pesticides in the EU regulatory framework Prof Andreas Kortenkamp

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1 Addressing combined effects of pesticides in the EU regulatory framework Prof Andreas Kortenkamp Brunel University London Info session on cumulative risk assessment for o sess o o cu u at e s assess e t o pesticides, EFSA Parma 11 Feb 2014

2 Legal requirements at present risk assessment on the combined effects of chemicals in a mixture is not commonly carried out, nor required by most EU regulations. SCHER, SCENIHR, SCCS (EU Scientific Committees on Health and Environmental Risks, Emerging and Newly Identified Health Risks, and Consumer Safety) (2011) Toxicity and Assessment of Chemical Mixtures. European Commission, DG Health & Consumers, Brussels 2

3 The long road to implementation 1996 US Food Quality Protection Act calls for CRA of pesticides with a common MoA 2002 US EPA Guidance on CRA of Pesticide Chemicals that have a Common MoA US EPA CRAs for organophosphates, p triazines, chloroacaetanilides, carbamates 2005 EU Pesticide MRL regulation calls for the development and use of methodologies for CRA of pesticide residues (introduced upon initiative of the EP) EFSA working groups on CRA established, Scientific Colloquium on CRA, Evaluation of existing methodologies, Recommendation of a tiered approach Test result of a suggested methodology for the case of triazole fungicides. Conclusions: appropriate but not yet applicable on a routine basis 2009 Requirement for mixture risk assessments established under the new EU PPP regulation: Active substances and plant protection products shall not have any harmful effects on human health, taking into account known cumulative and synergistic effects where the scientific methods accepted by the Authority to assess such effects are available,... (Article 4) Ongoing Dec 13 EFSA continues methodological work Scientific opinion on relevance of dissimilar mode of action and its appropriate application for cumulative risk assessment of pesticide residues in food 3

4 Synergisms killing mosquito larvae Deltamethrin Deltamethrin + piperonylbutoxide Piperonylbutoxide inhibits cyp isoforms, but is not toxic to larvae on its own Fakoorziba et al. (2008) Food Environ Toxicol 24, 19 4

5 Prediction of mixture effects Prediction of mixture effects when effects of components are known applicable only if all components produce effect of interest Assumption: chemicals act without interfering with each other Effects can be predicted by using dose (concentration) addition or independent action 5

6 Independent action Stochastic principles Additivity expectation: effect multiplication Simultaneous exposure: stochastic ti principles only fulfilled when components show different modes of action in inducing the same effect 6

7 Dose (concentration) addition Agents behave like dilutions of each other Contribute to joint effect in proportion to their dose Additivity expectation: addition of equi- effective doses Applied to combinations of similarly acting chemicals 7

8 Rat developmental toxicity Dosing Birth GD 7 PND 16 Dam Male offspring AGD PND 1 Retained nipples PND 13 Organ weights Malformations PND 16 Malformations PND 47 8

9 Three AR antagonists Hass et al EHP 115 Suppl 1, 122 Dose addition 9

10 16 algal toxicants Faust et al. (2003) Aquat Toxicol 63, 43 Aclonifen 8-Azaguanine Azaserine CCCP Chloramphenicol DTMAC Fenfuram Kresoxim-methyl Metalaxyl Metazachlor Metsulfuron-methyl Nalidixic acid Norflurazon Paraquat Terbutylazim Triadimenol Conc addition Conc addition Independent action Independent action 10

11 Prediction of combination effects Dose addition provides good approximations of observed effects Retained nipples Micronuclei Vtg induction (fish) Androgen receptor antagonism 11

12 Synergism: penile malformations Christiansen et al EHP 117, 1839 Finasteride Vinclozolin DEHP Prochloraz 12

13 What is the correct concept? DA or IA? Often, DA and IA predictions are identical irrespective of modes of action! Are hypotheses about modes of action a reliable basis for making choices? 13

14 Mixtures of anticancer drugs Different sites of action IA corre cted % ce ell killing CA e-6 1e-5 1e-4 1e-3 1e-2 1e-1 1e+0 1e+1 1e+2 1e+3 1e+4 1e+5 1e+6 Drug Concentration (µm) 14

15 Mixtures of aneugens Different sites and mechanisms of action Ermler et al. 2013, Arch Toxicol (in press) 15

16 What is the correct concept? WHO / IPCS (2009): Use dose addition as a default, unless there is evidence to the contrary Dose addition is sufficiently conservative, but sometimes independent action predicts stronger mixture effects Driver: slopes of dose-response curves 16

17 What should be grouped? Grouping criteria? US EPA: Common mechanisms similar chemical structures US National Acad of Sciences (2008): Similar structures too narrow - common adverse outcomes Mechanisms: an unreliable grouping g criterion information often not available Data on common adverse outcomes also often not available Data requirements for pesticide authorisation not geared towards making grouping decisions based on modes of action 17

18 When is a mixture safe? Dose addition Intake 1 Intake 2 + < 1 Tolerable Daily Intake 1 Tolerable Daily Intake 2 Mixture effect is equal to effect at TDI if every component is present at TDI / n Independent action E 12 1,2,..n = 1 - [(1-e 1 1)( )(1-e 2 2) )...(1-e n n)] No mixture effect if all components are present at zero effect levels 100 agents with 1% effect: joint effect = 63% 100 agents with 0.1% effect: joint effect = 9.5% 18

19 When is a mixture safe? Dose addition: dependent on number of components and sum of toxic units Independent action: Are ADI always zero effect levels? What about chemicals without ADI? A matter for risk assessment for Human Health effects, if the intended level of protection is achieved for each individual dua substance, the level e of concern ce for mixtures of dissimilarly acting substances should be assumed as negligible. SCHER, SCENIHR, SCCS (EU Scientific Committees on Health and Environmental Risks, Emerging and Newly Identified Health Risks, and Consumer Safety) (2011) Toxicity and Assessment of Chemical Mixtures. European Commission, DG Health & Consumers, Brussels 19

20 What is dissimilarity? Clear definitions not available Reference cases for strictly dissimilarly acting mixtures are rare in mammalian toxicology Only one example where independent action was shown to be applicable The number of chemicals exceeds the number of available dissimilar modes of action 20

21 Mixture risk assessment methods Can we apply experimental mixture prediction concepts in risk assessment practice? Requirements of experimental assessment concepts (DA, IA): The same endpoint was measured for single components and mixture Dose-response data for single components and mixture Allow predictions for a large range of effects Simplifications Hazard Index (HI) Point of Departure Index (PODI) Relative Potency Factors (RPF) 21

22 Hazard index EL - exposure level, l e.g. intake in mg/kg/d /d AL - acceptable level, e.g. ADI or TDI EL and AL must be expressed in the same unit Simplifications: AL not necessarily in relation to same endpoint Different uncertainty factors may have been used to define AL AL represent effect doses associated with the same (small or zero) effect 22

23 Example: Antiandrogens Kortenkamp and Faust 2010, Int J Androl 33,

24 Bottlenecks Information about exposures and reference doses must be available Data gaps are the rule a vast number of chemicals ca are not toxicologically assessed Approx 800 chemicals with ADI (TDI) vs 10,000, 20,000,???? with food relevance 134,000 chemicals pre-registered under REACH 24

25 Acknowledgements Financial support from European Union: ACE project EDEN project CONTAMED UK FSA Contamed 25

26 The end Thank you! 26