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The Role of ADME/PK in the Extrapolation of In Vitro Toxicity Results to Equivalent In Vivo Exposures: Where it started with the acrylamide example and where we are now
Bas J. Blaauboer Em. Doerenkamp-Zbinden Chair on Alternatives
Division of Toxicology Institute for Risk Assessment Sciences
Utrecht University, Utrecht, the Netherlands
23 February 2015
Conflict of Interest
None This research was carried out at Utrecht University and partners.
Overview
The development of risk assessment schemes on the basis of non-animal methods
The ECITTS programme: parallel testing The case of acrylamide General description of integrating in vitro toxicity data
with PBBK modelling Other examples Possibilities, limitations, pitfalls
In vitro toxicology?
European Reseach Group for Alternatives in Toxicity Testing
Group of friends from different European countries.
Crucial: a workshop in 1991, Sweden A parallel testing strategy
ERGATT
ERGATT: development of the ECITTS scheme
Goal: design of a parallel testing strategy Find in vitro methodologies that predict systemic
toxicity for as many endpoints as possible and practical
Indispensable: inclusion of biokinetic factors Which methods were available in the areas of
neuro-, hepato-, rheno-, immuno- toxicity
THE ECITTS INTEGRATED TOXICITY TESTING SCHEME: THE APPLICATION OF IN VITRO TEST SYSTEMS TO THE HAZARD ASSESSMENT OF CHEMICALS* B. J. BLAAUBOER, M. BALLS, V. BIANCHI, G. BOLCSFOLDI, A. ÜUILLOUZO, G. A. MOORE, L. ÜDLAND, C. A. REINHARDT, H. SPIELMANN and E. WALUM ERGATT, Secretariat: c/o Research Institute of Toxicology, Utrecht University, PO Box 80.176, 3508 TD Utrecht, The Netherlands
Toxic. in Vitro Vol. 8, No. 4, pp. 845--846, 1994
Conclusion The information produced will contribute to the establishment of a scientifically based and efficient toxicological procedure for hazard assessment, based on knowledge of the mechanisms of toxic action and of biokinetic parameters, relevant to the in vivo toxicity of chemicals.
7
The ECITTS programme
Focus on neurotoxicity Selection of a group of chemicals Perform in vitro neurotoxicity testing, find sensitive
parameters Use low effect concentrations as a Point of
Departure for a reverse dosimetry Calculate an in vivo dose that would result in the
effect observed in the in vitro systems.
The acrylamide example
In vitro data on toxicity Kinetic model to predict dose causing toxic
effects
uptake (Ka)
distribution
[plasma] (Vd)
metabolism (Vmax, Km, Cli)
KINETICS
degeneration C*t/(C*t + Ct50)
100% effect
20% effect CNC
0% effect
Recovery (Krepair*t)
DYNAMICS KINETIC-DYNAMIC MODELLING
in vivo systemic toxicity
prediction of systemic toxicity
prediction of dynamics
prediction of target tissue
concentrations
in vitro data on dynamics
kinetics in vivo kinetic modelling (use known physiological
parameters)
in vitro data on kinetics
Toxicity testing: a more efficient approach
Health Council of the Netherlands. The Hague: Health Council of the Netherlands, 2001; publication no. 2001/24E.
ISBN: 90-5549-415-1 http://www.gr.nl/
(go to reports, 20 November 2001)
The example of glycol ethers in reprotox
Van Dartel and Piersma, Reprod Tox 2011, 32: 235-244
QIVIVE for glycol ether reproductive toxicity
Louisse et al, ToxSci 2010
Check on kinetic model
Louisse et al, ToxSci 2010
QIVIVE result: prediction of embryotox
Louisse et al, ToxSci 2010
In Vitro Biokinetics
Groothuis et al., Toxicology in press
Groothuis et al., Toxicology in press
What to measure in vitro: adaptation vs adversity
Incorporation in a MOS approach
In Vitro Based Risk Evaluation Approach
Blaauboer et al 2012 Altex
Why repeated dose toxicity
Exposures are more often over a prolonged period of time (as opposed to acute exposure)
Therefore, risk assessment should take repeated (or prolonged) exposure into account
Why does toxicity change over time
Acute toxicity: - direct and imminent effects - a more clear-cut relation between dose and concentrations at the target site
Repeated dose toxicity: - apart from acute effects, a more complicated relationship between dose effect.
Repeated dose: consequences
1. the target (cell) concentration of the test compound may change: - by accumulation - by changing the metabolic rate (induction/inhibition) over time (e.g. lindane)
Repeated dose: consequences
1. target cell concentration 2. By changing the cellular or molecular response:
- by adapting defense mechanisms - by exhaustion of defense mechanisms
QSAR >In Vitro Tox >PBBK>QIVIVE
Conclusions
1. Need to take in vitro biokinetics into consideration: will improve quality of in vitro toxicity data
2. Use of kinetic parameters to correlate in vitro effective concentrations to a dose in vitro is absolutely essential.
3. Use integrated transparent approach in improving the applicability of in vitro data in risk assessment.
Conclusions
5. Make optimal use of chemical biological and physiological knowledge: QSAR’s, cellular biology, systems biology, “omics”, etc.
6. This is necessary to deal with the huge demand for toxicological data
7. And: more science, less animals