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HESI-ITC cytokine release assay working group: An update
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Abstracts / Toxicology Letters 229S (2014) S4–S21
PS3.1-O4 DNEL derivation under REACH: Assessment factors and dealing with uncertainty Karel de Raat ECHA, Helsinki, Finland
assessment process, i.e. hazard identification and characterisation, exposure assessment and risk characterisation. The EFSA working group is currently working at developing a harmonised framework applicable to all relevant working areas of EFSA also taking into account the work carried out by other international organisations. http://dx.doi.org/10.1016/j.toxlet.2014.06.055
The derived no-effect level or DNEL is an exposure level above which humans should not be exposed. Its derivation is based on the information on the toxic properties of chemical substances submitted under REACH in so-called registration dossiers by importers and manufacturers. Several DNELs can be derived, depending on exposure route, time dependence of effects (acute, subchronic) and exposed populations. Point of departure is in most cases a NOAEL or LOAEL, although the BMD can also be used. When the point of departure pertains to a toxicological effect without a threshold, such as carcinogenicity, another approach is used, resulting in the derived minimum-effect level or DMEL. As for most regulatory limit values for human exposure, DNEL derivation entails the extrapolation from the animal experiment to the human real-life situation. This extrapolation has to deal with many sources of uncertainty. Under REACH a default set of so-called assessment factors has to be applied to deal with this uncertainty, unless there is substance-specific information available to address the uncertainty. This default set will be discussed. Aspects that will be covered are: origin and basic philosophy, absence of a pre-defined level of protection, suggestions of DNELs being over protective and other default sets, among them the one suggested by ECETOC for REACH. In addition, the possibilities to use substance-specific assessment factors under REACH will be addressed. http://dx.doi.org/10.1016/j.toxlet.2014.06.054 PS3.1-O5 EFSA’s approach to characterising uncertainty in risk assessment Andrea Germini European Food Safety Authority, Parma, Italy The European Food Safety Authority (EFSA) Science Strategy for the period 2012–2016 identifies four strategic objectives: (i) further develop excellence of EFSA’s scientific advice, (ii) optimise the use of risk assessment capacity in the EU, (iii) develop and harmonise methodologies and approaches to assess risks associated with the food chain, and (iv) strengthen the scientific evidence for risk assessment and risk monitoring. The first and third of these objectives underline the importance of characterising in an harmonised way the uncertainties underlying EFSA risk assessments, and communicating these uncertainties and their potential impact on the decisions to be made in a transparent manner. In December 2006, the EFSA Scientific Committee adopted its opinion related to uncertainties in dietary exposure assessment, recommending a tiered approach to analysing uncertainties (1. qualitative, 2. deterministic, 3. probabilistic) and proposing a tabular format to facilitate qualitative evaluation and communication of uncertainties. EFSA defined as one of its priorities to continue working on uncertainty and expand the scope of the previously published guidance to cover the whole risk assessment process. Therefore an overarching working group was established in November 2013 aiming at developing guidance on how to characterise, document and explain uncertainties related to the various steps of the risk
Symposia 4: Cytokine release assays: current practice and interpretation toward clinical translation PS3.2-O1 HESI-ITC cytokine release assay working group: An update Deborah Finco Pfizer, Groton, CT, USA Significant progress has been made in designing and developing improved methods for cytokine release assays (CRAs) as a result of the CD28 superagonist biotherapeutic monoclonal antibody (TGN 1412) “cytokine storm” incident. Results from these efforts provide a number of assay options to consider when evaluating the potential for cytokine release by a novel therapeutic for hazard identification. In the past 2 years, the ILSI-Health and Environmental Sciences Institute (HESI) Immunotoxicology Committee CRA Working Group has surveyed the different approaches employed by the pharmaceutical industry, CROs and academic institutions for the use and application of cytokine release assays. As discussed in the resulting publication (Finco et al., 2014) and at the 2013 ILSI HESI CRA workshop, there is no standard approach to testing strategies, assay formats and reporting and interpretation of CRA data. Further, a ‘one-size-fits-all’ approach is not recommended because different biotherapeutics with varying mechanisms of actions may require different assay approaches. This presentation will provide an overview of the different approaches currently being used as well as the challenges and gaps that remain. In addition, possible means for future harmonization in some areas will be presented. http://dx.doi.org/10.1016/j.toxlet.2014.06.057 PS3.2-O2 Cytokine release assays post TGN1412 Sandrine Vessillier 1 , David Eastwood 1 , Susan Thorpe 1 , Richard Stebbings 1,2,∗ 1
NIBSC, Potters Bar, UK, 2 University of Liverpool, Liverpool, UK
In 2006, the anti-CD28 super-agonistic therapeutic mAb TGN1412, intended for the treatment of rheumatoid arthritis and B-cell chronic lymphocytic leukaemia, caused life-threatening multi-organ failure and cytokine release syndrome in all 6 volunteers during a first-in-man phase 1 clinical trial. The failure of pre-clinical safety testing applied to TGN1412 demonstrated the need for a new generation of immunotoxicity assays that are both sensitive and predictive of clinical outcome in man. Eight years later a range of different in vitro cytokine release assays (CRA) with reported predictivity for TGN1412 are in use. These include; solidphase PBMC CRA where therapeutic mAb is immobilised onto tissue culture plates; high-density pre-culture (HDC) PBMC CRA with therapeutic mAb in aqueous phase; undiluted and diluted whole blood CRA with therapeutic mAb in aqueous phase. Consequently, there is a lack of consistency across organisations performing CRA,
Abstracts / Toxicology Letters 229S (2014) S4–S21
PS3.1-O4 DNEL derivation under REACH: Assessment factors and dealing with uncertainty Karel de Raat ECHA, Helsinki, Finland
assessment process, i.e. hazard identification and characterisation, exposure assessment and risk characterisation. The EFSA working group is currently working at developing a harmonised framework applicable to all relevant working areas of EFSA also taking into account the work carried out by other international organisations. http://dx.doi.org/10.1016/j.toxlet.2014.06.055
The derived no-effect level or DNEL is an exposure level above which humans should not be exposed. Its derivation is based on the information on the toxic properties of chemical substances submitted under REACH in so-called registration dossiers by importers and manufacturers. Several DNELs can be derived, depending on exposure route, time dependence of effects (acute, subchronic) and exposed populations. Point of departure is in most cases a NOAEL or LOAEL, although the BMD can also be used. When the point of departure pertains to a toxicological effect without a threshold, such as carcinogenicity, another approach is used, resulting in the derived minimum-effect level or DMEL. As for most regulatory limit values for human exposure, DNEL derivation entails the extrapolation from the animal experiment to the human real-life situation. This extrapolation has to deal with many sources of uncertainty. Under REACH a default set of so-called assessment factors has to be applied to deal with this uncertainty, unless there is substance-specific information available to address the uncertainty. This default set will be discussed. Aspects that will be covered are: origin and basic philosophy, absence of a pre-defined level of protection, suggestions of DNELs being over protective and other default sets, among them the one suggested by ECETOC for REACH. In addition, the possibilities to use substance-specific assessment factors under REACH will be addressed. http://dx.doi.org/10.1016/j.toxlet.2014.06.054 PS3.1-O5 EFSA’s approach to characterising uncertainty in risk assessment Andrea Germini European Food Safety Authority, Parma, Italy The European Food Safety Authority (EFSA) Science Strategy for the period 2012–2016 identifies four strategic objectives: (i) further develop excellence of EFSA’s scientific advice, (ii) optimise the use of risk assessment capacity in the EU, (iii) develop and harmonise methodologies and approaches to assess risks associated with the food chain, and (iv) strengthen the scientific evidence for risk assessment and risk monitoring. The first and third of these objectives underline the importance of characterising in an harmonised way the uncertainties underlying EFSA risk assessments, and communicating these uncertainties and their potential impact on the decisions to be made in a transparent manner. In December 2006, the EFSA Scientific Committee adopted its opinion related to uncertainties in dietary exposure assessment, recommending a tiered approach to analysing uncertainties (1. qualitative, 2. deterministic, 3. probabilistic) and proposing a tabular format to facilitate qualitative evaluation and communication of uncertainties. EFSA defined as one of its priorities to continue working on uncertainty and expand the scope of the previously published guidance to cover the whole risk assessment process. Therefore an overarching working group was established in November 2013 aiming at developing guidance on how to characterise, document and explain uncertainties related to the various steps of the risk
Symposia 4: Cytokine release assays: current practice and interpretation toward clinical translation PS3.2-O1 HESI-ITC cytokine release assay working group: An update Deborah Finco Pfizer, Groton, CT, USA Significant progress has been made in designing and developing improved methods for cytokine release assays (CRAs) as a result of the CD28 superagonist biotherapeutic monoclonal antibody (TGN 1412) “cytokine storm” incident. Results from these efforts provide a number of assay options to consider when evaluating the potential for cytokine release by a novel therapeutic for hazard identification. In the past 2 years, the ILSI-Health and Environmental Sciences Institute (HESI) Immunotoxicology Committee CRA Working Group has surveyed the different approaches employed by the pharmaceutical industry, CROs and academic institutions for the use and application of cytokine release assays. As discussed in the resulting publication (Finco et al., 2014) and at the 2013 ILSI HESI CRA workshop, there is no standard approach to testing strategies, assay formats and reporting and interpretation of CRA data. Further, a ‘one-size-fits-all’ approach is not recommended because different biotherapeutics with varying mechanisms of actions may require different assay approaches. This presentation will provide an overview of the different approaches currently being used as well as the challenges and gaps that remain. In addition, possible means for future harmonization in some areas will be presented. http://dx.doi.org/10.1016/j.toxlet.2014.06.057 PS3.2-O2 Cytokine release assays post TGN1412 Sandrine Vessillier 1 , David Eastwood 1 , Susan Thorpe 1 , Richard Stebbings 1,2,∗ 1
NIBSC, Potters Bar, UK, 2 University of Liverpool, Liverpool, UK
In 2006, the anti-CD28 super-agonistic therapeutic mAb TGN1412, intended for the treatment of rheumatoid arthritis and B-cell chronic lymphocytic leukaemia, caused life-threatening multi-organ failure and cytokine release syndrome in all 6 volunteers during a first-in-man phase 1 clinical trial. The failure of pre-clinical safety testing applied to TGN1412 demonstrated the need for a new generation of immunotoxicity assays that are both sensitive and predictive of clinical outcome in man. Eight years later a range of different in vitro cytokine release assays (CRA) with reported predictivity for TGN1412 are in use. These include; solidphase PBMC CRA where therapeutic mAb is immobilised onto tissue culture plates; high-density pre-culture (HDC) PBMC CRA with therapeutic mAb in aqueous phase; undiluted and diluted whole blood CRA with therapeutic mAb in aqueous phase. Consequently, there is a lack of consistency across organisations performing CRA,