Lessons Learned from the Grouping of Chemicals to Assess Risks to Human Health

Wohlleben, Wendel; Mehling, Annette; Landsiedel, Robert

doi:10.1002/anie.202210651

Cited by 14 publications

(15 citation statements)

References 123 publications

(142 reference statements)

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“…The RIFM approach on safety assessments on well over 1000 fragrance substances in peer reviewed literature has shown clear benefit for applying grouping in managing the safe use of substances that are used in consumer products at low levels (< 0.01%). Also well-established principles of grouping utilized in the OECD Toolbox prescribed by ECHA for use by registrants, and the 12 grouping principles as recently published by BASF (Wohlleben et al 2022 ) give a solid basis how scientific grouping can be done.…”

Section: Discussionmentioning

confidence: 99%

ECHA ARN documents: chemical grouping without a toxicological rationale

Natsch

Adamsson²,

Rocha³

2023

Arch Toxicol

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The EU chemical strategy for sustainability (CSS) plans to use chemical grouping to “prioritise (…) substances for restrictions for all uses through grouping, instead of regulating them one by one”. Thus, toxicological grouping will become a key tool used by regulatory authorities in Europe. Over the last 2 years, ECHA has published a high number of documents labelled “Assessment of Regulatory Needs (ARN)” which are based on groups of chemicals based on structural considerations. The ARN documents are legally non-binding, yet they present the public impression of a conclusion about restrictions for groups or sub-groups of chemicals and hence may set a precedent for further binding actions. ECHA has set out definitions on what is considered a group in REACH Annex XI. However, as shown in this commentary based on five examples, the ARN do not follow these principles and propose toxicological groupings without taking into consideration mode of action and the toxicological information on the chemicals. Given the emphasis on grouping projected by the CSS, the groupings in the ARN set an unfortunate precedent on what a toxicological group means and they do not follow clear scientific standards or established toxicological principles. They also lead to a public image of guilt by association for chemicals, without any recourse for registrants to establish the scientific basis for their safe use, as presented within REACH registrations.

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Section: Discussionmentioning

confidence: 99%

ECHA ARN documents: chemical grouping without a toxicological rationale

Natsch

Adamsson²,

Rocha³

2023

Arch Toxicol

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“…Hierarchical clustering of cannabinoids by their predicted target profiles revealed that some targets were predicted exclusively for certain clusters of cannabinoids (the cannabinoids and their clusters are in Figure 4). Some Wohlleben et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

“…More extensive in vitro testing could further refine and confirm the cannabinoid clusters. Grouping cannabinoids by target binding profiles may help identify cannabinoids causing similar physiological effects (EFSA Scientific Committee et al, 2021; Organisation for Economic Co‐operation and Development [OECD], 2014; Wohlleben et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Predicting binding between 55 cannabinoids and 4,799 biological targets by in silico methods

Santillo

Sprando

2023

J of Applied Toxicology

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Recently, there has been an increase in cannabis‐derived products being marketed as foods, dietary supplements, and other consumer products. Cannabis contains over a hundred cannabinoids, many of which have unknown physiological effects. Since there are large numbers of cannabinoids, and many are not commercially available for in vitro testing, an in silico tool (Chemotargets Clarity software) was used to predict binding between 55 cannabinoids and 4,799 biological targets (enzymes, ion channels, receptors, and transporters). This tool relied on quantitative structure activity relationships (QSAR), structural similarity, and other approaches to predict binding. From this screening, 827 cannabinoid‐target binding pairs were predicted, which included 143 unique targets. Many cannabinoids sharing core structures (cannabinoid “types”) had similar binding profiles, whereas most cannabinoids containing carboxylic acid groups were similar without regards to their core structure. For some of the binding predictions (43), in vitro binding data were available, and they agreed well with in silico binding data (median fourfold difference in binding concentrations). Finally, clinical adverse effects associated with 22 predicted targets were identified from an online database (Clarivate Off‐X), providing important insights on potential human health hazards. Overall, in silico biological target predictions are a rapid means to identify potential hazards due to cannabinoid‐target interactions, and the data can be used to prioritize subsequent in vitro and in vivo testing.

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“…Exposure and emission information could serve in the prioritization of chemicals for testing. Utilising exposure information such as mode of exposure (chemicals in food or drinking water) [ 138 , 139 ] or Occupational Exposure Banding strategy for categorization of airborne substances lacking defined limits [ 140 ], could help identify chemicals with high exposure potential. In addition, the hazard level of the toxicity can be used as a criterion, where specific persistent and mobile substances with high toxicity can be targeted for prioritization.…”

Section: Perspectives For Grouping Strategiesmentioning

confidence: 99%

“…The use of in vitro, in vivo, and in silico approaches can aid the grouping and prioritization of chemicals for testing or assessments by regulatory bodies. This can be done by generating grouping hypotheses and justification for inclusion or exclusion criteria for substances in groups [ 140 ]. In particular, novel approaches may generate huge amounts of toxicological and high-throughput “omics” data including metabolomics, transcriptomics, and exposomics to support the validation and establishment of grouping hypotheses needed by regulatory authorities [ 141 ].…”

Section: Perspectives For Grouping Strategiesmentioning

confidence: 99%

Grouping strategies for assessing and managing persistent and mobile substances

Chirsir,

Palm,

Baskaran

et al. 2024

Environ Sci Eur

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Background Persistent, mobile and toxic (PMT), or very persistent and very mobile (vPvM) substances are a wide class of chemicals that are recalcitrant to degradation, easily transported, and potentially harmful to humans and the environment. Due to their persistence and mobility, these substances are often widespread in the environment once emitted, particularly in water resources, causing increased challenges during water treatment processes. Some PMT/vPvM substances such as GenX and perfluorobutane sulfonic acid have been identified as substances of very high concern (SVHCs) under the European Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulation. With hundreds to thousands of potential PMT/vPvM substances yet to be assessed and managed, effective and efficient approaches that avoid a case-by-case assessment and prevent regrettable substitution are necessary to achieve the European Union's zero-pollution goal for a non-toxic environment by 2050. Main Substance grouping has helped global regulation of some highly hazardous chemicals, e.g., through the Montreal Protocol and the Stockholm Convention. This article explores the potential of grouping strategies for identifying, assessing and managing PMT/vPvM substances. The aim is to facilitate early identification of lesser-known or new substances that potentially meet PMT/vPvM criteria, prompt additional testing, avoid regrettable use or substitution, and integrate into existing risk management strategies. Thus, this article provides an overview of PMT/vPvM substances and reviews the definition of PMT/vPvM criteria and various lists of PMT/vPvM substances available. It covers the current definition of groups, compares the use of substance grouping for hazard assessment and regulation, and discusses the advantages and disadvantages of grouping substances for regulation. The article then explores strategies for grouping PMT/vPvM substances, including read-across, structural similarity and commonly retained moieties, as well as the potential application of these strategies using cheminformatics to predict P, M and T properties for selected examples. Conclusions Effective substance grouping can accelerate the assessment and management of PMT/vPvM substances, especially for substances that lack information. Advances to read-across methods and cheminformatics tools are needed to support efficient and effective chemical management, preventing broad entry of hazardous chemicals into the global market and favouring safer and more sustainable alternatives.

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Lessons Learned from the Grouping of Chemicals to Assess Risks to Human Health

Cited by 14 publications

References 123 publications

ECHA ARN documents: chemical grouping without a toxicological rationale

ECHA ARN documents: chemical grouping without a toxicological rationale

Predicting binding between 55 cannabinoids and 4,799 biological targets by in silico methods

Grouping strategies for assessing and managing persistent and mobile substances

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