### Archive

Posts Tagged ‘doping’

Alberto Contador has tested positive for the banned substance clenbuterol. Contador claims that the positive test result was a result of food contamination and that he did not deliberately take the drug.

In this blogpost I do the pharmacokinetics calculation to see if Contador’s claim is feasible. My calculation is limited to this specific test result.

Here are some facts relevant to the case:

• Contador tested positive for clenbuterol on the 21st July, with a urine concentration of 50 picograms per millilitre (see UCI press release)
• A picogram is a very small amount, a millionth of a millionth of a gram.
• The UCI has said further scientific investigation is required before any conclusion could be drawn.
• Tests on July 19th and 20th showed no traces of the drug. After finding 50pg/ml on the 21st, Contador’s sample from the next day showed 20pg/ml and then only traces on the following two days.
• In the European Union, it is illegal to use clenbuterol in animal feed.
• Nevertheless some farmers use clenbuterol, since it increases the lean yield of livestock
• There have been of cases of human clenbuterol poisoning from contaminated meat. These have occurred in both pork and beef and in various countries including Spain, France, Ireland, Mexico, and China. The European cases occurred in the 1990s. (see Tainted Meat: Clenbuterol use in the meat industry)
• There have been no recent cases of human clenbuterol poisoning in the European Union.
• In the European Union it is legal to use clenbuterol as a tocalytic (that is to surpress premature labour) in cattle.

So could Contador’s test result be due to contaminated food? We can do a calculation to find out. Given the concentration of clenbuterol in Contador’s urine we make an estimate of how clenbuterol much was ingested. We can then compare this estimate with the residue levels of clenbuterol in contaminated meat and the therapeutic dosages of clenbuterol and thus decide which is more likely: cheat or bad meat.

According to “Clenbuterol Residues in Bovine Feed and Meat” (see reference 1) clenbuterol levels in contaminated beef (in Mexico) have values in the range 0.1 to 2.3 micrograms of clenbuterol per kilogram of meat. So a 100g piece of steak could contain between 0.01 and 0.23 micrograms, that is between 10 and 230 nanograms, of clenbuterol. Contamination levels may of course differ in European meat.

The European Union Maximum Residue Limit (MRL) for clenbuterol is 0.1 microgram per kilogram for bovine muscle and 0.05 microgram per kilogram for bovine milk. So a 100g piece of steak could legally contain up to 0.01 micrograms, that is 10 nanograms, of clenbuterol.

Therapeutic dosages of clenbuterol are in the range of 20 to 80 micrograms per day (that is 20,000 to 80,000 nanograms).

According to my calculation (full workings at end of blogpost), Contador ingested approximately 540 nanograms of clenbuterol. This is slightly higher than expected if Contador ate contaminated meat, but much much less than if Contador had taken a therapeutic dose of clenbuterol. This dosage is much higher than could be obtained from meat that complied with EU regulations.

### Conclusions

The amount of clenbuterol ingested by Contador (540 nanograms) is consistent with his assertion that he ate contaminated meat.

This amount is only 1/40th of the theraputic dose, and so seems unlikely to have resulted in any performance benefit.

On this occasion, I am inclined to believe Contador’s story.

There have been suggestions in the press that Contador’s positive test is the result of an autologous blood transfusion (blood doping) – that is he re-infused so of his own blood that was collected earlier in the year – and that this blood contained clenbuterol. This is indeed possible, but autologous blood transfusions can be detected in a blood test, and, as winner of the Tour de France, Contador would undoubtably have been subjected to a blood test. My assumption is that if the UCI had detected blood doping, then they would have already released the test results. To clarify this matter, the UCI should make a formal statement and publish the results of any such blood tests.

### Update – Sunday 3rd October 2010

There are currently three proposed explanations for Contador’s positive drug test:

2. Contador inadvertently took clenbuterol as a result of eating contaminated meat.
3. Contador had a blood transfusion and the clenbuterol was in the tranfused blood.

The calculations in this blog post show that it is unlikely that Contador deliberately took clenbuterol, and that it is feasible that eating contaminated meat could have resulted in his test result (namely urine with a concentration of 50 picograms/millilitre).

There remains the question of the blood transfusion. Nowadays it is possible to detect if someone has had a blood transfusion, whether that transfusion is autologous (from one’s own blood) or homologous (from someone else’s blood). We know that cyclists are tested to see if they have had blood transfusions – Alexander Vinokourov was tested positive in 2007. I see four possibilities:

1. Contador was tested for blood doping and the result was positive.
2. Contador was tested for blood doping and the result was negative.
3. Contador was tested for blood doping and the result was inconclusive.
4. Contador was not tested for blood doping.

Contador himself has denied receiving blood transfusions

The UCI and the World Anti-Doping Agency have refused to comment on L’Équipe’s story that raises the possibility of blood doping.

In my view the UCI’s reticence on the blood doping issue is inexcusable. Both in fairness to Contador and for their own credibility they must release the results of any blood doping tests they have made on Contador.

### References

1. Clenbuterol Residues in Bovine Feed and Meat (Research Journal of Biological Sciences)
2. Pharmacokinetics of plasma and urine clenbuterol in man, rat, and rabbit (PubMed)
3. Tainted Meat: Clenbuterol use in the meat industry (Serendip)
4. Press release – Adverse analytical finding for Alberto Contador (UCI press release)
5. Contador maintains innocence (The Press Association)
6. Maximum Residue Limits, Clenbuterol (European Agency for the Evaluation of Medicinal Products)
7. Contador’s scientific expert De Boer details defense (Cycling News)

### Calculation

From reference [2] we know that after ingesting clenbuterol reach a maximum level after 2.5 hours, remain at this level until 6 hours after ingestion. From this, and assuming that the rate of drug removal by the kidneys is proportional to its plasma concentration, we can model the concentration C of clenbuterol at time t (given in hours) in the urine as:

$C(t) = \left\{ \begin{array}{l l l} mt & \quad \mbox{0} \le {t} \le {2.5} \\ 2.5m & \quad \mbox{2.5} \le {t} \le {6.0} \\ 2.5me^{-k(t-6)} & \quad \mbox{t} \ge {6.0} \end{array} \right.$

The half life of clenbuterol in blood plasma is approximately 35 hours, so:

$k = \frac{ln(2)}{35} = 0.01980$

The cumulative urinary excretion is 20% of the dose, D after 72 hours, so:

$\int_{0}^{72} C(t)\: \mathrm{d}t = 0.2D$

that is

$D = {5}\left(\int_{0}^{2.5} mt\: \mathrm{d}t + \int_{2.5}^{6} {2.5}m\: \mathrm{d}t +\int_{6}^{72} {2.5}me^{-k(t-6)}\: \mathrm{d}t\right)$

$\quad = {5}\left[{0.5}mt^{2}\right]_{0}^{2.5} + {5}\left[{2.5}mt\right]_{2.5}^{6} + {5}\left[\frac{-2.5m}{k}e^{-k(t-6)}\right]_{6}^{35}$

so

$D = 378.63m \quad (equation 1)$

Let’s assume Contador’s urine sample was taken 24 hours after ingestion of the clenbuterol and consists of the urine produced in the previous hour. Then, assuming a typical urine production rate of 50ml/hour, the quantity of clenbuterol excreted, per ml of sample, E is given by:

$E = \frac{1}{50}\int_{23}^{24}C(t)\: \mathrm{d}t$

$\qquad = \frac{1}{50}\int_{23}^{24} {2.5}me^{-k(t-6)}\: \mathrm{d}t$

$\qquad = \left[\frac{-m}{20k}e^{-k(t-6)}\right]_{23}^{24}$

so

$E = 0.03536m \quad (equation 2)$

We know Contator’s test result – his urine sample contained 50 picograms per ml, this allows us to solve equation 2 for m and feed the result back into equation 1 to obtain the approximate dose of clenbuterol ingested by Contador. This gives an approximate dosage of 535,400 picograms, that is 540 nanograms (rounded).

Disclaimer: I’m a mathematician, not a medic or a pharmacologist. The above calculations have not been independently reviewed, so there may be errors in the model or the calculations. If you find any errors, please let me know and I will correct them.