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Co-authors: Henriqueta Louro, Bruno Costa Gomes, Maria João Silva, Ricardo Assunção, Carla Martins, Paula Alvito (INSA) The aim of this work was to exemplify the inclusion of human biomonitoring (HBM) data in risk assessment (RA) and health impact assessment (HIA) strategies. RA was performed for six compound groups on HBM4EU’s first list of priority substances: anilines, cadmium/chromium, flame retardants, PAHs, PFAS and phthalates. In addition, burden of disease (BoD) calculations were made for cadmium. The general approach used included: 1) identification of an existing RA for the substance, 2) identification of possible existing biological limit or guidance values or biological equivalents (BEs), or if lacking, existing health based limit values for external exposure, 3) identification of relevant biomonitoring data to be used in the RA, 4) in case no existing biological limit or guidance values or BEs existed, identification of approaches for reverse/forward calculation, including the use of PBPK modelling or calculation of BE values based on one-compartment modelling, 5) RA or BoD calculation based on HBM data, 6) analysing the benefits and challenges of using HBM data in RA compared to the use of external exposure data. The overall result of the work was that HBM can be included in RA even when relatively few data are available, and its inclusion generally benefits the RA. Several methods exist, and a tiered approach is suggested, based on the amount and quality of data available. The recommended 1st tier method is a one-compartment modelling based derivation of BE values or reverse calculation of external exposure based on biomarker levels. This approach is simple and rough, and uses only very basic parameters. However, in many cases this approach can be considered sufficient, especially when conservative assumptions have been used for the FUE, and the calculated RCRs remain well below 1, indicating a low risk. Also, in cases in which risk assessment using this approach supports the RA made based on external exposure estimates, it is often a sufficient approach. Nevertheless, in some cases e.g. where the RCR is close to 1, a more detailed approach may be needed to refine the RA. For the 2nd tier, PBPK modelling is recommended. For the most robust, 3rd tier approach, measured data on correlations between external exposure and internal doses from well controlled studies would be needed. Certain cases were identified where inclusion of HBM would be particularly important for performing RA: for compounds, for which several exposure routes may contribute to the body burden and the health effects, as HBM reflects the total body burden, and cumulative compounds. For cumulative compounds, HBM could also be useful for hazard assessment in addition to exposure assessment. One of the major challenges for the inclusion of HBM into RA is the often limited data available on toxicokinetics. In addition, in some cases, there is an urgent need for more specific biomarkers or more sensitive analytic methods than currently available. It should be noted that these risk assessments were performed purely to determine how HBM data can contribute to the risk assessment of chemicals, and they have no regulatory implications. Overall for the substances on the HBM4EU’s first list of priority substances, more HBM data are needed. This work is ongoing in WP8, and the RAs presented here will be updated when new data become available. HORIZON2020 Programme Contract No. 733032 HBM4EU info:eu-repo/semantics/publishedVersion

Summary Report of the first European Exposure Science StrategyWorkshop: Building a Roadmap 2020-2030

Submitted by Maria da Luz Antunes (mluz.antunes@estesl.ipl.pt) on 2019-02-01T11:53:28Z No. of bitstreams: 1 Assessment of needs for a European strategy on exposure science_summary report of the first European Exposure Science Strategy Workshop.pdf: 885211 bytes, checksum: 78ab240a5d91f9ede68ea01405d18eba (MD5) Made available in DSpace on 2019-02-01T11:53:28Z (GMT). No. of bitstreams: 1 Assessment of needs for a European strategy on exposure science_summary report of the first European Exposure Science Strategy Workshop.pdf: 885211 bytes, checksum: 78ab240a5d91f9ede68ea01405d18eba (MD5) Previous issue date: 2019 info:eu-repo/semantics/publishedVersion

This Memorandum is focussed on how to use the weight of evidence approach (WoE)to conduct a risk assessment for stressors to which humans and/or the environment may be exposed. It is intended to complement the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) report on the identification of emerging issues and the work on the challenges in future risk assessment. The aim of this document is to support the use of the WoE, wherever appropriate, for the risk assessment activities of the Scientific Committee on Health, Environmental and Emerging Risks (SCHEER). In addition, it should support the consistency in the work of different EU bodies performing risk assessments. Scientific evidence consists of observations, experimental and model results and expert judgements that serve to support, refute, or modify a scientific hypothesis or theory. The search for relevant information and data for the SCHEER comprises of identifying, collecting and selecting possible sources of evidence in order to perform a risk assessment and/or to answer the specific questions being asked. According to the issue being addressed, the SCHEER may utilise data provided by the DG tasking the SCHEER, or provided by a third party (e.g. stakeholder reports, submissions such as confidential data provided by companies or applicants), reports and Opinions of other scientific, governmental or international bodies, scientific (peer-reviewed) publications, meta-analysis and systematic reviews or personal communications. The WoE is an iterative process involving: - Problem formulation - Identification, collection and selection of the possible sources of evidence - Assessment and weighing of individual lines of evidence - Integration of lines of evidence - Description of uncertainties - Conclusion and reporting For each line of evidence, the criteria of validity, reliability and relevance need to be applied and the overall quality has to be assessed. Several tools for the analysis and description of uncertainties are presented. In the integration of the different lines of evidence, the strength of the overall evidence depends on the consistency and the quality of the results. The weighing of the total evidence should be presented in a standard format. A system is proposed that classifies results of analysis for human and environmental risks in terms of: −Strong weight of evidence: Coherent evidence from a primary line of evidence (human, animal, environment) and one or moreother lines of evidence (in particular mode/mechanistic studies) in the absence of conflicting evidence from one of the other lines of evidence (no important data gaps) −Moderate weight of evidence: good evidence from a primary line of evidence but evidence from several other lines is missing (important data gaps) −Weak weight of evidence: weak evidence from the primary lines of evidence (severe data gaps) −Uncertain weight of evidence: due to conflicting information from different lines of evidence that cannot be explained in scientific terms −Weighing of evidence not possible: No suitable evidence available

In chemicals risk assessment frameworks, the default approach is to assess external intake from different sources of exposure and via different routes of exposure. They are often assessed separately. This approach includes various uncertainties and often overestimates the real uptake since default, conservative estimates are used e.g. for the absorption of the chemical. At the same time, actual (real life) exposure may be underestimated by not taking into account that exposure to a chemical substance may occur from different sources, which may fall under separate legislative frameworks. Examples are triclosan that is used in biocidal products as well as in consumer products and importantly, most if not all chemicals that are produced by workers where at the same time these workers may be exposed as part of the general population. In some cases, other tools to assess exposure via all possible routes may be insufficient; an example is occupational exposure via hand-to-mount exposure, which has been shown to occur for example in the case of many metals, like lead, through contaminated hands. Without biomonitoring, exposure in these cases could become severely underestimated. Human Biomonitoring (HBM) is an important tool to survey the real life body burden – or internal exposure – of humans resulting from ‘total’ exposure to chemicals via different routes (lung, skin, digestive tract) and ‘via’ different legislative frameworks on chemicals. By providing more accurate data on actual body burdens (internal exposure), inclusion of HBM data could improve human health risk assessment for both the general population (exposure via air, consumer products, drinking water and food) as well as for workers (exposure via inhalation and/or skin) separately or as part of the population. info:eu-repo/semantics/publishedVersion

The default approach in the risk assessment (RA) of chemicals is to assess external exposure by combining different sources and routes of exposure. This kind of approach contains various uncertainties and may overestimate exposure, since conservative estimates are needed due to the limited data on, for example, the absorption of the chemical and interspecies and intraspecies differences. Human biomonitoring (HBM) can help improve RA by providing measured data on combined exposures. In some cases, biomonitoring data can even provide a direct link to health effects. In some cases, biomonitoring allows to link exposure to specific contexts such as occupational settings. Although recent years have seen good examples of the use of biomonitoring in the risk assessment of chemicals, much work is still needed to improve its use in regulatory RA and human impact assessment (HIA). The European Human Biomonitoring Initiative (HBM4EU) was recently launched for fulfilling the gap between the exposure to hazardous chemical agents and their impact on human health. One of the aims of the HBM4EU project is to enhance the use of HBM data in RA and HIA of chemicals in different regulatory contexts including legislations on chemicals, plant protection products and biocides, as well as legislation on cosmetics, food safety and occupational safety. RA models for mixtures are also considered. Firstly, current RA practices are evaluated: is the use of biomonitoring integrated in the available RA guidance, and do given RA schemes have good examples of the advanced use of biomonitoring? A survey is also conducted to gather information from national regulatory risk assessors (in the EU, but also in non-EU countries) on their risk assessment practices, the use of HBM, and the obstacles and challenges related to its use. The challenges of the use of HBM data in RA may include a lack of guidance in the use of biomonitoring, a lack of knowledge regarding the interpretation of biomonitoring results, or the inability to link biomonitoring data to different exposure sources. Using a selected group of priority chemicals as example, we can determine whether these challenges can be overcome by including the recent HBM data, collected during the HBM4EU project, in the existing RA schemes. Finally, proposals will be made for the better use of HBM in RA and HIA in different policy domains. HBM4EU project, Grant agreement No: 733032 info:eu-repo/semantics/publishedVersion

Betreft de engelse editie van rapport nr. 758473002. Bij dit rapport behoort een bijlage getiteld " Appendix to integrated ciriteria document dichloromethane, effects.", onder hetzelfde nummer.

Dit rapport is een practische gids voor de toepassing van probabilistische verdelingen van default assessment factoren in risicobeoordelingen voor de mens. RIVM en TNO ontwikkelden het gebruik van probabilistische assessment factoren als eerste stap naar nationale en internaitonale harmonisatie. Er was overeenstemming over de aard van de verdelingen van verschillende humane assessment factoren. De voorgestelde verdelingen zullen worden toegepast in RIVM- en TNO-risicobeoordelingen van nieuwe en bestaande stoffen en bestrijdingsmiddelen. Een voorbeeld van een dergelijke analyse is toegevoegd.

Het betreft een bedrijf dat vloerbedekking, wandbekleding en kunstleer op PVC-basis produceert in de situatie dat alle machines met mistfilters zullen zijn uitgerust. Op basis van gemeten uitworp, produktie-pakket en reguliere bedrijfsvoering werd het uitworppatroon van het bedrijf berekend. Met behulp van verspreidingsmodellen werd hieruit de jaargemiddelde verontreiniging en piekverontreiniging van de lucht in de omgeving voor 8 stoffen bepaald. Op basis hiervan is een toxicologische evaluatie uitgevoerd.

Dit rapport bevat een systematisch overzicht en een kritische evaluatie van de belangrijkste literatuurgegevens over de prioritaire stof enthyleenoxide in het milieucompartiment Lucht. Achtereenvolgens komen de volgende aspecten aan de orde: -fysisch-chemische eigenschappen ; -meetmethoden en meetstrategie; -uitworpen ; -verspreiding en omzetting ; -concentraties in het milieu en blootstellingsroutes ; -normen en richtwaarden ; -effecten ; De kern van dit document is het hoofdstuk over effecten. Naast de effecten van ethyleenoxide op mens en dier zijn ook de invloeden op het aquatische milieu en op materialen in ogenschouw genomen. Bovendien is aandacht besteed aan effecten op wereldschaal. Voornamelijk op basis van de effecten op mens en dier is een toxicologische evaluatie gegeven. Omdat de stof carcinogeen blijkt te zijn is het kankerrisico geschat bij bepaalde concentraties in de lucht.

The efficient assessment of the bioaccumulation potential of chemicals under REACH with integrated test strategies (ITS) requires multiple tools. Existing data have to be searched and information from chemical structures and physico-chemical properties need to be evaluated prior to considering to conduct in-vivo experiments with vertebrates. The OSIRIS inventory of chemistry-driven and in-silico BCF modules for ITS compiles: · Sources of existing data · Computational methods - B/nonB classification models - QSARs - Physiological models - Exposure models - Read across · in-vitro tools · 3R (Refine, Reduce, Replace) modules The ITS components for bioaccumulation listed in the ECHA Guidance on information requirements and chemical safety assessment [1,2] have been extended with new knowledge generated in OSIRIS and complemented with feedback from stakeholders on the actual problems in using ITS for chemical registration. The alternative ITS modules share three major objectives to save time and money by reducing the number of experimental animals required to come to a conclusion about the bioaccumulation potential of chemicals under REACH: · Classification of non-B/B/vB-compounds · Omission of BCF studies, that are scientifically unnecessary or technically not feasible · Waiving of BCF studies, that provide no risk-relevant information The OSIRIS ITS for bioaccumulation will be publicly available (webtool) after further refinement based on stakeholder feedback. Its concepts and modules, as well as validation results, are presented in detail in a dedicated poster corner. [1] ECHA. 2008. Guidance on information requirements and chemical safety assessment Chapter R.11: PBT assessment. (http://echa.europa.eu/reach_en.asp). Accessed 6 March 2009. [2] ECHA. 2008. Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance. (http://echa.europa.eu/reach_en.asp). Accessed 6 March 2009. Acknowledgement - This work was supported by the EU 6th Framework Integrated Project OSIRIS (contract no. GOCE-ET-2007-037017), http://www.osiris-reach.eu.

This report is a practical guide for the application of probabilistic distributions of default assessment factors in human health risk assessments. RIVM and TNO developed the use of probabilistic assessment factors as a first step towards further national and international harmonisation. Consensus was reached on the nature of distributions of several human assessment factors. The proposed distributions will be applied in risk assessments of new and existing substances and pesticides, produced at RIVM and TNO. A format for this analysis is presented in this report.

An evaluation was made of the recently developed risk assessment methodologies for new and existing chemicals in the European Communities. The evaluation also included the methodologies to prioritize chemicals and procedures for risk management, i.e., the (draft) guidance document for the development of strategies for risk reduction. The way in which chemicals are prioritized is accepted with only very few comments. Clear progress has been made in the development and harmonization of risk assessment methodologies and the application of estimation methodologies. Nevertheless, improvements are necessary for the estimation of consumer and occupational exposure, the derivation, use and transparency of assessment factors for chemicals and classes of chemicals based on the mode of toxic action, environmental exposure models and their validation and relation with monitoring data. As far as risk management is concerned it was recommended to improve the integration of the myriad of directives and regulations, to clarify definitions, to provide clear guidance on the determination and weighing of advantages and implications of risk reduction measures and to develop tools, including voluntary agreements, to speed up the slow chemical-by-chemical approach.