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

The toxicity of 17 active pharmaceutical ingredients (APIs) was investigated using standardized acute and chronic tests with Daphnia magna and 2 algae species. Chronic toxicity was generally greater for Daphnia than for algae. Compilation of additional data resulted in 100 APIs for which the acute‐to‐chronic ratio (ACR) was determined for Daphnia. The frequency of high ACRs (~20% with ACRs > 100) indicates that specific receptor‐mediated toxicity toward D. magna is rather common among APIs. The 11 APIs with ACRs > 1000 included lipid‐modifying agents, immunosuppressants, antibiotics, antineoplastics, antiobesics, antivirals, and antihistamines. There was no consistent association between ACR and chronic toxicity, ionization status, or lipophilicity. High ACRs were not exclusively associated with the presence of orthologs of the pharmacological target in Daphnia. Statins, acetylcholinesterase inhibitors, and antihistamines are discussed in more detail regarding the link between targets and toxic mode of action. For acetylcholinesterase inhibitors, receptor‐mediated toxicity was already apparent after acute exposure, whereas the high ACR and chronic toxicity of some antihistamines probably related to interaction with a secondary rather than the primary pharmacological target. Acute or modeled chronic toxicity estimates have often been used for prioritizing pharmaceuticals. This may be seriously misleading because chronic effects are currently not predictable for APIs with specific receptor‐mediated toxicity. However, it is exactly these APIs that are the most relevant in terms of environmental risks. Environ Toxicol Chem 2022;41:601–613. © 2021 SETAC