Christer Hogstrand King’s College London

Jean-Lou Dorne

European Food Safety Authority, Scientific Committee

EFSA’s perspective on risk assessment of chemical

mixtures

Past Activities on Chemical Mixtures in EFSA

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EFSA PPR (2008) Suitability of existing methodologies assessing cumulative and synergistic risks from pesticides to human health to set MRLs (Regulation (EC) 396/2005). EFSA Journal 704, 1-85.

EFSA PPR (2009) Assessment of cumulative human health effects of Triazole fungicides. EFSA Journal; 7 (9); 1167 [187 pp.].

EFSA PPR (2013) Identification of pesticides to be included in cumulative assessment groups on the basis of their toxicological profile. EFSA Journal 11(7):3293 [131 pp.].

EFSA PPR (2013) Relevance of dissimilar mode of action and its appropriate application for cumulative risk assessment of pesticides residues in food. EFSA Journal 11(12):3472 [40 pp.].

EFSA MIXTURE METHODS: HUMAN RISK ASSESSMENT: HUMAN RISK ASSESSMENT

Future Mixture RA EFSA

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EFSA PPR (2012) Science behind the development of a risk assessment of Plant Protection Products on bees (Apis mellifera, Bombus spp. and solitary bees). EFSA Journal 10(5):2668 [275 pp.]. o Methodologies to deal with mixture toxicity/synergistic

effects of pesticides in honey bees, bumble bees and solitary bees

o Key Recommendations:

• Need dose responses: lethal/sub-lethal effects in adults/larvae to predict magnitude of interactions for honey bees, solitary bees and bumble bees- Lab work performed on 6 compounds and 6 mixtures for 3 species.

• Include multiple stressors in risk assessment (e.g chemicals and bee diseases): MUST-BEE project on-going 2015-2019

EFSA MIXTURE METHODS: ECOLOGICAL RISK ASSESSMENT

Future Mixture RA EFSA

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Hazard identification: Identifying specific and unambiguous toxic effects that adversely affect an organ or system (e.g. imbalance of the thyroid system).

Hazard characterisation: describing the precise nature of this adverse effect to specific organs or systems (e.g. identifying the most appropriate indicator for the specific effect, for instance, a hormone).

Data collection: Gathering data on the indicators (e.g. changes in hormone levels at the dose where the advesre effect occurs) that point to a specific toxic effect in an organ/system (e.g. imbalance of the thyroid system).

Grouping of pesticides that exhibit a similar toxicological effect into cumulative assessment groups by organ or system (e.g. thyroid).

EFSA PPR DEFINITION OF CAG FOR PESTICIDES

Groups are formed by identifying pesticides that produce similar toxic effects in a specific organ or system. The methodology consists of four stages:

Main title

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EFSA PPR DEFINITION OF CAG FOR PESTICIDES

The following groups were proposed for the 68 pesticides identified as having specific effects on the nervous system:

Main title

Acute exposure (47) Motor division (45) Sensory division (20) Autonomic division (29)

Chronic exposure (64) Motor division (53) Sensory division (21) Autonomic division (24) Neuropathological changes (19)

EFSA Journal 2013;11(7):3293

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Main title

REVIEW OF FRAMEWORKS FOR MIXTURES RA

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Harmonised Terminology Harmonisation of terminology between EFSA and others Harmonisation of terminology between HRA and ERA

Harmonised Methodologies For HRA, between regulated compounds and contaminants Between animal health RA and ERA

Future Methods for risk assessment of multiple chemicals in combination with biological and biophysical stressors

Optimise process of problem formulation to identify chemicals of priority (exposure- and hazard-based) prior to embark on risk assessments of multiple chemicals

Integration of Exposure and Hazard-based problem formulation (Risk driven) Provide guidance taking into account differences in legal

frameworks

REVIEW OF FRAMEWORKS FOR MIXTURES RA: RECOMMENDATIONS (I)

Future Mixture RA EFSA

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Exposure assessment Generate means for cross-agency occurrence data collection for

multiple priority chemicals in food samples Develop case studies and training data sets comparing

deterministic vs. probabilistic methods of exposure assessment Develop methods for aggregate exposure assessment

Hazard assessment Support harmonisation of methodologies with regards to hazard

assessment Develop methods for whole mixture approach Design a scientific basis for setting Assessment Groups Facilitate data collection on TK/TD using systematic review

Risk characterisation and uncertainty analysis Support harmonisation of methodologies for risk characterisation

and uncertainty analysis Provide guidance document for hazard assessment/risk

characterisation

REVIEW OF FRAMEWORKS FOR MIXTURES RA: RECOMMENDATIONS (II)

Future Mixture RA EFSA

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Scientific Basis of Uncertainty Factors

Collection of data and generation of tools

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Main title

DATA COLLECTION PROCUREMENT 1(2)

“Metabolic interactions and synergistic effects of chemical mixtures for human risk assessment using systematic review”

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Main title

PROCUREMENTS TO COLLECT DATA 2(2)

“Combined toxicity of multiple chemicals: evidence-based approach for animal health and ecological risk assessment using systematic review”

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TK AND MULTIPLE CHEMICALS : TOOLS AND MODELS

Future Mixture RA EFSA

Procurement call on the integration of TK tools in chemical risk assessment applied to human health, animal health and the

environment aiming to develop models for single and multiple chemicals

Objective 1: Review models and tools in human, animal and environmental risk assessment

Objective 2: Collect physiological/biological parameters - Develop TK tools and models for single compounds (from

simple tools to generic PB-PK models). - Case studies 10 compounds relevant to food and feed safety

combining TK and TD Objective 3: Develop TK tools and models for multiple

chemicals (from simple tools to generic PB-PK models). - Case studies 10 compounds relevant to food/feed safety

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DYNAMIC ENERGY BUDGET (DEB) MODELS

Future Mixture RA EFSA

Procurement on modelling population dynamics of aquatic and terrestrial organisms using Dynamic Energy Budget Models aiming to develop models for the risk assessment of single and multiple chemicals

Objective 1: Review DEB models (Dec 2015) Objective 2: Collect physiological/ biological parameters-

calibration of models single compounds incl DEB (Jan 2016 - Apr 2017)

- Develop generic/specific models for aquatic and terrestrial organisms for single compounds-Endocrine case study

Objective 3: Develop tools and models for multiple chemicals (Jan 2016 - Jan 2018).

All tools in R and as Open sources on EFSA website

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Harmonisation of Human and Ecological

Risk Assessment of multiple Chemicals

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Main title

SCIENTIFIC COLLOQUIUM IN SEPTEMBER 2014

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TERMS OF REFERENCE 1(2)

The WG should review available tools for different risk assessment contexts and develop a harmonised framework for human and ecological risk assessment of combined exposure to multiple chemicals using tiered approaches.

The tiered approaches should start from first scientific principles for all relevant steps i.e.

• Problem formulation • Hazard identification and characterisation • Exposure assessment • Risk characterisation and Uncertainty analysis.

For each step, tiered approaches for harmonisation of methodologies should be developed where feasible, depending on purpose of the assessment, data availability, resources, and include explicit description of assumptions.

Future Mixture RA EFSA

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TERMS OF REFERENCE 2(2)

Circumstances under which harmonisation between human and ecological risk assessment may not be possible or relevant should also be discussed.

In developing the guidance, work should start from and build on European and international methods and frameworks, to ensure inter-agency cooperation, consistency and avoid duplication of the work.

Case studies should be annexed in the GD to explore the feasibility and spectrum of applications of the proposed methods and approaches for human health and ecological risk assessment.

In line with EFSA’s initiative on Transparency and Engagement in Risk Assessment (TERA), the draft GD will be subject to public consultation. The published GD will be presented and discussed at an international event.

Future Mixture RA EFSA

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TOR SUBJECTED TO PUBLIC CONSULTATION

Main title

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TIMELINE

Future Mixture RA EFSA

February 2016: Nomination of WG by the Scientific Committee

June 2016: First WG meeting November 2016: Launch Public Consultation of the ToR March 2017: Draft technical report on outcome of the

Public Consultation December 2017: Two technical reports on tiered

approaches for ecological and human risk assessment of combined exposure to multiple chemicals

June 2018: Draft guidance document prepared by WG June 2018: Public Consultation of draft Guidance December 2018: Adoption of the draft guidance

document Spring 2019: International workshop to present the SC

guidance documents

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THANK YOU FOR YOUR ATTENTION

Human Ecological

Future Mixture RA EFSA