Guidance on the use of the Threshold of Toxicological Concern approach in food safety assessment

Peer reviewedPublisher PD

In silico toxicology protocols

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions. It highlights the need to develop standardized protocols when conducting toxicity-related predictions. This contribution articulates the information needed for protocols to support in silico predictions for major toxicological endpoints of concern (e.g., genetic toxicity, carcinogenicity, acute toxicity, reproductive toxicity, developmental toxicity) across several industries and regulatory bodies. Such novel in silico toxicology (IST) protocols, when fully developed and implemented, will ensure in silico toxicological assessments are performed and evaluated in a consistent, reproducible, and well-documented manner across industries and regulatory bodies to support wider uptake and acceptance of the approaches. The development of IST protocols is an initiative developed through a collaboration among an international consortium to reflect the state-of-the-art in in silico toxicology for hazard identification and characterization. A general outline for describing the development of such protocols is included and it is based on in silico predictions and/or available experimental data for a defined series of relevant toxicological effects or mechanisms. The publication presents a novel approach for determining the reliability of in silico predictions alongside experimental data. In addition, we discuss how to determine the level of confidence in the assessment based on the relevance and reliability of the information

The Proteome‐Wide Potential for Reversible Covalency at Cysteine

Reversible covalency, achieved with, for instance, highly electron-deficient olefins, offers a compelling strategy to design chemical probes and drugs that benefit from the sustained target engagement afforded by irreversible compounds, while avoiding permanent protein modification. Reversible covalency has mainly been evaluated for cysteine residues in individual kinases and the broader potential for this strategy to engage cysteines across the proteome remains unexplored. Herein, we describe a mass-spectrometry-based platform that integrates gel filtration with activity-based protein profiling to assess cysteine residues across the human proteome for both irreversible and reversible interactions with small-molecule electrophiles. Using this method, we identify numerous cysteine residues from diverse protein classes that are reversibly engaged by cyanoacrylamide fragment electrophiles, revealing the broad potential for reversible covalency as a strategy for chemical-probe discovery

Application of the BRC Sequential Extraction Scheme for Assessing the Leaching of Elements in Wood-Based Ash Fractions from a Large-Sized (115 MW) Industrial Power Plant of a Pulp and Board Mill

Extractions tests are widely used as tools to estimate the potential release of constituents, for example from waste materials, over a range of possible waste management activities, including recycling, reuse and landfill disposal. Sequential extraction procedures offer the advantage of simulating, to a certain extent, the vari ous natural environmental conditions. In this study, the mobility and bioavailability of heavy metals in wood-based bottom ash and fly ash was evaluated by the three-stage BCR sequential extraction procedure, in which elements in the bottom ash and fly ash were fractionated between acidsoluble (CH3COOH; BCR1), reducible (NH2OH-HCl; BCR2) and oxidisable (H2O2 + CH3COONH4; BCR3) fractions. For the bottom ash, the extractable concentration of Al (88 mg/kg; d.w.) and Ba (82 mg/kg; d.w.) in the BCR1 fraction were moderate, whereas the extractable concentrations of Mn (110 mg/kg; d.w.), S (310 mg/kg; d.w.) and Zn (200 mg/kg; d.w.) were relatively high. In the fly ash, the highest extractable concentrations in the BCR1 fraction were observed for S (14,400 mg/kg; d.w.) and Ba (26 mg/kg; d.w.). Therefore, when these ashes are disposed of in a landfill or utilized, for example, in earth construction, the above-mentioned metals are likely to be released from the bottom ash and from the fly ash since the elements associated with the acid-soluble (CH3COOH) fraction are more mobile and bioavailable than the metals in easily reduced (NH2OH-HCl) and oxidisable (H2O2 + CH3-COONH4) fractions.</p

Safety assessment of titanium dioxide (E171) as a food additive

The present opinion deals with an updated safety assessment of the food additive titanium dioxide (E&nbsp;171) based on new relevant scientific evidence considered by the Panel&nbsp;to be reliable, including data obtained with TiO2&nbsp;nanoparticles (NPs) and data from an extended one-generation reproductive toxicity (EOGRT) study. Less than 50% of constituent particles by number in E&nbsp;171 have a minimum external dimension &lt; 100 nm. In addition, the Panel&nbsp;noted that constituent particles &lt; 30 nm amounted to less than 1% of particles by number. The Panel&nbsp;therefore considered that studies with TiO2&nbsp;NPs &lt; 30 nm were of limited relevance to the safety assessment of E&nbsp;171. The Panel&nbsp;concluded that although gastrointestinal absorption of TiO2&nbsp;particles is low, they may accumulate in the body. Studies on general and organ toxicity did not indicate adverse effects with either E&nbsp;171 up to a dose of 1,000 mg/kg body weight (bw) per day or with TiO2&nbsp;NPs (&gt; 30 nm) up to the highest dose tested of 100 mg/kg bw per day. No effects on reproductive and developmental toxicity were observed up to a dose of 1,000 mg E 171/kg bw per day, the highest dose tested in the EOGRT study. However, observations of potential immunotoxicity and inflammation with E&nbsp;171 and potential neurotoxicity with TiO2&nbsp;NPs, together with the potential induction of aberrant crypt foci with E&nbsp;171, may indicate adverse effects. With respect to genotoxicity, the Panel&nbsp;concluded that TiO2&nbsp;particles have the potential to induce DNA strand breaks and chromosomal damage, but not gene mutations. No clear correlation was observed between the physico-chemical properties of TiO2&nbsp;particles and the outcome of either&nbsp;in&nbsp;vitro&nbsp;or&nbsp;in&nbsp;vivo&nbsp;genotoxicity assays. A concern for genotoxicity of TiO2&nbsp;particles that may be present in E&nbsp;171 could therefore not be ruled out. Several modes of action for the genotoxicity may operate in parallel and the relative contributions of different molecular mechanisms elicited by TiO2&nbsp;particles are not known. There was uncertainty as to whether a threshold mode of action could be assumed. In addition, a cut-off value for TiO2&nbsp;particle size with respect to genotoxicity could not be identified. No appropriately designed study was available to investigate the potential carcinogenic effects of TiO2&nbsp;NPs. Based on all the evidence available, a concern for genotoxicity could not be ruled out, and given the many uncertainties, the Panel&nbsp;concluded that E&nbsp;171 can no longer be considered as safe when used as a food&nbsp;additive.</p