The COVID-19 pandemic has intensified the development of new antiviral agents specifically intended for the SARS-CoV-2 virus, but has also increased the use of some already known antiviral agents originally intended for other viruses. Although the pandemic has ended, the SARS-CoV-2 virus is expected to be present in the human population forever, as is the case with the influenza virus, for example. Such a scenario guarantees the continued use of SARS-CoV-2 antivirals and, accordingly, their continued release into the environment. Unfortunately, there is little or no information on the adverse potential of most of these antiviral agents. In this study, the acute toxicity of six antiviral agents used in the treatment of SARS-CoV-2 infections was determined. These are atazanavir, ribavirin, emtricitabine, nirmatrelvir, sofosbuvir and oseltamivir, sorted according to their toxicity, starting with the most toxic agent. Toxicity was determined using the marine bacterium Aliivibrio fischeri according to the ISO 11348-1:2007 standard. In addition to the toxicities of the individual antiviral solutions, the toxicities of binary antiviral mixtures were also determined. By comparing the experimentally determined toxicities of the mixtures with the values estimated by the concentration addition model and the independent action model, we analyzed the mode of joint toxic activity of these antiviral agents. Additive behavior was observed for most binary combinations. The combination of nirmatrelvir and sofosbuvir led to an antagonistic deviation from the concentration addition model, while a synergistic deviation was observed for the combinations of emtricitabine with atazanavir and with nirmatrelvir, as well as for the combinations of ribavirin with atazanavir, oseltamivir and sofosbuvir. All tested binary combinations showed a synergistic deviation from the independent action model.
