Fraunhofer-Institut für Molekularbiologie und Angewandte Oekologie IME
Fraunhofer-Institut für Molekularbiologie und Angewandte Oekologie IME

Special Session Setac 2024: Regulatory Needs for Scientific Development

The Session was initiated by ECHA to join views from regulation, industry and academia on further research needs. The chairs started with initial presentations, followed by statements from invited panellists and their answers to a list of questions.

 

Wim de Coen, ECHA, presented ECHA’s Scientific Research Needs: 1) Provide protection against most harmful chemicals with a focus on immunotoxicity, neurotoxicity and endocrine disruption. This comprises the Identification of the critical windows for the development of the respective system, foundational research on AOPs & establishment of their interlink with existing and potential New Approach Methods (NAMs). Also, thorough identification of reference chemicals to support NAM reliability testing and validation, addressing data gaps regarding toxicological information on metabolites and considering NAMs based on invertebrates. 2) Addressing chemical pollution in the environment. This includes bioaccumulation issues such as the development of non-vertebrate methods to predict the bioaccumulation potential of surfactants, ionisable substances, organometals as well as of super hydrophobic substances. Also, an improved bioaccumulation assessment for air-breathing organisms and for secondary poisoning via the environment especially for mixtures. Furthermore, approaches based on monitoring field data enabling persistence, long-range environmental transport and/or bioaccumulation assessment should be developed and the protection of biodiversity by use of NAMs should be expanded. 3) Shift away from Animal Testing. This comprises the development of case studies for Read across and NAMS, of in vitro/in silico ADME and Physiologically-Based Kinetic models, as well as the validation of a systematic in vitro/silico battery to direct the generation of chronic toxicity data for vertebrate species. 4) Improved availability of chemical data. This includes knowledge and methodologies to support hazard assessment for polymers, including bioavailability, stability to degradation under environmental conditions, bioavailability and relevance for human health hazard assessment. For micro- and nano-sized materials investigations of the long-range transport, uptake and toxicity for humans and other organisms. should be improved. Finally, analytical methods for enforcement, such as the characterisation of nanomaterials, including advance materials should be improved. In his conclusion, he asked for an ongoing dynamic dialogue between all stakeholders.

Blanca Serrano, ECETOC, stated in her talk Bridging science and regulation the goal to advance chemical safety assessment by providing scientifically sound, multi-stakeholder reviewed data and insights. She asked for approaches that make science implementable for regulatory purposes.

Christoph Schäfers, Fraunhofer IME, presented "Research Issues for regulatory purpose - a science perspective".

The Transciptomic Point Of Departure Concept.

For Intrinsic chemical property evaluation, criteria have to be agreed, applicability domains of tests be determined and the representativity of test methods should be confirmed. For Persistence (P) and Mobility (M), the realistic worst case of environmental conditions has to be agreed and how to approach it, e.g. by scenario-driven models or by the combination of relevant extremes. For M, a sound estimate is still under development. For Bioaccumulation (B), the development of methods to evaluate particle accumulation is needed. When using NAMs, a validation of appropriate exposure and applicability domains ensures appropriate (safe) results. The BMF trigger value needs to be scientifically derived and accepted. For Toxicity (T), the tPoD concept (transcriptomic Point of Departure) adds amplification and compensation processes to sensitivity and specificity. Research is needed to show whether it is able to determine the absolute zero point of toxicity for known MoAs and valid AOPs and whether there is across species and across life stages convergence of the results. This should be elucidated by comparison with the respective proteomic data (Fig. 1 an 2). For Mixture toxicity testing (Fig. 3 and 4), the (eco)toxicological relevance of the constituents should be in first place. With respect to the given challenges (animal protection; time & resources), the investigation of unknown mixtures (e.g. UVCBs, recyclates, environmental samples) should be based on product (sample) toxicity evaluation (even batchwise) rather than intrinsic chemical property testing. Thus, there is need for fast testing methods of comparable sensitivity, such as non-target effect screening/testing by OMICs and bioinformatic evaluation. Scientific issues are the identification of effect driving mechanisms (AOPs) and the interaction of the molecular initiating events at the primary receptor(s).

Non-Target Effect Screening by OMICs for Unknown Mixtures (UVCBs, recyclates, environmental samples)

As representatives of the regulatory authorities, Joop de Knecht (RIVM) and Anu Karpanen (ECHA) highlighted the regulatory needs to identify and address relevant research gaps in the emerging topics biodiversity, complex/difficult to test substances, Omics and AOPs for chronic toxicity, high throughput and grouping, ED (e.g. population relevance), coverage of more species using NAMs. New scientific information needs to be fit for purpose, all results should be reported, preferably the negative results as well. It is necessary to increase the communication and understanding of the reporting details of the substance and applicability domain, as well as the needed protection level. It should be clear on what regulatory need the information serves for.

 

As industry representatives, Johannes Tolls (Henkel) and Marie Collard (Firmenich) figured out that NAMs data / approaches / models help to bridge from scientific data to regulatory decision-making. There is need for clear and concise criteria/required parameters to ensure a consistent and transparent assessment of data. At the same time, there is need for translating science for regulatory practice / evaluating new academic science in view of regulatory application, which should be accomplished by tripartite exchange, e.g. via an appropriate institution. Finally, there is need for funding for regulatory applications of science, as validation reports, reviews of regulatory applicability etc. have little value from an academic perspective.

 

As representatives of university science, Thomas Backhaus (RWTH Aachen University, 1) and Miriam Diamond (University of Toronto, 2) focused on the following aspects: 1) Data from previous research and regulatory efforts need to be publicly available in a central European database on new toxicological, ecotoxicological, production, use and exposure data. Data that are not publicly available should not be used for regulatory decision making. Systematic data collections allow us to train (explainable) predictive AI-tools, for read-across, gap-bridging and groupwise assessments. The circular economy poses new challenges for exposure evaluation, as recyclates will be contaminated by unwanted chemicals which increases the need for constantly monitoring consumer products. The required data need to be constantly kept up-to-date. Effect-based tools are a promising approach, because they account for the totality of the leaching chemicals. The tools need further development, from scientific (endpoint coverage, sensitivity), from pragmatic (ease of use, speed, costs) and from regulatory perspectives (regulatory thresholds). Certain environmentally relevant organism groups are completely under-evaluated from a regulatory perspective, in particular fungi and bacteria. Without data on such organisms, we will never achieve the aim to protect biodiversity and ecosystem services. Data on marine organisms are particularly lacking. Especially data on taxa without a freshwater counterpart are urgently needed. Finally, we need to better account for a changing environment, i.e. additional stressors like temperature increases, droughts, ocean acidification. 2) From a scientific point of view, the risk and hazard assessment paradigm should be questioned by more critical analysis of connections of (human) population-level adverse effects to some well-studied??  chemicals, where exposures are << RfDs. Evidence suggests that the regulatory system has not been sufficiently protective, e.g., extensive contamination with "untested" PFAS, adverse neurotoxicity, lipid metabolism, endocrine effects especially in vulnerable populations. There are discrepancies between results of risk assessments and epidemiological evidence, e.g., PBDEs.

 

All participants agreed on the need for closer exchange between science and regulation on topics, needs, and challenges.