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Activiteiten (4)

De voorjaarsbijeenkomst vond plaats op 6 april 2017 bij AkzoNobel in Arnhem. De presentaties hiervan zijn beschikbaar. Het verslag is in het Engels, omdat dit de voertaal van de middag was.

 The afternoon workshop on the 6th of April about “Adversity in safety studies: How to set a NOAEL?” is hosted by the NVT risk assessment section together with the section Toxicological Pathology. We were welcomed to AkzoNobel by Kim Doornebosch. Theo Vermeire, chair of the NVT risk assessment section, introduced the program and the speakers.

This meeting addresses the contemporary view on “Adversity in animal studies” and its consequences for deriving a NOAEL. The reason for this meeting is the proposal by the Society of Toxicological Pathology (STP) to denote a test article effect as being “adverse” if it is harmful to the test animal resulting in impaired (organ) function/wellbeing of the test species. As recently supported by the Society of Toxicological Pathology (STP) in one of their recent publications. To underline the actuality of this topic, the EFSA recently published a Guidance of Biological Relevance which is open for comments (hyperlink).

In the first part of the meeting, the STP position on “adversity” was highlighted and an alternative view on “adverse” was presented. In a concluding presentation a comparison was made of the potential consequences of the new concept of adversity on both the NOAEL and Bench Mark Dose approach.

In the 2nd part of the meeting, the new concept of adversity has been dealt with in an interactive workshop in which the attendees discussed in small groups the setting of a NOAEL for a number of case studies.

The first speaker, Eveline de Rijk (CRL), gave an introduction to the papers written by the American (STP) as well as European Society on Pathology (ESTP) on what is adverse in animal safety studies?
The STP publication provides guidance on the declaration of adversity of an effect and how this is translated into a NOAEL. In addition, guidance is given on how to report and communicate a NOAEL and adversity of effects. The STP publication is a procedural publication based on historical issues and misinterpretations. There are many definitions of what is considered an adverse effect; statistical and biological differences are of importance, or effects on well-being, or highest level of exposure that does not lead to toxicity.
The STP publication recommends considering adversity as an effect indicating harm to the animal. In a study it should be considered if:
1. An effect is related to test item?
2. If yes: is the effect harmful?
A. If no: provide an unambiguous justification for non-adverse interpretation
B. If yes: incorporate in the decision of defining NOAEL
It is very important to keep in mind that adversity should be applied only to the test species and under the conditions of the study. Toxic effects should be assessed on their own merits. For example, effects considered as adaptive might actually be adverse. If there are sub reports, such as pathology reports, these should be consistent with the overall study report. For an overall hazard assessment NOAELs should be communicated in an overview document based on multiple studies including explanatory text and not just numbers. All the experts should be involved in assigning NOAELs and all data should be use.
In the ESTP publication a more practical approach is presented based on examples. The workshop was organized as follow up on the paper. In addition to the STP paper, the ESTP paper mentions that the NOAEL should take into consideration if there is an impairment of the capacity to respond to an additional challenge. The paper also defines at what levels adverse effects should be reported: pathological nature of effects (mortality, malignant neoplasms, neuronal necrosis), lesions severity (and incidence), exacerbation of spontaneous findings (in case of clear dose response, test item related), direct versus indirect effects (adversity depends on effect itself like severe depression of body weight), adaptive responses, MOA-exaggerated pharmacology, reversibility (which does not automatically imply a non-adverse effect), extrapolation to longer/higher exposure and translation to humans in overview documents.
In the end there should be no difference in the conclusion on adversity in studies for pharmaceutical, biocides or industrial chemicals. This should be independent of the application of a substance.

Next Frieke Kuper (TNO) presented a model that can be used to look at adversity in another way. In the current practice any negative impact on ‘good health’ is based on expert judgement. These experts generally perform evaluations per group of parameters and per expert (pathologist, toxicologist etc.). In the ‘other way’ model the data are interpreted at an individual animal level. Four studies have been performed with this model. Correlations and patterns are visualized. A principal component analysis has been performed on the dataset collected in a study. The model tries to identify for a 2D space in 26 dimensional space and calculates the best fit and at the same time tries to separate the animals as much as possible. In this way you can identify which parameters contribute the most to the effect. You also assess which animals stand out of the population. Keep a close eye on any outliers, they tell a lot also about variation in a population. In complex systems you can compare homeostasis with hills and valleys. It takes a lot of energy to reach another state (resistance up the hill); once you are over the hill there is high risk of transition/low resilience. The model helps to recognize recognition patterns. This benefits identification important parameters and group (population) responses. More research and evaluation is needed.

The third speaker is Bas Bokkers (RIVM). Bas gave an overview of adversity of effects, consequences for deriving a point of departure. He started with presenting results of a personal small survey at RIVM he performed among his colleagues on how risk assessors identify NOAEL. He identified a number of different approaches.
When statistical analysis is applied you look at the null hypothesis versus the alternative hypothesis; what is the borderline between zero effect and non-zero effect? What does non- zero mean? This distinction has no practical meaning. A frequent error is the interpretation of non-significant as no effect. The outcome should be that it is inconclusive and the NOAEL should not be based on statistical significance.
The benchmark dose (BMD) approach is a more sophisticated approach to derive a NOAEL. Using this analysis you can define a “small” effect size called the benchmark response (BMR). What is the acceptable additional risk for continuous data (individual level) and for quantal data (population level)? A pragmatic approach is to use a BMR of 5% for continuous and 10% for quantal data as a default. In the US a standard deviation approach is also used (to make sure you are outside the sampling error range). Drawback of this approach is that this highly depends on study and lab quality.
In a recent study (Slob, 2016) a new theory is presented on effect size, involving meta-analysis on a lot of toxicological endpoints and compares severities between endpoints.

The last part of the afternoon Anja Slikkerveer and Liesbeth Heijink (Astellas Pharma) facilitated an interactive workshop on adversity cases (from the STP workshop and EMA workshop in 2016). Within this workshop the audience was divided in small groups to debate on a total of 4 cases. The questions were simple: what is the NOAEL? And what are key points supporting your assignment of the NOAEL? However, during the discussion it became clear that the studies give sufficient reason for debate. It was concluded that it is realistic that people disagree on a NOAEL for a study. It is more important to be transparent about the rationale behind determination of the NOAEL.

Thanks to the contributors and the enthusiastic participants we look back on an interactive afternoon and good discussions.

Date: 6 April 2017
Location: AkzoNobel Arnhem
Time: 13.00 - 17.15
Title: Adversity in safety studies: How to set a NOAEL?

This meeting addresses the contemporary view on “Adversity in animal studies” and its consequences for deriving a NOAEL. The reason for this meeting is the flared up discussion whether to include organ function in setting a NOAEL, as recently supported by the Society of Toxicological Pathology (STP) in 2 of their recent publications. To underline the actuality of this topic, the EFSA recently published a Guidance of Biological Relevance which is open for comments (see link below).

In the first part of the meeting, the STP position on “adversity” will be highlighted and an alternative view on “adverse” will be presented. In a concluding presentation a comparison will be made of the potential consequences of the new concept of adversity on both the NOAEL and Bench Mark Dose approach.

In the 2nd part of the meeting, the new concept of adversity will be dealt with in an interactive workshop in which the attendees will discuss in small groups the setting of a NOAEL for a number of case studies.

https://www.efsa.europa.eu/en/consultations/call/170306?utm_source=EFSA+Newsletters&utm_campaign=114cbca56e-170308_MM&utm_medium=email&utm_term=0_7ea646dd1d-114cbca56e-59470537

 

Programme:

13.00-13.30: Reception with coffee
13.30-13.35: Introduction by session chair 
13.35-14.00: What is Adverse in animal safety studies? (visie van de Society of Toxicological Pathology)
 Eveline De Rijk (Charles River, Den Bosch)
14.00-14.25: Another way to look at adverse - Pattern recognition in (immune)toxicity
 Frieke Kuper (TNO)
14.25-14.50: Adversity of effects, NOAEL and Bench Mark dose approach
 Bas Bokkers (RIVM)
14.50-15.05 Pauze
15.05-16.30 Interactive workshop (4 case studies)
Moderators: Anja Slikkerveer en Liesbeth Heijink (Astellas)
16.30-16.45 Discussion
16.45-17.15 Drinks

Op 25 oktober 2016 vond de najaarsbijeenkomst plaats van de Sectie Risicobeoordeling van de Nederlandse Vereniging voor Toxicologie. Het thema voor deze bijeenkomst was: “Circulaire economie en recycling; gaat duurzaamheid samen met het beheersen van de risico’s?”

Her verslag kunt u hier vinden.

De volgende presentaties zijn ook beschikbaar:

Presentatie Hester Klein Lankveld

Presentatie Kim Doornebosch

Presentatie Hidde Rang en Jurgen van Belle

Presentatie Martien Janssen

 

 

 

Circulaire economie en recycling; gaat duurzaamheid samen met het beheersen van de risico’s?

25 oktober 2016

TNO, Utrechtseweg 48, 3704 HE, Zeist. Zaal 1.1.08

Met een toenemende vraag naar en een afnemend aanbod van grondstoffen op de wereld is het essentieel om onze grondstoffen zo goed mogelijk te benutten en, indien mogelijk, te hergebruiken. We bevinden ons in een overgangsfase van een lineaire naar een circulaire economie waarbij hergebruik van producten en grondstoffen gemaximaliseerd wordt en waardevernietiging geminimaliseerd. Een consequentie van hergebruik van producten en grondstoffen is dat producten een variabele samenstelling hebben en dat gevaarlijke stoffen zich kunnen ophopen. Illustratief is het voorbeeld van de minerale oliën in voedselverpakkingsmaterialen, dat recentelijk door Foodwatch onder de aandacht is gebracht. Hierdoor rijst de vraag of en hoe we de veiligheid van dergelijke producten kunnen beoordelen en borgen? En vervolgens of duurzaamheid en veiligheid hand in hand kunnen gaan?

Tijdens de najaarsbijeenkomst staan deze vragen centraal. We starten met een overzicht van huidige initiatieven in Nederland om producten en grondstoffen daaruit te hergebruiken. Daarna wordt door verschillende stakeholders inzicht gegeven in hoe men omgaat met duurzaamheid in relatie tot veiligheid. De middag wordt afgesloten met een interactieve sessie waarin de volgende vraag centraal staat: Zijn de huidige risicobeoordelingsmethoden voldoende om de veiligheid van hergebruikte producten te beoordelen?.

U bent van harte uitgenodigd om deze middag aanwezig te zijn. Aan deelname zijn geen kosten verbonden; TNO-Zeist is gastheer. U kunt zich aanmelden bij Sabine Jetten (Dit e-mailadres wordt beveiligd tegen spambots. JavaScript dient ingeschakeld te zijn om het te bekijken.).

 

 

Programma

13.00:  Ontvangst

13.20:  Opening en introductie door dagvoorzitter Lisette Krul (Senior toxicoloog bij TNO)

13.30:  Hester Klein Lankhorst (Directeur Kennisinstituut Duurzaam Verpakken (KIDV))

Gerecycled content: kansen en dilemma’s

13:55:  Kim Doornebosch (Programma manager Product Safety bij Akzo Nobel) -  

Priority Substance Management Program: designing out negative impacts

14.20:  Ger Standhardt (Manager kennisontwikkeling en projecten bij Nederlands Verpakkingscentrum)

Het einde van de verpakking als milieuprobleem

14.45:  Pauze

15.00:  Jurgen van Belle en Hidde Rang (senior beleidsmedewerkers bij ministerie van VWS, Directie Voeding, Gezondheidsbescherming en Preventie (VGP))

Het circulaire volksgezondheidsbelang

15:25:  Martien Janssen (Senior scientist bij centrum Veiligheid, Stoffen en Producten, RIVM)

Plastic recycling in de praktijk: hoe risico's te beheersen?

15:50:  Afsluitende discussie omtrent de vraag:

Zijn de huidige risicobeoordelingsmethoden voldoende om de veiligheid van hergebruikte producten te beoordelen?

16:20:  Conclusies van de middag door dagvoorzitter

16:30:  Borrel

Agenda

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