Hazard, risk and the need for a scientific approach - criteria and weight of evidence for ecotoxicology assessments

Transcription

1 Hazard, risk and the need for a scientific approach - criteria and weight of evidence for ecotoxicology assessments James Wheeler October 2012

2 Outline Background Proposed regulatory approaches in the EU Weight of evidence Regulatory needs an industry perspective Conclusions 2

3 Background 3

4 Background in the EU Plant Protection Products Directive 1107/2009 Biocides revisions to 98/8/EC REACH 1907/2006. All require that substances having endocrine disrupting properties are severely restricted or removed from the market However, no guidance available - Interim criteria for PPPs based on toxicology classification - No interim criteria for wildlife - Draft criteria to be provided by the Commission no later than13 th December Classification: EXTERNAL

5 Background in the EU Poorly defined hazard based cut-off criterion Different interpretations may lead to inappropriate classification and removal from the market Need for a robust and scientifically defensible method for identifying endocrine disrupters Clear guidance is needed on the nature and quality of technical data 5 Classification: EXTERNAL

6 Potential impact Plant Protection Products Several impact assessments have been performed - Vary greatly due to uncertainties and differences in the proposed criteria applied - Did not consider potential environmental criteria Numbers of active substances that may be lost - Swedish analysis based on interim toxicology criteria (carcinogen and reproductive toxicity classification phrases) 4% (11 of 271 substances) - Former UK Pesticide Safety Directorate (CRD) has conducted two review exercises 6.5% (18 out of 278 substances) most likely to be removed 15.5% (43 out of 278 substances) most likely and may be eliminated 6 Classification: EXTERNAL

7 Potential impact Plant Protection Products Agronomic impact - UK CRD Impacts on insecticides are likely to be minor - Risk to resistance management options if the availability of different modes of action is restricted - Intended EDs such as some insect growth regulators (favourable vertebrate toxicity profiles) Herbicides cut-off will most likely impact minor crops - But potentially the control of black grass in broad leaf crops with a risk of yield losses and resistance development Fungicides may face the largest impact - with reductions in wheat and oil seed rape yields of up to 20 and 50%, respectively. 7 Classification: EXTERNAL

8 Potential impact Plant Protection Products Endocrine disruption cut-off criteria have the potential to remove a significant number of active substances from the market - These are currently considered safe Will impact European farmers ability to - Control pests - Manage resistance - Maximise yields - Make a profit There has been no demonstration of meaningful benefits to public health protection from any [hazard] criteria, beyond those delivered by the existing risk assessment procedures. 8 Classification: EXTERNAL

9 Proposed regulatory approaches in the EU 9

10 The approaches Points of discussion - As highlighted by State of the art report (Kortenkamp et al) - Basis for EC technical meeting discussions ECETOC 2011 and 2012 German UBA 2011 UK CRD 2011 Danish EPA 2011 French ANSES

11 Points of discussion Adversity Mode-of-action To satisfy widely accepted definitions of endocrine disruption WHO/IPCS, Weybridge Potency Lead-toxicity Specificity Discriminatory factors Severity Irreversibility Intended endocrine disruptors? Negligible exposure? 11

12 ECETOC Integration of - Regulatory ecotoxicology / toxicology data - Mechanistic screening studies Aim of - Identifying endocrine mediated adverse effects of population relevance - Confirmed/explained by the endocrine mode of action - Satisfies accepted definitions of endocrine disruption (e.g. Weybridge, WHO/IPCS) 12

13 ECETOC Flowchart driven guidance - Toxicology - Wildlife Fish and amphibians Birds and mammals 13

14 ECETOC Bars et al Regulatory Toxicology and Pharmacology 59:

15 ECETOC Bars et al Regulatory Toxicology and Pharmacology 64,

16 Comparison of approaches Adversity Mode-ofaction ECETOC Germany UK Denmark France Yes to include pop relevance Yes pop relevance not specified Yes to include pop relevance Yes pop relevance mentioned Yes pop relevance included but extrapolatio n issues noted Yes Yes Yes Yes Yes Potency Yes Not mentioned but applied to tox Not mentioned but applied to tox No Yes birds possibly STOT-RE No other groups 16

17 Comparison of approaches ECETOC Germany UK Denmark France Leadtoxicity Yes Further guidance needed Yes Not mentioned but for tox no Specificity Yes Yes Yes Not mentioned Severity Yes No; not distinguishe d from adverse No; not distinguishe d from adverse No; not distinguishe d from adverse Yes in absence of other toxic effects / not secondary Not mentioned No; not distinguishe d from adverse 17

18 Comparison of approaches ECETOC Germany UK Denmark France Irreversibi lity Yes No; not distinguishe d from adverse No; not distinguishe d from adverse No; not distinguishe d from adverse No; not distinguishe d from adverse Intended EDs Yes Yes benefits vs risk exemptions Yes; potentially additional testing reqs Not mentioned Not mentioned Negligible exposure Yes Not mentioned Not mentioned Not mentioned Not mentioned 18

19 EU proposals summary Key factors identified - Used in varying degrees in different proposals All is in the detail in how these are put together and used in the overall evaluation Commission process (technical and ad hoc groups) is a forum to discuss these issues - Gaining consensus is proving difficult 19

20 Weight of evidence 20

21 Weight of evidence (WoE) Key to all assessment schemes - Fulfilling criteria in the EU - Triggering of tier 2 studies in the US Why do we need WoE? - Complex issue No one piece of data/study will be definitive - Many data types and qualities available - Interplay between human and environmental assessments What are we weighing? -. 21

22 What are we weighing? The OECD Conceptual Framework Level 1 Existing Data and Non-Test Information Mammalian and non mammalian Toxicology Physical & chemical properties, e.g., MW reactivity, volatility, biodegradability All available (eco)toxicological data from standardized or non-standardized tests. Read across, chemical categories, QSARs and other in silico predictions, and ADME model predictions Level 2 In vitro assays providing data about selected endocrine mechanism(s) / pathways(s) (Mammalian and non mammalian methods) Estrogen or androgen receptor binding affinity Estrogen receptor transactivation (OECD TG 455 [OECD TG 457]) Androgen or thyroid transactivation (If/when TGs are available) Steroidogenesis in vitro (OECD TG 456) MCF-7 cell proliferation assays (ER ant/agonist) Other assays as appropriate 22

23 Level 3 In vivo assays providing data about selected endocrine mechanism(s) / pathway(s) Mammalian Toxicology Uterotrophic assay (OECD TG 440) Hershberger assay (OECD TG 441) Non-Mammalian Toxicology Xenopus embryo thyroid signalling assay (When/if TG is available) Amphibian metamorphosis assay (OECD TG 231) Fish Reproductive Screening Assay (OECD TG 229) Fish Screening Assay (OECD TG 230) Androgenized female stickleback screen (GD 140) Level 4 In vivo assays providing data on adverse effects on endocrine relevant endpoints Repeated dose 28-day study (OECD TG 407) Repeated dose 90-day study (OECD TG 408) 1-generation assay (OECD TG 415) Male pubertal assay Female pubertal assay Intact adult male endocrine screening assay Prenatal developmental toxicity study (OECD TG 414) Chronic toxicity and carcinogenicity studies (OECD TG 451-3) Reproductive screening test (OECD TG 421 if enhanced) Combined 28-day/reproductive screening assay (OECD TG 422 if enhanced) Developmental neurotoxicity (TG 426) Fish sexual development test (OECD TG 234) Fish Reproduction Partial Lifecycle Test (when/if TG is Available) Larval Amphibian Growth & Development Assay (when TG is available) Avian Reproduction Assay (OECD TG 206) Mollusc Partial Lifecycle Assays (when TG is available) Chironomid Toxicity Test (TG ) Daphnia Reproduction Test (with male induction) (OECD TG 211) Earthworm Reproduction Test (OECD TG 222) Enchytraeid Reproduction Test (OECD TG 220) Sediment Water Lumbriculus Toxicity Test Using Spiked Sediment (OECD TG 225) 4 Predatory mite reproduction test in soil (OECD TG 226) Collembolan Reproduction Test in Soil (TG OECD 232) 2 species Level 5 In vivo assays providing more comprehensive data on adverse effects on endocrine relevant endpoints over more extensive parts of the life cycle of the organism Extended one-generation reproductive Toxicity Study (OECD TG 443) 2-Generation assay (OECD TG 416 most recent update) FLCTT (Fish LifeCycle Toxicity Test) (when TG is available) Medaka Multigeneration Test (MMGT) (when TG is available) Avian 2 generation reproductive toxicity assay (when TG is available) Mysid Life Cycle Toxicity Test (when TG is available) Copepod Reproduction and Development Test (when TG is available) Sediment Water Chironomid Life Cycle Toxicity Test (TG 233) 23

24 Weight of evidence approaches CEFIC 1999 Brown et al 2001 US-EPA Borgert et al

25 CEFIC EMSG (1999) and Brown et al Combined framework has four evaluation steps Study reliability quality of work For eco modified Klimisch codes SETAC project to formalise this Study relevance endpoint relevance to ED Study significance based on reliability and relevance Balance of the weight of evidence 25

26 US-EPA Intended for evaluation of tier 1 data - May include Other Scientifically Relevant Information (OSRI) Regulatory studies Peer reviewed literature studies Quality of information - EPA guidance - Recognise Klimisch and other approaches In principle, rely on - Adequacy - Reliability - Relevance 26

27 US-EPA Pathway targeted - Estrogen, Androgen, or Thyroid hormonal pathways (EAT) Do the data provide relevant, robust, and consistent evidence for the potential to interact with the normal function of the E, A, or T hormonal pathways - Agreement within an assay - Agreement amongst all assays If a potential to interact is demonstrated what kind of Tier 2 testing is appropriate? 27

28 US-EPA Suggested pathway analysis 28

29 Borgert et al 2011 Propose a more quantitative approach to weighting Pathway hypothesis driven - The chemical exhibits the potential to: - [a]-1 interact as an agonist with components of estrogen pathways - For each pathway lines of evidence assembled against tier 1 assay results - Response as expected for pathway based on validation studies - Response of negative control for pathway based on validation studies 29

30 Borgert et al Response of test item in the assay [response weighting] - OSRI data response assessed for validity and reliability [response weighting] - Relevance weighting for the endpoint Expert consensus workshops to establish values Or rank ordering of relevance for each endpoint for each hypothesis WoE determination - Combine score of each assay relevant to each hypothesis Removes some of the expert judgement - Standardization of data review and evaluation approaches - Transparency of the process 30

31 Regulatory needs 31

32 Regulatory needs an industry perspective Purely scientific perspective the optimal solution is - Characterisation of the hazard(s) - Extensive exposure assessment - Risk assessment Legislative wordings do not allow for exposure (beyond negligibility) and risk assessment Therefore, we need a clear, fact based and consistent approach - Predictability in the outcome of an endocrine assessment - Focus resources creating space for innovation 32

33 Regulatory needs an industry perspective Unified criteria across different legislations - Data requirements are very different so the information available for an assessment will vary greatly. Simultaneously, the generation of robust in vivo data conflicts with the aim of EU legislation to reduce the animal use in chemicals testing. - Unclear how differently regulatory approaches will be balanced opposite socio-economic benefit assessments Negligible exposure is allowed to negate the need for an endocrine assessment for plant protection products - No definition for environmental assessments One of the areas of disagreement between Member States (and other stakeholders) is the use of potency as a discriminator 33

34 Conclusions Hazard based cut-off for endocrine disruption will be implemented in 2013 It will have an impact on the availability of chemistry solutions - e.g. impact on agriculture yield, resistance management and the development of new crop protection solutions Scientifically risk assessment would be the optimal solution - Will be still be applied outside the EU (US and Japan) Weight of evidence methodologies need to be operationalized for regulatory application Hazard based criteria need to be clear, fact based and consistent - Giving industry predictability in the outcome of evaluations 34

35 ECETOC Acknowledgements Remi Bars Malyka Galay-Burgos Fabrice Broeckaert Sue O Hagan Ivana Fegert Nina Hallmark Tim Kedwards Dick Lewis Grace Panter Arnd Weyers Lennart Weltje Bayer CropScience (Chairman) ECETOC (Secretariat) Total Unilever BASF ExxonMobil SC Johnson Syngenta Astra Zeneca Currenta / Bayer CropScience BASF Melanie Gross WCA Environment Ltd 35 Classification: EXTERNAL

36 References Bars, R., Broeckaert, F., Fegert, I., Gross, M., Hallmark, N., Kedwards, T., Lewis, D., O Hagan, S., Panter, G., Weltje, L., Weyers, A., Wheeler, J., Galay-Burgos, M., Science based guidance for the assessment of endocrine disrupting properties of chemicals. Regulatory Toxicology and Pharmacology. 59, Bars, R., Fegert, I., Gross, M., Lewis, D., Weltje, L., Weyer, A., Wheeler, J., Galay-Burgos, M., Risk assessment of endocrine disrupting chemicals Regulatory Toxicology and Pharmacology. 64, Borgert, C., Mihaich, E., Ortego, L., Bentley, K., Holmes, C., Levine, S., Becker, R., Hypothesis-driven weight of evidence framework for evaluating data within the US EPA s Endocrine Disruptor Screening Program. Regulatory Toxicology and Pharmacology. 61, Brown, R., Greer, R., Mihaich, E., Guiney, P., A critical review of the scientific literature on potential endocrine-mediated effects in fish and wildlife. Ecotox Environ Saf. 49, Classification: EXTERNAL

37 37 Classification: EXTERNAL

38 Back-up slides on proposals 38 Classification: EXTERNAL

39 German UBA Call for clear scientific criteria and test results to satisfy the hazard based criteria Differentiated decision making or mechanism and adverse effect are required - In vitro evidence is not sufficient Intended EDs benefits vs risk exemptions - Human and veterinary pharmaceuticals, pesticides e.g. juvenile hormone analogues Further guidance needed on when an endocrine mediated effect is not relevant to overall ecotoxicological profile 39

40 UK CRD WHO/IPCS definition with modification for population relevance - Highlighting need for adversity and mechanism - Ecotoxicologically relevant effects are population relevant Reproduction, growth and development Clearly state with current methods it is only possible to assess fish and mammals Specificity ( lead toxic effect ) features with a limited regulatory relevance category Intended EDs might be handled differently with additional testing requirements 40

41 Danish EPA Data interpretation closely tied to the OECD Conceptual Framework Acknowledges population relevance (but unclear how it will be used) Categorisation - ED1 confirmed ED based on in vivo data - ED2a suspected ED mainly in vivo data - ED2b indications of ED based on in vitro / in silico data Departs from the other approaches greater emphasis on in vitro (or even just indications from in silico simulations, modelling and/or computer experiments) 41

42 French ANSES Need to identify both the adverse effects on animals and information on the mode of action Adverse effects in intact animals only - mechanism of action may be identified in all the available experimental models Endocrine disrupting effects when they occur in the absence of other toxic effects should not be secondary to another effect Preference for in vivo compared to in vitro for level of evidence Categorisation based on Danish EPA approach - Confirmed endocrine disruptor - Potential endocrine disruptor (suspected and indications of) 42

43 French ANSES Specifically for Plant Protection Products For human health potency limits applied (STOT-RE) and could also be applied to birds - State cannot be applied for environment Level of protection is at the population - But often difficult to integrate laboratory and field effects 43