Working Group

SETE subgroup agendas and minutes

Agendas and minutes from the COT and COC Synthesis and Integration of Epidemiological and Toxicological Evidence (SETE) subgroup meetings

Last updated: 16 October 2020

Tuesday 19th of November 2019

First meeting of the COT and COC SETE subgroup

COT/COC subgroup on the synthesis and integration of epidemiological and toxicological evidence in risk assessments

TC/Skype Meeting at 13:30-15:30 pm on Tuesday 19th of November 2019

Agenda

1. Welcome and introductions

2. Quick overview/reminder of the paper presented to COT/COC (BD)

3. Discussion of TOR

  • Agree TOR, aims and objectives (problem definition, knowledge gap to be addressed)
  • Agree the form of the output Members would wish to see
  • Reassess Membership for subgroup, any additional expertise needed

4. Plan next meeting(s)

  • Time line(s)
  • Information WG requires from the Secretariat for the next meeting, such as potential literature searches
  • Identify any existing schemes (that Members are aware off) for the next meeting

Minutes

Present:

Chair: Alan Boobis                     

Committee Members:

  • Gill Clare                
  • Gunter Kuhnle                  
  • David Lovell                     
  • Heather Wallace
  • Alison Gowers, PHE
  • Valentina Guercio, PHE

Secretariat:

  • Barbara Doerr, FSA
  • Frances Hill, FSA
  • Cath Mulholland, FSA
  • Britta Gadeberg, PHE

The Chair welcomed the Members and other attendees.

The Chair provided a brief overview of the scoping paper presented to both Committees, the COT and COC, earlier this year and concluded that the meeting today was foremost to discuss the problem definition and knowledge gaps the working group would be addressing.

The WG agreed, while data integration is already applied in the work of the Committees, there is a general feeling that there is no explicit explanation of the procedure used and that also there was scope for improvement in the Committees’ approaches. Therefore, the output of the WG will be a combination of current practice and a guidance document. Members stressed that the output would need to be applicable and realistic and that it would be useful to test the output/guidance on case studies, such as previously published assessments by COT and COC and if possible, by COM.

Members agreed that the output should be approved by both Committees and published on the respective websites. Members also agreed that, if appropriate, it would be useful to publish the outcome in a scientific journal.

The scoping paper presented to the Committees included a section on dose response modelling, which was included on behalf of the FSA. Members discussed the feasibility of including this in their work and noted that this would not be a trivial exercise, particularly when considering epidemiological data, and that additional expertise would be needed. Members raised concern that including quantitative dose response modelling in the discussions would take the WG beyond their remit and the output anticipated by the Committees. Members agreed that, overall, it would be important to consider dose response relationships and that they would do so, however without addressing quantitative dose-response modelling in detail.

Members discussed the application of scoring systems, such as the Klimisch Score for animal data and the questions of suitability around scoring systems. Concern was raised by Members that studies might be dismissed without consideration, based on low scores alone. Previous work such as the SEES report applied quality criteria, but no formal quality scores and it was agreed by Members that this would be an approach they would consider in the work of the WG. Quality scoring can be of particular use in sensitivity analysis. It was also pointed out that EFSA does excludes studies of low quality, however they are required to report basis of exclusion in detail, hence considering/examining all studies.

Members of PHE (Secretariat to COMEAP) noted that it would be useful to include an explanation of what is meant by integration as different groups/work use different definitions. It was agreed by the WG Members that the guidance/output would therefor need to capture how studies are used and conclusions are reached, without mathematical integration.

Members discussed the need for additional expertise and concluded that additional expertise on epidemiology would be helpful. It was suggested to contact Lesley Rushton, who had also previously worked on evidence integration, in addition to having epidemiological expertise. Additional expertise on adverse outcome pathways and PBPK modelling/kinetics was considered helpful and Members agreed to think about potential experts who would be suitable. It was suggested to ask George Loizou to become an ad hoc expert as time restrains might prevent him from joining the WG permanently. Members agreed that the WG could always be expanded at a later stage, should the work require. One such area could be dose response modelling, should the WG agree to include it in their output in more detail than currently set out. For the moment, David Lovell agreed that he could cover expertise in biostatistics.

Members noted that the Committees have a Scientific Council liaison and that it would be useful to obtain his input at an early stage of the process. Members also agreed that it would be useful to obtain input from the Members of COMEAP, when their expertise and experience is needed. In the meantime, the Secretariat to COMEAP agreed to participate in the WG meetings and provide their expertise/experience/feedback from previous work.

Going forward it was agreed that the next meeting should be face to face and that subsequent meetings could be held (mostly) by Skype/TC. The next meeting will be scheduled for February 2020, due to availability of Members and Committee meetings.

For the next meeting the Secretariat was asked to provide a tabled overview of the current/different approaches presented in the scoping paper. It was agreed that the Secretariat would provide column headings covering areas such as inclusion of animal/human data, scoring systems, etc and extract the information once the headings have been circulated and agreed by Members of the WG.

 

Monday 10th of February 2020

Second meeting of the COT and COC SETE subgroup

COT/COC subgroup on the synthesis and integration of epidemiological and toxicological evidence in risk assessments

Meeting at 10:00 am -14:00 pm on Monday 10th of February 2020 in Clive House, 70 Petty France, Westminster, London SW1H 9EX

Agenda

1. Welcome and goals of meeting

2. Short talks/presentations on

  • Epi-Tox Framework (AB)
  • Experience with data integration for PFOS/PFOA (VG)
  • Case study to refine inhalation risk (PB)

3. Discussion of talks/presentations and papers provided prior to the meeting

4. Work planning for next WG meeting

  • Information WG requires from the Secretariat for the next meeting, such as potential literature searches
  • Intended output of the group and intended audience

5. Plan next meeting(s)

  • Time line(s)
  • Additional expertise

Lunch will be provided at 12:00.

Minutes

Present

Chair: Alan Boobis                     

Committee Members:

  • Phil Botham
  • Gill Clare                
  • Gunter Kuhnle                  
  • David Lovell                     
  • Lesley Rushton
  • Alison Gowers, PHE
  • Valentina Guercio, PHE

Secretariat:

  • Barbara Doerr, FSA
  • Cath Mulholland, FSA
  • Britta Gadeberg, PHE

Apologies were received from Heather Wallace, Neil Pearce and Britta Gadeberg.

The Chair welcomed Members and other attendees.

Presentations were given on the Epid-Tox framework, the application of the Epid-Tox framework to the effects of PFOS/PFOA on fetal growth and the development and application of in vitro methods for evaluating respiratory irritants. Members discussed the presentations and the other guidance documents/frameworks, which had been summarised in table format by the Secretariat.

Members noted that the documents/frameworks had many elements in common. The majority assessed toxicological and epidemiological evidence streams separately and subsequently brought them together only qualitatively, using expert judgement. The documents/frameworks generally provide little information on how toxicological and epidemiological data could be integrated.

The starting point for a number of these approaches was a systematic literature review, something the Committees does not routinely undertake, this being done on a case-by-case basis. This is because resources and timelines of the Committees may not always allow for a full systematic review. Whilst acknowledging the usefulness of systematic review, some questions may not require a full review.

The output from the Working Group should be pragmatic guidance, and a transparent reflection of how the Committees review data and apply expert judgment, as applicable. Members furthermore agreed that the guidance would primarily address qualitative evidence synthesis. Guidance on full quantitative synthesis was considered outside the scope of the Working Group but could be a possible next step. However, where appropriate, some guidance on quantitative approaches could be provided.

Members stressed that transparency was key but considered that some thought might need to be given on how to achieve a balance between applying explicit, unified criteria for study rating and the use of expert judgement; this might entail synthesis of extensive and diverse expertise.

Members agreed to utilise the Epid-Tox framework as a starting point and to firstly assess the areas which would need to be changed/improved/expanded upon to fit the work of the Committees. Several aspects were raised at the meeting, such as the circumstances when (full) systematic reviews should be included, for example for meta-analysis, and the application of grid or table visualisation. Members noted these were included in a number of the documents reviewed and considered the use of a grid very helpful. Epid-Tox included a scaled axis, and the desirability of this will need to be considered by the Working Group.

The Secretariat was asked to provide an outline structure for the guidance in advance of the next meeting.

In addition, Members were informed that Croplife International are currently looking at data integration, from a pesticide point of view. Phil Botham will update the Working Group about the progress and any outputs that might be forthcoming in the next 6-12 months.

Members noted that the COT had previously looked at an evidence synthesis approach for contaminated land, however the approach may have moved forward since then. Alison Gowers was asked to forward the current work/approach, as it was considered worth re-visiting this.

Lesley Rushton and Alan Boobis have previously been involved in a cefic-LRI project on data integration. Although the outcome of this was not published, the results were written up in a number of reports. Members inquired if it would be possible for these to be shared with the Working Group. [Post meeting: Lesley has since obtained agreement of David Jones to share the documents with the Working Group].

The next (Skype) meeting will be held in April 2020.

 

Friday 17th of April 2020

Third meeting of the COT and COC SETE subgroup

COT/COC subgroup on the synthesis and integration of epidemiological and toxicological evidence in risk assessments

TC/Skype/Teams Meeting 10:00 am - 13:00 pm on Friday 17th of April 2020

Agenda

1. Welcome and goals of meeting

2. Discussion of the Cefic documents provided by Lesley and Alan prior to the meeting

3. Discussion of the outline of the guidance document provided prior to the meeting

  • Do Members agree with the outline and sections included
  • Additional sections Members wish to add
  • For the SEES WG, two documents were produced. One was a report on the activity of the group, and the other was a stand-alone guidance document. Should this also be applied to SETE.
  • Agreement on forward plan and assignments

4. Administrative

  • Could Members please confirm they are happy for their emails to be shared so it can be minute
  • Agreement of the minutes from the 1st and 2nd Meeting, so the SETE website can be finalised and the minutes can be made available on the website.
  • Plan next meeting(s)

Minutes

Present:

Chair: Alan Boobis                     

Committee Members:

  • Gill Clare  
  • Phil Botham               
  • Gunter Kuhnle                  
  • David Lovell                     
  • Neil Pearce
  • Lesley Rushton
  • Mireille Toledano
  • Heather Wallace
  • Valentina Guercio, PHE

Secretariat:

  • Barbara Doerr, FSA
  • Cath Mulholland, FSA
  • Britta Gadeberg, PHE

Apologies were received from George Loizou and Alison Gowers (PHE).

The Chair welcomed Members and other attendees.

Dr Lesley Rushton provided a brief summary of the work package reports of the Cefic-LRI project on comparing NOAELs from animal data with those from human data, which were circulated to Members in advance of the meeting. The (unpublished) documents described the approach taken on comparing and quantitatively integrating dose-response data from human and animal studies. Due to time restrictions during the project, no statistical methodology was developed, but a more general approach for comparing no observed adverse effect levels (NOAELs) and dose-response slopes was used. Members noted that currently there is no one method that fits all, hence a case by case approach is needed. Members did however agree, that the work included important information and that it would be beneficial to the WG and the intended guidance document to be able to refer to the work done by the Cefic-LRI project.

As it was unlikely for the material to be published in the scientific literature at this late stage, Dr Rushton offered to contact Cefic to discuss whether it would be possible to make the work packages available in the public domain (potentially on the Imperial College London website). 

Members were in favour of basing the guidance document on the general structure and approach of the Epid-Tox Framework, were applicable, and discussed the separate parts of the proposed guidance document.

Members agreed that the introduction and problem formulation should be focused and would need to consider the urgency/level of concern in which an answer might be sought. Therefore, Members further agreed, that it was not practical to suggest a formal systematic review for all cases, yet the document needed to cover separate (search) strategies to consider the relevance of studies. It was suggested that reference be made to the SEES framework as these aspects have been covered there previously.

Members discussed the quality assessment of studies and the potential criteria to apply. All types of studies were considered useful and applying a tick box approach, as regularly done by some other Committees/bodies, would exclude potentially relevant studies, especially epidemiology/observational studies. Often, studies deemed to be less reliable could be useful in combination with other evidence or if there was bias towards the null and an effect was still apparent. Members concluded that it would be useful and practical to include guidance on criteria indicating study quality and relevance, such as the endpoint being addressed and whether or how deficiencies in studies could be counteracted by other studies.

Members agreed that the Bradford-Hill considerations are a useful foundation for assessing the weight of evidence and that most of the considerations would be applicable within the context of the guidance document. The Epid-Tox framework focuses strongly on the mode of action (MoA) for weighing evidence and Members agreed that the approach developed would have to be more flexible than this. Members agreed that absence of knowledge of the MoA would not necessarily exclude a conclusion of a causal relationship. However, knowledge of the MoA (or any mechanistic data) would strengthen any conclusion of causality derived from other studies.

Members agreed that scaling the strength of evidence for the conclusions and visualising these graphically, as in the Epid-Tox Framework would be a useful means of communicating the process and conclusions. Members did, however, stress that this step requires expert judgement and that therefore there was a risk of bias, which needed to be addressed in the process. Members acknowledged the difficulties of explaining transparently conclusions based on expert judgment in which many years of accumulated knowledge and experience, some of which was axiomatic to the expert, were integrated.  However, such expert judgment would need to be reflected as explicitly and transparently as possible. In this respect, it is important that, where possible conclusions and their justification are challenged by colleagues, comprehensible (written) explanations of how a conclusion was reached and what factors influenced this, including discussions about data/studies that may have been excluded and why.

Following the discussions minuted above, the key elements for the guidance document were agreed and Members formed sub-groups to start drafting considerations on methods to assess epidemiological studies, toxicological and non-animal studies, and how to scale the lines of evidence.

Members further agreed that the guidance document should be short and practical and hence adopted the same approach as the SEES Working Group. There will be two outputs after the WG has concluded its work, a guidance document, focusing on the practical application and a report which will include information on the discussions of the working group and supplementary information such as future recommendations.

Several papers were provided by Members of the Working Group to the Secretariat prior and during the meeting and will be circulated to the group.

All Members and other attendees present at the meeting agreed for their email addresses to be shared among the WG. The agreement of Members and external experts not in attendance would be obtained via email. (Note: The agreement of all Members has been received)

Members were asked to send any comments on the minutes from the first (3/12/2019) and second (10/02/2020) meetings to the Secretariat within the next seven days, at which point the minutes would be considered agreed and would be finalised for web publication.

The next meeting will be held on 22nd June 2020, via TC.

 

Monday 22nd June 2020

Fourth meeting of the COT and COC SETE subgroup

COT and COC subgroup on the synthesis and integration of epidemiological and toxicological evidence (SETE) in risk assessments

Agenda of the third Meeting, Monday 22nd June 2020, 12:30 to 3:30 pm, via teleconference

1. Welcome and goals of meeting

2. Discussion of the outcome from the epidemiological subgroup

3. Discussion of the outcome from the toxicological subgroup

4. Next steps

  • Integration of epidemiological and toxicological evidence
  • Drafting of text for guidance document and report

5. Administrative

  • Update on SETE website
  • Plan next meeting(s)

Minutes

Present:

Chair: Alan Boobis                     

Committee Members:

  • Phil Botham
  • Gill Clare                 
  • Gunter Kuhnle  
  • George Loizou                 
  • David Lovell                     
  • Neil Pearce
  • Lesley Rushton
  • Mireille Toledano
  • Heather Wallace
  • Alison Gowers, PHE
  • Valentina Guercio, PHE

Secretariat:

  • Barbara Doerr, FSA
  • Cath Mulholland, FSA
  • Britta Gadeberg, PHE

The Chair welcomed Members and other attendees.

Prof Gunter Kuhnle introduced the work of the epidemiological subgroup. A lot of valuable information has previously been published, such as the Bradford Hill considerations and the SEES report. The epidemiological subgroup agreed with the SEES report, that it was not appropriate to apply a tick box approach to quality rating of studies, but that all the evidence would need to be considered and assessed. Members felt that the best way to do so would be a transparent approach documenting the biases, weaknesses and strengths of individual studies and to evaluate them as a whole. Members of the WG noted that this approach was similar to EFSAs uncertainty approach but pointed out that some studies are quite complex (environmental contaminants, sources in food) and it can therefore become complicated when biases work/pull in different directions.

Members noted that there are uncertainties surrounding occupational studies due to the relatively small numbers of participants and the need to extrapolate to the general population as well as biases around the publishing/reporting of negative data. Some methods of visualising or assessing publication bias and lack of negative data are available, such as meta-analysis or funnel plots which can provide an indication of where data are missing or in which direction data are weighing.

One of the more general issues raised by the epidemiological subgroup was the fact that it is often difficult to integrate epidemiological data/studies with toxicological information as the information provided from epidemiological studies is often not usable for toxicology. Members agreed in an ideal scenario, discussion about e.g. endpoints, exposure, mode of action, would happen at the start of an epidemiological study in conjunction with toxicology colleagues. In reality, exposures from epidemiological studies are often not relevant/informative to the problem being addressed. It is therefore important to acknowledge the limitation of these studies yet make the most of the information available.

Members agreed that it would be useful to have discussions throughout the assessment about the obvious differences and to continue the dialogue about what information would be useful and supportive of the overall question being addressed.

Dr Phil Botham introduced the work of the toxicological subgroup. As with the epidemiological evidence stream, there was a lot of work done on the assessment of toxicological studies prior to this. The Members of the subgroup pointed out four papers that they felt were the most relevant and to which they would be referring. These included a number of check lists as to which questions to be asked to assess the quality of a study. However, as with the epidemiological subgroup, Members did not feel comfortable with the idea of a check list or tick box approach as it would take away expert judgement. The Members tried to provide a more general approach about what questions should be considered and which questions would help to provide transparent expert judgement.

Rather than applying a check list approach, all Members were in favour of using expert judgement in a transparent way. Compliance with OECD guidelines and GLP are a good indication of the reliability of studies, however Members pointed out that while a study can be of good quality, the key information to a certain question can still be missing. Therefore, for studies which deviated from guidelines, it should be noted how they deviate and if or how this deviation affects interpretation as they may still be good quality and useful studies. Members also noted the problem surrounding data transparency (access to raw data) and replication and consistency in studies.

Members stressed that it was important to have a continued conversation between toxicological and epidemiological assessors/experts to ensure that the right questions were being asked and the endpoints and approaches were aligned. Members agreed that problem formulation was key to determine the information that would be helpful for a specific assessment and to include and stress this at the start of the guidance document. In doing so, it would not be a decision on good or bad studies but a transparent approach to decide which studies would be the critical ones and why these studies have been selected. Members stressed that transparency was key.

Following the discussions minuted above, the respective sub-groups will continue to draft their sections and also include information on exposure and criteria on how to assess the quality of exposure data, as Members felt this was a vital part to the overall assessment.

Members were still in agreement that the overall approach taken by the Epid-Tox framework using the two evidence streams to weaken or strengthen the causal relationship was appropriate. Therefore, the subgroup on scaling evidence will provide a first draft at the next meeting

The mode of action (MoA) was a key element in the Epid-Tox framework to link toxicological, epidemiological and exposure information and to strengthen causality and plausibility of effects. Members agreed that it would be useful to include a section on MoA in the guidance document and a first draft will be provided by the Chair for the next meeting.

The Secretariat will further provide a draft outline for the SETE report, using the SEES report for guidance.

The next meeting will be held on in early September 2020, via TC.

 

Monday 21st September 2020

Fifth meeting of the COT and COC SETE subgroup

COT and COC subgroup on the synthesis and integration of epidemiological and toxicological evidence (SETE) in risk assessments

Agenda of the fifth Meeting, Monday 21st September 2020, 10:00 am to 1:00 pm, via teleconference

1. Welcome and goals of meeting

2. Update on the work of the epidemiological and toxicological subgroup

3. Discussion of the outcome from the scaling of evidence subgroup; the WG input is especially sought on the

  • Scales/definition of the relationship grid
  • Examples

4. Discussion of the section on Mode of Action

5. Discussion of the section on

  • Problem formulation
  • Literature retrieval
  • General outline of the report

6. Next steps

  • Drafting of text for guidance document and report

7. Administrative

  • Update on COT/SETE website
  • TEAMs
  • Plan next meeting(s)

Minutes

Present

Chair: Alan Boobis                     

Committee Members:       

  • Phil Botham
  • Gill Clare      
  • Alison Gowers        
  • Gunter Kuhnle
  • George Loizou                 
  • David Lovell                                         
  • Mireille Toledano    
  • Heather Wallace                       

Secretariat:  

  • Barbara Doerr, FSA
  • David Gott, FSA
  • Cath Mulholland, FSA
  • Britta Gadeberg, PHE

Apologies were received from Lesley Rushton, Neil Pearce and Valentina Guercio.

The Chair welcomed Members and other attendees.

The general structure of the report was endorsed by all Members. For the next meeting Members were asked to consider the information to include in the guidance document, which should be a pragmatic and shorter version of the report. The Secretariat was asked to provide headings and brief information based on on the SEES guidance for the next meeting to facilitate discussion. 

Members raised the importance of ensuring that the SETE guidance is applied appropriately and suggested that additional text be added to the section on problem formulation, including considerations on exposure scenarios and the importance of identifying populations of potential concern. Members further concluded that the section needs to reflect more broadly the questions the Committees are asked to assess and suggested that the section on problem formulation is linked with the section on literature retrieval. Independent of a systematic literature review being required, the literature search may not necessarily focus on one end point but could include or focus on other aspects, such as a population or specific chemical of concern. Members asked for the Secretariat to link to the SEES report, where appropriate.

Prof Gunter Kuhnle provided an update on the work of the epidemiology subgroup. The main point emphasised by the subgroup was that the bias as well as the strength and weaknesses of each study should be assessed, rather than simply using a scoring system. In rating the overall body of evidence, the subgroup favoured a flexible approach to combine all studies and considered triangulation to be the most suitable approach. Members raised concerns about including all studies available, regardless of quality, but noted that no one method was suitable for all approaches and that expert judgment was required to determine which method is most appropriate for which assessment. Members suggested it may be useful to work through an example or provide examples of different cases and which methods of assessment may be the most appropriate or as an alternative to provide a set of criteria/questions/indications how best to approach this issue. Members concluded that it would be useful to reflect these discussions in the SETE guidance document and stressed the importance of understanding the uncertainties and limitations. Where possible, the document should refer to the SEES report, as several aspects would/should have been addressed in that report already.

Dr Phil Botham provided an update on the work of the toxicology subgroup. The work built on the previous document and additional information had been added on how to assess non GLP studies and exposure. Members asked for the text on the use of in vitro studies to be expanded and to include information regarding method validation/verification for non-OECD in vitro studies, mainly how and to which degree such studies would be assessed and the influence they may have on the overall assessment/integration of the data. Members were informed by the subgroup that the Kaltenhouser/Goodman paper provided tables with relevant information and Members agreed that where suitable, rather than reproducing identical questions, previous guidance would be endorsed by the working group and referred to in the SETE document.

Following the update by the toxicology subgroup, Members discussed the issues around exposure in detail and recognised that this aspect would require further work. For a risk from dietary exposure, other than for local effects, the chemical would need to be absorbed (in humans), if this is not the case then effects from systemic exposure (in animals) would not be informative. However, (systemic/experimental) exposure can play a role in defining the endpoint, if no systemic exposure occurs then the study itself would not usually be helpful. Members acknowledged the differences between exposure in animal/experimental and epidemiological studies, the latter often providing information on a general association rather than a specific hazard identification. The assessment of an effect from epidemiological data is often done on the totality of the database, not on individual studies. Members agreed that the first step in the integration process is the question whether or not the exposure to a substance causes an effect in humans and noted that it is often difficult to provide a clear answer. Members therefore concluded it would be useful to have a separate section on exposure in the SETE document and some Members volunteered to provide a first draft for the next meeting.

Prof Alan Boobis provided an introduction to the section on mode of action (MOA) and emphasised that the MOA and its key events provide a useful and powerful bridge between experimental studies (animal, in vitro, in silico) and observations in human populations. Identification of an MOA for an adverse effect in experimental animals that is considered relevant to humans would add appreciable evidence of causality to an association observed in humans. Members asked to what extent the group would agree with the more quantitative approach taken in the Negri et al. paper on PFAS, which included PBPK modelling and mode of action considerations. Members discussed the possibility of a more quantitative approach in the guidance document and concluded that while there are quantitative considerations in the current framework, anything further is outside the scope of this working group. Members acknowledged differences in opinion among experts on the relative importance of mechanistic and empirical data, however in principle the SACs utilise a mechanistic approach to the extent possible. Members agreed that the section would benefit from additional text covering the discussion and points raised.

The Secretariat provided an introduction to the section on scaling and integration of evidence, briefly outlining the more general considerations and questions that had been raised in the subgroup meeting regarding the criteria/scales of the causality grid and practical examples to consider. Members noted that the tabular presentation of the weighing of evidence was the important aspect of this section, once conclusions on the influence of the separate evidence streams had been drawn it was simply a matter of displaying said conclusions. Members acknowledged that the caffeine example and general considerations presented were drawing on previous work on uncertainties and would require a clearer separation of qualitative and quantitative information for the work undertaken here.

Members agreed that it would be useful to test the guidance document/framework produced by the Working Group on a complex example.

COT has recently decided to (re-)assess dioxins, and Members of the Working Group thought it could be a good and complex example to test the applicability of the framework. However, Members acknowledged that the assessment on dioxins would take extensive work and time and agreed that it would be useful to publish the first iteration of their framework prior to when the work on dioxins may be completed. Members agreed to initially apply/test the practicality of the suggested guidance on tropane alkaloids and hence adjust the integration of epidemiological and toxicological data, if necessary. The Working Group would then publish an interim/draft guidance/framework, which in turn, if COT and COC agree, would be put to a practical and complex test on dioxins later in 2021.

The next meeting will be held on 16th November 2020, via TC.