Toxicokinetic-toxicodynamic (TK-TD) models simulate the processes that lead to toxicity at the level of organisms over time. These dynamic simulation models quantify toxicity, but more importantly they also provide a conceptual framework to better understand the causes for variability in different species' sensitivity to the same compound as well as causes for different toxicity of different compounds to the same species. Thus TK-TD models bring advantages for very diverse ecotoxicological questions as they can address two major challenges: the large number of species that are potentially affected and the large number of chemicals of concern. The first important benefit of TK-TD models is the role that they can play to formalize established knowledge about toxicity of compounds, sensitivity of organisms, organism recovery times and carry-over toxicity. The second important aspect of TK-TD models is their ability to simulate temporal aspects of toxicity which makes them excellent extrapolation tools for risk assessment of fluctuating or pulsed exposures to pollutants.
General introduction to TKTD modelling
We provide a general introduction to the concept of TK-TD modelling for environmental scientists and discuss opportunities as well as current limitations in this paper here:
Ashauer R & Escher BI (2010): Advantages of toxicokinetic and toxicodynamic modelling in aquatic ecotoxicology and risk assessment. Journal of Environmental Monitoring, 12:2056 - 2061. (link at journal) or (download here).
The two papers listed below were the direct outcome of the 1st international workshop on toxicokinetic-toxicodynamic modelling, held in Kastanienbaum, Switzerland in 2010. Also presented at the workshop was the analysis on experimental design for TKTD models (see below or downloads section).
For a more technical review see this paper:
Jager T, Albert C, Preuss TG, Ashauer R (2011): General unified threshold model of survival - a toxicokinetic-toxicodynamic framework for ecotoxicology. Environmental Science and Technology, 45(7), 2529-2540. (link at journal) or (download here)
Toxicokinetic-toxicodynamic models (TKTD models) simulate the time-course of processes leading to toxic effects on organisms. Even for an apparently simple endpoint as survival, a large number of very different TKTD approaches exist. These differ in their underlying hypotheses and assumptions, although often the assumptions are not explicitly stated. Thus, our first objective was to illuminate the underlying assumptions (individual tolerance or stochastic death, speed of toxicodynamic damage recovery, threshold distribution) of various existing modeling approaches for survival and show how they relate to each other (e.g., critical body residue, critical target occupation, damage assessment, DEBtox survival, threshold damage). Our second objective was to develop a general unified threshold model for survival (GUTS), from which a large range of existing models can be derived as special cases. Specific assumptions to arrive at these special cases are made and explained. Finally, we illustrate how special cases of GUTS can be fitted to survival data. We envision that GUTS will help increase the application of TKTD models in ecotoxicological research as well as environmental risk assessment of chemicals. It unifies a wide range of previously unrelated approaches, clarifies their underlying assumptions, and facilitates further improvement in the modeling of survival under chemical stress.
--> There is a GUTS R-package available. Search for GUTS at www.r-project.org
--> Also Tjalling has produced a Matlab version (link)
Ashauer R, Agatz A, Albert C, Ducrot V, Galic N, Hendriks J, Jager T, Kretschmann A, O'Connor I, Rubach MN, Nyman A-M, Schmitt W, Stadnicka J, van den Brink PJ, Preuss TG: (2011): Toxicokinetic-toxicodynamic modeling of quantal and graded sublethal endpoints: A brief discussion of concepts. Environ Toxicol Chem 30:2519-2524. (link to journal here or download from here)
We report on the advantages and problems of using toxicokinetic-toxicodynamic (TKTD) models for the analysis, understanding, and simulation of sublethal effects. Only a few toxicodynamic approaches for sublethal effects are available. These differ in their effect mechanism and emphasis on linkages between endpoints. We discuss how the distinction between quantal and graded endpoints and the type of linkage between endpoints can guide model design and selection. Strengths and limitations of two main approaches and possible ways forward are outlined.
How do we best design experiments so that we can then use the data to fit TKTD models and get good parameter estimates? This question was addressed in this study:
Albert C, Ashauer R, Künsch HR, Reichert P (2012): Bayesian Experimental Design for a Toxicokinetic-Toxicodynamic Model. Journal of Statistical Planning and Inference, 142, 263-275.
Here are some indications on how to design the experiments:
Of course I recommend to read that paper and some others to learn about the details...
This scheme illustrates the relation of different conceptual models and terms. Toxicokinetic-toxicodynamic models are quantitative models for those entities and processes that make up the Adverse Outcome Pathways.
Adverse Outcome Pathways were proposed by members of the US EPA as a conceptual framework for risk assessment of chemicals (Ankley G, et al. (2010): Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment. Environmental Toxicology and Chemistry 29(3), 730-741). (link to journal)