Institute of Biomedical Studies

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Advancing chemical and biologically-based “Read across” through in silico, in vitro and in vivo techniques.
(2014-09-05) Connors, Kristin A.; Brooks, Bryan W.; Biomedical Studies.; Baylor University. Institute of Biomedical Studies.
Read across approaches include data leveraging across chemicals or among biological scales of organization or species, and may focus limited resources to support chemical hazard and risk assessment. Sustainable molecular design of less toxic industrial chemicals promises to preempt the production of organic contaminants with elevated toxicity. In chapter 2, probabilistic hazard assessment approaches were used to model potential reduction of aquatic toxicity hazards by using the ‘rule of two’ in the chemical design stage. Implementing this 'rule of two' was predicted to appreciably decrease chemicals designated of 'high' and 'very high' concern for standardized acute and chronic toxicity in common aquatic species. However, select modes of action and chemical classes will not have a reduced toxicity profile after following the 'rule of two.' Other read across techniques were examined to support chemical prioritization for safety assessments or to generate hypotheses for advanced research. Unlike most industrial chemicals, robust data exists for pharmaceutical physicochemical and biological properties, including human metabolism. Thus, it may be possible to employ existing mammalian pharmacological safety data to support screening-level bioaccumulation assessments. In chapter 3, a comparative pharmacology approach was used to determine whether rainbow trout biotransform pharmaceuticals known to be substrates for specific human CYPs. Only two general CYP substrates demonstrated measureable intrinsic clearance in vitro. No significant biotranformation was observed for substrates of human CYP2D6, CYP2C9, or CYP3A4. In chapter 4, enantiomer specific biotransformation profiles of chiral pharmaceuticals also deviated from human clearance rates. These observations demonstrate that relative clearance rates in trout are not predictable from human pharmacology data. Biological read across extrapolations were further explored in chapter 5 to characterize hazards of next generation therapeutics in zebrafish. Mechanistic and behavioral responses identified potential adverse outcomes from emerging antidepressants.
Leveraging available data for contaminants of emerging concern to develop an understanding of environmental hazard.
(2011-09-14) Berninger, Jason P.; Brooks, Bryan W.; Biomedical Studies.; Baylor University. Institute of Biomedical Studies.
Contaminants of emerging concern (CEC) are classes of compounds with relatively limited information available on environmental exposure, fate, and effects. The purpose of this research was to develop and test approaches that leverage available data using probabilistic models to advance an understanding of aquatic hazards of CECs. Pharmaceuticals are one such group of CECs. Though extrapolation approaches with fish models can provide important bridges between the biomedical and environmental sciences, little data is available addressing the sublethal effects of therapeutics in aquatic organisms. Seldom is the drug’s Mode of Action (MOA) considered in selection of chronic endpoints for an assessment, though mammalian pharmacological information is available for most drugs. A statistically significant relationship (r²=0.846, p<0.001) between mammalian pharmacology and toxicology data (margin of safety) and available fish acute to chronic data was identified, when therapeutic MOA was considered in selecting a chronic response variable. Based on this relationship, metrics to assess potency and internal effective dose were developed. These metrics were then evaluated using probabilistic distributions in an effort to prioritize drugs based on potential hazard. These probabilistic assessments identified specific drugs and drug classes as potentially presenting greater hazard to fish. To test these models, toxicity experiments with diphenhydramine, an antihistamine drug, were conducted to characterize standardized endpoints and novel, MOA-related ecotoxicological endpoints. The results confirmed that sublethal endpoints (e.g., behavior) related to therapeutic may be more appropriate for fish and that leveraging mammalian pharmacology and toxicology data may be predictive for MOA related responses when evolutionary conservation of targets are considered. It further highlighted the importance of carefully selecting model organisms for study of pharmaceuticals with multiple MOAs, because reproduction of the invertebrate Daphnia magna was sensitive to diphenydramine, potentially resulting from its histaminergic and cholinergic activities. A similar probabilistic approach was applied to oil dispersants, another CEC class, to assess potential impacts to aquatic systems. Leveraging the limited acute toxicity data available for an invertebrate and a fish model, probabilistic distributions were employed to predict the likelihood of oil dispersants exerting acute toxicity in the presence or absence of oil. This approach can be utilized in prospective and retrospective assessments to support emergency response decisions to oil spills and prioritize substances for further study. Lastly, probabilistic methods were used to develop uncertainty factors for acute to chronic rations for select biological active chemicals. For many chemical classes chronic effects data is lacking. Typically, default uncertainty factors are utilized to bridge this data gap. By leveraging the available chronic data using probabilistic methods, novel data-driven uncertainty factors were developed, potentially providing more protective extrapolation models.
Towards less hazardous chemicals : identifying chemical bioactivity through fish behavioral profiles.
(2019-04-02) Steele, William Baylor, 1983-; Brooks, Bryan W.
Because most chemicals in commerce lack empirical toxicology information, innovative approaches are needed to identify substances presenting elevated hazards and risks to public health and the environment. When larval fish models are employed with automated tracking technologies, behavioral studies can be used to perform rapid, diagnostic toxicity screens for large volumes of chemicals. Beyond utility in chemical safety screening applications, behaviors are integrated processes that are critical for organism survival and reproduction. This dissertation developed novel approaches to diagnostically examine chemicals for toxicity using larval fish models, and further extended these efforts beyond lab raised models to examine effects of neuroactive substances on wild fish populations. In Chapter two, methods used in the biomedical sciences to study therapeutic attributes of novel molecules were adapted for environmental screening applications. Using automated tracking software, a protocol was developed to quantify locomotor and photomotor responses (PMRs) of two common larval fish models, the zebrafish and fathead minnow. These developed methods were applied to study the behavioral effects of a common aquatic contaminant and neuro-stimulant, caffeine, which exerted photomotor and locomotor responses at environmentally relevant levels. In Chapter three, these methods were broadly applied to develop larval fish behavioral response profiles for a variety of different chemicals from diverse mode of action (MOA) categories. Both fish models demonstrated unique behavioral responses upon exposure to each chemical indicating that behavioral response may be informative of compound specific MOAs. Chapter four demonstrated that in the two most common larval fish models, refractory PMR and locomotor patterns appear informative of electrophilic properties associated with oxidative stress for SN2 chemicals. Property-based quantum mechanical modeling of electrophile reaction energies were predictive of experimental in vivo acute and sublethal toxicity, which provide important implications for identifying and designing less hazardous industrial chemicals. Because lab fish models cannot be expected to be representative of wild fish populations, Chapter five examined behavioral effects of two commonly prescribed psychiatric medications, oxazepam and sertraline, on perch collected from natural waters. Results from this study identified time related effects on fish boldness and neuroactive pharmaceutical related effects on fish activity levels.

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Browsing Institute of Biomedical Studies by Author "Brooks, Bryan W."