Roman Ashauer

General Unified Threshold Model of Survival - a Toxicokinetic- Toxicodynamic Framework for Ecotoxicology

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.

Predicting effects on aquatic organisms from fluctuating or pulsed exposure to pesticides

Exposure of aquatic nontarget organisms to pesticides almost always occurs as pulses or fluctuating concentrations. Extrapolation from laboratory to field thus depends on an understanding and ability to simulate effects resulting from these types of exposure. This paper reviews models that may be used to predict effects on aquatic organisms resulting from time-varying exposure to pesticides. We evaluate and compare the theoretical basis of these models and their applicability to the simulation of effects from fluctuating exposures. The many different models rest on only a few basic concepts with differing degrees of mechanistic character. Building on this critical review, we select the most appropriate models and propose modifications. Two process-based models, the threshold hazard model and the modified damage assessment model, represent the optimum descriptions that are available at present. They could facilitate a better understanding of the ecotoxicity of different compound and species combinations and even mixtures of noninteracting compounds. The possibility to model lethal and sublethal effects allows applications in risk assessment, standard setting, and ecological modeling.

Uptake and depuration of pharmaceuticals in aquatic invertebrates.

The uptake and depuration of a range of pharmaceuticals in the freshwater shrimp (Gammarus pulex) and the water boatman (Notonecta glauca) was studied. For one compound, studies were also done using the freshwater snail Planobarius corneus. In G. pulex, bioconcentration factors (BCFs) ranged from 4.6 to 185,900 and increased in the order moclobemide < 5-fluoruracil < carbamazepine < diazepam < carvedilol < fluoxetine. In N. glauca BCFs ranged from 0.1 to 1.6 and increased in the order 5-fluorouracil < carbamazepine < moclobemide < diazepam < fluoxetine < carvedilol. For P. corneus, the BCF for carvedilol was 57.3. The differences in degree of uptake across the three organisms may be due to differences in mode of respiration, behaviour and the pH of the test system. BCFs of the pharmaceuticals for each organism were correlated to the pH-corrected liposome-water partition coefficient of the pharmaceuticals.

Framework for traits‐based assessment in ecotoxicology

A key challenge in ecotoxicology is to assess the potential risks of chemicals to the wide range of species in the environment on the basis of laboratory toxicity data derived from a limited number of species. These species are then assumed to be suitable surrogates for a wider class of related taxa. For example, Daphnia spp. are used as the indicator species for freshwater aquatic invertebrates. Extrapolation from these datasets to natural communities poses a challenge because the extent to which test species are representative of their various taxonomic groups is often largely unknown, and different taxonomic groups and chemicals are variously represented in the available datasets. Moreover, it has been recognized that physiological and ecological factors can each be powerful determinants of vulnerability to chemical stress, thus differentially influencing toxicant effects at the population and community level. Recently it was proposed that detailed study of species traits might eventually permit better understanding, and thus prediction, of the potential for adverse effects of chemicals to a wider range of organisms than those amenable for study in the laboratory. This line of inquiry stems in part from the ecology literature, in which species traits are being used for improved understanding of how communities are constructed, as well as how communities might respond to, and recover from, disturbance (see other articles in this issue). In the present work, we develop a framework for the application of traits-based assessment. The framework is based on the population vulnerability conceptual model of Van Straalen in which vulnerability is determined by traits that can be grouped into 3 major categories, i.e., external exposure, intrinsic sensitivity, and population sustainability. Within each of these major categories, we evaluate specific traits as well as how they could contribute to the assessment of the potential effects of a toxicant on an organism. We then develop an example considering bioavailability to explore how traits could be used mechanistically to estimate vulnerability. A preliminary inventory of traits for use in ecotoxicology is included; this also identifies the availability of data to quantify those traits, in addition to an indication of the strength of linkage between the trait and the affected process. Finally, we propose a way forward for the further development of traits-based approaches in ecotoxicology.

Effects of agricultural conditions on the leaching behaviour of veterinary antibiotics in soils

Antibiotics may be released to soils during the application of manure as fertiliser to land. The compounds may subsequently be transported to and contaminate groundwater and surface waters. This paper describes a series of lysimeter-based studies to explore the leaching behaviour of three veterinary antibiotics (sulfachloropyridazine, oxytetracycline and tylosin) under different conditions that could occur in the agricultural environment. The specific objectives were to: (1) explore the influence of slurry amendment and incorporation on leaching; (2) assess the effects of climate on leaching behaviour; and (3) evaluate the predictive capability of a leaching model used in the regulatory assessment of veterinary medicines. Sulfachloropyridazine was detected sporadically in leachate at concentrations up to 0.66 microg L(-1) under typical irrigation conditions and more frequently at concentrations up to 8.5 microg L(-1) under extreme irrigation conditions. Incorporation and timing of rainfall had no effect on leaching behaviour. Oxytetracycline and tylosin were not detected in any leachate samples. These differences in behaviour were explained by the sorption and persistence characteristics of the compounds. Comparison of the experimental measurements with simulations from the leaching model indicated that the model greatly underestimates the transport of antibiotics to groundwater which raises questions over the application of these models in the regulatory risk assessment process.

Crucial role of mechanisms and modes of toxic action for understanding tissue residue toxicity and internal effect concentrations of organic chemicals

This article reviews the mechanistic basis of the tissue residue approach for toxicity assessment (TRA). The tissue residue approach implies that whole-body or organ concentrations (residues) are a better dose metric for describing toxicity to aquatic organisms than is the aqueous concentration typically used in the external medium. Although the benefit of internal concentrations as dose metrics in ecotoxicology has long been recognized, the application of the tissue residue approach remains limited. The main factor responsible for this is the difficulty of measuring internal concentrations. We propose that environmental toxicology can advance if mechanistic considerations are implemented and toxicokinetics and toxicodynamics are explicitly addressed. The variability in ecotoxicological outcomes and species sensitivity is due in part to differences in toxicokinetics, which consist of several processes, including absorption, distribution, metabolism, and excretion (ADME), that influence internal concentrations. Using internal concentrations or tissue residues as the dose metric substantially reduces the variability in toxicity metrics among species and individuals exposed under varying conditions. Total internal concentrations are useful as dose metrics only if they represent a surrogate of the biologically effective dose, the concentration or dose at the target site. If there is no direct proportionality, we advise the implementation of comprehensive toxicokinetic models that include deriving the target dose. Depending on the mechanism of toxicity, the concentration at the target site may or may not be a sufficient descriptor of toxicity. The steady-state concentration of a baseline toxicant associated with the biological membrane is a good descriptor of the toxicodynamics of baseline toxicity. When assessing specific-acting and reactive mechanisms, additional parameters (e.g., reaction rate with the target site and regeneration of the target site) are needed for characterization. For specifically acting compounds, intrinsic potency depends on 1) affinity for, and 2) type of interaction with, a receptor or a target enzyme. These 2 parameters determine the selectivity for the toxic mechanism and the sensitivity, respectively. Implementation of mechanistic information in toxicokinetic-toxicodynamic (TK-TD) models may help explain time-delayed effects, toxicity after pulsed or fluctuating exposure, carryover toxicity after sequential pulses, and mixture toxicity. We believe that this mechanistic understanding of tissue residue toxicity will lead to improved environmental risk assessment.

CREAM: a European project on mechanistic effect models for ecological risk assessment of chemicals.

Current risk assessments are mainly based on ecotoxicological endpoints at the level of individual organisms, but according to the EU directives, the protection goal aims at achieving sustainable populations (European Commission 2002a, b; Forbes et al. 2009; Preuss et al. 2009a; Thorbek et al. 2009). Population-level effects depend not only on exposure and toxicity, but also on important ecological factors that are impossible to fully address empirically. At present, a number of testing approaches exist that provide endpoints on the community and the population level, respectively (nontarget arthropod and earthworm field tests, aquatic and terrestrial model ecosystem tests). However, not all fields and regulatory questions can be covered by these approaches. To fill these gaps and to enhance the scientific quality of ecological risk assessments, we suggest implementing mechanistic effect models (MEMs), as these also

Toxicokinetic and Toxicodynamic Modeling Explains Carry-over Toxicity from Exposure to Diazinon by Slow Organism Recovery

Carry-over toxicity occurs when organisms exposed to an environmental toxicant survive but carry some damage resulting in reduced fitness. Upon subsequently encountering another exposure event stronger effects are possible if the organisms have not yet fully recovered. Carry-over toxicity was observed after exposure of the freshwater amphipod Gammarus pulex to repeated pulses of diazinon with varying intervals. Uptake, biotransformation and depuration kinetics were determined. Metabolites were identified and quantified (diazoxon, 2-isopropyl-6-methyl-4-pyrimidinol, one nonidentified metabolite). Parameters of a process-based toxicokinetic-toxicodynamic model were determined by least-squares fitting followed by Markov Chain Monte Carlo parameter estimation. Model parametrization was based on the time-course of measured internal concentrations of diazinon and its metabolite diazoxon in combination with the pulsed toxicity experiment. Prediction intervals, which take the covariation between parameters into account, were calculated for bioaccumulation factors, organism recovery time and simulations of internal concentrations as well as the time-course of survival under variable exposure. Organism recovery time was 28 days (95% prediction interval 25-31 days), indicating the possibility for carry-over toxicity from exposure events several weeks apart. The slow organism recovery and carry-over toxicity was caused by slow toxicodynamic recovery; toxicokinetic processes alone would have resulted in a recovery time of only 1-2 days.

Nanopesticides: guiding principles for regulatory evaluation of environmental risks

Nanopesticides or nano plant protection products represent an emerging technological development that, in relation to pesticide use, could offer a range of benefits including increased efficacy, durability, and a reduction in the amounts of active ingredients that need to be used. A number of formulation types have been suggested including emulsions (e.g., nanoemulsions), nanocapsules (e.g., with polymers), and products containing pristine engineered nanoparticles, such as metals, metal oxides, and nanoclays. The increasing interest in the use of nanopesticides raises questions as to how to assess the environmental risk of these materials for regulatory purposes. Here, the current approaches for environmental risk assessment of pesticides are reviewed and the question of whether these approaches are fit for purpose for use on nanopesticides is addressed. Potential adaptations to existing environmental risk assessment tests and procedures for use with nanopesticides are discussed, addressing aspects such as analysis and characterization, environmental fate and exposure assessment, uptake by biota, ecotoxicity, and risk assessment of nanopesticides in aquatic and terrestrial ecosystems. Throughout, the main focus is on assessing whether the presence of the nanoformulation introduces potential differences relative to the conventional active ingredients. The proposed changes in the test methodology, research priorities, and recommendations would facilitate the development of regulatory approaches and a regulatory framework for nanopesticides.

Predicting Concentrations of Organic Chemicals in Fish by Using Toxicokinetic Models

Quantification of chemical toxicity continues to be generally based on measured external concentrations. Yet, internal chemical concentrations have been suggested to be a more suitable parameter. To better understand the relationship between the external and internal concentrations of chemicals in fish, and to quantify internal concentrations, we compared three toxicokinetic (TK) models with each other and with literature data of measured concentrations of 39 chemicals. Two one-compartment models, together with the physiologically based toxicokinetic (PBTK) model, in which we improved the treatment of lipids, were used to predict concentrations of organic chemicals in two fish species: rainbow trout (Oncorhynchus mykiss) and fathead minnow (Pimephales promelas). All models predicted the measured internal concentrations in fish within 1 order of magnitude for at least 68% of the chemicals. Furthermore, the PBTK model outperformed the one-compartment models with respect to simulating chemical concentrations in the whole body (at least 88% of internal concentrations were predicted within 1 order of magnitude using the PBTK model). All the models can be used to predict concentrations in different fish species without additional experiments. However, further development of TK models is required for polar, ionizable, and easily biotransformed compounds.