Authorisation Process for Plant Protection Products (PPPs) in … · 2018-08-09 · Scoping paper:...

1

Steering Group Meeting on the

SAM HLG topic for Scientific Opinion

Authorisation Process for

Plant Protection Products (PPPs) in Europe

from a Scientific View

ndash A Forward Look

Day One - 30 Aug 2017 1300-1730

Palais des Acadeacutemies

rue Ducale 1 1000 Brussels

High Level Group

REQUEST FOR ADVICE

From the College of EU Commissioners

Policy Challenge

2

2

2

Consultation of the scientific

community and stakeholders

Review of scientific evidence

Consortium of European and National Academies

(SAPEA)

High Level Group

+

2

3

Proposals for Policy or Legislation

High Level Group Scientific Advice

2

4

3

bull HLG adopted the scoping paper on 23-24 March 2017

Question A EU dual system for approval and authorisation of PPPs bull Could the current EU dual system for approval and authorisation of plant

protection products rendered more effective efficient and transparent and if so how could this be achieved SAPEA

bull To this end the SAM HLG may wish to consider comparing the situation in the EU with non-EU OECD countries and to discuss the advantages and disadvantages of different systems SAM secretariat (with input from experts)

Question B Risk perception and acceptance by society bull How are risks perceived by society and which factors and mechanisms influence

risk acceptance and the authorisation and use of PPPs In this respect which is the role of NGOs and media SAPEA (later time)

Scoping paper Authorisation Process for Plant Protection Products (PPPs) in Europe from a Scientific View

2

5

Presentation and review of a) Progress against plan for the production of an Evidence

Review Report (ERR)

b) draft structure of the ERR (and its relationship with the Opinion)

c) Main findings to date (draft text)

d) Plans to complete the review

Todays Objective

2

6

4

1 Teacoffee on arrival 2 Welcome House-keeping Introductions Agenda and Todays

Objective

3 Progress against plan ndash a brief summary

4 Draft structure of the evidence review a) Sections ndash main themes b) Format and Style c) How the Evidence Review Report (ERR) relates to the

Scientific Opinion document

5 Main findings to date and emerging messages a) Early draft ERR b) Comparison with non-EU OECD countries

6 Next meetings amp recap

Todays Agenda

2

7

Break

Science Advice for Policy by European Academies

8

Authorisation Process for Plant Protection Products (PPPs) in Europe from a

Scientific View ndash A Forward Look

5


Could the current EU dual system for approval and authorisation of PPP be rendered more effective efficient and transparent and if so how

9

Improving scientific input to the authorization of plant protection products

in the EU

Effectiveness

To which extent have the objectives been achieved as a result of the implementation of Regulations (EC) No 3962005 and 11072009

Where expectations have not been met what factors have hindered their achievement

Which unintended effects were observed Did other factors influence the results observed The answers to these questions should address

the situation at both EU and at MS level

6

Efficiency

To which extent the costs for the Commission including EFSA Member States operators involved in the approval of substances and authorisation of plant protection products in the setting of MRLs have been justified and evenly distributed given the effects achieved

Are there issues which pose particular problems for SMEs and micro-enterprises

Which benefits were achieved from the implementation of the legislation

Is the legal framework generating unnecessary regulatory burden and which actions could reduce regulatory burden or potential alternative policy mechanisms that could improve cost-effectiveness

Scientific opinion on the authorisation processes for PPPs in Europe ndash

A scientific point of view a) EU dual system for approval and authorisation of plant protection

products a) Could the current EU dual system for approval and authorisation of

plant protection products be rendered more a) effective b) efficient and c) transparent

b) If so how could this be achieved

ldquoTo this end the SAM HLG may wish to consider comparing the situation in the EU with non-EU OECD countries and to discuss the advantages and disadvantages of different systems The assessment should be in scientific terms and not examine legal and policy issuesrdquo

a) Methods of arbitration

7

Original EER question SAPEA

What is the scientific state-of-the-art and promising novel methods and procedures for assessing potential harmful effects on human health from the use of plant protection products

8

Current status - Specifics

Word-count 13366

72 references

Sections

1 Main findings

2 Introduction

3 Methodology

4 Authorization aims and constrains

5 The current EU authorization background

6 Scientific shortcomings of the current EU system

7 Possible future scientific approaches

8 Recommendations for policy makers

9

Sections I

1 Main findings 2 Introduction

1 Authorization background 2 Perceived problems 3 Scope of the review

3 Methodology 4 Authorization aims and constrains 5 The current EU authorization background

1 Approaches to hazard risk and uncertainty

6 Scientific shortcomings of the current EU system 1 Uncertainty in the risk assessment and expressing it 2 Coformulants 3 Mixtures 4 Uncertainty in the risk assessment and expressing it 5 Data requirements ndash discussion in relation to microorgansims

Sections II 7 Possible future scientific approaches

1 Human epidemiology and Surveillance 2 Data Quality for epidemiological studies of potential pesticide toxicity 3 Options for improving epidemiological input to regulatory decision making 4 Public Perception 5 Evidence synthesis methods for combining disparate data sources (in vitro

laboratory animals human epidemiology) 6 Assessment of exposures 7 Assessment of health outcomes 8 Other uses of epidemiology 9 Evaluation of epidemiological evidence 10 The future use of epidemiology in the task of assessing the safety of

pesticides suggested strategies 1 The nature of epidemiology 2 Identification of exposures

1 Timing of exposure 2 Methods currently used to identify exposures 3 Possible future strategies for identifying human exposures

3 Choice of outcomes for the future

11 The future of toxicity testing


10

Methodology of the Evidence Review Successful example

Two formed groups a Review Team

To find and collate the informationevidence upon which the Note was produced

Invited staff members from SAPEA four members of the SAM Unit members of the SAM-HLG technical experts from the JRC

a Steering Group To advise the RT to contribute to the identification of evidence

make the final selection of source literature and to conduct the bulk of the evidence synthesis to produce the draft and final Note

Leader two members of the HLG five academy fellows as technical experts in the field (nominated by and supplied via the SAPEA consortium) a technical expert from JRC four members of the SAM Unit EC policy representatives (occasionally invited to attend parts of the SG meetings)

Sources of Evidence

A scientific literature search performed on four separate platformsdatabases Web of Science SCOPUS BIOSIS and Find-eR (ECs own database)

Other sources of literature (references identified mostly by topic experts)

Web using search engines (for illustrations and texts) Largely due to time constraints reviews reports and

existing scientific opinions were the main focus of the search and screening exercise Only publicly accessible scientific evidence in English was used in the development of the Note

11

Medical literature look up

PubMed

1991 to 72017

No directly relevant research synthesis efforts

(pesticides OR plant protection products) AND (law OR regulation OR legislation OR approval OR authorization)

7984 citations


22

Sections ndash main themes 1) EXECUTIVE SUMMARY

2) INTRODUCTION 21 Background to PPP Authorisations (High Level Overview of existing system) 22 Perceived problems with current system 23 Scope of the Review 3) METHODOLOGY The evidence gathering and review process consists of several steps such as evidence review needs and questions on PPPs evidence review plan with identified keywords and search strings evidence review search in PubMed and Scopus databases and shared and stored in Mendeley and Dropbox repositories Articles stored were screened and appraised data and information gathered are assessed and synthesized in to the evidence review report

Draft structure of the evidence review (Evangelia)

12


23

Sections ndash main themes 4) AIMS OF PPP AUTHORISATION AND CONSTRAINTS 5) THE CURRENT EU PPP AUTHORISATION SYSTEM

5) SCIENTIFIC SHORTCOMINGS OF THE CURRENT AUTHORISATION SYSTEM

5) POSSIBLE FUTURE SCIENTIFIC APPROACHES Format and Style (APA 6th Edition Referencing Style)



24

How to bridge the evidence review report to the Opinion document


13


25

2 INTRODUCTION ( Colin ) 21) Background to PPP Authorisations High level overview of existing system 22) Perceived problems with current system Following the conclusion of the reapproval process for glyphosate there was extensive support from all but one of the EU member states for the RMS risk assessment conclusions During the process conclusions drawn by IARC and the EU RA were highlighted in a widely observed debate and became controversial However they were arrived at following different reviews An apparent conflict followed for the following reasons-

Main findings to date and emerging messages ndash DRAFT ERR review by the PPP Working Group (Alan Boobis Coggon David Colin Ockleford Evangelia Ntzani Jean Golding Paul

Miller and Susanne Hougaard Bennekou)


26

14


27


28

15


29

22) Perceived problems with current system Possible explanations for such inconsistencies including problems in scientific interpretation and its

communication to decision-makers

Following the conclusion of the reapproval process for glyphosate there was extensive support from all but one

of the EU member states for the RMS risk assessment conclusions During the process conclusions drawn by IARC and the EU RA were highlighted in a widely observed debate and became controversial However they were arrived at following different reviews An apparent conflict followed for the following reasons-

1 Inconsistent consideration of evidence relating to use of AS or formulation (communication gaps) 2 The IARC and EU systems used non-identical reference criteria and categories (anthropocentric IARC 2A

not identical to Category 1B in CLP) (scope for harmonization) 3 The reviews amp RAs of EFSA and the RMS addressed different evidence base with EU using data not

considered by IARC (communicate available transparency) 4 Expert knowledge judgements on the quality of evidence were not congruent(scope for harmonization

of approach) 5 There were differences over which statistical tests were appropriate for analysis (specialist support

need) 6 Weight of evidence appraisal was applied to a greater extent by the RMS




Biological relevance of AS is less to animals

30

16


Relative toxicity of AS amp Coformulant

31

Glyphosate POE tallowamine(b)

End point

Acute toxicity Rat LD50 oral Dagger gt 5000 mgkg bw gt 864 mgkg bw Rabbit LD50 dermal Dagger gt 2000 mgkg bw gt 907 mgkg bw

Skin irritation non irritant irritant Eye irritation moderately to severely irritant severely irritant Skin sensitisation non sensitising sensitising

Mutagenicity Gene mutations negative negative Chromosome aberrations negative negative

Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)

Short term toxicity Rat oral 90-day 150 300 20 60

Dog oral ca 90-day 300 1000 21 42 2-generation Reproduction toxicity (rat)

Parental toxicity 700 2000 38 74 Reproductive toxicity 2000 gt 2000 12 38

Offspringrsquos toxicity 700 2000 12 38 Developmental toxicity (rat)

Maternal toxicity 300 1000 108 72 Developmental toxicity 300 1000 72 216

DNA damage negative Equivocal (some evidence at high and toxic doses)

EFSA (European Food Safety Authority) 2015 Statement of EFSA on the request for the evaluation of the toxicological assessment of the co-formulant POE-tallowamine EFSA Journal 201513(11)4303 13 pp doi102903jefsa20154303


Regulation 11072009 requires an assessment of the physical health and environmental hazards presented by active substances in PPP and a proposal by the applicant on the classification under Regulation 12722008 of the active substance and PPP This proposal is assessed by the MS and in the case of the active substance by EFSA Some classifications trigger non-approval or only exceptional approval of the active substance

EFSA amp ECHA

First category CLP Known or presumed human carcinogens

A substance is classified in category 1 for carcinogenicity on the basis of epidemiological andor animal data

Category 1A

Substances known to have carcinogenic potential for humans

The classification in this category is largely based on human evidence human studies that establish a causal relationship between human exposure to a substance and the development of cancer

Category 1B

Substances presumed to have carcinogenic potential for humans

The classification in this category is largely based on animal evidence animal experiments for which there is sufficient evidence to demonstrate animal carcinogenicity

32

IARC Group 2A The agent is probably carcinogenic to humans This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals In some cases an agent may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans Exceptionally an agent may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans An agent may be assigned to this category if it clearly belongs based on mechanistic considerations to a class of agents for which one or more members have been classified in Group 1 or Group 2A

Regulation (EC) No 12722008 of the European Parliament and of the Council of 16

December 2008 on classification labelling and packaging of substances hellipndash Annex

I classification and labelling requirements for hazardous substances and mixtures

17


The basics US EPA is considering-

33

Once the critical study demonstrating the toxic effect of concern has been identified the selection of the NOAEL results from an objective examination of the data available on the chemical in question The ADI is then derived by dividing the appropriate NOAEL by a safety factor (SF) as follows ADI (human dose) = NOAEL (experimental dose)SF (Equation 1) a Too narrow a focus on the NOAEL means that information on the shape of the dose-response curve is ignored Such data could

be important in estimating levels of concern for public safety The BMDL approach which is supported by EFSA Scientific

Committee is potentially more scientific as an RA method It will probably require risk managers to set protection goals and

consider how either or both of the two methods should be used

b As scientific knowledge increases and the correlation of precursor effects (eg enzyme induction) with toxicity becomes

known questions about the selection of the appropriate adverse effect arise

c Guidelines have not been developed to take into account the fact that some studies have used larger (smaller) numbers of

animals and hence are generally more (less) reliable than other studies


Uncertainty in the risk assessment and expressing it

ldquoEFSA is striving to increase the transparency in risk assessment outputs related to the food chain and has recently developed a guidance on how it will deal with uncertainties in risk assessment (EFSA 2016)ldquo

This together with recently published guidance on using weight of evidence and the guidance on biological relevance of data (EFSA 2017) relate to the EFSA PROMETHEUS programme which aims to ensure consistency of methodological approaches1 across areas of activity including that of the Unit and PPR Panel responsible for pesticides Options for the SAM group include the decision on the degree and extent that such procedural consistency is applied to all aspects of regulation and to any bodies that aim to influence regulatory outcomes 1(EFSA (European Food Safety Authority) 2016 Technical report on the Analysis of EFSA methodological needs for evidence use in scientific assessments EFSA supporting publication 2016 EN-1092 55 pp)

34

18


35

Inadequacy to protect adequately against toxicity in humans (Susanne) Particular effectshealth outcomes where concerns have been raised Developmental Neurotoxicity (OECDEFSA 2016) bull not captured well with the current animal models bull the data are not available during the assessment bull two accepted guidelines TG426 and TG443 with the DNT cohort bull across the different chemical regulations in Europe (Pesticides Biocides and industrial

chemicals) and the US (pesticides) DNT testing can be triggered based on neurotoxic effects in repeat-dose testing known neurotoxic mode of action or structural activity relationships

bull Europe ~485 approved pesticides the TG426 have been available in 35 cases - the TG443 has not been applied

Main findings to date and emerging messages ndash DRAFT ERR review by the PPP Working Group (Alan Boobis Coggon David Colin Ockleford Evangelia Ntzani Jean

Golding Paul Miller and Susanne Hougaard Bennekou)


36

Inadequacy to protect adequately against toxicity in humans Lack of Developmental Neurotoxicity data ndash reasons 1 Being very animal demanding and costly 2 There are no understanding of the underlying processes for most of the endpoints

measured 3 The endpoints measured currently does not capture or reflect well the complex end

points of relevance for humans for example cognitive functions 4 There is a high variability and reproducibility of the data can be poor even for the

positive controls



19


37

Inadequacy to protect adequately against toxicity in humans ndash other health effects Association between pesticide exposure (non-dietary) and EE Ntanzi et al 2013 602 epidmemiological studies - gt 6000 data analysis Parkinsonlsquos disease (EFSA 2017) Childhood leukemia (EFSA 2017) Type II diabetes Asthma Amyotropic lateral sclerosis Some cancer types ndash liver breast stomach Many of the complex multi-factorial human diseases are difficult to replicate in the standardised animal test




38

3 METHODOLOGY (Evangelia) PubMed look-up Aims We sought to provide a comprehensive overview of the imprint that plant protection product legislation has had so far in the health-related scientific literature by critically appraising the published evidence The aim of this rapid review and horizon scan was to effectively collect review (and appraise) peer-reviewed publications related to the authorization and approval of plant production products with a special focus on human health Methods Evidence identification We searched MEDLINE from January 1991 to July 2017 using the search algorithm ldquo(pesticides OR plant protection products) AND (law OR regulation OR legislation OR approval OR authorization)rdquo and employing one filter publication date (1991 onwards) We also perused the references included in eligible studies whenever pertinent Alternative search algorithms with different specificity and sensitivity properties were tested before finalizing the process We screened citations for eligibility using the open-source abstrackr software (accessible at wwwcebmbrownedusoftware) To ensure consistency two reviewers performed a calibration exercise and screened the first 100 citations in two rounds of 100 citations each using broad inclusion criteria Disagreements were discussed and analyzed to clarify screening criteria Once it was deemed that all reviewers were applying the criteria in the same way we continued with single screening of the remaining abstracts All included papers were assessed for eligibility by two reviewers Conflicts and questions were resolved by discussion with a third reviewer



20


39

3 METHODOLOGY (Evangelia) Preliminary Results As of August 17 2017 abstract and full-text screening is in process 7984 citations were retrieved from the

PubMed literature search Based on the current progress 2577 citations are probably relevant based on the titleabstract screening

As an additional step we aimed to identify whether there have been any relevant evidence synthesis attempts with specific focus on legislation We thus performed a literature search using the algorithm ldquo(pesticides OR plant protection products) AND (policy OR law OR regulation OR legislation OR approval OR authorization) AND (meta-analysis OR ldquosystematic reviewrdquo)

Our search yielded 40 citations of which fourteen publications passed through the abstract screening Of these nine were considered further (Table X) After full text scrutiny of the assessed publications and due to the low number of relevant evidence synthesis efforts in the field we confirmed that a broader generic non-systematic-review focused algorithm was appropriate




40

3 METHODOLOGY (Evangelia) Table 1 Systematic reviews and meta-analysis relevant to PPP legislation

Main findings to date and emerging messages ndash DRAFT ERR review by the PPP Working Group (Alan Boobis Coggon David Colin Ockleford Evangelia Ntzani Jean Golding Paul Miller and Susanne Hougaard Bennekou)

Lancet Glob Health 2017

Prevention of suicide with regulations aimed at restricting access to highly hazardous pesticides a systematic review of the international evidence

Rev Panam Salud Publica 2016 Interventions that facilitate sustainable development by preventing

toxic exposure to chemicals an overview of systematic reviews

Environ Int 2016

Reflections on the process of using systematic review techniques to

evaluate the literature regarding the neurotoxicity of low level

exposure to organophosphate pesticides

Environ Sci Pollut Res Int 2015 Pesticide authorization in the EU-environment unprotected

Ann Intern Med 2012 Are organic foods safer or healthier than conventional alternatives

a systematic review

Environ Sci Technol 2011 Global trends and diversity in pentachlorophenol levels in the

environment and in humans a meta-analysis

Environ Health 2011 Knowns and unknowns on burden of disease due to chemicals a

systematic review

Scand J Work Environ Health 2008 Effectiveness of interventions in preventing injuries in agriculturemdasha

systematic review and meta-analysis

Regul Toxicol Pharmacol 2000 Dichlorvos and carcinogenicity a systematic approach to a

regulatory decision

21


41

4) AIMS OF PPP AUTHORISATION AND CONSTRAINTS (Colin) In considering whether and how the PPP authorisation system might be improved scientifically need first to consider its objectives and also the practical constraints under which it operates The overall aim is to maximise the social economic and health benefits from use of PPPs while avoiding unacceptable adverse impacts on human health and the environment With regard to adverse impacts on human health the objective is zero risk of other than minor toxic effects when products are used in accordance with the conditions of approval (nocebo effects are not covered by this and are more challenging) In addition the regulatory system should be trusted by and fair to stakeholders To this end its methods should be open transparent internally consistent and reflect the state of the science and those conducting scientific risk assessments should be suitably experienced and manifestly free from potential conflicts of interest In the pursuit of these objectives there are however a number of practical constraints bull Any standards and control measures that are mandated must be enforceable bull The system must be efficient and its costs proportionate (resources and relevant scientific expertise are

limited and must be used optimally) bull Avoid unnecessary animal testing



Historical Control Experiments

COMMISSION REGULATION (EU) No 2832013 of 1 March 2013

Section 5 (3)

ldquoWhere available historical control data shall be provided routinely The data submitted shall be for endpoints that could represent critical adverse effects and shall be strain-specific and from the laboratory which carried out the index study They shall cover a five-year period centred as closely as possible on the date of the index studyrdquo

42

22


bull There is scientific concern about inconsistent reporting management and use of historical control experiments ldquowhere availablerdquo

bull The economic and animal welfare arguments for the use of these are not well founded as the data have to be renewed every 5 years and at present similar data may be held by several organisations

bull If Mammalian toxicology testing were centralised and conducted by IndependentCommission laboratories control populations offering adequate power could be used for more than one experimental group simultaneously

43


WORKING GROUP OF THE ADVISORY GROUP ON THE FOOD CHAIN ANIMAL AND PLANT HEALTH

Ad hoc Dialogue event on risk assessment of active substances in plant protection products 24 April 2015 0930h ndash 1730h Summary report extract

ldquoDE uses historical control data for validityquality control purposes when certain criteria are met and finds it useful for rare tumours or malformations It sees a need for a free

publicly accessible database This request was supported by several other experts

Currently a database on historical control data exists but it is not freely available since it was sponsored by industryrdquo

44

23


bull The suggested option would be readily enforceable as it would be carried out centrally at European level

bull The system would be more efficient and its costs would still be borne by the applicants

bull Would avoid much presently unnecessary animal testing

bull Would give reassurance to those members of the public that favour greater transparency in the system of approval

45


Constant review of fundamentals eg ldquoThe ADI is an estimate of the amount of a chemical that can be ingested daily over a lifetime without appreciable health risk It is derived from No-Observed-Adverse-Effect-Levels (NOAELs) determined in a battery of toxicity tests in animals and augmented by human data where available The toxicity tests are intended (with a few exceptions) to embrace all the circumstances of human exposure to dietary chemicals Hence these tests include chronic studies sometimes with prior exposure in utero and reproduction tests covering the reproductive phase including effects on the parental animals and the offspring The tests should also cover the rapid growth phase from weaning to maturing The ADI is calculated from the lowest NOAEL in the most sensitive test and the most sensitive species unless other data indicate otherwise and if the reproductive neonatal or rapid growth phases indicate particular periods of sensitivity this should drive the numerical derivation of the ADI In calculating the ADI the NOAEL is divided by appropriate arbitrary or data-derived safety or uncertainty factors Care in selecting the pivotal test the NOAEL and the safety factors should ensure that the ADI does apply to children (or other age groups) However because of the higher food intake of children on a body weight basis specific risk management measures may be needed to ensure that the ADI is not exceededrdquo

Walker R School of Biological Sciences University of Surrey Guildford UK

46

24


The ADI

Acceptable Daily Intake is commonly defined as the amount of a chemical to which a person can be exposed on a daily basis over an extended period of time (usually a lifetime) without suffering a deleterious effect It was introduced in 1961 by the Council of Europe

The average male lifetime ie expectancy when born in United Kingdom in 1961 68 years but by 2015 it was 80 years httpdataworldbankorgindicatorSPDYNLE00MAINlocations=GB

This probably has relevance to how risk managers may in future consider long term exposure and possible effects on health outcomes whose incidence increases with age

Lifetime approaches can benefit from acquisition of more high quality data on population weights and more molecular developmental and physiological information to support RA

47


48

5) THE CURRENT EU PPP AUTHORISATION SYSTEM (Coggon) Description Approaches to hazard risk and uncertainty In the formal assessment and management of potential harm from pesticides and other chemicals a distinction is drawn between the terms ldquohazardrdquo ldquoriskrdquo and ldquouncertaintyrdquo A hazard is an adverse effect which a chemical could cause at least in certain circumstances Hazards range

from minor and reversible effects such as transient irritation of the eyes nose and throat through to serious and sometimes fatal diseases

Risk is the probability (chance) that the chemical will cause a hazardous outcome in specified circumstances of

exposure Among other things risk depends on the route by which a person is exposed (eg inhalation ingestion skin contact) the extent of exposure (in general higher exposures carry larger risks) and the susceptibility of the individual who is exposed (because of differences in genetic constitution age pre-existing health and other factors some people may be at higher risk than others from a given exposure)

In decisions on whether to authorise a use of a pesticide account is taken of the seriousness of the hazards with which it is associated and of the risk that those hazards will be realised given the types and levels of exposure that the use will engender


25


49

5) THE CURRENT EU PPP AUTHORISATION SYSTEM (Coggon) Over the years pesticide regulation has tended to become progressively more precautionary ndash ie requiring

more certainty that when the chemical is used as intended the risk of any serious toxic effects will be zero This has been achieved by the so-called cut-off criteria where a negligible exposure has to be shown if the active substance possesses certain hazards

However so far negligible exposure has not been agreed upon and there making it difficult to assess whether the protection goal has been met For genotoxic compounds (in category 1A and 1B) no approval can be granted Moreover for some hazards (eg cancers) there is a default assumption that risks will be unacceptable unless strongly convincing evidence is available to the contrary However most aspects of scientific uncertainty cannot readily be quantified and their evaluation is more a matter of expert opinion Standard requirements can be specified regarding the range and design of toxicological tests that must be carried out in support of an application for regulatory approval and standard assessment (uncertainty) factors can be applied when their results are used to determine what would be a maximum acceptable level of exposure

Inevitably however interpretation is to some extent subjective giving a potential for inconsistency in decisions



50

6) SCIENTIFIC SHORTCOMINGS OF THE CURRENT AUTHORISATION SYSTEM Uncertainty in the risk assessment and expressing it (Colin) Following ldquoEFSA is striving to increase the transparency in risk assessment outputs related to the food chain

and has recently developed a guidance on this describing uncertainties in risk assessment (EFSA 2016) ldquo

This together with recently published guidance on using weight of evidence (EFSA 2017 EFSA 2017 and the guidance on biological relevance of data (relate to the EFSA PROMETHEUS programme which aims to ensure consistency of methodological approaches across areas of activity including that of the Unit and panel responsible for pesticides (EFSA (European Food Safety Authority) 2016 Technical report on the Analysis of EFSA methodological needs for evidence use in scientific assessments EFSA supporting publication 2016 EN-1092 55 pp)

Options for the SAM group include the decision on the degree and extent that such procedural consistency is applied to all aspects of regulation and to other bodies that challenge the outcomes of the regulators conclusions


26


51


52

6) SCIENTIFIC SHORTCOMINGS OF THE CURRENT AUTHORISATION SYSTEM 61 Coformulant (Susanne) The protection is that there should be no risk of harmful effects of the use of PPPrsquos Detailed data requirements are laid out in regulation 2832013 for the active substance and 2842013 for the PPP There is a lot of data on the active substance synergist safener but much less on the co-formulants bull Co- formulants are REACH regulated ndash currently difficult to align to two regulations bull No co-formulants on Annex III bull No harmonised approach for assessing safeners and synergist

Main findings to date and emerging messages ndash DRAFT ERR review by the PPP Working Group (Alan Boobis Coggon David Colin Ockleford Evangelia Ntzani Jean Golding Paul Miller and Susanne

Hougaard Bennekou)

27


53

6) SCIENTIFIC SHORTCOMINGS OF THE CURRENT AUTHORISATION SYSTEM Mixtures (Susanne) Dietary Exposure bull The pesticide and MRL regulation both calls for addressing cumulative including

synergistic effects risk assessment of pesticide use bull In regard to addressing the issue for MRL setting this is currently being developed and

will soon be implemented (EFSA 2008 EFSA 2012 EFSA 2013) bull Exposure to multiple compounds of operators workers bystanders residents and the

environment this is conducted to a very limited extent Non-dietary Exposure bull PPP containing more than one active ingredient is being risk assessed in regard to

operators workers bystanders and residents the combined effect is taken into account in a simple tiered approach bull not harmonised across Europe and the Northern and the mid zone have

developed their separate guidance on this bull On environmental exposures the situation is the similar and there are even

examples where national rules are being applied bull More complex scenarios eg tank mixes and crop scenarios over a season this is not

addressed currently no risk assessment methodology has been developed and secondly regulatory tools unclearlacking if a risk is identified to manage the risk Major challenge in addressing the more complex situations lack data ndash exposure and hazard (co-formulants) tools ndash models


Hougaard Bennekou)


54

64 Data requirements ndash discussion in relation to micro-organsims (Susanne) Bio-pesticides have attractive properties - would fulfil the intention of the sustainable use directive bull managing resistance bull more targeted bull environmental friendly Obstacles bull The current data-requirements are not geared to them ndash made for chemicals ndash

technically not feasible or irrelevant bull Should be made more relevant unambiguous and flexible


Hougaard Bennekou)

28


55

63 Uncertainty in the risk assessment and expressing it Article 1 of the regulation 11072009 states that ldquoIn particular Member States shall not be prevented from applying

the precautionary principle where there is scientific uncertainty as to the risks with regard to human or animal health or the environment posed by the plant protection products to be authorised in their territoryrdquo Thus the regulation clearly states that the scientific uncertainty shall be identified and described for the different assessment outputs

As for now in the very vast majority of cases determining the Point of Departure is done by determining the No

Observed Adverse Effect Level (NOAEL) However this has several drawbacks amongst those that the uncertainty in the NOAEL is not quantified This can be overcome by applying the Bench March Dose (BMD) approach instead where the PoD will be determined more precisely quantitatively as has lately also again been recommended by EFSA (2017)

64 Data requirements ndash discussion in relation to microorgansims There is consensus that bio-pesticides potentially have many attractive properties that would fulfil the intention of

the sustainable use directive they could be important in managing resistance they are more targeted and environmental friendly

However the present data requirements were established in 1991 and to a large extent based on the data requirements for chemical active substances and plant protection products A number of guidance documents have been developed mostly in the OECD regime to overcome challenges of how different data requirement should be interpreted and methods taking into account current scientific and technical knowledge

The status is that the current data requirements are not geared for this category of substances but are rather obstacles In essence data are required which can technically not be produced or are scientifically irrelevant as they are not addressing a health or environmental concern



56

7) POSSIBLE FUTURE SCIENTIFIC APPROACHES (Colin) New approaches and techniques that might benefit future PPP authorisation schemes in a) the short term 71 Human epidemiology and Surveillance Human epidemiology concerns human specific risks where health outcomes are integrated measures of the

effects of all exposure to toxins such as pesticides and their results reflect factors that interact to alter the effects of toxins Such studies have the potential to elicit subjective experience from potentially affected people as just one advantage over laboratory animal studies However ldquoreal worldrdquo exposures to pesticides are frequently complex

The effect of a specific active ingredient is not easily isolated to be specifically studied Exposures occur in various settings where precisely controlled conditions are lacking Quantitative dose-response data leading to points of departure (NOAEL and BMDLs) that are routinely derived from regulatory animal studies are likely to be rarely the outcome of epidemiological studies because of this

Most published epidemiological studies on pesticides contain data that reflect the responses of mixed populations and many of these studies show low level associations that are inconsistently repeatable and require sophisticated analysis The likely consequence of this is that presently the most valuable use of epidemiology in the context of pesticide risk assessment is in the first stage hazard identification This value has the potential to increase through contributions to the re-approval procedures


29


ldquoEpidemiologic studies have the potential to inform both the experimental toxicologist and the regulatory manager of possible sources of harm in human populations However like all information considered in risk assessments the quality and reliability of the information provided by epidemiologic studies needs to be closely scrutinized This SAP report is intended to provide specific guidance to OPP with respect to incorporation of epidemiologic data into risk assessmentrdquo[February 2010 SAP report p 7]

Quoted by Epidemiologist David Miller US EPA

57


ldquoWe hope that this report will provide a useful input into the

development of European Commission guidance to Member States on the development of systems for identifying and recording information on the health impacts of exposure to pesticides as required by article 7 of the Sustainable Use directive (2009128EC) ldquo

58

ADVISORY COMMITTEE ON PESTICIDES

REPORT OF THE PESTICIDES ADVERSE HEALTH EFFECT SURVEILLANCE

SCHEME WORKING GROUP (PAHES)

Prof Jon Ayres ACP Paul Adamson CRD - HHEIS Prof Nick Bateman NPIS Dr Charlie Clutterbuck Independent consultant Dr John Cocker ACP Prof Gay Hawksworth ACP Nick Mole PAN UK Prof Colin Ockleford ACP Dr Andy Povey ACP Dr Huw Rees ACP Dr Dil Sen HSE PIAP Dr Stephen Waring ACP

30


Excerpt from Table 4

59

SCHEME NHANES CALIFORNIAN

SCHEME

US NPDS SYSTEM WASHINGTON

SCHEME

Health Canada PIRS WHO FAO AumlRZTLICHE

MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers

occupational or non-

occupational

exposure and

employmentself-

employment

Usually Yes No Potentially Usually

SYMPTOMS Yes but not linked

to biological

monitoring

Yes Yes with detailed

follow up over short

periods in some

No Yes Yes Yes

CLINICAL SIGNS Yes but not linked

to biological

monitoring

Yes Yes for patients

confirmed by

clinician

Biomedical not

necessarily Clinical

Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician

INVESTIGATIONS Yes but not linked

to biological

monitoring

AChE levels where

appropriate

Yes for patients No Results of

investigations where

relevant

No information

available

Yes

TREATMENTS Yes Yes Yes for all Removed from job Treatment received

medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES

No Yes Yes Removed from job Yes length of

symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic

characteristics listed

Unlikely Medium term Entry into database

search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No


The group concluded that no single scheme is capable of delivering the best information about possible short and long term health effects that may arise following short or long term exposures Surveillance is better suited to gathering information on short term exposures and effects and alternative epidemiological methods are more appropriate for the consideration of longer term exposures and effects The report therefore recommends a combination of approaches perhaps collated through a central independent co-ordinating body

60

31


61

7) POSSIBLE FUTURE SCIENTIFIC APPROACHES (Colin) New approaches and techniques that might benefit future PPP authorisation schemes in a) the short term 72 Data Quality for epidemiological studies of potential pesticide toxicity Regarding health outcomes the current lack of harmonised diagnostic criteria across Europe and the storage of

data in insufficiently detailed combinable form for integrated analysis are limiting available data quality The poor training of medical and paramedical staff in relevant toxidromes that will allow optimum quality of data entered into Health Statistics Databases National Poisons Control Centres and Pesticide Incident Databases are also areas where there are gains to be made Similarly the record of where and when active substances and co- formulants have been applied could be better maintained for public benefit and as input for GIS systems that could be used to collocate with health information in time and space to at least post-code levels of resolution

73 Options for improving epidemiological input to regulatory decision making There are options to benefit risk assessment of pesticides using human epidemiology These include the freeing Of access to data from very large numbers of potentially exposed citizens of the EU for studies of increased statistical power that when stratified can reveal subtle health effects and reveal the experience of sensitive sub-groups The prospect of improving exposure estimation by better record keeping and by using biomonitoring and new molecular approaches to establish tissue burdens of potential toxins and their residues is also timely 74 Public Perception Widespread perception of risk levels to the human population or to wildlife and the environment that are

unrealistic are derived from poorly designed and interpreted epidemiological studies They cause misplaced anxiety and sometimes act as a drag on economic progress and restrict social benefit The ability better to define risks and separate the concept from the concept of hazard in the minds of the public and decision makers will bring benefits to society by supporting public reassurance and proportionate responses It is only when adequate surveillance and an appropriate system of independent oversight are seen to be enforced that the wider community will become less concerned about this area



62

The future use of epidemiology in the task of assessing the safety of

pesticides

Suggested strategies

32


63


pesticides



64

Epidemiology can only be helpful if there are accurate

assessments of both environments and outcomes

33


65

Pesticides are among the most difficult exposures to study


66


bull People generally are unaware of exposure

34


67



bull There is usually a long lag time between exposure and

consequence


68

Measurement of pesticides

35


69


bull Ask individuals


70


bull Ask individuals bull Measure exposure in the

workplace bull Measure using biological markers

36


71





72

Exposure of the most vunerable will likely give different results

37


73


Unborn children and infants


74



The elderly andor frail

38


75

Methods of assessing exposure

bull Mapping bull Questioning bull Occupation bull Assaying biological samples


76



39


77




78



40


79




80

Examples from the CHAMACOS study

One off biosamples in pregnancy have demonstrated many

associations in the offspring with pesticides of various sorts

41


81

Methods of assessing causation from epidemiological associations

bull Mendelian randomisation bull Repetition bull DNA Methylation signature bull Exposome techniques


82



42


83




84



43


85




86

What are the important outcomes

bull Traits or diagnoses bull Physical or neurocognitive bull This generation or the next

44


87




88



45


89




90

How can we get useful quick

answers

By using data already available especially longitudinal cohort studies

with stored biological samples

46


91


answers




92

Possible European birth cohorts that have relevant large datasets

Norway [MObA] Denmark [DNBC]

Holland [Generation R] UK [ALSPAC Born in Bradford]

Total N gt 100000 births

47


93

UK adult aging cohorts that have relevant large databases

UK Biobank

1946 1958 and 1970 birth cohorts English Longitudinal Study of Aging

The Million Women study Total N gt 1000000


94

In conclusion

1 Diagnoses are feasible outcomes for the aging cohorts with large Ns 2 Continuous traits (eg IQ) are very powerful outcomes for prenatal exposures

48


95

In conclusion

1 Diagnoses are feasible outcomes for aging cohorts with large Ns 2 Continuous traits (eg IQ) are very powerful outcomes for prenatal exposures


96

In conclusion


49


97

In conclusion

3 There is much that can be done immediately given the funding and appropriate biological assay techniques


98

7) POSSIBLE FUTURE SCIENTIFIC APPROACHES (David and Jean) New approaches and techniques that might benefit future PPP authorisation schemes in b) the medium terms 75 Evidence synthesis methods for combining disparate data sources (human epidemiology) Epidemiology contributes to risk assessment for plant protection products mainly by providing information

on statistical associations between exposures to pesticides and potential health effects Studies are mostly observational rather than experimental and as such are liable to ldquoconfoundingrdquo

Moreover because of the practical and ethical constraints on research with human participants they are usually subject to various forms of ldquobiasrdquo In addition the associations that are observed may be unrepresentative simply by chance especially when studies include only small numbers of people who have both experienced the exposure of interest and subsequently developed the health outcome

Depending on the exact circumstances confounding bias and chance can cause the health effects of a pesticide to be under- or over- estimated and epidemiological findings must therefore be interpreted with caution With appropriate care however useful conclusions can be drawn For example epidemiological research has helped to establish and characterise the hazards of skin cancer from arsenical pesticides [IARC] of various cancers from dioxin contaminants in 245-T and chlorophenols [IARC] and of male infertility from dibromochloropropane [Goldsmith 1997]


50


99

7) POSSIBLE FUTURE SCIENTIFIC APPROACHES 76 Assessment of exposures The biggest challenge in pesticide epidemiology is the assessment of exposures Epidemiology is best at distinguishing high relative risks When increases in risk are only small (lt 15 fold) even if statistically robust it is difficult to rule out spurious effects of bias andor confounding although there are a number of techniques nowadays that may help with this [ref] Confounding occurs when the pesticide exposure of interest is associated with other factors which independently determine risk of the health outcome Bias is a systematic tendency to underestimate or overestimate a parameter of interests because of deficiency in the design or execution of a study Relative risk is the ratio of risk in a person with specified exposure to that in someone who is unexposed or exposed at some other specified level Relative risks are normally highest when exposures are high but in developed countries exposures to pesticides tend to be relatively low and are generally well below the levels at which acute toxic effects occur This is in contrast to pharmaceuticals therapeutic doses of which are often close to the level at which acute toxicity can occur 77 Assessment of health outcomes Approaches to the assessment of health outcomes in epidemiological studies of pesticides are much the same as in other areas of epidemiology and do not pose any unique challenges Historically many studies have focused on cancer which can be ascertained from cancer registrations as well as from death certificates and hospital records In addition because many widely used insecticides are neurotoxic there has been substantial research on neurological and neuropsychological outcomes such as neuropathy and aspects of cognitive function Developmental abnormalities have been another focus because the fetus and small infant may be particularly vulnerable to some toxic effects Other potential health outcomes have received less attention often because toxicological evaluation suggests that they are less likely to be a problem However there may be benefit from more epidemiological research on some less serious health effects such as contact dermatitis and acute irritancy Other uses of epidemiology While most epidemiological research on pesticides focuses on their associations with illness and disease epidemiological methods can also contribute to regulatory risk assessment in other ways For example with biomarkers as outcome measures they can be used to explore the distribution and determinants of personal exposures to pesticides in different situations One study of this type showed that a major determinant of operatorsrsquo exposure to sheep dip was the handling of the concentrate used to make up the dip [IOM] and this encouraged improved design of containers for pesticide concentrates with wider necks to reduce splashing Another study explored levels of exposure to several pesticides in residents living near to fields treated with pesticides and provided useful reassurance that residential proximity per se was not a major determinant of individual exposures [IOM] There is scope for further research of this type to help validate and refine the modelling of potential exposures that is carried out as part of regulatory risk assessment Evaluation of epidemiological evidence



100

7) POSSIBLE FUTURE SCIENTIFIC APPROACHES 77 Assessment of health outcomes Approaches to the assessment of health outcomes in epidemiological studies of pesticides are much the

same as in other areas of epidemiology and do not pose any unique challenges Historically many studies have focused on cancer which can be ascertained from cancer registrations as well as from death certificates and hospital records In addition because many widely used insecticides are neurotoxic there has been substantial research on neurological and neuropsychological outcomes such as neuropathy and aspects of cognitive function Developmental abnormalities have been another focus because the fetus and small infant may be particularly vulnerable to some toxic effects

Other potential health outcomes have received less attention often because toxicological evaluation suggests that they are less likely to be a problem However there may be benefit from more epidemiological research on some less serious health effects such as contact dermatitis and acute irritancy

78 Other uses of epidemiology While most epidemiological research on pesticides focuses on their associations with illness and disease

epidemiological methods can also contribute to regulatory risk assessment in other ways For example with biomarkers as outcome measures they can be used to explore the distribution and determinants of personal exposures to pesticides in different situations

One study of this type showed that a major determinant of operatorsrsquo exposure to sheep dip was the handling of the concentrate used to make up the dip [IOM] and this encouraged improved design of containers for pesticide concentrates with wider necks to reduce splashing Another study explored levels of exposure to several pesticides in residents living near to fields treated with pesticides and provided useful reassurance that residential proximity per se was not a major determinant of individual exposures [IOM]


51


101

7) POSSIBLE FUTURE SCIENTIFIC APPROACHES 79 Evaluation of epidemiological evidence Epidemiological data are rarely available when approval is first sought for new pesticides because up to

that point there has been little human exposure However when registration is reviewed for previously approved pesticides there is a requirement to evaluate any relevant epidemiological studies that have been published

This may present problems because currently there is little epidemiological expertise among the staff at EFSA or national regulatory authorities in Member states

Algorithms have been developed to assist in the systematic review of epidemiological research but they can be a little simplistic For example according to some algorithms the weight given to a positive study could be reduced because it had high potential for bias even though the bias if present would be expected to reduce rather than inflate risk estimates

In addition to the potential for bias and confounding within individual studies and the need to account for statistical uncertainties in their findings another major challenge in epidemiological review can be selective publication of positive findings

Small non-positive studies may fail to get published at all and reports of larger studies may focus on the more interesting results and omit information on others that seem less notable

Analytical techniques such as funnel plots can be used to check for publication bias but require suitable expertise



102

7) POSSIBLE FUTURE SCIENTIFIC APPROACHES Concluding comments A number of authors have recently summarised the literature and made the following statements (1) lsquoAvailable evidence supports the concept that epigenetics holds substantial potential for furthering our understanding of the molecular mechanisms of pesticidesrsquo health effects as well as for predicting health- related risks due to conditions of environmental exposure and individual susceptibilityrsquo [Collotta et al 2013] (2) lsquoImportant questions for future research include the need for larger and longitudinal studies Future

studies should also consider hellip the role of underlying genetic variantsrsquo [Ruiz-Hernandez et al 2015]

(3) lsquoRapidly growing evidence has linked environmental pollutants with epigenetic variations including changes in DNA methylation histone modification and microRNAsrsquo [Hou et al 2011] (4) lsquolarge prospective studies will be needed to understand whether changes in risk factors are associated with changes in DNA methylation patterns and if changes in DNA methylation patterns are associated with changes in disease endpointsrsquo [Terry 2011] Finally there is an important working paper from the USA on the implications of epigenetics for environmental law [Vandenbergh 2017] This considers the implications for world-wide regulations on chemical exposures of the fact that epigenetic effects can be transmitted down the generations


52


103

7) POSSIBLE FUTURE SCIENTIFIC APPROACHES (AlanSusanne) Current Approaches assessing safety of chemicalspesticides in humans bull Expensive bull Time consuming bull Limited relevance as predictors of adverse effect

Consensus across academia industry and regulators that the sensitivity and specificity of animal-based safety testing too often leads to wrong predictions of human adversities

US NRC 2007 Toxicity testing in the 21st Century A vision and a strategy bull Key concept most xenobiotic toxicities are related to effects on a limited number of

physiological pathways required for normal cellular maintenance regulation or adaptation

bull toxicological assessment based on human cell responses and a comprehensive mechanistic understanding of cause-consequence relationships of chemical adverse effects

bull Defining AOPs allow toxicologists moving away from a lsquoblack box approachrsquo investigating lsquoapical endpointsrsquo towards an approach where effects are mechanistically understood allowing prevention and monitoring


Hougaard Bennekou)

104

53

Chemical Toxico- Kinetics

Molecular Effect

Cellular Effect

Tissue Organ

Organism Population

Adverse Outcome Pathway

QSAR ModelingExposure amp TK

In Vitro

In Vivo

Epidemiological

Biomonitering

Mechanism-based Toxicity Testing and Risk Assessment

2D HepG2 (GPF-reporter) plusmn CYP450s iPSC-derived hepatocytes (+reporters)

HepaRG + 3D HepG2

Throughput Complexity

2D3D primary human hepatocytes + liver microtissues

multicellular andor diseased

microtissues

precision cut human

liver slices

archived rodent liver material

Variabilities Human and in vivo anchoring Primary long-term differentiated Speed cost

organ-on-a-chip microfluidics connection

to other tissues

Multi-organ integration

EU-ToxRisk Model Systems Rationale

Need addressed

In vitro systems

54

107

108

55

109

EU-Pestides Re-think the data requirements


110

8) Recommendations for policy makers

SAPEA experts will use their considerable expertise to consider the evidence and examine options but will not explicitly publish or make recommendations The HLG in extensive dialogue with SAPEA experts makes a critical appraisal of these options in order to make its eventual recommendations It is likely and indeed desirable that consensus is reached between the HLG and SAPEA experts and that the thread from options to recommendations is evident (or in case of minority opinions that these are clearly explained)


56

SCOPING DOCUMENT

HLG ESTABLISH OVERSIGHT

HLG amp SAPEA ESTABLISH PLANS FOR ScO amp ER

Title

Intro to OP

OP Method Policy Context

ISSUE summary OPTIONS summary

RECOMMENDATIONS OBSERVATIONS

Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS

SAPEA WORKING GROUP - EVIDENCE

REVIEW REPORT

HLG SCIENTIFIC OPINION

SAPEA WORKSHOP amp REPORT

RISK PERCEPTION ACCEPTANCE

4c

111

5b

112

Comparison with non-EU OECD countries

(progress to date)

Dual system bull geographical (EU member states)

bull US federal states (eg California) bull Codex MRLs encouraged by WTOs (phyto)sanitary agreement bull harmonisation OECD UN (GHS) NAFTA

bull technical (active substance product) bull default for pre-marketing scientific assessments

Differences in implementation bull EU first active substance then product assessment bull non-EU mostly joint submission (assessment in parallel)

bull EU-level approval active substance + representative useformulation

additional usesformulations assessed at member state (zonal) level bull non-EU all assessments on same level

57

5b

113


(progress to date)

Advantage of dual system bull Taking into account local circumstances However local circumstances may also be considered by a single overarching system in collaboration with member states regions Drawbacks of dual system risks of bull Inefficiency unnecessary duplication use of resources and bureaucracy bull Inconsistency different decisions without adequate justification

However apparent inconsistencies may also arise from bull Different local circumstances bull Compatibility with local (non-pesticide) legislation bull Different value placed on uncertainties bull Different scientific interpretation (weight of evidence) by experts

5b

114


(progress to date)

Useful aspects non-EU OECD countries bull New Zealand has innovative approach to hazardous substances

bull has led to simplification and increased speed bull group approval (similar nature type or use) under group

standards (conditions for safe management) bull however presently excludes pesticides veterinary medicines

timber treatment chemicals and vertebrate toxic agents

bull US EPA approach for cumulative risk assessment of pesticides bull considered focusedpragmatic (includes intentional mixtures) bull proven to be applicable to certain (currently only 5) chemical

classes for which the mode of action is well established bull approaches supported by Canada

58

6

25-26 Oct Expert Workshop (discuss final draft ERR bridge to Opinion)

Nov (tbd) 1-day Workshop on question B

(societal aspects factors and mechanisms that influence risk perception and acceptance)

12 Feb (tbc) Stakeholder meeting - frac12 day

(voicing positions by relevant interest parties such as NGOs industrial organisations user groups and civil society no influence on ERR)

Next formal meetings

115


116

SAPEA Seminar on question B ndashSocial aspects factors and mechanisms that influence risk perception and acceptance Seminar on risk perception and acceptability of human exposure to pesticides Based on the scoping paper the question 2 focuses on acuteacuteWhat are the causes for variation in the perception and acceptance of human-health risks from the use of PPPs within the EUacuteacute Purpose of the seminar

To reach a better understanding of the underlying mechanisms and triggers for public concern about human exposure to pesticides

To provide and discuss empirical evidence about risk perception and its implication for individual and political behavior

To delineate risk management and communication strategies that address public concerns and their psychological and social causes

Tentative Date 7th December Berlin with IASS

2

Consultation of the scientific

community and stakeholders

Review of scientific evidence

Consortium of European and National Academies

(SAPEA)

High Level Group

+

2

3

Proposals for Policy or Legislation

High Level Group Scientific Advice

2

4

3








2

5


Review Report (ERR)




Todays Objective

2

6

4


Objective






Todays Agenda

2

7

Break


8



5



9


in the EU

Effectiveness





6

Efficiency












7



8


Word-count 13366

72 references

Sections

1 Main findings

2 Introduction

3 Methodology






9

Sections I














10








Sources of Evidence





11


PubMed

1991 to 72017



7984 citations


22




12


23






24



13


25





26

14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






3








2

5


Review Report (ERR)




Todays Objective

2

6

4


Objective






Todays Agenda

2

7

Break


8



5



9


in the EU

Effectiveness





6

Efficiency












7



8


Word-count 13366

72 references

Sections

1 Main findings

2 Introduction

3 Methodology






9

Sections I














10








Sources of Evidence





11


PubMed

1991 to 72017



7984 citations


22




12


23






24



13


25





26

14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






4


Objective






Todays Agenda

2

7

Break


8



5



9


in the EU

Effectiveness





6

Efficiency












7



8


Word-count 13366

72 references

Sections

1 Main findings

2 Introduction

3 Methodology






9

Sections I














10








Sources of Evidence





11


PubMed

1991 to 72017



7984 citations


22




12


23






24



13


25





26

14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






5



9


in the EU

Effectiveness





6

Efficiency












7



8


Word-count 13366

72 references

Sections

1 Main findings

2 Introduction

3 Methodology






9

Sections I














10








Sources of Evidence





11


PubMed

1991 to 72017



7984 citations


22




12


23






24



13


25





26

14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






6

Efficiency












7



8


Word-count 13366

72 references

Sections

1 Main findings

2 Introduction

3 Methodology






9

Sections I














10








Sources of Evidence





11


PubMed

1991 to 72017



7984 citations


22




12


23






24



13


25





26

14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






7



8


Word-count 13366

72 references

Sections

1 Main findings

2 Introduction

3 Methodology






9

Sections I














10








Sources of Evidence





11


PubMed

1991 to 72017



7984 citations


22




12


23






24



13


25





26

14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






8


Word-count 13366

72 references

Sections

1 Main findings

2 Introduction

3 Methodology






9

Sections I














10








Sources of Evidence





11


PubMed

1991 to 72017



7984 citations


22




12


23






24



13


25





26

14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






9

Sections I














10








Sources of Evidence





11


PubMed

1991 to 72017



7984 citations


22




12


23






24



13


25





26

14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






10








Sources of Evidence





11


PubMed

1991 to 72017



7984 citations


22




12


23






24



13


25





26

14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






11


PubMed

1991 to 72017



7984 citations


22




12


23






24



13


25





26

14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






12


23






24



13


25





26

14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






13


25





26

14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






14


27


28

15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






15


29














30

16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






16



31


End point




Glyphosate

NOAEL(c)

Glyphosate

LOAEL(c)

POE-tallowamine

NOAEL(c)

POE-tallowamine

LOAEL(c)










EFSA amp ECHA



Category 1A



Category 1B



32





17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






17



33













34

18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






18


35







36




positive controls



19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






19


37





38




20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






20


39








40







Environ Int 2016






a systematic review




systematic review




regulatory decision

21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






21


41







Section 5 (3)


42

22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






22





43







44

23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






23






45




46

24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






24


The ADI





47


48







25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






25


49







50






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






26


51


52



Hougaard Bennekou)

27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






27


53










Hougaard Bennekou)


54




Hougaard Bennekou)

28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






28


55











56






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






29




57




58





30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






30



59


SCHEME


SCHEME


MITTEILUNGEN

SUBJECTS

OCCUPATION

Yes but not linked

to biological

monitoring

Considers


occupational

exposure and

employmentself-

employment



to biological

monitoring



periods in some

No Yes Yes Yes


to biological

monitoring


confirmed by

clinician

Biomedical not


Test results where

relevant

Yes (hospital

based)

Yes confirmed by

clinician


to biological

monitoring

AChE levels where

appropriate



relevant

No information

available

Yes


medications (no

doctors details

privacy act)

No information

available

Yes

IMMEDIATE

OUTCOMES


symptoms and

hospitalisation

Potentially Yes

FOLLOW UP (LONG

TERM)

No Not clear but

chronic



search for patterns

of incidents review

of serious cases

evaluation of these

No information

available

No



60

31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






31


61







62


pesticides


32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






32


63


pesticides



64



33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






33


65



66



34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






34


67




consequence


68


35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






35


69




70




36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






36


71





72


37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






37


73




74




38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






38


75




76



39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






39


77




78



40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






40


79




80




41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






41


81




82



42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






42


83




84



43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






43


85




86



44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






44


87




88



45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






45


89




90


answers



46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






46


91


answers




92





47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






47


93


UK Biobank




94

In conclusion


48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






48


95

In conclusion



96

In conclusion


49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






49


97

In conclusion



98






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






50


99




100








51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






51


101










102





52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






52


103








Hougaard Bennekou)

104

53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






53


Molecular Effect

Cellular Effect

Tissue Organ

Organism Population



In Vitro

In Vivo

Epidemiological

Biomonitering



HepaRG + 3D HepG2




microtissues

precision cut human

liver slices




to other tissues



Need addressed

In vitro systems

54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






54

107

108

55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






55

109



110




56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






56

SCOPING DOCUMENT



Title

Intro to OP




Annexes STAKEHOLDER

MEETING

EXPERT WORKSHOP

LITERATURE REVIEWS

EXPERT MEETINGS

EVENTS


REVIEW REPORT




4c

111

5b

112


(progress to date)







57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






57

5b

113


(progress to date)



5b

114


(progress to date)







58

6







115


116






58

6







115


116






Date post:	02-Jun-2020
Category:	Documents
Upload:	others
View:	2 times
Download:	0 times

Authorisation Process for Plant Protection Products (PPPs) in … · 2018-08-09 · Scoping paper:...

Documents