Advancing chemical and biologically-based “Read across” through in silico, in vitro and in vivo techniques.
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Access changed 10/6/16.
Connors, Kristin A.
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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.