Uptake and Effects of the Beta‐Adrenergic Agonist Salbutamol in Fish: Supporting Evidence for the Fish Plasma Model

Abstract

The fish plasma model (FPM) predicts the fish blood plasma concentration of a pharmaceutical from the water concentration to which the fish is exposed and compares it with the human therapeutic plasma concentration (HtherPC) with the postulate that no adverse toxic effects occur below the HtherPC. The present study provides several lines of evidence supporting the FPM for the beta‐adrenergic agonist salbutamol, a small cationic molecule at ambient pH. Salbutamol exhibited very low acute toxicity to early and adult life stages of fish. Biomass reduction in fish early life stages was the most sensitive apical endpoint, with no‐observed‐effect concentrations (NOECs) in the low mg/L range after continuous exposure for up to 120 d. Given that predicted and measured environmental concentrations are at least 1000‐fold lower, the risk of salbutamol in freshwater is deemed very low. Increase in heart beat rate and decrease in total triglyceride content in fish also occurred at the low mg/L range and resembled effects known from humans. This finding supports the FPM assumption of conserved targets in fish with similar functionality. Plasma concentrations measured in adult and juvenile fish exposed to water concentrations at approximately the NOECs exceeded HtherPC and even approached plasma concentrations toxic to humans. This result confirms for salbutamol the FPM hypothesis that no adverse (i.e., population‐relevant) toxic effects occur in fish below the HtherPC. Environ Toxicol Chem 2019;38:2509–2519. © 2019 SETAC

Effect of Water pH on the Uptake of Acidic (Ibuprofen) and Basic (Propranolol) Drugs in a Fish Gill Cell Culture Model

“…Human and veterinary pharmaceuticals are biologically active compounds with concentrations in global freshwater environments being measured at the pg−μg/L range and accumulation in biota being observed. , This raises concerns about the effect these compounds may have on aquatic organisms because many human drug targets are evolutionarily conserved in fish and aquatic invertebrates. − Adverse effects have been observed for a number of drugs when internal concentrations in fish exceed the human therapeutic plasma concentrations, for example, ethinyl oestradiol, fluoxetine, , glucocorticoids, − ibuprofen, propranolol, and salbutamol . Identification and characterization of environmental risks posed by chemicals currently involve lengthy and costly acute and chronic fish toxicity studies, and there is a need to develop alternative methods, whether computational such as QSARs or in vitro techniques. , This is extremely pertinent to pharmaceuticals because there are over 11,000 small molecule drugs and approximately 2500 approved (), most of which are legacy compounds with little environmental impact data …”

“…4−7 Adverse effects have been observed for a number of drugs when internal concentrations in fish exceed the human therapeutic plasma concentrations, 8 for example, ethinyl oestradiol, 9 fluoxetine, 10,11 glucocorticoids, 12−15 ibuprofen, 16 propranolol, 17 and salbutamol. 18 Identification and characterization of environmental risks posed by chemicals currently involve lengthy and costly acute and chronic fish toxicity studies, 19 and there is a need to develop alternative methods, whether computational such as QSARs 20 or in vitro techniques. 21,22 This is extremely pertinent to pharmaceuticals because there are over 11,000 small molecule drugs and approximately 2500 approved (https://www.drugbank.ca/stats), most of which are legacy compounds with little environmental impact data.…”

Minimizing Experimental Testing on Fish for Legacy Pharmaceuticals

“…However, greater trust in a (potentially improved) FPM model would be required to defend a threshold of, e.g., 0.01 instead of 0.001 for PEC/TWC. Experimental studies have demonstrated that the FPM (an in silico tool) provides reasonably reliable predictions of blood plasma concentrations of APIs in exposed fish, , even for small cationic molecules that fall outside the applicability domain of the original model . Data derived from in vitro models, e.g., cultured fish gill cells or in silico tools modeling passive transport across membranes, may help to confirm or rebut the assumption of relevant uptake into fish and thereby inform on the reliability and plausibility of a predicted TWC.…”

“…Experimental studies have demonstrated that the FPM (an in silico tool) provides reasonably reliable predictions of blood plasma concentrations of APIs in exposed fish, 30 , 31 even for small cationic molecules that fall outside the applicability domain of the original model. 32 Data derived from in vitro models, e.g., cultured fish gill cells 33 or in silico tools modeling passive transport across membranes, 34 may help to confirm or rebut the assumption of relevant uptake into fish and thereby inform on the reliability and plausibility of a predicted TWC. In silico prediction models of bioconcentration in fish e.g, refs ( 35 − 37 ), eventually including consideration of metabolism, 38 may also be useful as supporting evidence for TWC.…”

Evaluation of Terbutaline Adsorption from Aqueous Medium by Mechanically Generated [Cu (INA)2]-MOF Metal-Organic Framework and its Modified Magnetic Composite ([Cu (INA)2]-MOF@Fe3O4)

“…Possible health impacts from longterm exposure to pharmaceutical β-agonists through drinking water have been well hypothesized [5], and subsequent studies determined their effects on living species as hazardous to aquatic life and people [20] [25]. Higher concentrations of β-agonist in fish plasma are linked to human pharmacological effects [26]. While frequent reports of their occurrences in our environmental waters raises more concerns [27] [5].…”