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

Acknowledgements: The Panel wishes to thank the following for the support provided to this scientific output: Ana Campos Fernandes, Laura Ciccolallo, Esraa Elewa, Galvin Eyong, Christina Kyrkou, Irene Munoz, Giorgia Vianello, the members of the SCER Cross-cutting WG nanotechnologies: Jacqueline Castenmiller, Mohammad Chaudhry, Roland Franz, David Gott, Stefan Weigel and the former member of the SCER Cross-cutting WG Genotoxicity Maciej Stepnik. The FAF Panel wishes to acknowledge all European competent institutions, Member State bodies and other organisations that provided data for this scientific output.Peer reviewedPublisher PD

The Frequent Stressor and Mental Health Monitoring-Paradigm: A Proposal for the Operationalization and Measurement of Resilience and the Identification of Resilience Processes in Longitudinal Observational Studies

Resilience has been defined as the maintenance or quick recovery of mental health during and after times of adversity. How to operationalize resilience and to determine the factors and processes that lead to good long-term mental health outcomes in stressor-exposed individuals is a matter of ongoing debate and of critical importance for the advancement of the field. One of the biggest challenges for implementing an outcome-based definition of resilience in longitudinal observational study designs lies in the fact that real-life adversity is usually unpredictable and that its substantial qualitative as well as temporal variability between subjects often precludes defining circumscribed time windows of inter-individually comparable stressor exposure relative to which the maintenance or recovery of mental health can be determined. To address this pertinent issue, we propose to frequently and regularly monitor stressor exposure (E) and mental health problems (P) throughout a study's observation period [Frequent Stressor and Mental Health Monitoring (FRESHMO)-paradigm]. On this basis, a subject's deviation at any single monitoring time point from the study sample's normative E–P relationship (the regression residual) can be used to calculate that subject's current mental health reactivity to stressor exposure (“stressor reactivity,” SR). The SR score takes into account the individual extent of experienced adversity and is comparable between and within subjects. Individual SR time courses across monitoring time points reflect intra-individual temporal variability in SR, where periods of under-reactivity (negative SR score) are associated with accumulation of fewer mental health problems than is normal for the sample. If FRESHMO is accompanied by regular measurement of potential resilience factors, temporal changes in resilience factors can be used to predict SR time courses. An increase in a resilience factor measurement explaining a lagged decrease in SR can then be considered to index a process of adaptation to stressor exposure that promotes a resilient outcome (an allostatic resilience process). This design principle allows resilience research to move beyond merely determining baseline predictors of resilience outcomes, which cannot inform about how individuals successfully adjust and adapt when confronted with adversity. Hence, FRESHMO plus regular resilience factor monitoring incorporates a dynamic-systems perspective into resilience research

Evidence for a causal-mechanistic role for positive appraisal style in stress resilience

Stress resilience is the maintenance of mental health despite adversity. We have predicted that a tendency to appraise stressors in a realistic to slightly unrealistically positive fashion (positive appraisal style, PAS) is prospectively associated with more resilient outcomes; that PAS is a proximal and integrative resilience factor, mediating the pro-resilience effects of other protective factors (e.g., social support); and that PAS is modifiable, with changes in PAS leading to corresponding changes in resilience. In two independent observational samples (N=132 and N=1034), we find PAS to predict resilience over three and more years and to mediate the positive effects of social support. Analyzing the effects of a multi-component intervention (N=232) that targets a broad set of resilience factors, we find that the intervention increases PAS and that this prospectively mediates the intervention-induced increases in resilience. This establishes PAS as a proximal and plastic resilience factor with likely causal effects on resilience

Comparative investigation of appraisal style measures in their predictive potential for stress resilience and implications for predictive modeling of resilience

Appraisal refers to the evaluation of stimuli or situations with respect to an individual’s goals and needs. Stimuli or situations that are appraised as a threat to one’ goals and needs (‘stressors’) induce stress responses (‘stress’). Stressor appraisal occurs on various dimensions, of which the magnitude or cost of a potential adverse outcome, the probability of the outcome, and an individual’s coping potential are the most important. Individuals show subjective biases on each of these dimensions, which can range from extremely unrealistically negative to extremely unrealistically positive. Positive appraisal style (PAS) is an integrative construct. Individuals with a PAS have an average tendency to appraise stressors in a realistic to mildly unrealistically positive fashion across the different stressor appraisal dimensions; hence, they typically avoid both negative and also delusionally positive appraisals. Positive appraisal style theory of resilience (PASTOR) posits that this global bias is key for stress resilience, as it enables individuals to generate stress responses when needed but also to avoid unnecessary and over-shooting stress responses that will exhaust one’s resources and prevent resource replenishment during times of severe or lasting stressor exposure. We here use data from three prospective-longitudinal studies to compare recently validated self-report instruments for PAS with existing measures of appraisal biases in single dimensions in their relative predictive potential for resilience, using regularized regression methodology. We find that one PAS instrument, reflecting a tendency to produce general positive appraisal contents (PASS-content), and an optimism instrument, supposed to reflect a positive appraisal bias on the probability dimension, are consistent predictors of resilience over long time frames and superior in this quality to the other instruments (measures of positive appraisal processes, self-efficacy, and control). Generally, our results confirm the important role of appraisal biases in resilience. Item and nomological network analyses further indicate that the PASS-content instrument may more closely reflect individual differences in appraisal than the optimism instrument and thus be well suited for mechanistically interpretable prediction models based on well-defined psychological constructs. By contrast, the optimism instrument may reflect differences in life perspectives in addition to differences in appraisal. This makes the instrument less mechanistically interpretable; however, it may be better suited for clinical prediction models aiming at individual-level prognosis on the basis of maximized explained variance

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 171) based on new relevant scientific evidence considered by the Panel to be reliable, including data obtained with TiO2 nanoparticles (NPs) and data from an extended one-generation reproductive toxicity (EOGRT) study. Less than 50% of constituent particles by number in E 171 have a minimum external dimension 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 171 and potential neurotoxicity with TiO2 NPs, together with the potential induction of aberrant crypt foci with E 171, may indicate adverse effects. With respect to genotoxicity, the Panel concluded that TiO2 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 particles and the outcome of either in vitro or in vivo genotoxicity assays. A concern for genotoxicity of TiO2 particles that may be present in E 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 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 particle size with respect to genotoxicity could not be identified. No appropriately designed study was available to investigate the potential carcinogenic effects of TiO2 NPs. Based on all the evidence available, a concern for genotoxicity could not be ruled out, and given the many uncertainties, the Panel concluded that E 171 can no longer be considered as safe when used as a food additive