Pharmacodynamic activity of drugs and ecotoxicology--can the two be connected?
Therapeutic agents, active substances as well as metabolites, have been detected in the environment, notably in the aquatic compartment. Such contamination may induce adverse environmental effects, and the question is, whether respective hazards could be deduced from their pharmacodynamic properties and activities, and whether there could indeed be relevant risks at the (very low) environmental concentrations observed. While it would seem that, in many cases, the concentrations of drugs needed to elicit pharmacodynamic responses will exceed the environmental concentrations by factors in the range of 10(4)-10(6), and while, furthermore, pharmacodynamically-mediated influences by drug residues on eco-organisms are possible only if the pharmacodynamic target (enzyme, receptor) is expressed and functionally active in some way in the respective eco-organism, such considerations should not, however, deflect from the fact that the specificities of drug substances are defined in terms of the human target structures, and that other organisms may exhibit different specificity profiles. Examples of such species specificities are discussed in this paper and lead to the conclusion that, on the one hand, pharmacodynamic effects, classified as secondary and considered irrelevant for the therapeutic activity in humans, might potentially play a major role in other (non-mammalian) eco-organisms, and that, on the other hand, the--"anthropocentrically" defined--primary pharmacodynamic activities of drugs could induce effects in (non-mammalian) eco-organisms totally different from the therapeutic effects. It is further argued that even slight, non-significant influences on single components within regulatory cascades, like cellular division or signal transduction, that would not result in any acutely discernible effect, might ultimately, through sequential propagation or through interaction with additional, unrelated factors, affect a whole population by its negative consequences on fitness: disturbances in hormonal homeostasis ("endocrine disruption"), in immunological status, in signal transduction or gene activation may serve as examples. From these considerations it is concluded that a more "mechanism-based" approach to the experimental investigation of potential environmental hazards through the contamination of, especially, the aquatic compartment by drug residues should therefore yield more meaningful results and insights than the indiscriminate use of a standard battery of ecotoxicology assays.
Seiler
Jürg P
JP
Swissmedic, Swiss Agency for Therapeutic Products, Erlachstrasse 8, CH-3000 Bern, Switzerland. juerg.seiler@swissmedic.ch
D000818:Animals; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D004784:Environmental Monitoring / Q000379:methods*; D004785:Environmental Pollutants / Q000493:pharmacokinetics* / Q000633:toxicity; D006801:Humans; D019055:No-Observed-Adverse-Effect Level; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D018570:Risk Assessment
D004785:Environmental Pollutants; D004364:Pharmaceutical Preparations