The findings in this thesis improve the understanding of 1) the relationship between exposure characteristics and toxicity of ENPs, 2) the joint toxic action of ENP mixtures and the comparison to... Show moreThe findings in this thesis improve the understanding of 1) the relationship between exposure characteristics and toxicity of ENPs, 2) the joint toxic action of ENP mixtures and the comparison to metal salt mixtures, 3) how NOM affects the individual and joint toxicity of ENPs, 4) the extent of trophic transfer of ENPs along aquatic food chains, 5) the influence factors on trophic transfer, and 6) bioaccumulation, distribution and toxic effect on predators. This knowledge would provide a basis for data on individual and joint toxicity, bioaccumulation, and trophic transfer of ENPs for more realistic environmental risk assessment. Show less
Similarity assessment is one of the means of optimally using scarcely available experimental data on the fate and hazards of nanoforms (NFs) for regulatory purposes. For a set of NFs that are shown... Show moreSimilarity assessment is one of the means of optimally using scarcely available experimental data on the fate and hazards of nanoforms (NFs) for regulatory purposes. For a set of NFs that are shown to be similar it is allowed in a regulatory context to apply the information available on any of the NFs within the group to the whole set of NFs. Obviously, a proper justification for such a similarity assessment is to be provided. Within the context of exemplifying such a justification, a case study was performed aimed at assessing the similarity of a set of spherical metallic NFs that different with regard to chemical composition (three metals) and particle size (three different sizes). The endpoints of assessment were root elongation and biomass increase of lettuce (Lactuca sativa L.) seedlings and exposure assessment was performed in order to express the actual exposure concentration in terms of time-weighted average particle concentrations. The results of the study show that for the specific endpoints assessed, chemical composition is driving NF toxicity and this is mostly due to impacts on the fate of the NFs. On the other hand, particle size of Cu NFs had a negligible impact on the dose-response relationships for the specific endpoints assessed. It is thus concluded that hazard data available on spherical Cu NF tested in our case can be used to inform on the hazards of any spherical Cu NF within the size range of 25–100 nm, but only applies for the certain endpoints. Also, toxicity data for the Cu2+-ion are suited for such a similarity assessment. Show less
Fate and toxicity of copper nanoparticles was related to the water chemistry of the environment and pristine size. Connection between fate and toxicity of copper nanoparticles could be drawn. The... Show moreFate and toxicity of copper nanoparticles was related to the water chemistry of the environment and pristine size. Connection between fate and toxicity of copper nanoparticles could be drawn. The particle-specific toxicity of copper nanoparticles was dependent on water chemistry. Show less
Our study emphasizes the importance of two toxicity-modifying factors (the composition of the surrounding exposure media and mixture effects) in the assessment of toxic effects of metals and... Show more Our study emphasizes the importance of two toxicity-modifying factors (the composition of the surrounding exposure media and mixture effects) in the assessment of toxic effects of metals and metal-based NPs on higher plants. Based on the affinity of metals for binding sites on the biotic ligand at the water-organism interface, the mechanistic models we developed provide better links with the toxicity of metal mixtures. We also recommend that finding a statistically significant deviation from additivity can be the starting point for further mechanistic research concerning toxicologically relevant interactions between substances, instead of the endpoint of research used so far. As an extension of the research discussed in the third chapter of this thesis, the commonly known model for the toxicity of mixtures was proven to be suitable for preliminarily assessing the effects of metal-based NPs on terrestrial organisms. The experimental design of nested combinations helps establish a more realistic exposure scenario for the environment and makes it possible to identify where and how chemical-chemical interactions occur with metal-based NPs. Consequently, our findings enrich the rapidly evolving field of toxicology regarding metals and metal-based NPs. Show less
There are only a limited number of studies that have developed appropriate models which incorporate bioavailability to estimate mixture toxicity. Here, we explored the applicability of the extended... Show moreThere are only a limited number of studies that have developed appropriate models which incorporate bioavailability to estimate mixture toxicity. Here, we explored the applicability of the extended biotic ligand model (BLM) and the WHAM-F tox approach for predicting and interpreting mixture toxicity, with the assumption that interactions between metal ions obey the BLM theory. Seedlings of lettuce Lactuca sativa were exposed to metal mixtures (Cu-Ni, Cu-Cd, and Ni-Cd) contained in hydroponic solutions for 4 days. Inhibition to root elongation was the endpoint used to quantify the toxic response. Assuming that metal ions compete with each other for binding at a single biotic ligand, the extended BLM succeeded in predicting toxicity of three mixtures to lettuce, with more than 82 % of toxicity variation explained. There were no significant differences in the values of f mix50 (i.e., the overall amounts of metal ions bound to the biotic ligand inducing 50 % effect) for the three mixture combinations, showing the possibility of extrapolating these values to other binary metal combinations. The WHAM-F tox approach showed a similar level of precision in estimating mixture toxicity while requiring fewer parameters than the BLM-f mix model. External validation of the WHAM-F tox approach using literature data showed its applicability for other species and other mixtures. The WHAM-F tox model is suitable for delineating mixture effects where the extended BLM also applies. Therefore, in case of lower data availability, we recommend the lower parameterized WHAM-F tox as an effective approach to incorporate bioavailability in quantifying mixture toxicity. Show less
Copper nanoparticles (CuNPs) are used extensively in a wide range of products and the potential for toxicological impacts in the aquatic environment is of high concern. In this study, the fate and... Show moreCopper nanoparticles (CuNPs) are used extensively in a wide range of products and the potential for toxicological impacts in the aquatic environment is of high concern. In this study, the fate and the acute toxicity of spherical 50 nm copper nanoparticles was assessed in juvenile rainbow trout (Oncorhynchus mykiss), fathead minnow (Pimephales promelas) and zebrafish (Danio rerio) for in vivo aqueous exposures following standardized OECD 203 guideline tests. The fate of the CuNPs in the aqueous media was temperature dependent. At the higher study temperature (26 ± 1 C), there was both an enhanced particle aggregation and higher rate of dissolution compared with that at the lower study temperature (15 ± 1 C). 96 h LC50s of the CuNPs were 0.68 ± 0.15, 0.28 ± 0.04 and 0.22 ± 0.08 mg Cu/L for rainbow trout, fathead minnow and zebrafish, respectively. The 96 h lowest-observed-effect concentration (LOEC) for the CuNPs were 0.17, 0.023 and <0.023 mg/L for rainbow trout, fathead minnow, and zebrafish respectively, and are below the predicted environmental concentration of CuNPs for some aquatic environments suggesting a possible ecotoxicological risk to fish. Soluble copper was one of main drivers for the acute toxicity of the copper nanoparticles suspensions. Both CuNPs suspension and copper nitrate caused damage to gill filaments and gill pavement cells, with differences in sensitivity for these effects between the fish species studied. We show therefore common toxicological effects of CuNPs in different fish species but with differences in sensitivity with implications for hazard extrapolation between fish species. Show less
This thesis focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is proposed to 1) ensure that... Show moreThis thesis focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is proposed to 1) ensure that pharmacological concepts are incorporated into the evaluation of safety and toxicity; 2) facilitate the integration of historical evidence and thereby the translation of findings across species; and 3) promote the use of experimental protocols tailored to address specific safety and toxicity questions. Nonlinear-mixed effects modelling is recommended as a tool to account for such requirements. Our goal was to explore the feasibility of a model-based approach to toxicology assessment and risk prediction in humans and, where possible, to compare the performance of this approach to traditional safety assessment approaches. The investigational plan of the thesis was divided into two sections where the development of methodology is followed by a case study with real data. A variety of analysis strategies and protocol designs are investigated where we set the constraint that proposals to deviate from existing protocols be minimal. We finally compile recommendations for protocol optimisation and data analysis/interpretation strategies to facilitate the implementation of model-based techniques in safety pharmacology and toxicology research Show less
Metals in soils can pose a serious threat to soil dwelling organisms, plants, and human beings. A major uncertainty in terrestrial ecological risk assessment for metals is theintegrated effect of... Show moreMetals in soils can pose a serious threat to soil dwelling organisms, plants, and human beings. A major uncertainty in terrestrial ecological risk assessment for metals is theintegrated effect of the physicochemical properties of soil on toxicity and how this allows for extrapolation of toxicity data across soils. The recognition that soil type is an important factor that determines metal toxicity, goes along with the increasing insight into bioavailability. There is a growing consensus that only a proportion of the total amount of metal in soil isavailable for uptake by organisms and subsequently induces toxic effects. Development of mechanistically underpinned approaches for explaining and predicting availability effects onmetal toxicity has been the subject of many research efforts in terrestrial ecotoxicology. Show less
Environmental life cycle assessment (LCA) is a method for the quantitative assessment of the environmental impacts of products. A number of impact categories are related to toxic effects of... Show moreEnvironmental life cycle assessment (LCA) is a method for the quantitative assessment of the environmental impacts of products. A number of impact categories are related to toxic effects of chemicals. Multimedia models for substance fate, supplemented with models for human exposure, have been developed in the context of human and environmental risk assessment (HERA). Different authors have adapted such models for use in LCA, largely on a continental level. It has sometimes been suggested to merge LCA toxicity assessment and HERA into one common tool. Here, it is demonstrated that LCA and HERA cannot be merged, due to a fundamental difference concerning their respective goals. Subsequently, adaptations to existing multimedia models are proposed to make it possible to extend multimedia models with a module for metals. The core of the thesis is formed by the GLOBOX model: a global, regionally differentiated fate, intake and effect model for LCA toxicity assessment. For emissions of any organic chemical or metal to any compartment in any country or at any sea, this model calculates region-specific characterisation factors. Finally, an updated set of LCA normalisation factors is provided, with which the relative contributions of a product to the different impact categories can be evaluated. Show less
