Toxicological and ecotoxicological risk assessments of chemical mixtures as well as their regulation are getting more and more discussed. The debate focuses on both plant protection products and biocides and chemicals regulated under REACH. The first International Akademie Fresenius Conference “Toxicity of Chemical Mixtures: Risk, Hazard and Exposure Assessment” from 9 to 10 December 2014 in Mainz (near Frankfurt)/Germany presented an overview of the current state of affairs in Europe and background information regarding the topic.
To date, during authorization procedures at an European level, the focus was on the hazard, exposure and risk of the active substances and only limited information needed to be provided on chemical mixtures. In the future, exposure and risk assessments will concentrate more on mixtures and components other than the active substances. Nevertheless, there are no consistent, harmonized approaches available yet for the human health risk assessment of mixtures and regulatory bodies are in the process of gathering first experiences in that particular area. Michael Werner (SCC, Germany) summarized the current status regarding toxicity assessments of chemical mixtures in Mainz. In regulatory procedures, the assessment of human health effects of mixtures was largely performed on the basis of the properties of the individual components, the expert began. In this connection, the additivity principle plays an important part. Mixture toxicity testing is in most cases, however, restricted to acute effects, because mixture studies with regard to higher tier endpoints such as, mutagenicity, reproductive toxicity or carcinogenicity are generally not available and not required in the context of product authorization procedures, Werner elucidated. Furthermore, a systematic testing for higher tier endpoints in order to investigate to potential combined actions of the ingredients is not feasible due to the large number of products and for reasons of animal welfare (in many cases, investigations of mixture toxicity and examinations of interactions are conducted on vertebrates), he added. Beyond that, the “Guidance on the application of the CLP criteria” would only allow animal testing of mixtures for a proper assessment of the potential toxicity of the mixture if no reliable and valid data of the individual components exist.
Human health risk assessments – status quo
Concerning human health risk assessments of chemical mixtures, Werner commented that for the purpose of the authorization of the concerned products, the assessments take now also components other than the active substances into account. However, a big challenge is to identify the mixture components which should be considered in these assessments. A practical approach is to focus on active substances and substances of concern, meaning potentially hazardous, non-active substances, the expert advised. For the majority of mixtures, there was still a lack of knowledge on the mode and mechanism of action of the components, he added for consideration. For human health risk assessment purposes, the concentration/dose addition approach should be applied by default unless it can be demonstrated that target tissues or target organs of the individual components or the mode/mechanism of action were different, Werner pointed out. He concluded that for a refinement of cumulative/combined risk assessments, it would be required to revisit the toxicological data package to derive target tissue / target organ specific reference doses.
Grouping of pesticides based on common effects
With regard to the assessment of pesticides and the setting of maximum residue levels (MRLs), the EFSA pursues a tiered approach which starts with the identification of cumulative assessment groups (CAGs). Susanne Hougaard Bennekou (Environmental Protection Agency, EPA, Denmark) commented at the conference on the grouping of pesticides and the authority’s approach to combined exposure. Theoretically, multiple mixtures of pesticides could occur in consumer diet, but the exposure to each pesticide might vary greatly – also over time, the expert began. Therefore, the grouping of active substances related to chemical mixtures in CAGs could not be driven by exposure assessments, but had to be based on criteria solely derived from the intrinsic properties of the chemicals under consideration (e.g. their modes of action or common adverse effects), Hougaard Bennekou emphasized. EFSAs methodology for identifying and grouping pesticides for CAGs was related to hazard assessment, she went on. It would follow a phenomenological approach based on organ or system toxicity. According to that, all pesticides causing a specific (adverse) effect are included within one cumulative assessment group in the lower tier of the hazard assessment. Thus 287 pesticides have already been assessed for grouping. The CAGs can include substances acting by similar or dissimilar modes of action. A distinction between similar and dissimilar modes of action is important for the evaluation of experimental data, but is of limited relevance in cumulative risk assessment practice on deciding on the risk assessment concept, the expert told the audience. However, knowledge about modes of action could be helpful for refined tiers, she added.
All together EFSA recommends grouping of pesticides that produce common adverse outcomes on the same target organ respectively target system. Their combined effects shall be assessed by using the concept of dose addition. This would be a pragmatic and conservative default approach for the purpose of assessing cumulative risk in relation to MRL setting or risk assessment of chemical mixtures, the expert explained.
EFSA’s scientific strategy envisages the development of harmonised methodologies for combined exposure to multiple chemicals until 2016. At the end of her presentation, Hougaard Bennekou elaborated on EFSA’s 21st Scientific Colloquium which took place in September and which dealt with the harmonisation of human and ecological risk assessment of combined exposure to multiple chemicals. There are many similarities between both areas already: Because of common underlying scientific rationale, ecotoxicological and toxicological tiers were analogous, Hougaard Bennekou elucidated. Data gaps were also a commonality. On top of that, some aspects were already harmonised. Ecotoxicology as well as toxicology would both expect dose additions for same modes of action and their default assumptions were similar at lower tiers, the expert went on. A need for harmonisation would exist with regard to the regulatory frameworks. Especially the requirements and approaches for both areas should be assimilated, the expert underlined. Furthermore, criteria for filling the current data gaps had to be developed. For future assessment of combined exposure to multiple chemicals, it was encouraged to develop alternative methods to animal testing and increase knowledge on determinants of synergism, Hougaard Bennekou remarked.
Unknown toxic mechanisms: dose addition assures sufficient protection for human health
Upon request of the General Directorate of Health and Consumers of the European Commission (DG SANCO), its three Scientific Committees developed an opinion on the toxicity and assessment of chemical mixtures in 2011. Helmut Greim (Technical University Munich, Germany) spoke at the conference about the most important aspects of that opinion, which described the three possible scenarios of mixture toxicology: similar or dissimilar mode of action and interference. The expert confirmed that different chemical substances had the potential to act jointly in a way which could affect their toxicity for humans and/or the environment. With current assessment methods, the effects of chemical mixtures can be reasonably well predicted – both for similarly or dissimilarly acting substances. Principally, chemicals with similar modes of action can produce combination effects that are larger than the effects of each mixture component, which can be well described by the principle of dose respectively concentration addition. The use of dose/concentration addition is also sufficiently protective for unknown toxic mechanisms. On the other hand, there is no robust evidence available that the exposure to a mixture consisting of chemicals with both common or different modes of action represents a health concern, given that the components are present at or below their zero-effect levels Greim admitted, however, that it was a significant limitation of component-based approaches that they were only applicable to mixtures of which the major components were already known.
One had to take also into consideration that interaction of chemical substances such as interference with their metabolism or excretion would usually only occur at medium or high dose levels, he added. At low exposure levels they were either not occurring or toxicologically insignificant. In general, interactions would be difficult to assess and ever require expert judgement on a case-by-case basis, Greim underlined.
The complete Akademie Fresenius conference documentation including scripts from all the presentations can be purchased at the Akademie Fresenius for 295,00 € (plus VAT) or here.
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