Veterinary medicines and competition animals: the question of medication versus doping control.

Abstract: In racing and other equine sports, it is possible to increase artificially both the physical capability and the presence of a competitive instinct, using drugs, such as anabolic steroids and agents stimulating the central nervous system. The word doping describes this illegitimate use of drugs and the primary motivation of an equine anti-doping policy is to prevent the use of these substances. However, an anti-doping policy must not impede the use of legitimate veterinary medications and most regulatory bodies in the world now distinguish the control of illicit substances (doping control) from the control of therapeutic substances (medication control). For doping drugs, the objective is to detect any trace of drug exposure (parent drug or metabolites) using the most powerful analytical methods (generally chromatographic/mass spectrometric techniques). This so-called "zero tolerance rule" is not suitable for medication control, because the high level of sensitivity of current screening methods allows the detection of totally irrelevant plasma or urine concentrations of legitimate drugs for long periods after their administration. Therefore, a new approach for these legitimate compounds, based upon pharmacokinetic/pharmacodynamic (PK/PD) principles, has been developed. It involves estimating the order of magnitude of the irrelevant plasma concentration (IPC) and of the irrelevant urine concentration (IUC) in order to limit the impact of the high sensitivity of analytical techniques used for medication control. The European Horserace Scientific Liaison Committee (EHSLC), which is the European scientific committee in charge of harmonising sample testing and policies for racehorses in Europe, is responsible for estimating the IPCs and IUCs in the framework of a Risk Analysis. A Risk Analysis approach for doping/medication control involves three sequential steps, namely risk assessment, risk management, and risk communication. For medication control, the main task of EHLSC in the risk management procedure is the establishment of harmonised screening limits (HSL). The HSL is a confidential instruction to laboratories from racing authorities to screen in plasma or urine for the presence of drugs commonly used in equine medication. The HSL is derived from the IPC (for plasma) or from the IUC (for urine), established during the risk assessment step. The EHSLC decided to keep HSL confidential and to inform stakeholders of the duration of the detection time (DT) of the main medications when screening is performed with the HSL. A DT is the time at which the urinary (or plasma) concentration of a drug, in all horses involved in a trial conducted according to the EHSLC guidance rules, is shown to be lower than the HSL when controls are performed using routine screening methods. These DTs, as issued by the EHSLC (and adopted by the Fédération Equestre Internationale or FEI) provide guidance to veterinarians enabling them to determine a withdrawal time (WT) for a given horse under treatment. A WT should always be longer than a DT because the WT takes into account the impact of all sources of animal variability as well as the variability associated with the medicinal product actually administered in order to avoid a positive test. The major current scientific challenges faced in horse doping control are those instances of the administration of recombinant biological substances (EPO, GH, growth factors etc.) having putative long-lasting effects while being difficult or impossible to detect for more than a few days. Innovative bioanalytical approaches are now addressing these challenges. Using molecular tools, it is expected in the near future that transcriptional profiling analysis will be able to identify some molecular "signatures" of exposure to doping substances. The application of proteomic (i.e. the large scale investigation of protein biomarkers) and metabolomic (i.e. the study of metabolite profiling in biological samples) techniques also deserve attention for establishing possible unique fingerprints of drug abuse.