead, a group ARfD of 0.25 μg/kg bw, applying to TTX and its analogues, was derived based on a TTX dose of 25 μg/kg bw at which no apathy was observed in an acute oral study with mice, applying a standard uncertainty factor of 100. Estimated relative potencies for analogues are lower than that of TTX but are associated with a high degree of uncertainty. Based on the occurrence data submitted to EFSA and reported consumption days only, average and P95 exposures of 0.00–0.09 and 0.00–0.03 μg/kg bw, respectively, were calculated. Using a large portion size of 400 g bivalves and P95 occurrence levels of TTX, with exception of oysters, the exposure was below the group ARfD in all consumer groups. A concentration below 44 μg TTX equivalents/kg shellfish meat, based on a large portion size of 400 g, was considered not to result in adverse effects in humans. Liquid chromatography with tandem mass spectroscopy (LC–MS/MS) methods are the most suitable for identification and quantification of TTX and its analogues, with LOQs between 1 and 25 μg/kg.

Application of the Margin of Exposure (MoE) approach to substances in food that are genotoxic and carcinogenic Example: Benzene, CAS: 71-43-2

The role of genotoxic events in the aetiology of benzene induced tumours cannot be ruled out. Dose response modelling of the data for benzene gave a BMDL10 for female Zymbal gland carcinoma of 17.6 mg/kg-bw/d following adjustment to daily average doses. The MOEs ranged from 2 x 10(6) to 0.4 x 10(6) depending on the assumptions used in the exposure estimation.

Appropriateness to set a group health based guidance value for T2 and HT2 toxin and its modified forms

Abstract The EFSA Panel on Contaminants in the Food Chain (CONTAM) established a tolerable daily intake (TDI) for T2 and HT2 of 0.02 μg/kg body weight (bw) per day based on a new in vivo subchronic toxicity study in rats that confirmed that immune‐ and haematotoxicity are the critical effects of T2 and using a reduction in total leucocyte count as the critical endpoint. An acute reference dose (ARfD) of 0.3 μg for T2 and HT2/kg bw was established based on acute emetic events in mink. Modified forms of T2 and HT2 identified are phase I metabolites mainly formed through hydrolytic cleavage of one or more of the three ester groups of T2. Less prominent hydroxylation reactions occur predominantly at the side chain. Phase II metabolism involves conjugation with glucose, modified glucose, sulfate, feruloyl and acetyl groups. The few data on occurrence of modified forms indicate that grain products are their main source. The CONTAM Panel found it appropriate to establish a group TDI and a group ARfD for T2 and HT2 and its modified forms. Potency factors relative to T2 for the modified forms were used to account for differences in acute and chronic toxic potencies. It was assumed that conjugates (phase II metabolites of T2, HT2 and their phase I metabolites), which are not toxic per se, would be cleaved releasing their aglycones. These metabolites were assigned the relative potency factors (RPFs) of their respective aglycones. The RPFs assigned to the modified forms were all either 1 or less than 1. The uncertainties associated with the present assessment are considered as high. Using the established group, ARfD and TDI would overestimate any risk of modified T2 and HT2.

Acute health risks related to the presence of cyanogenic glycosides in raw apricot kernels and products derived from raw apricot kernels

Amygdalin is the major cyanogenic glycoside present in apricot kernels and is degraded to cyanide by chewing or grinding. Cyanide is of high acute toxicity in humans. The lethal dose is reported to be 0.5–3.5 mg/kg body weight (bw). An acute reference dose (ARfD) of 20 lg/kg bw was derived from an exposure of 0.105 mg/kg bw associated with a non-toxic blood cyanide level of 20 micro mol (lM), and applying an uncertainty factor of 1.5 to account for toxicokinetic and of 3.16 to account for toxicodynamic inter-individual differences. In the absence of consumption data and thus using highest intakes of kernels promoted (10 and 60 kernels/day for the general population and cancer patients, respectively), exposures exceeded the ARfD 17–413 and 3–71 times in toddlers and adults, respectively. The estimated maximum quantity of apricot kernels (or raw apricot material) that can be consumed without exceeding the ARfD is 0.06 and 0.37 g in toddlers and adults, respectively. Thus the ARfD would be exceeded already by consumption of one small kernel in toddlers, while adults could consume three small kernels. However, consumption of less than half of a large kernel could already exceed the ARfD in adults.

Appropriateness to set a group health based guidance value for nivalenol and its modified forms

Abstract The EFSA Panel on Contaminants in the Food Chain (CONTAM) reviewed new studies on nivalenol since the previous opinion on nivalenol published in 2013, but as no new relevant data were identified the tolerable daily intake (TDI) for nivalenol (NIV) of 1.2 μg/kg body weight (bw) established on bases of immuno‐ and haematotoxicity in rats was retained. An acute reference dose (ARfD) of 14 μg/kg bw was established based on acute emetic events in mink. The only phase I metabolite of NIV identified is de‐epoxy‐nivalenol (DE‐NIV) and the only phase II metabolite is nivalenol‐3‐glucoside (NIV3Glc). DE‐NIV is devoid of toxic activity and was thus not further considered. NIV3Glc can occur in cereals amounting up to about 50% of NIV. There are no toxicity data on NIV3Glc, but as it can be assumed that it is hydrolysed to NIV in the intestinal tract it should be included in a group TDI and in a group ARfD with NIV. The uncertainty associated with the present assessment is considered as high and it would rather overestimate than underestimate any risk.