Study By The University Of Tübingen Traces Toxicity Of Drugs In Water Depends On Acidity
Depending on the acidity of the water, the toxicity of chemicals in the aquatic environment can vary by several orders of magnitude. This was the result of a study led by Professor Heinz Köhler from the Institute for Evolution and Ecology at the University of Tübingen with researchers from the Universities of Tübingen and Athens and the Federal Environment Agency. The team examined the effect of 24 substances, mostly used as medicines, on the development of fish embryos in realistic scenarios. It developed a model for the reliable prediction of the toxicity of ionizable chemicals in water – with practical relevance. The results were used by the EU Commission at the end of 2022 for the derivation of an important limit value within the framework of the Water Framework Directive, the environmental quality standard, for the active pharmaceutical ingredient ibuprofen. The study was published in the journal Water Research.
To ensure the effectiveness of medicines, the human body should not normally break down the active ingredients. Therefore, most of it is often excreted unchanged after ingestion. Due to the increasing use of medicines in connection with demographic change, ever larger quantities of numerous different substances are entering water bodies and the environment via wastewater.
The substances examined in the study, such as the painkillers diclofenac and ibuprofen, the cholesterol-lowering drug clofibric acid and the beta-blocker metoprolol, are ionizable molecules, meaning they can be in a neutral or electrically charged form. Natural bodies of water, on the other hand, can have different acid-base ratios, measured as a pH value. “All of these factors have an influence on the absorption of the substances in the cells of living beings that can damage them,” explains Heinz Köhler.
Orientation towards worst-case scenarios
The zebrafish served as the test organism, and the developing eggs were exposed to the chemicals. The so-called LC50 value is determined in each case, which reflects the pollutant concentration at which 50 percent of the fish embryos die. In the study, the researchers tested the toxicity – or toxicity – of the chemicals at up to four different pH values from slightly acidic to alkaline water in more than 1200 individual experiments.
“For some active pharmaceutical ingredients such as diclofenac, the beta-blocker propranolol and the antidepressant fluoxetine, the LC50 value in the fish embryos varied more than a thousand times between pH 5 and pH 9,” reports Köhler. It is therefore necessary to assume realistic worst-case scenarios so that such substances do not cause too much damage to living beings in water when they are released and the worst possible conditions come together. The substances in the uncharged state turned out to be more toxic on average than in their ionized form.
Reliable simulations
Based on various assumptions as to how effectively the respective substance molecules penetrate the cell membrane and what harmful effects they could have in the cells, the research team developed their respective modeling approaches. To simulate toxicity at different pH values of the surrounding water, they compared six mathematical models. “For the practical application, we chose the model with which it is possible to reliably simulate the different toxic effects on fish over three orders of magnitude,” says the scientist.
According to Köhler and the second lead author of the study, Dr. Peter von der Ohe from the Federal Environment Agency, the study results should have an impact on the registration and authorization of chemicals in the EU and on the definition of environmental quality standards. A start has been made with the eight times lower EU water limit value for ibuprofen than it would have been based on the previous method. “This study contributes to a better understanding of the toxicity of ionizable substances and has significantly improved the prediction of their toxicity. We assume that our results will also be taken into account in the registration and approval of chemicals in the future,” say the two scientists.