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<p>Several investigations have described adverse effects in fish inhabiting polluted areas, though the causative, or aetiologic compounds have not been substantiated. Since environmental pollutants exist as complex mixtures, reliable risk estimations are difficult to obtain. Chemical analyses of known toxicants are not sufficient since unknown toxic compounds will not be identified. Diagnostic tools – biomarkers – will provide information on the potential toxicity, but only limited information on the aetiologic compounds. A promising strategy for pinpointing the major toxicants in environmental samples is to fractionate samples in several steps, guided by the toxicity of the isolated fractions. This enables a more precise identification of aetiologic compounds than the analysis of a non-fractionated sample.</p><p>The present thesis describes the toxicological and chemical characterization of organic pollutants in the polychlorinated biphenyl (PCB) polluted bay Örserumsviken on Sweden’s Baltic coast. Compounds in organic extracts of abiotic matrices collected in the bay were separated by degree of aromaticity prior to exposing early life-stages of rainbow trout (Oncorhynchus mykiss). The fraction containing PCBs and other dicyclic aromatic compounds (DACs) was less potentially toxic than the fraction containing polycyclic aromatic compounds (PACs). An estimated 1-5% of the total ethoxyresorufin O-deethylase (EROD) induction could be explained by PCBs, and less than 4% by the most commonly monitored PACs. Though the aetiologic compounds were not identified, a significant part of the EROD induction was isolated in a PAC-subfraction containing compounds with more than five rings and the major part of teratogenicity was isolated in a fraction containing three- and four-ringed PACs. As markers for the unidentified potent compounds in the DAC- and PAC-fractions, PCBs and polycyclic aromatic hydrocarbons (PAHs) were analyzed in feral fish eggs from the bay. Adult northern pike (Esox lucius) had elevated levels of hepatic DNA adducts, which correlated with PAH concentrations in their eggs. ΣPCB concentration in pike eggs was equal to the injected concentration in the highest dose of the DAC-fraction, which caused a 50-fold EROD induction in rainbow trout larvae. This demonstrates that the compounds present in the abiotic matrices posed a threat to all life-stages of fish in this area.</p><p>The findings in this thesis clearly reveal the limits of our knowledge regarding compounds responsible for potential toxicity in field situations. We need to place greater emphasis on the toxicological and chemical implications of our continuous release of PACs and to work for much more restrictive regulations.</p>

Thesis (Ph. D.)--Texas A&M University, 2005. / "Major Subject: Toxicology" Title from author supplied metadata (automated record created on Feb. 23, 2007.) Vita. Abstract. Includes bibliographical references.

Thesis (Ph. D.)--Texas A&M University, 2005. / "Major Subject: Toxicology" Title from author supplied metadata (automated record created on Sep. 15, 2006.) Vita. Abstract. Includes bibliographical references.

Aquatic sediments are of major importance for the cycling of environmental pollutants, acting as both sinks and secondary sources of contaminants to the ecosystem. Sediment-living organisms can affect the fate and transport of contaminants through activities like feeding and burrowing, collectively called bioturbation. Apart from high contaminant levels, the Baltic benthic ecosystem is affected by stressors such as eutrophication-induced anoxic conditions and invading alien species. The main objectives of this thesis were to determine the effects of bioturbation on contaminant fluxes in Baltic Sea sediments and to increase the understanding of how these other stressors act together upon contaminant fate in the benthic ecosystem. Bioturbation affected contaminants in a species-specific way. The native species Monoporeia affinis and Macoma balthica increased the incorporation of BDE-99 and Cd deposited on the sediment surface, enhancing their retention in the sediment. The invasive polychaete Marenzelleria sp. did not contribute to the incorporation of surface-deposited contaminants, however, significantly increased the release of contaminants back to the water column. Reoxygenation of anoxic laminated sediments and bioturbation by Marenzelleria increased the sediment-to-water flux of dissolved organic contaminants. When the bioturbation-driven release of PCB was compared to the release caused by physical sediment resuspension, results indicated that the continuous activities of benthic infauna can be just as, or even more, important than physical disturbance for the remobilization of sediment-bound contaminants. Bioaccumulation was significantly higher when contaminants were deposited associated to phytoplankton compared to lignin or sediment, suggesting that there are likely seasonal differences in the mobilization of contaminants in the benthic ecosystem. In summary, bioturbation is an important process influencing contaminant fate in Baltic Sea sediments, and the risk of remobilization of historically buried contaminants may increase with improved benthic redox conditions and the invasion of new deeper-digging species, such as Marenzelleria.

Several investigations have described adverse effects in fish inhabiting polluted areas, though the causative, or aetiologic compounds have not been substantiated. Since environmental pollutants exist as complex mixtures, reliable risk estimations are difficult to obtain. Chemical analyses of known toxicants are not sufficient since unknown toxic compounds will not be identified. Diagnostic tools – biomarkers – will provide information on the potential toxicity, but only limited information on the aetiologic compounds. A promising strategy for pinpointing the major toxicants in environmental samples is to fractionate samples in several steps, guided by the toxicity of the isolated fractions. This enables a more precise identification of aetiologic compounds than the analysis of a non-fractionated sample. The present thesis describes the toxicological and chemical characterization of organic pollutants in the polychlorinated biphenyl (PCB) polluted bay Örserumsviken on Sweden’s Baltic coast. Compounds in organic extracts of abiotic matrices collected in the bay were separated by degree of aromaticity prior to exposing early life-stages of rainbow trout (Oncorhynchus mykiss). The fraction containing PCBs and other dicyclic aromatic compounds (DACs) was less potentially toxic than the fraction containing polycyclic aromatic compounds (PACs). An estimated 1-5% of the total ethoxyresorufin O-deethylase (EROD) induction could be explained by PCBs, and less than 4% by the most commonly monitored PACs. Though the aetiologic compounds were not identified, a significant part of the EROD induction was isolated in a PAC-subfraction containing compounds with more than five rings and the major part of teratogenicity was isolated in a fraction containing three- and four-ringed PACs. As markers for the unidentified potent compounds in the DAC- and PAC-fractions, PCBs and polycyclic aromatic hydrocarbons (PAHs) were analyzed in feral fish eggs from the bay. Adult northern pike (Esox lucius) had elevated levels of hepatic DNA adducts, which correlated with PAH concentrations in their eggs. ΣPCB concentration in pike eggs was equal to the injected concentration in the highest dose of the DAC-fraction, which caused a 50-fold EROD induction in rainbow trout larvae. This demonstrates that the compounds present in the abiotic matrices posed a threat to all life-stages of fish in this area. The findings in this thesis clearly reveal the limits of our knowledge regarding compounds responsible for potential toxicity in field situations. We need to place greater emphasis on the toxicological and chemical implications of our continuous release of PACs and to work for much more restrictive regulations.

There is a great concern about children’s health as the developing brain in foetuses and children is much more vulnerable to injury caused by different classes of chemicals than the adult brain. This vulnerability is partly due to the fact that the adult brain is well protected against chemicals by the blood brain barrier (BBB) and children have increased absorption rates and diminished ability to detoxify many exogenous compounds, in comparison to that of adults. Moreover, the development of the central nervous system (CNS) is a very complex process involving several different important events, e.g. proliferation, migration and differentiation of cells. These events are occurring within a strictly controlled time frame and therefore create different windows of vulnerability. Furthermore, the brain consists of numerous different cell types (neuronal, glial and endothelial cells) that have specific functions. The development of each cell type occurs within a specific time window and is therefore susceptible to environmental disturbances at different time periods. Evidence indicates that exposure to industrial chemicals, pesticides or drugs, contributes to the increasing incidence of neurodevelopment disorders. However, due to lack of studies only a few industrial chemicals have been identified as developmental neurotoxicants so far. The current developmental neurotoxicity (DNT) guidelines (OECD TG 426 and US EPA 712-C-98-239) are based entirely on in vivo studies that are time consuming, complex, costly and not suitable for the testing of a high number of chemicals. Applying alternative approaches such as in silico, in vitro and non-mammalian models as a part of an integrated test strategy, could speed up the process of DNT evaluation and reduce and refine animal usage. Both in vitro and non-mammalian test systems offer the possibility of providing an early screening for a large number of chemicals, and could be particularly useful in characterising the compound-induced mechanism of toxicity of various developmental processes. This thesis has characterised two primary neuronal cultures (cerebellar granule cells (CGCs) and cortical neuronal cultures) and identified them as relevant models for DNT testing, since the key processes of brain development are present, such as cell proliferation, migration and neuronal/glial differentiation. Furthermore, two emerging technologies (gene expression and electrical activity) have been evaluated and were identified as promising tools for in vitro DNT assessment. In combination with other assays they could be included into a DNT intelligent testing strategy to speed up the process of DNT evaluation mainly by prioritising chemicals with DNT potential for further testing. / The work of this thesis was performed at ECVAM, European Commission, Italy.At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 3: In progress. Paper 4: In progress.

The aryl hydrocarbon receptor (AhR) is a ligand dependent transcription factor ubiquitously expressed in mammalian cells. It is a genetically ancient protein mostly known for binding the extremely toxic contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Binding to the AhR explains the variety of toxic responses of TCDD as well as the induction of several drug metabolizing enzymes. Induction of cytochrome P4501A1 (CYP1A1) is the most well characterized of the AhR regulated responses. The physiological functions of AhR and the endogenous ligand(s) for the receptor are under investigation but are not yet unraveled. Several tryptophan (TRP) derived indol-containing compounds have been reported to possess AhR affinity/CYP1A1 inducing capacity and TRP mediates CYP1A1 induction by UV light. The TRP photoproduct, 6-formylindolo[3,2-b]carbazole (FICZ) has the highest AhR affinity described so far and it causes a rapid and transient induction of the CYP1A1 gene in human cells. A number of reports on constitutive CYP1A1 activity in cultured cells is therefore most likely explained by the presence of TRP-derived AhR ligands in cell culture media. The aims of the studies were to investigate the impact of FICZ and FICZ metabolism on CYP1A1 gene regulation, to explore the metabolic fate of FICZ and to identify whether normal laboratory light could lead to formation of FICZ and thereby contribute to earlier observed CYP1A1 inducing effects by cell culture media. Metabolic studies using fractions of Aroclor-induced and non-induced rat liver and human liver as well as heterologously expressed enzymes revealed that FICZ can be efficiently metabolized by the CYP enzymes 1A1 and 1A2 and by an unknown cytosolic enzyme, to a number of hydroxylated and other oxidized metabolites. All of the hitherto identified 11 hydroxylated metabolites of FICZ are prone to conjugation reactions by glucuronosyltranferases and sulfotransferases. The metabolites formed by human enzymes are primarily sulfated. Thus, the sulfated metabolites of FICZ will be crucial in the future analyzes of FICZ formation in vivo. FICZ was identified to be formed, not only by UV illumination, but also by normal laboratory light. The constitutive CYP1A1 activity was significantly induced through the formation of several TRP related photoproducts in light-exposed medium. One of these photoproducts was identified as FICZ. Thus, the TRP photoproduct, FICZ, fits into a model in which FICZ auto-regulates the expression of induced enzymes. It is hypothesized that FICZ might function as a chemical messenger that activates AhR in response to light and might be one of several possible endogenous AhR ligands.

Thesis (M.Tech.)--Technikon Witwatersrand, 2000. / Also available via World Wide Web.

Thesis (Ph. D.)--University of Queensland, 2002. / Includes bibliographical references.