Guidance on the use of the benchmark dose approach in risk assessment.

The Scientific Committee (SC) reconfirms that the benchmark dose (BMD) approach is a scientifically more advanced method compared to the no-observed-adverse-effect-level (NOAEL) approach for deriving a Reference Point (RP). The major change compared to the previous Guidance (EFSA SC, 2017) concerns the Section 2.5, in which a change from the frequentist to the Bayesian paradigm is recommended. In the former, uncertainty about the unknown parameters is measured by confidence and significance levels, interpreted and calibrated under hypothetical repetition, while probability distributions are attached to the unknown parameters in the Bayesian approach, and the notion of probability is extended to reflect uncertainty of knowledge. In addition, the Bayesian approach can mimic a learning process and reflects the accumulation of knowledge over time. Model averaging is again recommended as the preferred method for estimating the BMD and calculating its credible interval. The set of default models to be used for BMD analysis has been reviewed and amended so that there is now a single set of models for quantal and continuous data. The flow chart guiding the reader step-by-step when performing a BMD analysis has also been updated, and a chapter comparing the frequentist to the Bayesian paradigm inserted. Also, when using Bayesian BMD modelling, the lower bound (BMDL) is to be considered as potential RP, and the upper bound (BMDU) is needed for establishing the BMDU/BMDL ratio reflecting the uncertainty in the BMD estimate. This updated guidance does not call for a general re-evaluation of previous assessments where the NOAEL approach or the BMD approach as described in the 2009 or 2017 Guidance was used, in particular when the exposure is clearly lower (e.g. more than one order of magnitude) than the health-based guidance value. Finally, the SC firmly reiterates to reconsider test guidelines given the wide application of the BMD approach.

Long-term add-on therapy (compassionate use) with oral artesunate in patients with metastatic breast cancer after participating in a phase I study (ARTIC M33/2).

BACKGROUND: The antimalarial artesunate (ART), a semisynthetic derivative of artemisinin from the Chinese herb artemisia annua has remarkable anticancer properties in vitro and in vivo. Its excellent safety profile known from short-term therapy in malaria was confirmed in an open phase I trial (ARTIC M33/2) for dose-finding as add-on therapy for four weeks. PURPOSE: Patients with metastatic breast cancer, who had not experienced any clinically relevant adverse events (AE) during participation in ARTIC M33/2, were offered to continue ART as compassionate use (CU). Regular monitoring was continued in order to ensure adequate individual safety and tolerability and to collect information about long-term treatment with ART. Clinically relevant AEs or second progression of disease during ART were reasons for discontinuation of the add-on therapy. STUDY DESIGN: Compassionate use was offered open-label to participants of ARTIC M33/2. METHODS: Patients continued to take 100, 150 or 200 mg oral ART daily as add-on therapy to their guideline-based oncological therapy. Clinical and laboratory monitoring included audiological and neurological examination, ECG, NTproBNP and reticulocyte determination. Cumulative treatment days and cumulative ART doses encompass both the phase I study as well as the continued add-on treatment period (CU). RESULTS: Following the 4 ±â€¯1 weeks of the phase I trial, thirteen patients continued the add-on therapy as CU, resulting in a total of 3825 treatment days. In individual patients up to 1115 cumulative treatment days (37 months) and cumulative ART doses up to 167.3 g were reached. A total of 25 AEs grade ≥ 2 at least possibly related to ART long-term add-on therapy were documented, two, six and 17 in dose groups 100, 150 and 200 mg/d ART respectively. Six of these AEs were classified as grade 3, two in patients taking 150 and four in patients on 200 mg/d, none of them being probably or certainly related to ART. CONCLUSIONS: In thirteen patients with metastatic breast cancer up to 200 mg/d long-term oral ART (2.3-4.1 mg/kg BW/d) in up to 1115 cumulative treatment days (37 months) did not result in any major safety concerns.

A critical evaluation of health risk assessment of modified mycotoxins with a special focus on zearalenone.

A comprehensive definition introducing the term "modified mycotoxins" to encompass all possible forms in which mycotoxins and their modifications can occur was recently proposed and has rapidly gained wide acceptance within the scientific community. It is becoming increasingly evident that exposure to such modified mycotoxins due to their presence in food and feed has the potential to pose a substantial additional risk to human and animal health. Zearalenone (ZEN) is a well-characterized Fusarium toxin. Considering the diversity of modified forms of ZEN occurring in food and feed, the toxicologically relevant endocrine activity of many of these metabolites, and the fact that modified forms add to a dietary exposure which approaches the tolerable daily intake by free ZEN alone, modified forms of ZEN present an ideal case study for critical evaluation of modified mycotoxins in food safety. Following a summary of recent scientific opinions of EFSA dealing with health risk assessment of ZEN alone or in combination with its modified forms, uncertainties and data gaps are highlighted. Issues essential for evaluation and prioritization of modified mycotoxins in health risk assessment are identified and discussed, including opportunities to improve exposure assessment using biomonitoring data. Further issues such as future consideration of combinatory effects of the parent toxin with its modified forms and also other compounds co-occurring in food and feed are addressed. With a particular focus on ZEN, the most pressing challenges associated with health risk assessment of modified mycotoxins are identified and recommendations for further research to fill data gaps and reduce uncertainties are made.

Update of the risk assessment on 3-monochloropropane diol and its fatty acid esters.

The CONTAM Panel updated the assessment of the risks for human health related to the presence of 3-monochloropropane diol (3-MCPD) and its fatty acid esters in food published in 2016 in view of the scientific divergence identified in the establishment of the tolerable daily intake (TDI) in the Joint FAO/WHO Expert Committee on Food Additives and Contaminants (FAO/WHO) report published in 2017. In this update, dose-response analysis was performed following the recent EFSA Scientific Committee guidance on the use of benchmark dose (BMD) approach in risk assessment, and a review of available data on developmental and reproduction toxicity was included. The outcome of this review indicates that in rats short-term exposure to 3-MCPD above 1 mg/kg body weight (bw) per day can induce reduced sperm motility associated with reduced male fecundity. Decreased sperm count and histopathological changes in the testis and epididymis were observed following longer treatment periods at higher doses. Regarding increased incidence kidney tubular hyperplasia, BMD analysis using model averaging resulted in a BMDL 10 of 0.20 mg/kg bw per day in male rats, which was selected as the new Reference Point (RP) for renal effects. For the effects on male fertility, decreased sperm motility was selected as the most sensitive relevant endpoint and a BMDL 05 of 0.44 mg/kg bw per day was calculated. The RP for renal effects was considered to derive an updated group TDI of 2 µg/kg bw per day for 3-MCPD and its fatty acid esters and was considered protective also for effects on male fertility. The established TDI of 2 µg/kg bw per day is not exceeded in the adult population. A slight exceedance of the TDI was observed in the high consumers of the younger age groups and in particular for the scenarios on infants receiving formula only.

Risk for animal and human health related to the presence of dioxins and dioxin-like PCBs in feed and food.

The European Commission asked EFSA for a scientific opinion on the risks for animal and human health related to the presence of dioxins (PCDD/Fs) and DL-PCBs in feed and food. The data from experimental animal and epidemiological studies were reviewed and it was decided to base the human risk assessment on effects observed in humans and to use animal data as supportive evidence. The critical effect was on semen quality, following pre- and postnatal exposure. The critical study showed a NOAEL of 7.0 pg WHO2005-TEQ/g fat in blood sampled at age 9 years based on PCDD/F-TEQs. No association was observed when including DL-PCB-TEQs. Using toxicokinetic modelling and taking into account the exposure from breastfeeding and a twofold higher intake during childhood, it was estimated that daily exposure in adolescents and adults should be below 0.25 pg TEQ/kg bw/day. The CONTAM Panel established a TWI of 2 pg TEQ/kg bw/week. With occurrence and consumption data from European countries, the mean and P95 intake of total TEQ by Adolescents, Adults, Elderly and Very Elderly varied between, respectively, 2.1 to 10.5, and 5.3 to 30.4 pg TEQ/kg bw/week, implying a considerable exceedance of the TWI. Toddlers and Other Children showed a higher exposure than older age groups, but this was accounted for when deriving the TWI. Exposure to PCDD/F-TEQ only was on average 2.4- and 2.7-fold lower for mean and P95 exposure than for total TEQ. PCDD/Fs and DL-PCBs are transferred to milk and eggs, and accumulate in fatty tissues and liver. Transfer rates and bioconcentration factors were identified for various species. The CONTAM Panel was not able to identify reference values in most farm and companion animals with the exception of NOAELs for mink, chicken and some fish species. The estimated exposure from feed for these species does not imply a risk.

Risk to human health related to the presence of perfluorooctane sulfonic acid and perfluorooctanoic acid in food.

The European Commission asked EFSA for a scientific evaluation on the risks to human health related to the presence of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) in food. Regarding PFOS and PFOA occurrence, the final data set available for dietary exposure assessment contained a total of 20,019 analytical results (PFOS n = 10,191 and PFOA n = 9,828). There were large differences between upper and lower bound exposure due to analytical methods with insufficient sensitivity. The CONTAM Panel considered the lower bound estimates to be closer to true exposure levels. Important contributors to the lower bound mean chronic exposure were 'Fish and other seafood', 'Meat and meat products' and 'Eggs and egg products', for PFOS, and 'Milk and dairy products', 'Drinking water' and 'Fish and other seafood' for PFOA. PFOS and PFOA are readily absorbed in the gastrointestinal tract, excreted in urine and faeces, and do not undergo metabolism. Estimated human half-lives for PFOS and PFOA are about 5 years and 2-4 years, respectively. The derivation of a health-based guidance value was based on human epidemiological studies. For PFOS, the increase in serum total cholesterol in adults, and the decrease in antibody response at vaccination in children were identified as the critical effects. For PFOA, the increase in serum total cholesterol was the critical effect. Also reduced birth weight (for both compounds) and increased prevalence of high serum levels of the liver enzyme alanine aminotransferase (ALT) (for PFOA) were considered. After benchmark modelling of serum levels of PFOS and PFOA, and estimating the corresponding daily intakes, the CONTAM Panel established a tolerable weekly intake (TWI) of 13 ng/kg body weight (bw) per week for PFOS and 6 ng/kg bw per week for PFOA. For both compounds, exposure of a considerable proportion of the population exceeds the proposed TWIs.

Assessment of a decontamination process for dioxins and PCBs from fish meal by hexane extraction and replacement of fish oil.

Following a request from the European Commission, the EFSA Panel on Contaminants in the Food Chain (CONTAM) provided a scientific opinion on the assessment of a decontamination process for fish meal. This process entails solvent (hexane) extraction of fish oil from fish meal to remove dioxins (polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs)) as well as dioxin-like (DL-) and non-dioxin-like (NDL-) polychlorinated biphenyls (PCBs) followed by replacement with decontaminated fish oil. All feed decontamination processes must comply with the acceptability criteria specified in the Commission Regulation (EU) 2015/786. The data provided by the feed business operator were assessed with respect to the efficacy of the process, absence of solvent residues, and on information demonstrating that the process does not adversely affect the nature and characteristics of the product. According to data provided, the process was effective in removing PCDD/Fs and DL-PCBs by approximately 70% and NDL-PCBs by about 60%. The data showed that it is possible to meet the current EU requirements with respect to these contaminants, provided that the level of contamination of untreated fish meal is within the range of the tested batches. It is unlikely that hazardous substances (i.e. hexane) remain in the final product. The Panel considered that there is no evidence that fish oil extraction followed by replacement with decontaminated fish oil leads to detrimental changes in the nutritional composition of the fish meal, although some beneficial constituents (e.g. lipophilic vitamins) might be depleted. The feed business operator submitted information to demonstrate safe disposal of the waste material. The CONTAM Panel concluded that the proposed decontamination process to remove dioxins (PCDD/Fs) and PCBs from fish meal by means of solvent extraction and fish oil replacement was assessed to be compliant with the acceptability criteria provided for in Commission Regulation (EU) 2015/786 of 19 May 2015.

Assessment of a decontamination process for dioxins and PCBs from fish meal by replacement of fish oil.

Following a request from the European Commission, the EFSA Panel on Contaminants in the Food Chain (CONTAM) provided a scientific opinion on the assessment of a decontamination process of fish meal. It consisted of extraction of the fish oil, filtration and adsorption with activated carbon, and replacement with decontaminated fish oil in order to reduce the amount of dioxins (polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs)), and dioxin-like (DL-) and non-dioxin-like (NDL-) polychlorinated biphenyls (PCBs). All feed decontamination processes must comply with the acceptability criteria specified in the Commission Regulation (EU) 2015/786. Data provided by the feed business operator were assessed for efficacy of the process and to demonstrate that the process did not adversely affect the characteristics and the nature of the product. The process was effective in removing PCDD/Fs (97%) and DL- and NDL-PCBs (93%). The fish meal produced complied with EU regulations for these contaminants. The Panel considered that the reference to information available in published literature was a pragmatic approach to demonstrate that the replacement of fish oil and the use of activated carbon to adsorb these contaminants does not lead to any detrimental changes in the nature of the fish meal. However, it was noted that the process could deplete some beneficial constituents (e.g. oil-soluble vitamins). Information was provided to demonstrate the safe disposal of the waste material. The CONTAM Panel concluded that on the basis of the information submitted by the feed business operator the proposed decontamination process to remove dioxins (PCDD/Fs) and PCBs from the fish meal by oil extraction followed by replacement with decontaminated fish oil, was compliant with the acceptability criteria provided for in Commission Regulation (EU) 2015/786 of 19 May 2015.

Effect on public health of a possible increase of the maximum level for 'aflatoxin total' from 4 to 10 µg/kg in peanuts and processed products thereof, intended for direct human consumption or use as an ingredient in foodstuffs.

EFSA was asked to deliver a scientific opinion regarding the effect on public health of a possible increase of the maximum level (ML) for 'aflatoxin total' (AFT; sum of aflatoxin B1, aflatoxin B2, aflatoxin G1 and aflatoxin G2) from 4 to 10 µg/kg in peanuts and processed products thereof. Aflatoxins are genotoxic and cause hepatocellular carcinomas in humans. The Panel on Contaminants in the Food Chain (CONTAM Panel) evaluated 8,085 samples of peanuts and 472 samples of peanut butter, with > 60% left-censored. The mean concentration of AFT in peanuts was 2.65/3.56 µg/kg (lower bound (LB)/upper bound (UB)) with a maximum of 1,429 µg/kg. The mean concentration in peanut butter was 1.47/1.92 µg/kg (LB/UB) with a maximum of 407 µg/kg. Peanut oil was not included since all data were left-censored and the ML does not apply for oil. Exposure was calculated for a 'Current ML' and 'Increased ML' scenario, and mean chronic exposure estimates for consumers only, amounted to 0.04-2.74 ng/kg body weight (bw) per day and 0.07-4.28 ng/kg bw per day, respectively. The highest exposures were calculated for adolescents and other children. The CONTAM Panel used the cancer potencies estimated by the Joint FAO/WHO Expert Committee on Food Additives for the risk characterisation. Under the scenario of the current ML, the cancer risk was estimated to range between 0.001 and 0.213 aflatoxin-induced cancers per 100,000 person years. Under the scenario of the increased ML, it ranged between 0.001 and 0.333 aflatoxin-induced cancers per 100,000 person years. Comparing these data calculated under the current ML scenario with the yearly excess cancer risk of 0.014 shows a higher risk for consumers of peanuts and peanut butter in some surveys. The calculated cancer risks indicate that an increase of the ML would further increase the risk by a factor of 1.6-1.8.

Appropriateness to set a group health-based guidance value for fumonisins and their modified forms.

The EFSA Panel on Contaminants in the Food Chain (CONTAM) established a tolerable daily intake (TDI) for fumonisin B1 (FB 1) of 1.0 µg/kg body weight (bw) per day based on increased incidence of megalocytic hepatocytes found in a chronic study with mice. The CONTAM Panel considered the limited data available on toxicity and mode of action and structural similarities of FB 2-6 and found it appropriate to include FB 2, FB 3 and FB 4 in a group TDI with FB 1. Modified forms of FBs are phase I and phase II metabolites formed in fungi, infested plants or farm animals. Modified forms also arise from food or feed processing, and include covalent adducts with matrix constituents. Non-covalently bound forms are not considered as modified forms. Modified forms of FBs identified are hydrolysed FB 1-4 (HFB 1-4), partially hydrolysed FB 1-2 (pHFB 1-2), N-(carboxymethyl)-FB 1-3 (NCM-FB 1-3), N-(1-deoxy-d-fructos-1-yl)-FB 1 (NDF-FB 1), O-fatty acyl FB 1, N-fatty acyl FB 1 and N-palmitoyl-HFB 1. HFB 1, pHFB 1, NCM-FB 1 and NDF-FB 1 show a similar toxicological profile but are less potent than FB 1. Although in vitro data shows that N-fatty acyl FBs are more toxic in vitro than FB 1, no in vivo data were available for N-fatty acyl FBs and O-fatty acyl FBs. The CONTAM Panel concluded that it was not appropriate to include modified FBs in the group TDI for FB 1-4. The uncertainty associated with the present assessment is high, but could be reduced provided more data are made available on occurrence, toxicokinetics and toxicity of FB 2-6 and modified forms of FB 1-4.

Risks to human and animal health related to the presence of moniliformin in food and feed.

Moniliformin (MON) is a mycotoxin with low molecular weight primarily produced by Fusarium fungi and occurring predominantly in cereal grains. Following a request of the European Commission, the CONTAM Panel assessed the risk of MON to human and animal health related to its presence in food and feed. The limited information available on toxicity and on toxicokinetics in experimental and farm animals indicated haematotoxicity and cardiotoxicity as major adverse health effects of MON. MON causes chromosome aberrations in vitro but no in vivo genotoxicity data and no carcinogenicity data were identified. Due to the limitations in the available toxicity data, human acute or chronic health-based guidance values (HBGV) could not be established. The margin of exposure (MOE) between the no-observed-adverse-effect level (NOAEL) of 6.0 mg/kg body weight (bw) for cardiotoxicity from a subacute study in rats and the acute upper bound (UB) dietary exposure estimates ranged between 4,000 and 73,000. The MOE between the lowest benchmark dose lower confidence limit (for a 5% response - BMDL05) of 0.20 mg MON/kg bw per day for haematological hazards from a 28-day study in pigs and the chronic dietary human exposure estimates ranged between 370 and 5,000,000 for chronic dietary exposures. These MOEs indicate a low risk for human health but were associated with high uncertainty. The toxicity data available for poultry, pigs, and mink indicated a low or even negligible risk for these animals from exposure to MON in feed at the estimated exposure levels under current feeding practices. Assuming similar or lower sensitivity as for pigs, the CONTAM Panel considered a low or even negligible risk for the other animal species for which no toxicity data suitable for hazard characterisation were identified. Additional toxicity studies are needed and depending on their outcome, the collection of more occurrence data on MON in food and feed is recommended to enable a comprehensive human risk assessment.

Risks for animal health related to the presence of fumonisins, their modified forms and hidden forms in feed.

Fumonisins, mycotoxins primarily produced by Fusarium verticillioides and Fusarium proliferatum, occur predominantly in cereal grains, especially in maize. The European Commission asked EFSA for a scientific opinion on the risk to animal health related to fumonisins and their modified and hidden forms in feed. Fumonisin B1 (FB 1), FB 2 and FB 3 are the most common forms of fumonisins in feedstuffs and thus were included in the assessment. FB 1, FB 2 and FB 3 have the same mode of action and were considered as having similar toxicological profile and potencies. For fumonisins, the EFSA Panel on Contaminants in the Food Chain (CONTAM) identified no-observed-adverse-effect levels (NOAELs) for cattle, pig, poultry (chicken, ducks and turkeys), horse, and lowest-observed-adverse-effect levels (LOAELs) for fish (extrapolated from carp) and rabbits. No reference points could be identified for sheep, goats, dogs, cats and mink. The dietary exposure was estimated on 18,140 feed samples on FB 1-3 representing most of the feed commodities with potential presence of fumonisins. Samples were collected between 2003 and 2016 from 19 different European countries, but most of them from four Member States. To take into account the possible occurrence of hidden forms, an additional factor of 1.6, derived from the literature, was applied to the occurrence data. Modified forms of fumonisins, for which no data were identified concerning both the occurrence and the toxicity, were not included in the assessment. Based on mean exposure estimates, the risk of adverse health effects of feeds containing FB 1-3 was considered very low for ruminants, low for poultry, horse, rabbits, fish and of potential concern for pigs. The same conclusions apply to the sum of FB 1-3 and their hidden forms, except for pigs for which the risk of adverse health effect was considered of concern.

Update of the Scientific Opinion on opium alkaloids in poppy seeds.

Poppy seeds are obtained from the opium poppy (Papaver somniferum L.). They are used as food and to produce edible oil. The opium poppy plant contains narcotic alkaloids such as morphine and codeine. Poppy seeds do not contain the opium alkaloids, but can become contaminated with alkaloids as a result of pest damage and during harvesting. The European Commission asked EFSA to provide an update of the Scientific Opinion on opium alkaloids in poppy seeds. The assessment is based on data on morphine, codeine, thebaine, oripavine, noscapine and papaverine in poppy seed samples. The CONTAM Panel confirms the acute reference dose (ARfD) of 10 µg morphine/kg body weight (bw) and concluded that the concentration of codeine in the poppy seed samples should be taken into account by converting codeine to morphine equivalents, using a factor of 0.2. The ARfD is therefore a group ARfD for morphine and codeine, expressed in morphine equivalents. Mean and high levels of dietary exposure to morphine equivalents from poppy seeds considered to have high levels of opium alkaloids (i.e. poppy seeds from varieties primarily grown for pharmaceutical use) exceed the ARfD in most age groups. For poppy seeds considered to have relatively low concentrations of opium alkaloids (i.e. primarily varieties for food use), some exceedance of the ARfD is also seen at high levels of dietary exposure in most surveys. For noscapine and papaverine, the available data do not allow making a hazard characterisation. However, comparison of the dietary exposure to the recommended therapeutical doses does not suggest a health concern for these alkaloids. For thebaine and oripavine, no risk characterisation was done due to insufficient data. However, for thebaine, limited evidence indicates a higher acute lethality than for morphine and the estimated exposure could present a health risk.

Update: methodological principles and scientific methods to be taken into account when establishing Reference Points for Action (RPAs) for non-allowed pharmacologically active substances present in food of animal origin.

EFSA was asked by the European Commission to update the Scientific Opinion on methodological principles and scientific methods to be taken into account when establishing Reference Points for Action (RPAs) for non-allowed pharmacologically active substances in food of animal origin. This guidance document presents a simple and pragmatic approach which takes into account both analytical and toxicological considerations. The RPA shall be based on the reasonably achievable lowest residue concentration that can unequivocally be determined by official control laboratories, i.e. the reasonably achievable lowest decision limit (CCα). The aim is to check whether this concentration is low enough to adequately protect the consumers of food commodities that contain that substance. The proposed step-wise approach applies toxicological screening values (TSVs), based on genotoxic potential, pharmacological activity, as well as other effects of the substance. The highest dietary exposure corresponding to the reasonably achievable lowest CCα for the substance has to be estimated and compared with the TSV. Where equal to or lower than the TSV, the reasonably achievable lowest CCα can be accepted as the RPA. If higher, the sensitivity of the analytical method needs to be improved. In the case where no further analytical improvements are feasible within a short to medium time frame, a substance-specific risk assessment should be considered. This also applies when the potential adverse effects do not allow use of the decision tree, as for high potency carcinogens, inorganic substances or compounds with allergenic effects or causing blood dyscrasias. The CONTAM Panel concluded that RPAs should be food matrix independent. RPAs cannot be applied to non-edible matrices, which are also monitored for non-allowed pharmacologically active substances.

Risk to human and animal health related to the presence of 4,15-diacetoxyscirpenol in food and feed.

4,15-Diacetoxyscirpenol (DAS) is a mycotoxin primarily produced by Fusarium fungi and occurring predominantly in cereal grains. As requested by the European Commission, the EFSA Panel on Contaminants in the Food Chain (CONTAM) assessed the risk of DAS to human and animal health related to its presence in food and feed. Very limited information was available on toxicity and on toxicokinetics in experimental and farm animals. Due to the limitations in the available data set, human acute and chronic health-based guidance values (HBGV) were established based on data obtained in clinical trials of DAS as an anticancer agent (anguidine) after intravenous administration to cancer patients. The CONTAM Panel considered these data as informative for the hazard characterisation of DAS after oral exposure. The main adverse effects after acute and repeated exposure were emesis, with a no-observed-adverse-effect level (NOAEL) of 32 µg DAS/kg body weight (bw), and haematotoxicity, with a NOAEL of 65 µg DAS/kg bw, respectively. An acute reference dose (ARfD) of 3.2 µg DAS/kg bw and a tolerable daily intake (TDI) of 0.65 µg DAS/kg bw were established. Based on over 15,000 occurrence data, the highest acute and chronic dietary exposures were estimated to be 0.8 and 0.49 µg DAS/kg bw per day, respectively, and were not of health concern for humans. The limited information for poultry, pigs and dogs indicated a low risk for these animals at the estimated DAS exposure levels under current feeding practices, with the possible exception of fattening chicken. Assuming similar or lower sensitivity than for poultry, the risk was considered overall low for other farm and companion animal species for which no toxicity data were available. In consideration of the similarities of several trichothecenes and the likelihood of co-exposure via food and feed, it could be appropriate to perform a cumulative risk assessment for this group of substances.

Chemosensitivity-directed therapy compared to dacarbazine in chemo-naive advanced metastatic melanoma: a multicenter randomized phase-3 DeCOG trial.

Chemotherapy still plays an important role in metastatic melanoma, particularly for patients who are not suitable or have no access to highly efficacious new therapies. Pre-therapeutic chemosensitivity testing might be useful to identify optimal chemotherapy regimens for individual patients. This multicenter randomized phase-3 trial was aimed to test for superiority of chemosensitivity-directed combination chemotherapy compared to standard dacarbazine monochemotherapy, and to demonstrate the chemosensitivity test result as prognostic in metastatic melanoma. Chemo-naive patients with advanced melanoma were biopsied from metastatic lesions. Tumor cells were isolated and tested ex-vivo for sensitivity to chemotherapeutic agents using an ATP-based viability assay. Patients with evaluable test results were randomly assigned to receive either chemosensitivity-directed combination chemotherapy (paclitaxel+cisplatin, treosulfan+gemcitabine, treosulfan+cytarabine), or dacarbazine. The primary study endpoint was overall survival (OS). After inclusion of 287 patients and a median follow-up of 26 months, the per-protocol population (n=244) showed no difference in OS between chemosensitivity-directed therapy and dacarbazine (median 9.2 vs 9.0 months, HR=1.08, p=0.64). The disease control rate (CR+PR+SD) tended to be higher in patients treated with chemosensitivity-directed therapy (32.8% vs 23.0%, p=0.088); objective response rates (CR+PR) showed no difference between groups (10.7% vs 12.3%, p=0.90). Patients whose tumors were tested chemosensitive showed no better OS or response rate than patients with chemoresistant tumors. Severe toxicities (CTC grade 3-4) were significantly more frequently observed with chemosensitivity-directed combination chemotherapy than with dacarbazine (40.2% vs 12.3%, p<0.0001). These results indicate, that chemosensitivity-directed combination chemotherapy is not superior to dacarbazine, but leads to significantly more severe toxicities.

Prospective open uncontrolled phase I study to define a well-tolerated dose of oral artesunate as add-on therapy in patients with metastatic breast cancer (ARTIC M33/2).

PURPOSE: The antimalarial drug artesunate (ART) is a promising candidate for cancer treatment as it displays anticancer effects in various models. While in short-term treatment of malaria, an excellent safety profile has been found for ART, the potential long-term treatment of cancer patients demands a phase I dose-finding clinical trial determining the daily ART dose which would be well tolerated as add-on therapy. METHODS: Patients with metastatic breast cancer were to receive either 100 or 150 or 200 mg oral ART daily as add-on to their guideline-based oncological therapy for a study period of four weeks with frequent clinical and laboratory monitoring until 4-8 weeks thereafter. According to the statistical design, recruitment was scheduled in groups of three patients in order not to miss a more than 33% frequency of dose-limiting adverse events (DL-AE) prior to dose escalation. RESULTS: Twenty-three patients were recruited, and all planned dose levels were applied. During the actual trial period of 4 ± 1 weeks, three patients experienced six DL-AEs altogether (leucopenia, neutropenia, asthenia, anemia) possibly related to ART (not exceeding 33% in any dose level). CONCLUSIONS: Up to 200 mg/d (2.2-3.9 mg/kg/d) oral ART were safe and well tolerated; therefore, 200 mg/d are recommended for phase II/III trials. Safety monitoring should include reticulocytes, NTproBNP, as well as audiological and neurological exploration.

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

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.

Scientific opinion on the evaluation of substances as acceptable previous cargoes for edible fats and oils.

Shipping of edible fats and oils into Europe is permitted in bulk tanks, provided that the previous cargo is included in a positive list. The European Commission requested EFSA to evaluate the acceptability as previous cargoes for fats and oils the substances calcium lignosulphonate, methyl acetate, ethyl tert-butyl ether (ETBE) and ammonium sulphate. The evaluation was based on the same criteria as those used for the evaluation of the substances currently on the list in the Annex to Commission Directive 96/3/EC as acceptable previous cargoes for edible fats and oils. Methyl acetate and ETBE meet the criteria for acceptability as previous cargoes. Due to uncertainties, mainly with regard to the composition and toxicity of the low molecular mass fraction, and the fact that the toxicological database is limited to the 40-65 grade and does not cover all grades of calcium lignosulphonate shipped as previous cargoes, the EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) concluded that calcium lignosulphonate does not meet the criteria for acceptability as a previous cargo. Only food-grade ammonium sulphate meets the criteria for acceptability as a previous cargo due to uncertainties about impurities in other (non-food) grades.

Update: use of the benchmark dose approach in risk assessment.

The Scientific Committee (SC) reconfirms that the benchmark dose (BMD) approach is a scientifically more advanced method compared to the NOAEL approach for deriving a Reference Point (RP). Most of the modifications made to the SC guidance of 2009 concern the section providing guidance on how to apply the BMD approach. Model averaging is recommended as the preferred method for calculating the BMD confidence interval, while acknowledging that the respective tools are still under development and may not be easily accessible to all. Therefore, selecting or rejecting models is still considered as a suboptimal alternative. The set of default models to be used for BMD analysis has been reviewed, and the Akaike information criterion (AIC) has been introduced instead of the log-likelihood to characterise the goodness of fit of different mathematical models to a dose-response data set. A flowchart has also been inserted in this update to guide the reader step-by-step when performing a BMD analysis, as well as a chapter on the distributional part of dose-response models and a template for reporting a BMD analysis in a complete and transparent manner. Finally, it is recommended to always report the BMD confidence interval rather than the value of the BMD. The lower bound (BMDL) is needed as a potential RP, and the upper bound (BMDU) is needed for establishing the BMDU/BMDL per ratio reflecting the uncertainty in the BMD estimate. This updated guidance does not call for a general re-evaluation of previous assessments where the NOAEL approach or the BMD approach as described in the 2009 SC guidance was used, in particular when the exposure is clearly smaller (e.g. more than one order of magnitude) than the health-based guidance value. Finally, the SC firmly reiterates to reconsider test guidelines given the expected wide application of the BMD approach.