Challenges in environmental risk assessment (ERA) for birds and mammals and link to endocrine disruption (ED) Katharina Ott, BASF SE, Crop Protection Charles River Symposium, Den Bosch, 3rd October 2017
Content Challenges within B&M environmental risk assessment (ERA) High failure rate in tier 1 RA Refinement options in GD and their acceptance Revision of EFSA GD B&M Endocrine disruption in B&M area Current situation Future developments Summary & Conclusions 2
Challenges in the birds & mammals risk assessment 3
Challenges in the birds & mammals RA Regulatory background - EFSA GD 2009 First GD under EFSA procedures 2009: Guidance Document (GD) 2010: Implementation started Utilised now for >6 years Sufficient experience by regulators & industry to assess its performance Revision planned by ~July 2019 4
% Challenges in the birds & mammals RA Tier 1 risk assessment Analysis of official EU evaluations published in 2014-2016 Foliar sprays EFSA Conclusions, 37 a.s. Seed Treatments EFSA Conclusions, DARs, conf data, 4 a.s. 80 70 60 50 40 30 20 10 0 % of a.s. failing Tier 1 75 50 47 25 12.5 13 Insecticides (n=8) Fungicides (n=16) Herbicides (n=13) Only 4 a.s. (1 insecticide, 3 fungicides) Acute risk: 50% fails Chronic risk: 100% fails Acute Chronic Tier 1 acute RA good tool to identify high risk PPP Tier 1 chronic RA Birds refinements & Mammals ERA, Charles (higher River tier) Symposium, required 3rd October for 2017many a.s. 5
Challenges in the birds & mammals RA Tier 1 risk assessment Tier 1 worst case Exposure: indicator species (high feeding rate, low body weight) 100% diet obtained in treated fields default residue data Tier 1 conservative Toxicity endpoint (chronic): Lowest endpoint of conservative lab studies Birds: reproduction test (1-gen) Mammals: 2-generation and developmental toxicity for mammals lowest human relevant endpoint 6
Challenges in the birds & mammals RA Higher tier assessment Several refinement options proposed in the EFSA GD 2009: Lab/ desk work Toxicity tests (lab) Population modelling Avoidance tests Body burden modelling Ecologically relevant tox endpoint Field Studies Selection of focal species PT data (radio tracking) PD (diet) Residues in food items Field effects studies Generic Active substance/ Formulation Focus on exposure refinement Many options, but refinement (use & interpretation) varies between regulators 7
Generic Field Studies e.g. Radio Tracking PT (Proportion of Time) biological & ecological information, not publicly available Actual time spent by radiotracked individuals in crop Very time and cost intensive studies Guideline Data analysis Regulators acceptance EFSA GD, Appendix P Different PT (home range, ) New approach: 21-day PT Studies widely accepted No agreement on -Mean PT / 90 th PT - Consumers / All birds Widely accepted studies but PT value selection by regulators differs 8
A.S./Formulation studies e.g. Field Effects Studies highest tier to address mortality (acute) & reproductive impairment (chronic) Logistically complex & expensive Guideline None (just suggestions) Regulators acceptance Acceptance of protocol by one MS does not guarantee wider acceptance Regulatory use unpredictable Frequently criticised by risk assessors Data analysis Complex Proposals unspecific Few studies used by regulators for approval Evaluation & acceptability by regulators highly variable clarification of value of these studies for regulators important for the revision of GD harmonization helpful for industry 9
EFSA GD Birds & Mammals Future: Update of GD EFSA s Charter for Revision published (July 2017) terms of reference: EFSA Guidance on Protection Goals Regulation 1107/2009, 283/2013, 283/2014 Update risk assessment methods (scientific research & developments) Feedback from Member States & other stakeholders Clarifications to current methodology Provide calculator tool Harmonization of higher tier risk assessment within EU zone Methodology: the current risk assessment methodology will not be significantly changed but will be updated and improved. Timelines for update: July 2019 10
Challenges in the B&M risk assessment Summary Conservative Tier 1 RA with high failing rate refinements crucial GD unclear in several areas different interpretation by risk assessors Some refinement options not accepted at all by regulators Increased conservatism by regulators in respect of laboratory data and default GD values vs. field data Industry anticipates specific guidance on crucial refinements within GD revision aiming at harmonized acceptance and interpretation of data 11
Endocrine disruption and the birds & mammals RA 12
Regulatory background EU Regulation 1107/2009 Defines endocrine disruption as cut-off criteria for a.s. Draft ED criteria shall be proposed by Dec 2013 Pending the adoption of criteria, interim criteria are in place for human health Contains no interim criteria for ecotox Final criteria still not in place 13
Regulatory background EFSA GD 2009: Chapter 5.3 RA for substances with ED properties in B&M Basic considerations: - If ED cut-off in humans, no B&M assessment necessary - Reference to EC 2002 (working document GD on B&M RA under 91/414/EEC): - RA based on ecological relevance of observed effects, independent of the mode of action that are (or may be) responsible for such effects. Therefore the general procedure for risk assessment can also be used for substances with endocrine-disrupting properties. 14
Regulatory background 5 step approach in EFSA GD 2009 1. Check in vivo data for any ED concern (different taxa) 2. Check screening data (different taxa) for potential ED MoA 3. Use potential ED mediated apical endpoint for wild mammal RA (2-gen provides info if overall productivity on population level is affected) 4. Assess standard bird studies but in general data package not sufficient 5. Assess specific bird study, but consider uncertainty of these non-validated methods Wild mammals ED RA covered by rat 2-gen & mammalian mechanistic data Unclear how to assess birds no test guideline available for step 5 15
Bird testing (1) Avian reproduction test: Conservative test design to assess repro effects; several endpoints under endocrine control, but no mechanistic information. 1998: 2-generation study first mentioned in EDSTAC Report that started the EDSP 2002: Initiation by US EPA to develop a protocol within OECD 2007: Detailed Review Paper by OECD - Review current knowledge on avian biology and findings from bird laboratory and field studies of potential ED compounds - Identify research areas - define purpose of a 2-gen study and propose initial protocol EDSTAC: Endocrine Disruptor Screening and Testing Advisory Committee EDSP: Endocrine Disruptor Screening Program of US EPA 16
Bird testing (2) 2013 Validation report by EPA - Evaluation of inter-laboratory trials (3 labs) - Study design in general considered suitable to address ED - Criticism by experts on low sensitivity, inconsistencies among the laboratories and high number of endpoints with low specificity (false positives) 2014 OECD stopped development of 2-generation test guideline - Despite efforts to demonstrate the robustness and reproducibility of the test, given the logistical complexity, the numerous sources of possible failure of the test, and the large animal number used in the test to achieve statistical power, countries decided to stop the development of a harmonised OECD Test Guideline in 2014. 2015 June: EDSP evaluation published (52 compounds within tier 1): - in general, standard avian repro test considered sufficient to address bird RA - For none of the compounds further testing recommended 2015 July: EPA Guideline was published Currently no further method development ongoing 17
Regulatory decisions in EU reviews (1) - Up to 2013/14 ED and birds regularly mentioned as data gap; confirmatory data requested in implementation regulation - Deadline connected to adoption of OECD or community agreed test guidelines - Since ~ mid 2014 EFSA concludes: Chemical X did not indicate an endocrine disrupting potential in mammals; however, no firm conclusion can be drawn regarding fish and birds No specific concerns on the potential for endocrine disruption have been identified from the available ecotoxicological data set on birds and fish. However, no firm conclusion can be drawn from the available information, as in general, these studies alone are not sufficient to investigate all the relevant mechanisms and they may not be sufficient to detect all adverse effects which could be caused by an endocrine mechanism 18
Regulatory decisions in EU reviews (2) Analysis of official EFSA conclusions published in 2013-2014 (n=37) Birds & ED: Never critical area Never unlikely ED 5x real data gap asking for additional data 8x mentioned that no conclusive data available, RA cannot be finalized, but no data gap 24x not addressed at all 19
Regulatory decisions in EU reviews (3) Analysis of official EFSA conclusions published in 2015-2017 (n=32) Birds & ED: Never critical area Never unlikely ED Since 2015 ED generally addressed in ecotox section Standard: no firm conclusion can be drawn regarding birds 1x real data gap for ecotox 31x can not be finalized, no conclusive data, but no official data gap 20
Summary of current ED assessments EFSA B&M GD (2009): General RA principles can be followed Mammals: ED related apical endpoint can be used in wild mammal RA Birds: in case of potential ED MoA, specific study may be considered, however: no internationally agreed test method available work on 2-gen and avian reproduction testing strategy stopped no attempts to develop other test methods EFSA conclusions: in general, evaluation is not finalized for birds, but does not conclude in a data gap that precludes renewal EPA concluded for assessed 52 EDSP compounds that standard avian test is sufficient for RA and never asked for 2-gen testing Common understanding that standard study is sufficiently protective? Will this change Birds with & Mammals implementation ERA, Charles River Symposium, of the new 3rd October ED 2017 definition? 21
Proposed ED definition within EU Regulation 1107/2009 3.6 Toxicology 3.8 Ecotoxicology Adverse effect Adverse effect on population level link link Human relevant ED MoA ED MoA Will implementation of the new ED definition change the current assessment process? Birds & Mammals Does ERA, ED Charles MoA River need Symposium, to 3rd be October addressed 2017 in birds? 22
ED Guidance document Oct 2016 Mandate to EFSA and ECHA Dec 2016 Outline published - Birds & Mammals within scope of the guidance document Work on guidance ongoing public consultation planned after adoption of the criteria Uncertain if final ED definition and ED GD or GD revision will change current approach and lead to data gap for birds 23
Summary & Conclusions Chronic RA the most frequent issue in ERA birds & mammals Many refinement options available, but acceptability by regulators differs Revision of EFSA GD is coming Specific guidance on study protocols and harmonized acceptance of key field studies anticipated by industry Currently, bird ED assessment can not be finalized, but does not result in a data gap Unclear if final ED definition, ED GD or B&M GD revision will change this and lead to data gap 24
Thank you 25