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The news hasmade headlines on sport pages around the world. Both theFederation Internationale de Ski (FIS) and theUnion CyclisteInternationale (UCI) have implemented random blood tests prior tocompetition to deter the alleged use of DNA-recombinant humanerythropoetin (rhEPO), a hormone known to increase the rate of redblood cell production. These decisions have come after years offinger-pointing and unsubstantiated claims that some of the world'smost competitive cyclists and cross-country skiers are receiving anillegal performance advantage by injecting rhEPO. The governingbodies for these two endurance sports have decided upon slightlydifferent methods and cut-off values for screening blood samples.Whereas FIS have identified specific hemoglobin concentrations (16.5g/dl women; 18.5 g/dl men), the UCI have decided to use a 50%hematocrit for male cyclists.

Seiler (1997) has recentlyreported on blood testing cross-country skiers to deter the use ofrhEPO. This report will focus on similar issues faced by theinternational cycling community.

At their annual meeting in Geneva (24 January 1997), UCIdelegates, in consultation with medical professionals, decided toimplement blood testing to deter the alleged use of rhEPO byselecting a 50% hematocrit as an upper limit. In an article entitled"Cycling Pro's Saddled with Blood Tests" appearing in The European(30 Jan - 5 Feb, 1997), it was reported that random blood tests wouldbegin on March 22 at the Milan to San Remo Classic bike race. UCIpresident, Hein Verbruggen, has stressed that the testing is a "health check" and that a positive test does not imply rhEPO use. Thetesting has been primarily established to insure that professionalcyclists will not begin a major road race with a dangerously highhematocrit. In contrast to a positive drug test, which can result inprolonged suspension from competition, riders with a hematocritgreater than 50% would be suspended only until values decreased to anacceptable level. But are there data indicating that a 51% hematocritis dangerous for a professional road cyclist? And more importantly,what is the normal incidence of a hematocrit above 50% inprofessional cyclists not taking rhEPO? It appears that answers tothese questions are currently not available.

It is now well recognized that the uncontrolled use of rhEPO canbe dangerous. Within the first four years of rhEPO's introduction,this synthetic hormone was suggested to have caused over 17 athletedeaths (Ramotar, 1990). Some news reports are now suggesting thatover 20 competitive cyclists have died as a result of rhEPOadministration (The European, 12-18 Dec, 1996). Never-the-less,international competition is fierce and many competitive cyclistsdesire the financial gains and prestige associated with being achampion. Perhaps this is why the suspected incidence of rhEPO useamong professional cyclists in high. An article presented in TheEuropean (5-11 Dec, 1996) has summarized a controversial dossierprepared by Sandro Donati, an Italian professor of exercisephysiology. Donati's reports suggests that, "rhEPO was being used by60-70% percent of all professional cyclists." Additionally, thedossier presents the names of 21 professional riders including threewell known cyclists. Donati also names seven Italian sport doctorswho supposedly administered rhEPO to road cyclists for large annualfees ($50,000-$100,000). Some of those implicated have adamantlydenied allegations indicating that there is no proof to support theoutlandish claims.

Although the UCI should be congratulated for their efforts toprevent the illegal use of rhEPO, the 50% hematocrit limit(approximately 16.5 g/dl) may be too aggressive and result in manyfalse positive tests. The UCI cut-off is obviously much lower thanthe 18 g/dl hemoglobin limit selected by FIS. In response to a querymade by the Department of Physiology and Applied Nutrition at theAustralian Institute of Sport, the UCI explained that the 50% cut-offvalued was agreed to by sport doctors and team directors working forthe major professional cycling teams. The UCI explained that, a 53%hematocrit limit was initially proposed (based on three standarddeviations above the average hematocrit value for a normalpopulation) but then decreased to 50% to ensure that all professionalteam delegates were in agreement. Why would doctors with professionalcycling teams push for a lower detection limit? Maybe "clean" cyclingprograms want to insure that drug users will be caught or at least bemore limited with their illegal activities. Or perhaps there isevidence indicating that a 51% hematocrit is dangerous for enduranceathletes.

Unfortunately, the prevalence of a hematocrit greater than 50% inelite road cyclists not taking rhEPO is not well established.Additionally, the effects of body posture, dehydration and altitudetraining on the hematocrit of professional cyclists is not welldocumented. At theAustralian Institute of Sport , top Australian RoadCyclists (including five Professional Australian Cyclists who are nowracing in Europe) have participated in routine blood tests to monitorhealth and training stress. As part of the normal venous bloodanalysis, hematocrit is determined using routine laboratory equipment(a Coulter Counter). A retrospective analysis of 360 blood samplescollected from Australia's top road cyclists between 1987-1996resulted in 10 hematocrit values of 50% or more. Thus, 2.8% of bloodsamples from the Australian Road Cyclists exceed the 50% hematocritvalue recently set by the UCI as an acceptable limit. It is believedthat these cyclists were training and competing in a "cleanenvironment" at the time of testing. In other words, it is unlikelythat they were taking rhEPO. The maximum hematocrit 52.0%, recordedin one cyclist.

In a much larger data set (12,359 blood samples) that includingmale and female athletes participating in a variety of sports (e.g.,swimming, athletics, water polo, weight lifting, rowing, tennis,soccer, basketball, netball, gymnastics) 3.4% of blood samples had ahematocrit value greater than 50%. The percentage of hematocritscores greater than 50% is therefore similar between the Australiancyclists and other Australian athletes competitive at the nationallevel. A more detailed examination of the hematocrit data from allsports determined that the percentage of tests where hematocrit wasgreater than 50% ranged from 0.3% in netball to 25.7% in weightlifting.

Hematocrit reflects the balance between red blood cell productionand destruction but is also known to be influenced by dehydration andbody posture. Heart rate and blood pressure are higher when standingcompared to sitting or lying down. The higher blood pressure whenstanding is associated with the movement of intravascular fluid(i.e., plasma) into interstitial compartments. This causes plasmavolume to decrease and hematocrit to rise. Gore and Colleagues (1992)have reported a 6% decrease in plasma volume associated with 30minutes of standing following 30 minutes of sitting. The followingexample illustrates how body position could determine whether acyclist is disqualified or not based on the 50% hematocrit UCIruling. If a cyclist has a blood volume of 6.0 liters and ahematocrit when sitting of 49%, then the blood would be composed of2.94 liters of red blood cells and 3.06 liters of plasma. If thecyclist stands for 30 minutes and undergoes a 6% reduction in plasmavolume, hematocrit would now rise to 50.5% and under the new UCIruling the cyclist would be disqualified. It is worth noting, that atthe Australian Institute of Sport venipucture blood draws wereperformed on athletes in the morning in a fasted state afterremaining in a supine position for 5-10 minutes. If blood wascollected from the Australian cyclists in a seated or standingposition, it is likely that more than 2.8% of the blood samples wouldhave a hematocrit greater than 50%. In attempts to control forextraneous variables such as posture, the UCI has established thatblood will be taken from cyclists in the morning, before breakfast,in a seated position.

Techniques have been developed to test for rhEPO use but thus far,none have proven to be completely satisfactory for screeningathletes. Wide et al. (1995) have demonstrated that rhEPO can bedistinguished from endogenous EPO in both urine and serum samplesusing electrophoretic techniques. The electrophoretic technique isbased on the observation that endogenous EPO generally has a greaternegative charge than rhEPO. Although no false positive tests aredetected using this technique, it appears that the use of rhEPO canonly be confirmed up to three days after injections have stopped. Thesuccess of this technique would therefore depend upon random"out-of-competition" sample collections.

Another potential method for determining whether an athlete isusing rhEPO has been suggested by Casoni et al., (1993). Usingsophisticated scattering laser technology Bayer has introduced aseries of hematology analyzers that allow for red blood cell volumeand hemoglobin content to be evaluated on a cell by cell basis. TheTechniconBayer H*1, H*2, and H*3 analyzers allow for thedistribution of cell size to be plotted against cell hemoglobincontent resulting in a nine quadrant cytogram. Casoni and colleagues(1993) observed that the percentage of cells that were macrocytic(>120fl) and hypochromic (<28 pg) was greater than 0.6% only inthose subjects who underwent rhEPO therapy. A limitation to thistechnique was is that more than 0.6% macrocytic-hypochromic cellscould only be observed towards the end of, and for 10 days followinga 45 day course of rhEPO. Also, approximately 60% of rhEPO treatedsubjects tested below the 0.6% cut-off value.

Recently, Bayer Health Care Australia has entered into asponsorship agreement with the Sports Haematology and BiochemistryLaboratory at the Australian Institute of Sport. This sponsorship hasresulted in the acquisition of a Technicon H*3 analyzer which iscurrently being used to analyze athletes' blood. A retrospectiveanalysis of blood samples provided by 50 male endurance athletes (8swimmers, 12 cyclists, 30 rowers) was performed to evalute theincidence of macrocytic-hypochromic red blood cells. In all but onesample the percentage of macrocytic hypochromic cells was equal to orless than 0.2%. The highest value measured in this group was only0.3%. It should be noted that all of these athletes were testedduring the initial phases of a competitive season in the summer. Asmentioned by Wide and co-workers (1993), a combination of direct andindirect techniques will likely emerge in the near future to enablerhEPO use to be confidently detected.

The decision of the UCI to test the blood of professional cycliststo deter the use of rhEPO is admirable. However, the 50% hematocritlimit appears too aggressive on the basis of 10 years of datacollected from road cyclists tested at the Australian Institute ofSport. A 52% hematocrit limit would result in fewer false positivetests and could still deter the suspected use of rhEPO. While eliteathletes wait for sensitive rhEPO detection techniques to emerge,measurements of hematocrit may represent a temporary deterrent.However, prior to implementing blood testing for hematocrit it wouldseem worth while to carefully evaluate the cut-off level and alsoconsider the influence of body position, altitude training anddehydration on hematocrit values in professional cyclists. It is nowpossible that the leader in the Tour de France could be preventedfrom competing in the final stage because his hematocrit is"dangerously" high. With lucrative salaries at stake, it will beinteresting to see if the 50% hematocrit rule will last throughoutthe 1997 professional cycling season.

 
April 97. The UCI 50% Hematocrit rulehas been implemented at the 1997 Paris-Nice Road Race. Three out ofthe 20 professional cyclists tested registered hematocrit measuresgreater than 50%. Their fate? An individual fine of 1,000 SwissFrancs and a team fine of 10,000 Swiss Francs. In addition, theriders with the "dangerously high" hematocrits were removed fromcompetition for a period of 15 days. Erwan Mentheour (Fra, LaFrancaise des Jeux), Luca Colombo (Ita, Batik-Del Monte) and MauroSantaromita are the riders who have lost money and a chance to winUCI points in Paris-Nice despite any evidence of rhEPO use.

Martin, D. T., Ashenden, M., Parisotto, R., Pyne, D., Hahn, A. G.(1997). Blood testing for professional cyclists: what's a fairhematocrit limit?Sportscience News,(Mar-Apr),http://www.sportsci.org/news/news9703/AISblood.html

Casoni I., Ricci G., Ballarin E., et al. (1993). Hematologicalindices of erythropoietin administration in athletes.International Journal of Sports Medicine, 14, 307-311.

Gore C., Scroop G., Marker J., Catcheside P. (1992). Plasmavolume, osmolarity, total protein and electrolytes during treadmillrunning and cycle ergometer exercise.European Journal of AppliedPhysiology and Occupational Physiology, 65, 302-310.

Ramotar J. (1990). Cyclists' deaths linked to erythropoietin?Physician and Sports Medicine, 18, 48-49.

Seiler, S. (1997). Tighter control on EPO use by skiers.Sportscience News, (Jan-Feb),http://www.sportsci.org/news/news9701/EPOfeat.html

Wide L., Bengtsson C., Berglund B., and Ekblom B. (1995).Detection in blood and urine of recombinant erythropoetinadministered to healthy men.Medicine and Science in Sports andExercise, 27, 1569-1576.