Scientific Publications

The hazard identification of chemicals is a key step of the ‘Safe and Sustainable by Design’ (SSbD) framework introduced by the European Commission, aiming to eliminate hazardous substances early in innovation. In this context, in silico methods such as (Quantitative) Structure-Activity Relationship ((Q)SAR) models offer rapid, cost-effective, and animal-free alternatives for early-stage hazard screening. The Partnership for the Assessment of Risks from Chemicals (PARC) is developing a toolbox to facilitate SSbD assessments containing numerous (Q)SAR models. Challenges, however, exist in using and combining multiple in silico tools. Here, we developed a workflow to assess chemical hazards using multiple in silico tools within the PARC toolbox. The workflow consists of three phases: 1) the preparation stage, 2) running the models, and 3) the evaluation stage. To demonstrate the approach, we applied it to a case study comparing Bisphenol A, Isosorbide, and Bisphenol AP. Tools from the PARC toolbox were screened for relevance, transparency, and open access availability. Only models aligned with SSbD required endpoints and adequately documented via (Q)SAR Model Reporting Formats were retained. The properties assessed in this study cover carcinogenicity, germ cell mutagenicity, reproductive toxicity, endocrine disruption, persistence, bioaccumulation, and aquatic toxicity. Predictions were filtered using applicability domain criteria and reliability scores. Next, three strategies were applied for integrating different model outputs. Model agreement varied across endpoints and integration methods. This emphasizes the possibility of different SSbD assessment outcomes and thus the need for transparent documentation of the chosen strategy and explicit handling of uncertainty. Our study demonstrates how multiple models can systematically and transparently be integrated via the developed workflow. Key areas for improvement are to refine integration strategies, harmonize the definition and communication of applicability domains across tools, expand in silico coverage for currently underrepresented endpoints, and to develop approaches to consider data gaps in SSbD assessments.

In response to increasing evidence of human and environmental health impacts of endocrine disrupting chemicals (EDCs), screening and testing programs for EDC assessment are being developed, requiring characterization of potential adverse health effects. The development of the lateral line (LL), a neurosensory system in fish, has been suggested as a potential toxicological target of EDCs. The LL contains neuromasts with hair cells (HCs) which convert mechanical stimuli intoneural signals. An exploratory study was performed to assess whether neuromast development is affected by a selection of model EDCs with different modes of action. Zebrafish embryos were exposed to EDCs, targeting estrogen and thyroid pathways, immediately after fertilization. The number of HCs in four neuromasts was counted at 120 h post fertilization. Methimazole and resorcinol (thyroid hormone [TH] synthesis inhibitors) elicited the strongest response, characterized by a reduction in HC numbers, while fulvestrant (anti-estrogen) slightly increased HC numbers. Further investigation confirmed a reduction of HCs and neuromasts after exposure to methimazole during late embryonic development, when TH synthesis is active. Gene transcript level analysis revealed a decreased marker for HC activity and increased markers of support cells, essential for HC regeneration. Taken together, neuromast development appears to be affected by certain EDCs in zebrafish embryos, at concentrations similar to those causing other effects (e.g., impaired swim bladder inflation). However, variability in the responses complicates characterization using the FM1-43 method. Further research, including rescue experiments and more sensitive or functionally relevant methods, is needed to clarify the mechanisms underlying EDC-induced HC disruption.

Obesity is a global pandemic that affects people of all ages. While behavioral, nutritional, and socioeconomic factors all contribute to weight gain, other factors in our immediate environment play an insidious role in the prevalence of obesity. Exposure to environmental and pharmaceutical compounds can be a contributing factor to increased weight gain. Using the zebrafish obesogenic test, our study demonstrates that amiodarone, dibutyl phthalate, rosiglitazone, tributyltin, and triclosan induce a thrifty phenotype under short-term fasting conditions. Diazepam significantly reduces locomotion without exhibiting any obesogenic effect, whereas tributyltin, which has the highest obesogenic potential among the tested compounds, has no effect on locomotion. The obesogen-induced resistance to fat loss is not correlated to inhibition of physical activity and a corresponding reduction in energy expenditure nor to food consumption. Primary prevention measures to fight against the obesity pandemic may include reducing exposure to obesogens that can induce a thrifty phenotype.

The Partnership for the Assessment of Risks from Chemicals (PARC) represents a joint effort among risk assessors, regulatory authorities, and the scientific community to advance the implementation of the Next Generation Risk Assessment (NGRA) in line with the objectives of the EU Chemicals Strategy for Sustainability. Addressing the challenges faced by national and European regulators in integrating data generated by innovative methodologies is central to achieving this goal.

Following an initial phase of the Partnership, in which projects were defined based on a first prioritization of methodologies, a second prioritization round was conducted with input from the Governing Board representatives of all participating entities. This second process also considered the Key Areas of Regulatory Challenge introduced by ECHA in 2023, ensuring that the evolving research agenda within PARC is closely aligned with current and future regulatory needs.

As a result, WP5 Hazard Assessment has updated its project portfolio to include four new projects that bridge identified regulatory gaps and strengthen the implementation phase of PARC. Two projects address newly prioritized endpoints, Developmental and Reproductive Toxicity and Developmental Immunotoxicity, while a third explores Sexual Dimorphism Associated with Hepatotoxicity. In addition, a transversal project, Regulatory Readiness of NAMs, was launched to accelerate the regulatory uptake of promising methods developed under WP5.

This article complements the previous PARC special issue by providing an overview of the updated WP5 project portfolio, illustrating the progression from prioritization to implementation, and highlighting how these new projects respond to evolving regulatory needs and contribute to the effective integration of NAMs into chemical risk assessment.