Josef Schlatter

Update: use of the benchmark dose approach in risk assessment

Abstract 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.

The benchmark dose approach in food risk assessment: Is it applicable and worthwhile?

The benchmark dose (BMD) approach is being increasingly used in the area of food risk assessment because it offers several advantages compared to the conventional no-observed-adverse-effect-level approach. The aim of this work was to check the applicability of the BMD approach on toxicity data available from pesticides, mycotoxins and natural toxins. Based on toxicological evaluations, the pivotal study was identified. Detailed data from the original study were retrieved and used for BMD modelling. Twenty-five studies used for BMD modelling were analysed with regard to study design: total number of animals, number of dose levels, and spacing between dose levels. The quality of the modelled endpoints was evaluated according to the following aspects: BMD/BMDL ratio, test for goodness of fit and BMD in the range of dose levels. If one of these aspects was not fulfilled, the BMD derived from this endpoint was considered to be uncertain to some extent and corresponding modelled data sets were examined. The present work demonstrates that the BMD approach is in principle applicable to pesticides, mycotoxins, and natural toxins. Although large differences relating to data availability and data quality were noticed, 69 of 82 modelled endpoints (84%) fulfilled the three quality aspects of BMD modelling.

Guidance on the use of the weight of evidence approach in scientific assessments

Abstract EFSA requested the Scientific Committee to develop a guidance document on the use of the weight of evidence approach in scientific assessments for use in all areas under EFSAs remit. The guidance document addresses the use of weight of evidence approaches in scientific assessments using both qualitative and quantitative approaches. Several case studies covering the various areas under EFSAs remit are annexed to the guidance document to illustrate the applicability of the proposed approach. Weight of evidence assessment is defined in this guidance as a process in which evidence is integrated to determine the relative support for possible answers to a question. This document considers the weight of evidence assessment as comprising three basic steps: (1) assembling the evidence into lines of evidence of similar type, (2) weighing the evidence, (3) integrating the evidence. The present document identifies reliability, relevance and consistency as three basic considerations for weighing evidence.

Study parameters influencing NOAEL and LOAEL in toxicity feeding studies for pesticides: Exposure duration versus dose decrement, dose spacing, group size and chemical class

The effect of exposure duration on no observed adverse effect levels (NOAEL) and lowest observed adverse effect levels (LOAEL) in rodent pesticide feeding studies was evaluated. Ratios of NOAEL (and LOAEL), expressed as pesticide concentrations in feed, were calculated from subacute to subchronic, subchronic to chronic and subacute to chronic studies. There was no statistical significant effect of exposure duration on ratio distributions. Whereas geometric means of ratios were in a narrow range of 1.1-2.5, the geometric standard deviations and 95th percentiles increased with dose spacing of the involved studies. With the exception of carbamates, the chemical class of pesticides had no influence on the ratio distributions. However, the number of animals in the shorter-term study of ratio couples being ≤ 1 was statistically significantly higher than in ratio couples being >1. Ratios ≤ 1 may be partly explained by the dose decrement over time observed in feeding studies applying the test substances in constant concentrations. The dose decrement possibly converts initially toxic doses to less toxic doses beyond the subacute phase. Ratios >1 seem to be caused predominantly by differences in study design parameters. In dietary risk assessment, the acceptable daily intake (ADI) is compared to pesticide intake estimates based on mean food consumption (i.e. the so called theoretical maximum daily intake, TMDI) being orders of magnitude lower than actual food consumption on eating occasions for certain food commodities. As subacute, subchronic and chronic NOAEL (and LOAEL), expressed as pesticide concentration in feed did not differ statistically significantly, the TMDI as benchmark for the ADI may underestimate the significance of the toxicity of subacute exposure.

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.

Critical appraisal of the assessment of benefits and risks for foods, ‘BRAFO Consensus Working Group’

BRAFO, Benefit-Risk Analysis for Foods, was a European Commission project funded within Framework Six as a Specific Support Action and coordinated by ILSI Europe. BRAFO developed a tiered methodology for assessing the benefits and risks of foods and food components, utilising a quantitative, common scale for health assessment in higher tiers. This manuscript reports on the implications of the experience gained during the development of the project for the further improvement of benefit-risk assessment methodology. It was concluded that the methodology proposed is applicable to a range of situations and that it does help in optimising resource utilisation through early identification of those benefit-risk questions where benefit clearly outweighs risk or vice versa. However, higher tier assessments are complex and demanding of time and resources, emphasising the need for prioritisation. Areas identified as requiring further development to improve the utility of benefit-risk assessment include health weights for different populations and endpoints where they do not currently exist, extrapolation of effects from studies in animals to humans, use of in vitro data in benefit-risk assessments, and biomarkers of early effect and how these would be used in a quantitative assessment.

Guidance on Uncertainty Analysis in Scientific Assessments

Abstract Uncertainty analysis is the process of identifying limitations in scientific knowledge and evaluating their implications for scientific conclusions. It is therefore relevant in all EFSAs scientific assessments and also necessary, to ensure that the assessment conclusions provide reliable information for decision‐making. The form and extent of uncertainty analysis, and how the conclusions should be reported, vary widely depending on the nature and context of each assessment and the degree of uncertainty that is present. This document provides concise guidance on how to identify which options for uncertainty analysis are appropriate in each assessment, and how to apply them. It is accompanied by a separate, supporting opinion that explains the key concepts and principles behind this Guidance, and describes the methods in more detail.

The significance of the subchronic toxicity in the dietary risk assessment of pesticides

Based on 289 public pesticide evaluations, geometric means of subchronic/chronic No Observed Adverse Effect Level (NOAEL) ratios of 2.6, 2.5 and 1.6 in mice, rats and dogs were calculated. The 75th percentiles are 5.5, 5.1 and 3.2. Higher ratios correlate with increased dose spacing in chronic studies and may be mainly explained therewith. In rats fed at constant pesticide concentrations in feed, the mean chronic dose decreases by 1.7- and 2.7-fold compared to the subchronic and subacute phase. These dose decreases match the subchronic/chronic NOAEL ratios. The ratio of predicted rat chronic NOAEL (dose decrement adjusted subchronic NOAEL) to experimental chronic NOAEL is 1.5 and the 75th percentile is 3.0. In dietary risk assessment, the Acute Reference Dose and the Acceptable Daily Intake (derived from acute and chronic NOAEL) are compared to acute (IESTI) or mean (TMDI) exposure estimates. Because IESTI and TMDI base on acute or mean food consumption they differ by orders of magnitude for certain commodities. As subchronic and chronic NOAEL are similar, it remains to be shown whether pesticide intake estimates based on mean food consumption are adequate measures to compare against the ADI if repeated daily exposures considerably higher than mean exposures may occur.

Safety of hydroxytyrosol as a novel food pursuant to Regulation (EC) No 258/97

Abstract Following a request from the European Commission, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on hydroxytyrosol, which is chemically synthesised, as a novel food (NF) pursuant to Regulation (EC) No 258/97. The information provided on the composition, specifications, batch‐to‐batch variability, stability and production process of the NF is sufficient and does not raise concerns about the safety of the NF. The applicant intends to add hydroxytyrosol to fish and vegetable oils up to 215 mg/kg and to margarines up to 175 mg/kg. The target group is the general population which excludes children under 36 months of age, pregnant women and breastfeeding women. Considering the no observed adverse effect level (NOAEL) of 50 mg/kg body weight per day from a subchronic oral toxicity study with the NF and the maximum anticipated daily intake for the NF, the margin of exposure (MoE) would result in 100 for children (3–9 years of age) and at least 200 for adolescents, adults (excluding pregnant and breastfeeding women) and elderly. Taking into account that the anticipated daily intake of the NF would be in the range of or even less than the exposure of hydroxytyrosol from the consumption of olive oils and olives, which has not been associated with adverse effects, and considering the similar kinetics of hydroxytyrosol in rats and humans, the Panel considers that the MoE for the NF at the intended uses and use levels is sufficient for the target population. The Panel concludes that the novel food, hydroxytyrosol, is safe under the proposed uses and use levels.

Guidance on the risk assessment of substances present in food intended for infants below 16 weeks of age

Abstract Following a request from the European Commission to EFSA, the EFSA Scientific Committee (SC) prepared a guidance for the risk assessment of substances present in food intended for infants below 16 weeks of age. In its approach to develop this guidance, the EFSA SC took into account, among others, (i) an exposure assessment based on infant formula as the only source of nutrition; (ii) knowledge of organ development in human infants, including the development of the gut, metabolic and excretory capacities, the brain and brain barriers, the immune system, the endocrine and reproductive systems; (iii) the overall toxicological profile of the substance identified through the standard toxicological tests, including critical effects; (iv) the relevance for the human infant of the neonatal experimental animal models used. The EFSA SC notes that during the period from birth up to 16 weeks, infants are expected to be exclusively fed on breast milk and/or infant formula. The EFSA SC views this period as the time where health‐based guidance values for the general population do not apply without further considerations. High infant formula consumption per body weight is derived from 95th percentile consumption. The first weeks of life is the time of the highest relative consumption on a body weight basis. Therefore, when performing an exposure assessment, the EFSA SC proposes to use the high consumption value of 260 mL/kg bw per day. A decision tree approach is proposed that enables a risk assessment of substances present in food intended for infants below 16 weeks of age. The additional information needed when testing substances present in food for infants below 16 weeks of age and the approach to be taken for the risk assessment are on a case‐by‐case basis, depending on whether the substance is added intentionally to food and is systemically available.