Leveraging mammalian pharmaceutical toxicology and pharmacology data to predict chronic fish responses to pharmaceuticals

Abstract

Comparative pharmacology and toxicology approaches with fish models provide important linkages between the biomedical and environmental sciences. Because chronic fish responses to select pharmaceuticals are observed at very low (e.g., ng/L) concentrations, approaches are needed to identify therapeutics for robust environmental hazard and risk assessments. Whereas we observed no obvious relationship between acute toxicity data for rodent (LD(50)) and fish (LC(50)) models, using a probabilistic hazard evaluation approach, rodent and fish acute toxicity distributions predicted limited potential for acute toxicity at low concentrations, which is consistent with the peer-reviewed literature. Similar probabilistic distributions were developed to examine mammalian C(max) and an Acute to Therapeutic Ratio (ATR), a surrogate for mammalian therapeutic index that is similar to an Acute to Chronic Ratios (ACRs) commonly calculated for fish models. Probabilistic distributions of ATRs for fifteen drug classes were also examined, which showed specific groups with higher (e.g., reproductive hormones, corticosteroids, antihistamines) and lower (e.g., antibiotics, NSAIDs) ATR values than the distribution for all available pharmaceutical ATRs. A statistically significant relationship (r(2)=0.846, p<0.001) was determined between mammalian ATR and fish ACR values, which may support a screening approach to examine chronic pharmaceutical effects in fish based on the magnitude of mammalian ATR values.