Age matters : developmental stage of Zebrafish (Danio rerio) influences bioconcentration, and survival and behavioral photomotor response thresholds.

Toxicology information for the tens of thousands of compounds in commerce is severely lacking, and with continual introduction of new substances, this global chemical space is only increasing in complexity. Thus, generating data pertinent to legislation, regulation and risk assessment has become paramount. Significant hurdles exist for the production of such data sets as traditional whole organism studies have exorbitant costs, are time intensive, and are low throughput. To meet these goals alternative methods have been developed that shift the focus from a traditional, high dose, apical endpoint, based study design to a higher throughput, systems-biology, based design, however, as this is realized, critical evaluations of the newly introduced methodologies are warranted. Transitioning to high throughput screening (HTS) and predictive methodologies will further require focused efforts to not only identify these assays but also their intrinsic uncertainties. This novel dissertation employed two of the proposed alternative methodologies, probabilistic environmental hazard assessment and the fish embryo toxicity (FET) test, and probed their efficacy with an understudied class of contaminant, antihistamines. In Chapter 2, global hazards of antihistamines in surface waters were assessed with a probabilistic environmental hazard approach (PEHA) to identify global trends in occurrence. Subsequently, the capacity of the FET method to examine mixture interactions with a comparative pharmacology and toxicology approach (Chapter 3), and to extend to include behavioral observations (Chapter 4), was evaluated. Finally, to further elucidate the applicability domain of the FET, Chapter 5 investigated the driver for the age specific shifts in sensitivity evidenced in Chapters 3 and 4. These observations demonstrate the utility of both methods, and underline the importance of method selection and application.