Martina Iulini is a Ph.D. student at the Laboratory of Toxicology and Risk Assessment at the  University of Milan (Italy). She studied Pharmacy and Industrial Pharmacy, and during the master’s thesis, she started her toxicology experience. Martina focused her attention on the in vitro immunotoxicology field, and she had the opportunity to study different aspects of immunotoxicity,  such as the investigation of the molecular mechanism underlying drug-induced sensitization. But also, she studied the effects of endocrine disruptors on the immune system and their ability to modulate the expression of the RACK1 protein. Furthermore, she contributed to study the role of protein kinase C in dendritic cell activation following allergen exposure, focusing on microRNA expression. Actually, the topic of her Ph.D. project program, is focused on the development of new approach methodologies (NAMs) to study immunotoxicity of PFAS, supported by the European Food  Safety Authority (EFSA). On this occasion, she started to approach different in silico models and tools in collaboration with esqLABS GmbH. This opportunity allowed her to broaden her knowledge and range between in vitro and in silico models to implement her research and carry forward her goal of developing and using NAMs in the field of toxicology. 

OpenTox Virtual Conference 2023

In silico method to study immunotoxicity: PFAS case study  

Perfluorinated substances (PFAS) are a class of synthetic chemicals widely used in industry to which  people and the environment are exposed. Human studies have shown that PFAS can cause  immunosuppression, lower resistance to disease, and an increased risk of infections with a  decreased response to vaccination. However, not much is known about the mechanism of action via  which these substances act. Therefore, the aim of the project is to evaluate the immunotoxic effects  of PFAS and identify underlying mechanisms through the design of new approach methodologies  (NAMs)-based approaches. To reach these goals, an integrated testing strategy (ITS) consisting of  in vitro and in silico methods was developed. Based on the in vivo evidence, suitable in vitro models  were identified to evaluate parameters relevant to the immunotoxicity in vivo. The effects of PFAS  on the most important immune cells were studied using only human models, and the results obtained  with the selected NAMs support the in vivo evidence. Furthermore, mathematical fate and distribution  models were used to identify the nominal concentration of PFAS in the in vitro cell system and  physiologically based kinetics (PBK) modelling was used to perform quantitative in vitro to in vivo  extrapolation (QIVIVE) to extrapolate in vitro effect concentrations to external doses. Moreover, the  ‘Universal Immune System Simulator’ was used to complete the ITS and investigate the effects on  vulnerable populations and predict the threshold dose for which we have an immunotoxic effect. This  work will show the approach, with insight into the application of the in silico distribution models, to  obtain an ITS, for the immunotoxicity of PFAS, in support of chemical risk assessment. 

Funding: This study was supported by the European Food Safety Authority (Case Studies  NAMS_PFAS Immunotox - OC/EFSA/SCER/2021/13).