Factors Affecting the Binding of Diltiazem to Rainbow Trout Plasma: Implications for the Risk Assessment of Pharmaceuticals in Aquatic Systems.

The accumulation of organic toxicants in fish plasma, and how they partition between the bound and unbound fraction once absorbed, are important metrics in models that seek to predict the risk of such contaminants in aquatic settings. Rapid equilibrium dialysis of diltiazem, an ionizable weak base and important human pharmaceutical contaminant of freshwaters, was conducted with rainbow trout (Oncorhynchus mykiss) plasma. The effect of fed state, fish sex, fish strain/size, and dialysis buffer pH on the binding of radiolabeled diltiazem (9 ng ml-1 ) was assessed. In fed fish, 24.6%-29.5% of diltiazem was free, unbound to plasma proteins. Although starvation of fish resulted in a decrease in plasma protein, the bound fraction of diltiazem remained relatively constant. Consequently, the protein-bound concentration of diltiazem increased with length of starvation. In general, rainbow trout strain was a significant factor affecting plasma binding, although the two strains tested also differed markedly in size. Dialysis buffer pH significantly influenced plasma binding, with a higher unbound diltiazem fraction at pH 6.8 than pH 8.0. These data indicate that empirical measures of plasma binding in fish are important for accurate risk assessment and that the physiological status of a fish is likely to impact its sensitivity to toxicants such as diltiazem. Environ Toxicol Chem 2022;41:3125-3133. © 2022 SETAC.

Global scanning assessment of calcium channel blockers in the environment: Review and analysis of occurrence, ecotoxicology and hazards in aquatic systems.

As an urban water cycle is increasingly realized, aquatic systems are influenced by sewage and wastewater effluent discharges of variable quality. Such urbanization results in exposures of non-target aquatic organisms to medicines and other contaminants. In the present study, we performed a unique global hazard assessment of calcium channel blockers (CCB) in multiple environmental matrices. Effluent and freshwater observations were primarily from North America (62% and 76%, respectively) and Europe (21% and 10%, respectively) with limited-to-no information from rapidly urbanizing regions of developing countries in Asia-Pacific, South America, and Africa. Only 9% and 18% of occurrence data were from influent sewage and marine systems, though developing countries routinely discharge poorly treated wastewater to heavily populated coastal regions. Probabilistic environmental exposure distribution (EED) 5th and 95th percentiles for all CCBs were 1.5 and 309.1 ng/L in influent, 5.0 and 448.7 ng/L for effluent, 1.3 and 202.3 ng/L in freshwater, and 0.17 and 12.9 ng/L in saltwater, respectively. Unfortunately, global hazards and risks of CCBs to non-target organisms remain poorly understood, particularly for sublethal exposures. Thus, therapeutic hazard values (THV) were calculated and employed during probabilistic hazard assessments with EEDs when sufficient data was available. Amlodipine and verapamil in effluents and freshwater systems exceeded THVs 28% of the time, highlighting the need to understand ecological consequences of these CCBs. This global scanning approach demonstrated the utility of global assessments to identify specific CCBs, chemical mixtures with common mechanisms of action, and geographic locations for which environmental assessment efforts appear warranted.