ToxSci Advance Access published online on November 28, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm291
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Effects and interactions in an environmentally relevant mixture of pharmaceuticals
1 School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney, Australia 2 Department of Clinical and Biological Sciences, University of Insubria, Varese, Italy 3 Department of Biomedical, Experimental and Clinical Sciences, University of Insubria, Varese, Italy 4 Department of Environmental Health Sciences, "Mario Negri" Institute for Pharmacological Research, Milan, Italy
* To whom correspondence should be addressed. Phone: +612 9385 3659. Fax: +612 9385 1591. E-mail: f.pomati{at}unsw.edu.au
Received October 9, 2007; revision received November 25, 2007; accepted November 26, 2007
 |
Abstract |
|---|
With the goal of assessing the environmental risk of pharmaceuticals we have previously observed that a mixture of thirteen different drugs at environmentally relevant concentrations had adverse consequences on human and zebrafish cells in vitro. Here we aimed to identify both main and interaction effects within the same environmentally relevant mixture of pharmaceuticals. We studied in vitro cytotoxicity in E. coli, human embryonic HEK293 and oestrogen-responsive OVCAR3 tumour cells using fractional-factorial experimental design. Our approach identified a subset of compounds of primary environmental concern, namely atenolol, bezafibrate, ciprofloxacin, and lincomycin, that had statistically significant effects on prokaryotic and eukaryotic cells at environmentally relevant exposure levels (ng/L). Drugs could interact and behave as chemosensitisers, with joint-effects representing a statistically significant element of mixture toxicity. Effects and interactions were concentration-dependent, confirming the difficulty of dose-extrapolation in mixture toxicity data. This study suggests that a thorough investigation of mixture effects can direct environmental concerns towards a handful of pharmaceuticals, which may represent an actual risk at environmental concentrations. We indicate that risk identification may strongly depend on the use of environmentally relevant exposure scenarios. Antagonistic/synergistic interactions and dose-dependency of effects may hamper the modelling and prediction of mixture toxicity with pharmaceuticals. Hazard identification for micropollutants depends heavily on appropriate study designs, and we indicate the use of in vitro cytotoxicity threshold and statistical design of experiments as a valid approach.
Key Words: E. coli; HEK293; interaction; mixtures; OVCAR3; pharmaceuticals.