Avoiding a reproducibility crisis in regulatory toxicology—on the fundamental role of ring trials

The ongoing transition from chemical hazard and risk assessment based on animal studies to assessment relying mostly on non-animal data, requires a multitude of novel experimental methods, and this means that guidance on the validation and standardisation of test methods intended for international applicability and acceptance, needs to be updated. These so-called new approach methodologies (NAMs) must be applicable to the chemical regulatory domain and provide reliable data which are relevant to hazard and risk assessment. Confidence in and use of NAMs will depend on their reliability and relevance, and both are thoroughly assessed by validation. Validation is, however, a time- and resource-demanding process. As updates on validation guidance are conducted, the valuable components must be kept: Reliable data are and will remain fundamental. In 2016, the scientific community was made aware of the general crisis in scientific reproducibility—validated methods must not fall into this. In this commentary, we emphasize the central importance of ring trials in the validation of experimental methods. Ring trials are sometimes considered to be a major hold-up with little value added to the validation. Here, we clarify that ring trials are indispensable to demonstrate the robustness and reproducibility of a new method. Further, that methods do fail in method transfer and ring trials due to different stumbling blocks, but these provide learnings to ensure the robustness of new methods. At the same time, we identify what it would take to perform ring trials more efficiently, and how ring trials fit into the much-needed update to the guidance on the validation of NAMs

Application of the TTC concept to unknown substances found in analysis of foods

Unknown substances, not previously observed, are frequently detected in foods by quality control laboratories. In many cases, the assessment of these 'new' substances requires additional chemical analysis for their identification prior to assessing risk. This identification procedure can be time-consuming, expensive and in some instances difficult. Furthermore, in many cases, no toxicological information will be available for the substance. Therefore, there is a need to develop pragmatic tools for the assessment of the potential toxicity of substances with unknown identity to avoid delays in their risk assessment. Hence, the 'ILSI Europe expert group on the application of the threshold of toxicological concern (TTC) to unexpected peaks found in food' was established to explore whether the TTC concept may enable a more pragmatic risk assessment of unknown substances that were not previously detected in food. A step-wise approach is introduced that uses expert judgement on the source of the food, information on the analytical techniques, the dietary consumption of food sources containing the unknown substance and quantitative information of the unknown substance to assess the safety to the consumer using the TTC. By following this step-wise approach, it may be possible to apply a TTC threshold of 90. µg/day for an unknown substance in food. © 2011 Elsevier Ltd

Three-tiered approach for standard information requirements for polymers requiring registration under REACH

Polymers are a very large class of chemicals comprising often complex molecules with multiple functions used in everyday products. The EU Commission is seeking to develop environmental and human health standard information requirements (SIRs) for man-made polymers requiring registration (PRR) under a revised Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Regulation. Conventional risk assessment approaches currently used for small molecules may not apply to most polymers. Therefore, we propose a conceptual three-tiered regulatory approach for data generation to assess individual and groups of polymers requiring registration (PRR). A key element is the grouping of polymers according to chemistry, physico-chemical properties and hazard similarity. The limited bioavailability of many polymers is a prominent difference to many small molecules and is a key consideration of the proposed approach. Methods assessing potential for systemic bioavailability are integral to Tier 1. Decisions for further studies are based on considerations of properties and effects, combined with systemic bioavailability and use and exposure considerations. For many PRRs, Tier 1 data on hazard, use and exposure will likely be sufficient for achieving the protection goals of REACH. Vertebrate animal studies in Tiers 2 and 3 can be limited to targeted testing. The outlined approach aims to make use of current best scientific evidence and to reduce animal testing whilst providing data for an adequate level of protection

Thresholds of Toxicological Concern for Cosmetics-Related Substances: New Database, Thresholds, and Enrichment of Chemical Space

A new dataset of cosmetics-related chemicals for the Threshold of Toxicological Concern (TTC) approach has been compiled, comprising 552 chemicals with 219, 40, and 293 chemicals in Cramer Classes I, II, and III, respectively. Data were integrated and curated to create a database of No-/Lowest-Observed-Adverse-Effect Level (NOAEL/LOAEL) values, from which the final COSMOS TTC dataset was developed. Criteria for study inclusion and NOAEL decisions were defined, and rigorous quality control was performed for study details and assignment of Cramer classes. From the final COSMOS TTC dataset, human exposure thresholds of 42 and 7.9 μg/kg-bw/day were derived for Cramer Classes I and III, respectively. The size of Cramer Class II was insufficient for derivation of a TTC value. The COSMOS TTC dataset was then federated with the dataset of Munro and colleagues, previously published in 1996, after updating the latter using the quality control processes for this project. This federated dataset expands the chemical space and provides more robust thresholds. The 966 substances in the federated database comprise 245, 49 and 672 chemicals in Cramer Classes I, II and III, respectively. The corresponding TTC values of 46, 6.2 and 2.3 μg/kg-bw/day are broadly similar to those of the original Munro dataset

Application of the TTC concept to unknown substances found in analysis of foods

Unknown substances, not previously observed, are frequently detected in foods by quality control laboratories. In many cases, the assessment of these 'new' substances requires additional chemical analysis for their identification prior to assessing risk. This identification procedure can be time-consuming, expensive and in some instances difficult. Furthermore, in many cases, no toxicological information will be available for the substance. Therefore, there is a need to develop pragmatic tools for the assessment of the potential toxicity of substances with unknown identity to avoid delays in their risk assessment. Hence, the 'ILSI Europe expert group on the application of the threshold of toxicological concern (TTC) to unexpected peaks found in food' was established to explore whether the TTC concept may enable a more pragmatic risk assessment of unknown substances that were not previously detected in food. A step-wise approach is introduced that uses expert judgement on the source of the food, information on the analytical techniques, the dietary consumption of food sources containing the unknown substance and quantitative information of the unknown substance to assess the safety to the consumer using the TTC. By following this step-wise approach, it may be possible to apply a TTC threshold of 90. µg/day for an unknown substance in food. © 2011 Elsevier Ltd