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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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« Hobson's Choice | Main | A Law of the Lab: Yields and Variations »

August 1, 2006

Testosterone, Carbon Isotopes, and Floyd Landis

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Posted by Derek

The New York Times broke the story today that the testosterone found in Tour de France champion Floyd Landis's blood was not from a natural source. Just how do they know that, and how reliable is the test?

The first thing an anti-doping lab looks for in such a case is the ratio of testosterone to the isomeric epitestosterone - too high an imbalance is physiologically unlikely and arouses suspicion. Landis already is in trouble from that reading, but the subject of the Times scoop is the isotopic ratio of the testosterone itself. And that one is going to be hard to get away from, if it's true.

Update: people are asking me why athletes don't just take extra epistestosterone to even things out. That they do - that's the most basic form of masking, and if Landis's ratio was as far off as is being reported, it's one of the odd features about this case. But the isotope test will spot either one, if it's not the kind your body produces itself - read on.

Steroids, by weight, are mostly carbon atoms. Most of the carbon in the world is the C-12 isotope, six protons and six neutrons, but around one per cent of it has an extra neutron to make it C-13. Those are the only stable isotopes of carbon. You can find tiny bits of radioactive C-14, though, and you can also get C-11 if you have access to a particle accelerator. Work fast, though, because it's hot as a pistol.

So, testosterone has 19 carbon atoms, and if on average every one out of a hundred carbon atoms is a C-13, you can calculate the spread of molecular weights you could expect, and their relative abundance. One out of every ten thousand molecules would have two C-13 atoms in there somewhere, one out of every million or so would have three, and so on. A good mass spectrometer will lay this data out for you like a deck of cards.

But here's the kicker: those isotopic forms of the elements behave a bit differently in chemical reactions. The heavier ones do the same things as their lighter cousins, but if they're involved in or near key bond-breaking or bond-making steps, they do them more slowly. It's like having a heavier ball attached to the other end of a spring. This is called a kinetic isotope effect, and chemists have found all sorts of weird and ingenious ways to expoit it. But it's been showing up for a lot longer than we've been around.

The enzymatic reactions that plants and bacteria use when they take up or form carbon dioxide have been slowly and relentlessly messing with the isotope ratios of carbon for hundreds of millions of years. And since decayed plants are food for other plants, and the living plants are food for animals, which are food for other animals and fertilizer for still more plants. . .over all this time, biological systems have become enriched in the lighter, faster-reacting C-12 isotope, while the rest of the nonliving world has become a bit heavier in C-13. You can sample the air next to a bunch of plants and watch as they switch from daytime photosynthesis to nighttime respiration, just based on the carbon isotope ratios. Ridiculously tiny variations in these things can now be observed, which have led to all sorts of unlikely applications, from determining where particular batches of cocaine came from to figuring out the dietary preferences of extinct herbivores.

So, if your body is just naturally cranking out the testosterone, it's going to have a particular isotopic signature. But if you're taking the synthetic stuff, which has been partly worked on with abiotic forms of carbon derived from a different source (see below), the fingerprints will show. (Update: yes, this means that the difference between commercial testosterone and the body's own supply isn't as large as it would be otherwise, since the commercial synthesis generally starts from plant-derived steroid backbones. But it's still nothing that a good mass spec lab would miss). If the news reports are right, that's what Landis's blood samples have shown. And if they have, there seems only one unfortunate conclusion to be drawn.

Chem-Geek Supplemental Update: for the folks who have been wondering where exactly the isotopic difference comes in, here's the story: synthetic testosterone is made from phytosterol percursors, typically derived from wild yams or soy. Those are both warm-climate C3 plants, which take up atmospheric carbon dioxide by a different route than temperate-zone C4 plants, leading to noticeably different isotope ratios. That's where all the isotope-driven studies of diet start from. The typical Western industrial-country diet is derived from a mixture of C3 and C4 stocks, so the appearance of testosterone with a C3-plant isotopic profile is diagnostic.

Comments (300) + TrackBacks (0) | Category: Analytical Chemistry | Current Events


COMMENTS

1. T Rivard on August 1, 2006 10:22 PM writes...

I don't trust the french labs. If Landis loses, who wins? I believe that Landis earned it fairly and is being set up.

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2. Process Wannabe on August 1, 2006 10:37 PM writes...

My question is about some comments Landis' physician made, how taking synthetic testosterone would be pretty pointless for a competative cyclist. His argument that the testosterone would only help build muscle mass, but wouldn't help the type of endurance competition found in the Tour de France. He also pointed out that taking a shot of testosterone during the competition would not give the sort of "pick-me-up" seen in Landis' miracle come-back. Because of these points, he says that there'd be no benefit to the testosterone, so that was his evidence for Landis' innocence. What sort of validity do these claims have?

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3. Jumbo on August 1, 2006 10:44 PM writes...

A little less vociferously than T, I would nonetheless ask those reading who are isotopically inclined, what is the actual reliability of the isotope assay? I find it a strange coincidence that two internationally prominent athletes (Landis and the sprinter Gaitlin) turn up testosterone postive in the same week. These are athletes that have a remarkably sophisticated understanding of the physiological effects of steroids. Unless Landis has made a startling breakthrough, taking exogenous testosterone 4 days before the end of the Tour would be extremely unlikely to have a beneficial effect on performance. Derek himself has shown that assay reproducibility (the notorious vial 33) is hard to come by. But likewise, having 2 assays agree is not a guarantee that the positive result is true. It all just seems strange to me...

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4. GC on August 1, 2006 11:32 PM writes...

Carbon in testosterone is ultimately derived from acetate, which comes from any number of sugars (or amino acids, occasionally). Who's to say he wasn't taking some snake-oil supplement (say, synthetic D-ribose or amino acids) and it didn't make its way in through the pentose phosphate pathway, transaminases, etc?

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5. Justin on August 1, 2006 11:39 PM writes...

I cant help but think that Mr Landis has put himself in this mess by his own actions.

If he did administer or was administered testosterone, then he is a fool who deserves to be caught and banned. Unfortunately, I think we will never know the truth about this point. After all, Mr Landis is hardly gonna stand up and say 'I did it' while there are other defenses around.

And speaking of other defences, what if Mr Landis' claim of elevated testosterone levels due to alcohol consumption is true? Who administered the alcohol? Mr Landis. Who claims that he has a history of high T/E ratios? Mr Landis. Who is an elite athelete with knowledge of his elevated T/E ratios and, more than likely, a knowledge of the effects of alcohol on that ratio? Mr Landis. If this latter point is in doubt (concerning Mr. Landis' knowledge of the effects of alcohol on T/E ratios), then who is surrounded by people who could advise/warn/caution on the use of alcohol during competition? You guessed it - Mr. Landis.

Mr Landis drank the alcohol himself. However, I severely question his wisdom of doing this during a big race AND the collective wisdom of his team for letting him do it! I also find it hard to believe that his team bosses and doctors and dieticians and whoever else helps Mr Landis with his elite training would not have warned him about the risks of drinking too much alcohol during a competition - especially with the already documented effects that alcohol can have on human physiology! Are we to understand that Mr. Landis sat and drunk alone that fateful night? That nobody knew what he was doing? And if he was alone, then I go back to the previous point about the wisdom of drinking alcohol during a competition.

A knowledge of the drug testing rules and regulations MUST be know by someone in a professional cycling team, especially given the number of scandals abounding in this sport. The knowledge MUST be passed onto the riders for their own protection. Those riders MUST understand the risks involved with putting things into their bodies - illegal or otherwise.

This whole issue is a sorry state of affairs for everyone involved AND the sport of pro cycling. But the rules and regulations are clear and available to see for all concerned. As are the consequences.

Im afraid Mr Landis has to take some responsibility for the sticky situation he finds himself in.

Although 'innocent until proven guilty' is a legal principal, cannot the same be said about 'ignorance of the law is no defence against breaking the law'....?

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6. dopingbust on August 2, 2006 12:14 AM writes...

American cyclists continue to dominate the Tour, and, the French, as well as others will continue to contest with allegations of wrongdoing. Floyd kickes the French and Spanish asses of those on the tour, whether he loses the title or not, we know he beat them all. Period.

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7. Louise on August 2, 2006 3:17 AM writes...

what I would like to know....why don't the dopesters also ingest epitestosterone?

Is it possible?

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8. jojo on August 2, 2006 4:54 AM writes...

Boohoooo it's the french's fault, they hate us, Floyd is innocent, he's not a cheater, we are the best
Hahahahahahahahahahahahahah
Pathetic
but very funny

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9. bob on August 2, 2006 6:34 AM writes...

1. If you can clearly test for synthetic testosterone, why bother doing a ratio test for high levels. Wouldn't they just test for the synthetic substance?

2. How can you raise your "natural" levels of testosterone in an illegal manner?

These seem like the real questions to me?

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10. Realist on August 2, 2006 6:48 AM writes...

The nationaliy of Landis is irrelavant. He failed the test and should be punished accordingly.

All the talk of conspiracies on this page are as embaressing and outlandish as the list of excuses Landis has trotted out so far.

As the saying goes, 'love is blind'.

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11. Still Scared of Dinosaurs on August 2, 2006 7:22 AM writes...

The simplest answer would be that he was unwittingly dosed with an agent that was very likely to show up in testing. I've been expecting this to happen for real some time-imagine what would happen if you could hit the right players from an NFL or MLB team and bet against them.
I've also been expecting this to be used as an excuse, valid or not, but haven't seen it yet.
What I don't understand is why we don't have unmasking agents for commercially available drugs like steroids, with greatly increased penalties for possession of drugs without the markers. There was a (sort of) precedent for this once where explosives had microscopic inclusions that would identify the production lot, but the industry had the law mandating them overturned.

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12. MTK on August 2, 2006 7:37 AM writes...

I really don't care whether Landis is innocent or not, becuase I think the whole system is a sham. The definition of cheating vs. advanced training and nutrition is so arbitrary it means nothing. Throw in the fact that the testing labs and agencies themselves seem to be up to shenanigans and you've got a total snakepit. If you don't believe me then read the Dutch arbiter's report which exonerated Armstrong in the latest EPO allegations. It's a farce.

More to the science point. I still don't quite understand the isotope thing. For one thing, I'm assuming that synthetic testosterone is actually semi-synthetic made from some sterol from yams, soybeans, or something, so wouldn't it also be deficient in 13C? The other thing is let's say that synthetic testosterone is enriched in 13C, and let's say in theory this whole thing works, how was the doping control test validated? Did they actually shoot some people up, take urine samples, and do blind studies?

Wondering,
MTK

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13. J'hn1 on August 2, 2006 7:45 AM writes...

Well, the "markers" or taggents, are included in civilian explosives. They were to be included in certain compounds that could easily be used to make explosives.
Fertilizer.
The markers in question did not break down in the soil, and the proponents admitted that they could not guarantee that the taggents would not end up contaminating the entire US food supply.The supporters also were not willing to assume the liability for their doing so.

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14. Phil-Z on August 2, 2006 7:51 AM writes...

The carbon isotope ratio has been used to determine if a food additive or vitamin is "natural" or "not" for at least a decade. It's easy enough to get around if you start with non petrochemical feedstocks and let fermentation do a lot of your work for you. Pretty clever, using this to spot doping.
I doubt he could have consumed enough C-13 enriched food to make a difference without it killing him. No doubt everyones already heard the old tale about the "deuterated dog" experiment and understands the enzyme kinetics implications of using "heavy" food.
(Supposedly a mug of D2O coffee would be enough to kill someone and would be nearly undetectable. I await publication of the murder mystery featuring this plot device. Mass Spectroscopists finally star!)
If as stated above testosterone would have no noticable effect and if he's really a big time social drinker it would have been trivial to slip him some when he was at a bar.

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15. Pat Rand on August 2, 2006 7:59 AM writes...

Interesting that the "doping" showed up only on the single most spectacular leg of the event. I thought that these compounds were more persistent in the bloodstream...traceable even several days after an event. Also, aren't the heavier carbon isotopes more abundantly available in the atmosphere, especially at higher elevations?

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16. Hmmm on August 2, 2006 8:02 AM writes...

Some rumors are circulating that he wasn't purposely using testerone. Instead he was blood doping (which they do not have a test for) and used a bag from earlier in the year when he was using testerone on accident. Would this be possible?

If so it would explain why he used it when there was no apparent benefit to using it.

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17. Kenneth Payne on August 2, 2006 8:05 AM writes...

Hi

Excellent piece--very informative and clearly written. You should consider writing one of those popular science books that I can't get enough of. The world could benefit from another Timothy Ferris.

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18. Process Chemist on August 2, 2006 8:10 AM writes...

The entire sport of cycling is a fraud. 100% of the athletes running the big races are under some sort of performance enhancing treatment or drug.

These guys put their bodies in the hands of doctors who tell them what they have to take. If everything goes well, the doctors will get their doses right and the tests will be negative. One little screw up will make news headlines and all the guilt will be placed on the athlete, ruining his career.

If you ask me, let's just ban competitive cycling, for the sake of those poor guinea pigs.

Defending Landis just because he's American and claiming a French conspiracy is just plain pathetic.

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19. Bryan on August 2, 2006 8:13 AM writes...

In response to Justin; It is a common practice for cyclists to have a few drinks after a stage win or defeat. Read any cyclists book and you will almost always find a paragraph or two about the "Night at the bar".

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20. Realist on August 2, 2006 8:22 AM writes...

Please can everyone stop this "The simplest answer would be that he was unwittingly dosed...", "it would have been trivial to slip him some when he was at a bar.." and so forth.

The simplest answer is that he cheated and was caught.

People may not like it, but the facts are he failed a test.

Like Millar and Virenque before him, he'd be doing himself and the sport a great favour by admitting to his mistake. Sadly from his actions to date and these posts, it seems denial is part of the American psyche.

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21. Brian Moore on August 2, 2006 8:33 AM writes...

Thank you for your lucid, infomative, and entertaining explanation of Landis's problem.

I used to be a literary agent, years ago. If you had the right idea, I'm pretty sure you could sell a mass market oriented science book. You can flat-out write, which is rare in your field.

Good luck to you.

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22. davod on August 2, 2006 8:43 AM writes...

How many times did the authorities accuse the other American champion (sorry, I am not a fan of cycling) of using drugs. I beleive it was something like six times?

Initially, everyone was saying this cyclist must be guilty as this was the simplest solution. He was not guilty.

I am sceptical of any drug testing.

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23. Bryan on August 2, 2006 8:43 AM writes...

I’m not saying that some one slipped him something in the bar. But if alcohol does have an effect then we should wait until the B test is released. If he is guilty then strip him of the win and ban him from the sport, not just for two years but permanently! I think that we are too lenient on professional athletes; if they are caught then they should be banned for life. Taking their lively hood might make the rest of them stop and think before they try to chemically enhance their performance.

As far as Floyd is concerned I think we should wait for the results. Too many times, especially in cycling, these tests have been overturned.

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24. PharmaChemist on August 2, 2006 8:46 AM writes...

Like MTK (post #12 above), I still don't quite understand why supplemental T would have a different isotope level than endogenously produced testosterone. Isn't the feedstock for synthetic/semi-synthetic testosterone obtained from a plant or animal? Or is it a petroleum-based feedstock? Clearly the links that Derek refer to show that there is a difference in the isotopic ratios but I don't understand why this would be unless the synthetic T is derived from a non-living feedstock.

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25. grayp on August 2, 2006 9:00 AM writes...

I am the last person on the planet qualified to comment on the chemistry/biology involved. But there is one aspect of all this that really befuddles me.

Why on earth would Landis (or anyone else, for that matter) knowingly take a banned drug/supplement they knew would be detected in mandatory testing?

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26. Ron Nelson on August 2, 2006 9:00 AM writes...

In response to Justin (post #5), it must be remembered that Floyd had "lost" the Tour in Stage 16. So what was the harm (thinking at the time) of doing a bender? This would not have been an issue if Floyd's "what the hell" ride in Stage 17 had been contested earlier by the teams that were leading after Stage 16. It's easy to see now what a mistake it was to drink away the blues, but at the time no one thought there was anything to lose.

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27. ian on August 2, 2006 9:00 AM writes...

I appreciate the article. It is my understanding that Landis' prior and subsequent tests at the Tour were normal. Is that explainable?

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28. Ed Minchau on August 2, 2006 9:10 AM writes...

Fact is, Landis made it from point A to point B faster than anyone else. As MTK (#12) pointed out, the difference between cheating and advanced training and nutrition is trivial. The only problem with Landis is that he got caught. The only reason Florence Griffith-Joyner kept her gold medal was that she didn't get caught (although the mustache should have been a dead giveaway).

To hell with it. If atheletes want to juice up, let them. Who cares if they kill themselves doing it? They are only there for our amusement anyhow.

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29. JBass on August 2, 2006 9:22 AM writes...

I'm an analytical/physical chemist. Derek, do you have any links to papers that actually show mass spectrograms which differentiate synthetic and natural testosterone?

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30. Bryan on August 2, 2006 9:26 AM writes...

Ed, you are right; they are there for our entertainment, and so what if they kill them selves. But if you let it happen then you are telling the future generations of athletes that they will have to do it to compete. I don’t want any of the kids in my family to think that the only way to win is to juice up. By the way, at least she shaved before she took the podium!

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31. absorber on August 2, 2006 9:29 AM writes...

Does anyone know about the skin absorbability of this stuff? It makes a difference if you start examining the sabotage possibilities. You see these guys getting cups from fans at the side of the road amd then dumping it over their backs to cool off.

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32. Reid on August 2, 2006 9:35 AM writes...

Agree with #21. This was well written.

To others on both sides, you are not compelled to reach a verdict before all the evidence is in. Yes, he could have been set up. Yes, he could be guilty. Let's just wait and see, huh?

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33. RKN on August 2, 2006 9:36 AM writes...

Derek, Curious minds wonder alike. ;-)

...

  what is the actual reliability of the isotope assay?

Evidently pretty reliable.

  The entire sport of cycling is a fraud. 100% of the athletes running the big races are under some sort of performance enhancing treatment or drug.

Your evidence for this is where?

  I still don't quite understand why supplemental T would have a different isotope level than endogenously produced testosterone.

Endogenously produced T is a metabolic derivative of cholesterol (in eukaryotes) which, as I understand it, has a certain c13/c12 ratio in every individual. Hence, endogenous T will also have this ratio. Synthetic forms of T are, I think, depleted in their c13 content. If synthetic forms of T are present in the overall pool of T in your urine, the expected ratio of c13/c12 will be different than expected (i.e. if it was all endogenous), and this can be detected on a decent mass spectrometer.

  2. How can you raise your "natural" levels of testosterone in an illegal manner?

That seems irrelevant at this point, since the CIR test concluded exogenous testosterone was present. The puzzling question that remains is why Landis would dope himself the night before stage 17 when, by most reports, it would do nothing to improve his performance on the bike the next day. I did read one report that claimed a BIG spike in testosterone could have swift effects, but I haven't seen this corroborated.

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34. UncleHoot on August 2, 2006 9:39 AM writes...

Cortisone injections?

Floyd Landis admits that he was taking daily cortisone injections. Presumably, this is a synthetic drug and would show the same elevated levels of Carbon 13. It's strange that I haven't even heard this mentioned.

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35. Another Bob on August 2, 2006 9:41 AM writes...

While the biochemistry discussion is interesting, the two main points remain unaddressed.

One (as someone asked above), why would Landis take something that he *knew* would be detected?

Two, can chain-of-custody of the samples be reliably documented?

A third point might be to ask whether the testing process is as cut-and-dried as is suggested here. I have my doubts, but am not qualified to pursue it.

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36. PCT on August 2, 2006 9:47 AM writes...

In your final paragraph, you discuss "warm-climate C3 plants" and "temperate zone C4 plants." This is new terminology to me. Could you point to a reference?

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37. Jeff on August 2, 2006 9:47 AM writes...

Testosterone can be absorbed through the skin (in a non estered form), just look up male hormone replacement therapy and Androgel.

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38. RKN on August 2, 2006 9:54 AM writes...

  Floyd Landis admits that he was taking daily cortisone injections. Presumably, this is a synthetic drug and would show the same elevated levels of Carbon 13. It's strange that I haven't even heard this mentioned.

The molecular mass of cortisone and testosterone are different (~290 vs ~360). I think the ion products on the mass spec would therefore be differentiable, as would the respective c13/c12 ratios in the two.

It is not simply a matter of measuring the total amount of c13 in the urine sample, it's the ratio of c13/c12 in testosterone, *specifically*, that's of interest.

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39. Sam on August 2, 2006 10:02 AM writes...

#33: It was well known that Landis was receiving cortisone injections--it had been previously cleared with the race authorities. The cortisone injections were for his hip, Landis is suffering from osteonecrosis, a degenerative bone condition, caused by a crash from several years ago. He needs and intends to get a hip replacement later this year.

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40. Bryan on August 2, 2006 10:05 AM writes...

Nobody sabotaged him, nobody set him up. There are only two answers; He is either really stupid and juiced, or the test results were misleading. Either way we will not know until Saturday when the B Test results are published.

I personally hope that he is cleared of the charges, although at this stage it will always be remembered as a tainted victory.

If he is innocent then it was probably the single greatest comeback in sports history, if he is guilty, then take the win away and ban him for life.

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41. ajfakjw4e3tjh21 on August 2, 2006 10:06 AM writes...

Why would anyone who knows he will be tested take anything that would disqualify him?

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42. Bryan on August 2, 2006 10:11 AM writes...

Fame and fortune make otherwise smart people do stupid things. Just look at baseball.

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43. Derek Lowe on August 2, 2006 10:14 AM writes...

Here are some literature references, as requested. For mass spectra of testosterone, see J. Chromatog. B (2006), 831(1-2), 324-327; Current Organic Chemistry (2005), 9(9), 825-848; and J. Chromatog. A (2005), 1067(1-2), 323-330. Note that that last reference applies to doping in cattle!

For C3-C4 plants and photosynthesis, see here and here from Wikipedia, and here as well.

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44. mike on August 2, 2006 10:18 AM writes...

The whole issue of 'cheating' is meaningless. Who cares? Right now some people luck into having a superior genetic profile for a given sport.

One guy might naturally produce more testosterone or be more efficient at using oxygen. Why shouldn't somebody else use modern biochem to even the playing field?

As has been pointed out: the difference between 'cheating' and good training and nutrition is meaningless -- it's all about modifying and optimizing your biochemistry. And the biggest 'cheat' of all is the starting genetic lottery.

Sports should just let people inject whatever they want and try to publish any known negative long term health consequences, so athletes can make more informed decisions about the risks they take.

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45. rjschwarz on August 2, 2006 10:21 AM writes...

Maybe they need to take a before and after bloodsample and check all this stuff before the race starts so the sample can simply be a confirmation that the person is still clean.

Maybe the French need to have an international board verify the results since clearly Gaulic pride is not trusted.

Maybe someone should check Landis's head if he *did* cheat and thought the French wouldn't look at every possibility under a microscope after being dominated by Lance for so many years.

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46. Anonymous on August 2, 2006 10:30 AM writes...

"One (as someone asked above), why would Landis take something that he *knew* would be detected?"

Because they usually aren't. The athletes are so far ahead of the testers it isn't close. Did Ullrich and Basso (banned before the tour) ever test positive? Did the Austrian X-country skiers caught in a house with a virtual lab full of drugs and needles during the olympics ever test positive? Are there really only about a dozen NFL players out of 1500 using PEDs?

Davod is right to be skeptical, but not about false positives. False negatives are a much bigger problem.

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47. RKN on August 2, 2006 10:30 AM writes...


My earlier link didn't parse properly:

"Performance characteristics of a carbon isotope ratio method for detecting doping with testosterone based on urine diols: controls and athletes with elevated testosterone/epitestosterone ratios."

Full article: http://tinylink.com/?8yiYrGb5KK


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48. Bart Hall (Kansas, USA) on August 2, 2006 10:37 AM writes...

"synthetic testosterone is made from phytosterol percursors, typically derived from wild yams or soy. Those are both warm-climate C3 plants, which take up atmospheric carbon dioxide by a different route than temperate-zone C4 plants, leading to noticeably different isotope ratio"

I'm an agronomist and soil chemist by training. You don't quite have it right. Yams and soy are indeed C3 plants (glycerol pathway), and they like warm climates, but C4 plants (oxalacetic pathway) are not temperate zone plants.

C4s such as maize(corn) and sugarcane are noticeably enriched in 13C compared to all the C3s, including soy and yams.

Where this gets interesting is that the standard American diet gets substantial amounts of its carbon from C4 plants, the Europeans get nearly all of their carbon from cereals, potatoes, and beet sugar, all of which are 13C impoverished compared to an American diet.

I don't know the specifics of the Landis testing, but I would expect natural testosterone in an American to be 13C-enriched compared to a European. If derived from soybean and yam phytosterols, synthetic testosterone should be relatively LOWER in 13C than an American's natural hormone.

Soybean or yam-derived synthetic testosterone should display an isotopic ratio much closer to the natural testosterone of a European, and if a European lab is flagging high 13C in an American as a sign of synthetic testosterone I think they may be missing an important factor.

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49. tommy on August 2, 2006 11:13 AM writes...

France uses the Napoleonic Code where it is guilty until you prove yourself innocent.
I am in a profession that require random drug and alcohol testing. Positives occur at a very low level and most entirely for alcohol. Smart people will do stupid things.
Riders never take water or anything else from unknown spectators along the coarse. Riders have been poisoned or doped this way in the past.

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50. Derek Lowe on August 2, 2006 11:13 AM writes...

Bart Hall's comment is very interesting, but I don't think that it will quite explain the test results. That J. Chrom. B reference I listed in comment #43, for example, addresses this point directly. While they did see measurable changes, still:

"Throughout the study, the subjects were living in Switzerland and were residing every year for a month or two in an African country. . . The steroids of interest in each sample did not show significant isotopic fractionation that could lead to false positive results in anti-doping testing."

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51. Jim Hu on August 2, 2006 11:14 AM writes...

#47 Bart Hall,
Interesting idea. This would show up in other metabolites. I wonder if they do controls for diet.

The NYT piece says the 13C test was only "mildly elevated". Who knows what that means?

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52. MTK on August 2, 2006 11:23 AM writes...

Alright, Bart Hall, that's a nice twist.

This is what I meant in my previous post about how is this type of test appropriately validated.
Like I said, the whole thing is a farce.

And to RKN (post #38)I think that they actually measure metabolites of testosterone in the urine and not testerone itself, so the questions becomes what happens to the testosterone vs. what happens to cortisone metabolically. I still think you're right, thought, that it's easy to tell the difference.

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53. Novice Chemist on August 2, 2006 2:25 PM writes...

I have a poll question for all, but especially those who believe in false negatives.

Are doping athletes rarely caught:

A. because of difficulty in testing?
B. because of advances in masking?
C. because of advances coming from clandestine sources?

I have always doubted (C), because I believe that it's impractical for there to be a team somewhere of Ph.D. chemists making medchem-type analogues of known PEDs. I am more willing to believe that there are MDs who may be willing to help abusers obtain legal drugs that can be misused, but that's just my personal bias. P.S. I am aware of the history of THG -- I think it's the exception that proves the rule.

My vote is (A) -- it's probably difficult to obtain enough to detect. Short of collecting athletes blood, sweat and urine 24/7, that is.

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54. MTK on August 2, 2006 2:44 PM writes...

Derek,

In regard to the comment in the J. Chrom. paper, does anyone know the metabolic carbon turnover? What is the effect of a lifelong high C4 diet vs. a month-long diet? These Swiss that spent a month in Africa, did they take cases of muesli with them? OK, being facetious there, but I guess I'm just not convinced this test has been validated enough.

Even if dietary changes were not enough to trip a false positive, doesn't the fact that it influences the base level, mean the test as a doping control is faulty? In other words, somone on a high beet sugar/low sugarcane diet has more room to dope before crossing the threshold than someone who doesn't.

In the days before direct EPO testing, the International Cycling Union (UCI) used hematocrit levels as a de facto marker. If your hematocrit was over 50 you were out of the race. Well, guess what. In the 90's the average hematocrit level in cyclists increased as people manipulated their EPO dosages to get as close to 50 as possible without going over.

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55. dan on August 2, 2006 2:45 PM writes...

Re the influence of diet: The NYT article says that the test actually compares the isotopic ratio in testosterone to the ratio in another hormone (cholesterol?) A difference of more than 3% constitutes a positive test. Landis came in at approx. 4%.

It sounds like a very tough rap to beat. Sad.

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56. Chrispy on August 2, 2006 2:47 PM writes...


If using banned drugs would make one more competitive, and some athletes in the competition have been shown to use banned drugs and are not more competitive, then it follows that ALL the athletes are using these drugs.

These drugs are highly effective, and they ALL take them IMHO.

And I agree -- let 'em train as they see fit. And let them ride recumbent bycles for that matter, too!

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57. Joe on August 2, 2006 2:54 PM writes...

intersting...

"But Trevor Graham, Gatlin's coach, has contended Gatlin was the victim of a vengeful massage therapist who rubbed testosterone cream on his legs without his knowledge.

http://sports.espn.go.com/oly/trackandfield/news/story?id=2537229&campaign=rss&source=ESPNHeadlines

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58. Jose on August 2, 2006 2:57 PM writes...

Hey Novice Chemist-

link about a very sophisticated anabolic steroid that was specifically designed to be invisible to the sreening agencies. Some VERY high level (clandestine) med chem and analytics here. "C" may be more likely-

http://pubs.acs.org/cen/science/8146/8146sci2.html

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59. DFW on August 2, 2006 3:13 PM writes...

At the Tour, riders are tested before the race; in addition, at the conclusion of each stage the stage winner, the race leader, and six to eight cyclists selected at random throughout the field are tested. That means Landis should have been tested six other times (before and as race leader after stages 11, 12, 15, 19, 20) in addition to the positive sample after his stage win of stage 17. Presumably, those samples were negative.

I wonder, as did Ian in 27 above, how could all Landis' other tests be negative.

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60. Novice Chemist on August 2, 2006 3:21 PM writes...

Jose:

As I said in my comment, I am aware of the history of THG. It's the hydrogenation of a triple bond. Child's play, as far as I'm concerned. Patrick Arnold was the chemist involved -- it's my understanding that he has no more than a BS.

It is my opinion that 'designed steroids' is mostly a term for the media; 'slightly modified steroids', I think, is a better term.

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61. Maetenloch on August 2, 2006 3:35 PM writes...

Novice chemist,
I suspect that almost all elite athletes use substances like HGH, IGF, etc. that are currently undetectible. However many also use steroids for which no test exists at this time. You don't need a team of Ph.Ds developing compounds from scratch - drug companies spent most of the 60's and 70's developing and cataloging steroids in search of the holy grail, a steroid with all the benefits of testosterone but none of the side effects. Most of these were never developed commercially for one reason or another, but the original research is still available. A quick look at the history of BALCO shows that you really only need a smart chemist or two with access to pharmaceutical databases. Right now there are chemical companines in China that are selling compounds that have never been marketed commercially like 1-testosterone, turinabol, and methyl-trenbolone. It wouldn't be hard to have them manufacture a compound from the literature for which no urine test exists.

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62. Jose on August 2, 2006 4:06 PM writes...


Novice-

Notice I wrote "high level med chem" and not "synthesis." Most of med chem involves fairly simple chemistry; the difficulties lie in retaining, or improving activity. Picking out gestrinone (buried in thousands upon thousands of other steroids in patents, journals, etc.), obtaining some, and doing the chemistry on it strikes me as a fairly involved operation.

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63. secret milkshake on August 2, 2006 4:28 PM writes...

If you make living by peddling anabolics, the chances are that you have quite a good understanding what is available for abuse and what are the pros/cons, including the detectability. It is only logical that you would then think about new analogs that are not known in the forensic literature. Often you could propose a structure that has a reasonable chance of working just by combining data from some review in literature. You would be limited by feasibility of chemistry - you need some close precursor, like those contraceptive steroids they used - but you could come up with new analogs, whuch would buy you a year or two, before they will be known and tested for. In case of BALCO, I think there was a lucky coincidence that their steroid alcohol was quite hindered and acid-sensitive and would decompose under the standard conditions used for GC derivatization.

So all and all, you need one or two guys to pull this off. And they don't have to be geniuses, just competent and greedy.

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64. JB on August 2, 2006 4:37 PM writes...

There's an article about this on news@nature.com titled "Isotopes help pin down artificial testosterone"

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65. loikll on August 2, 2006 5:01 PM writes...

C'mon 'Roid Landis, say it ain't so.

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66. JB on August 2, 2006 5:35 PM writes...

Here's the link
http://www.nature.com/news/2006/060731/full/060731-4.html

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67. weirdo on August 2, 2006 5:48 PM writes...

The curious thing to me is the fact that the isotope ratio test should apparently show a difference for at least 7-8 days after administration of the exogenous testosterone (Steroids, 1997, 62:379-387). Since Landis was tested periodically throughout the race, a one-day difference is a highly suspicious and unlikely result.

Any analytical chemists (non-conspiracy theorists only please!) out there care to comment?

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68. slank on August 2, 2006 6:04 PM writes...

It's amazing how many people trust science to give them cars, big screen TV's, and airplanes. Yet, when this science shows that our athletes are cheating (most professional bicyclists are) or that global warming is occurring then we'd better pout because it's going against something we want to believe. landis, lance, all of the other top finishers in le tour are doping.

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69. RKN on August 2, 2006 6:42 PM writes...

Yet, when this science shows that our athletes are cheating (most professional bicyclists are) or that global warming is occurring then we'd better pout because it's going against something we want to believe. landis, lance, all of the other top finishers in le tour are doping.

Specifically what "science" has shown that Lance Armstrong has cheated - ever? All the evidence -- and there's a lot of it in his case - points to exactly the opposite.

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70. John K on August 2, 2006 8:09 PM writes...

I would like to see the B sample tested by a DIFFERENT lab. I'm surprised that in high-profile cases like this the authorities don't do that to add legitimacy to the testing process.

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71. Another Chemist on August 2, 2006 8:10 PM writes...

Some thoughts;

1) I note in the Clinical Chem paper that Derek cites: Among the "high T/E testers", i.e. those >6, the T/E ratio for those who 'failed' the isotope test were typically >20 and those that 'passed' were 5-13. Landis tested at 11. Of course this doesn't prove that Landis is clean, but his score is more consistent with those who 'passed'. Also, this does point out that elevated T/E ratios among athletes does occur.

2) The only news item I could find, re: testing of sample A with the isotope test, was a suggestion by an anonymous official to the New York Times that Landis failed the isotope test. Anonymous objective source for the Times? Hmmmmm.

3) The worst case senario for Landis, if he is innocent, is that the results of the isotope test might not be clear cut. One could imagine a 5BP-5BA of 3.0, in between those who passed and failed, with the rest of the parameters being likewise ambiguous. How would one interperate such a result? I can guess that the Landis fans will have a different view from the anti-American crowd. Unfortunately, such indeterminent results are not so uncommon in my experience.

My conclusion to this is that the most rational position is "We don't know....yet." There is plenty of room to doubt the significance of T/E ratio and suggestions from anonymous sources to the Times haven't held too much weight lately. Hopefully, the actual numbers will be released this weekend and the results will be clear cut.

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72. Jim S on August 2, 2006 8:44 PM writes...

Why would he take something that he knew would show up in a test? Because he didn't think he'd be tested.

If my memory is correct, it's the guy wearing the yellow jersey and the stage winner who are always tested. The guy was in 11th place and riding on dead legs after the prior stage. No one, including Landis, thought he would make a "miraculous" recovery.

If Landis took the drugs - and that is not a big "if" - he was probably trying to regain some time in hopes of making the podium. Instead, he kicked everyone's tail by an unbelievable margin.

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73. Phunny Pharm on August 2, 2006 9:08 PM writes...

Landis is straight, the French chemist are cheating jackasses. They always will be as long as Americans are making them look bad in the mother land. Oh, and all of you Floyd bashers, check his record for the year. Four major wins aint bad for an old man with a bad hip. Maybe, just maybe he trained real real hard and earned his way to the top step. Perhaps you could appreciate it better if you would spend a little more time on your bike (if you had one) doing some hard road miles up the side of some mountain. Go out and teach yourself something about motivation, realizing impossible goals, all or nothingness and hell, even carrying the weight of an entire countries hopes of just one more yellow jersey on your shoulders. That may, however afford you a little less time on your fat asses in front of the computer figuring out ways to bash a fellow American on a subject about which you are mostly ignorant. You smart sounding chemists, nice explanations. Now get a life and go ride.

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74. Nicholas on August 2, 2006 9:09 PM writes...

"...when science shows global warming is occurring..."

www.climateaudit.org

If you read a definition of "science" it requires independent verification. Climate "scientists" mostly refuse to give out data and methods, making such verification impossible. Therefore it is not science by definition. That web site documents the pain one guy has to go through in order to attempt to independently verify the results.

What does this have to do with drug tests for cyclists? Not much, other than to point out that science isn't always infallible. I wouldn't have brought it up if slank didn't try to use this throw-away slur...

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75. Joe Blow on August 2, 2006 9:13 PM writes...

Landis has said my high testosterone level is due to:

*Cortizone, which I take legally for my bum hip.
*Medication, which I take for a thyroid condition.
*Alcohol
*a naturally high reading, which I've had for years.

Go ahead and blame the French or whomever you want. But if you're nine-year-old were talking the way Landis is, you'd say, "Floyd, you're fibbing."

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76. Dave on August 2, 2006 9:19 PM writes...

The fact that all of Floyd's other samples taken before, during, and after the race were negative implies that, if he did cheat, he must have cheated only between stages 16 and 17. I agree with the majority of posters here: elite athletes are exquisitely well aware of what they can and cannot get away with in using PEDs. An efficacious dose would have produced a test result far more abnormal than what was reported for the A sample.

This story absolutely does not add up.

The lab running these tests should have already been disbarred based on its shady history.

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77. there is no santa claus on August 2, 2006 10:06 PM writes...

Why does everyone assume that the one positive test after stage 17 means Landis could only have been cheating on that one stage - which, the reasoning goes, would make no sense, ergo he was framed/the test was screwed up/the French are against him?

As was mentioned waaaay upthread, there is good reason to believe that false negatives are far more common than false positives.

So maybe on that day he just screwed his dosage up.

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78. Plunger on August 2, 2006 11:20 PM writes...

Get over it! Your conspiracy theories are embarrassing and pathetic. Landis will most likely be proved guilty and should be banned for life. He is a cheat and should be humiliated! And no, THIS IS NOT SOME ANTI-AMERICAN CONSPIRACY - YOU ARE NOT BEING PERSECUTED.

PS HMMM - I like your blood doping rumor - sounds plausible to me.

PPS I am a biochemist, avid cyclist and cycling fan - so Phunny Pharm you can keep your rabid, nationalistic panties on.

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79. Pete Blackwell on August 2, 2006 11:31 PM writes...

If Landis is disqualified, I believe a Spaniard wins. Hardly the stuff of a French conspiracy.

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80. Rascal on August 3, 2006 4:34 AM writes...

I think the french slipped him a mickey.

Regardez-vous!

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81. Drugs are good on August 3, 2006 7:40 AM writes...

All of the elite cyclists are using something to enhance performance; that includes Armstrong, who will never say "I have NEVER used these substances". It doesn't matter, they still have to train and ride like hell. I say we eliminate drug testing and see if the performance really improves...

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82. pdino on August 3, 2006 8:33 AM writes...

I sure hope that either the IRMS results of the Landis B sample or subsequent analysis/testing prove and explain that he was "clean" and his performances during the TDF were unaided by banned drugs.

I do, however, want to comment on the motive for professional cyclists using testosterone (synthetic or real) supplementation to help performance. If you talk to any cyclist about what it takes to win a 3 week long stage race, one of the key qualities is RECOVERY. Successful stage racers can RECOVER between stages and have sufficient strength for the next day's stage.

Testosterone is a proven muscle recovery booster. Seems like it would be a good "performance enhancer" for a stage racer, especially during the last week of a stage race when all the racers are fatigued!? Former pro rider Jesus Manzano has stated that Testosterone IS in fact a beneficial drug to take during stage races in that is aids recovery and improves aggressiveness/morale.

Like I said, I'm not jumping to any conclusions yet and I sincerely HOPE that Floyd Landis' performance during the 2006 TDF were 100% a result of hard training and natural abilities. Let's not be naive, however, and deny that testosterone is a proven performance enhancer.

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83. DFW on August 3, 2006 12:28 PM writes...

In 77 there is no santa claus wrote: "As was mentioned waaaay upthread, there is good reason to believe that false negatives are far more common than false positives." However, the first upthread mention I can see of false negatives is in 46 where anonymous wrote: "False negatives are a much bigger problem."

Nowhere in this discussion can I find any citations quantifying false negatives. Where is the source that "false negatives are far more common than false positives?"

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84. Stephen on August 3, 2006 5:50 PM writes...

Landis did a one-time "cheat", and used a testosterone patch following his disasterous stage 16, in order to recover for his miraculous stage 17. He probably administered the patch himself, and took a chance that he'd be under the 4:1 limit when tested the following day. It was a calculated risk. He needed a miracle, and went for it. There was some thought that a one-time application wouldn't be detectable: http://www.cyclingnews.com/news.php?id=news/2006/jul06/jul07news3

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85. Mim on August 4, 2006 12:36 AM writes...

Here's another article explaining the isotope test and its basis in some detail for those who want more info.

http://www.raci.org.au/chemaust/docs/pdf/2006/CiAMarch2006p3.pdf

Seems like it's fairly robust by all accounts.

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86. Anonymous on August 4, 2006 9:48 AM writes...

Re comment #14: I'm SURE it will interest you to know you are now the number one result on Google if one searches "deuterated dog". LOL

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87. Anonymous on August 4, 2006 2:53 PM writes...

DFW,

I don't have any scientific evidence that false negatives are more common than false negatives. My assertion is based on the fact many users of PEDs make it through testing regimes without being caught.

Had Basso and Ullrich just started using PEDs this year? How many times were Justin Gatlin, Marion Jones and others tested with nothing showing up. I repeat my comment from above about the NFL -- is the usage rate really about 1%? Obviously tests have limitations -- and it makes sense from a fairness/civil liberties perspective to err on the side of false negatives. As I said above, the cheaters are always ahead of the testers. No doubt there are more THG's out there today.

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88. BCL on August 4, 2006 7:25 PM writes...

There are no false negatives, let's all be clear on this fact. See comment number 84 for all your answers, Landis cheated, he got caught, he wasn't expecting that an isotope would be his one achiles heal and he faltered at cheating. The french were waiting to pounce on this and had the test and the clear situation of a miracle time or comeback during a stage already figured out for their isotope reasoning to be an acceptable reason for his guilt.
Plain and simple, he got out thought and he relied upon a mythe that the ratio would be low enough by the next day not to test positive, he calculated wrong and got caught.the c-13 isotope was his un-doing and unless he had been eating c-13 isotopes for breakfast then he took the synthetic form of BALL JUICE. plain and simple. he cheated.

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89. Mark Heinicke on August 5, 2006 7:04 AM writes...

It seems to me that the desire of the French to retain the prestige of the Tour de France would outweigh any temptation to manipulate test results. Ergo, I believe the testing and results were fair, and devastatingly credible.

And speaking of the Tour's prestige, I don't quite understand why more of the French conspiracy theorists don't bother to express some gratitude to the French for putting on the greatest race in the world--a race which has made international heroes out of Greg Lemond and Lance Armstrong.

BTW, I wonder what the testing regime is for World Cup soccer? Artifically elevated testosterone might go some way to explain Zinedine Zidane's belligerence in the WC Final head-butting incident which may well have lost France the Cup.

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90. jim on August 5, 2006 2:46 PM writes...

Anyone who is familiar with testosterone knows this steroid doesn't have a physiologic effect overnight...takes weeks to build up red blood cell count and muscle mass. It is not a stimulant, doesn't cause "bursts of superhuman strength", and wouldn't have affected the outcome of this race. Someone has "slipped him a mickie" or the French lab has screwed up. Problem is most physicians and scientists have no experience with this drug "in vivo", and honestly don't know what they are talking about!!!!! Looks like you're framed Floyd....good luck. Jim Princeton M.D.

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91. Dean on August 5, 2006 6:23 PM writes...

My questions are:

Could DNA samples be conducted upon the urine which is said to be the sample given by Landis to determine if it is in fact Landis' urine, and not urine belonging to a horse, another person, etc.?

If Landis is innocent of the charges of doping, which we MUST presume he is, is it possible that his urine samples could have been switched or tampered with? How is the chain of custody ensured?

Is it possible that testosterone was administered covertly to Landis by a jealous competitor (ie: mixed in with food eaten or beverages drank by Landis without his knowledge)??

How long would a single dose of testosterone (since we must assume a single dose, based on the fact that other samples given by Landis during the course of the Tour did not test positive for high ratios of testosterone to epitestosterone) remain present in the body and more specifically in one's urine?

Would a test, taken the day the allegations surfaced, be helpful in proving the results reported by the UCI were false or induced by tampering??

My comments:
I must believe that Landis is innocent until he is PROVEN guilty. If Landis should be found guilty after exercising due process, including appeals, then it will definitely be disappointing to many of his fans and to the cycling world. However, I believe there will be a discovery of "foul play" involving either the test results or the authenticity of the sample which was labeled as Landis'.

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92. Phunny Pharm on August 5, 2006 8:39 PM writes...

Sorry to have embarrassed you Plunger (#78). I'm not a conspiracy theorist, just an optimist trying to support a fellow cyclist in the best way that I can while he is technically still innocent. As I am also American, Landis just happened to be first in line. The French/American love affair has been a little shakey over the past few years in case you hav'nt noticed so I was poking a little lite hearted fun at Francois' expence. I also feel that the Germans, Italians and others were handed an even bigger bone job by the Spanish. Anyway, I and my fellow cyclist, regardless of nationality sincerly appreciate your support. There Plunger, how are my panties now?

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93. jon redmond on August 5, 2006 8:49 PM writes...

Why would someone slip a micky to a rider that was 8 minutes behind the yellow jersey?

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94. Tired of hearing it on August 5, 2006 11:00 PM writes...

S@rew you Realist with your Anti-American comment. If Landis did do wrong he should be punished. If on the other hand it is found that he did nothing wrong, you might want to rethink your attitude....

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95. Smoking Man on August 6, 2006 2:32 AM writes...

Actually, the entire race was faked in a
sound stage in the Arizona desert.

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96. Craig on August 6, 2006 3:13 AM writes...

Finally, an article that intelligently discusses the science behind the testing! Thanks.

I look forward to a follow-up report that includes more answers to the various thoughts expressed by the commenters.

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97. kvon on August 6, 2006 12:11 PM writes...

I'm very pleased to have stumbled on this site....it answered alot of questions. I really am a novice chemist, currently finishing my BS. Novice chemist above doesn't sound very novice to me. I would be very interested in seeing the actual chemical compounds of both synthetic and biological T. I have looked through my P-chem and O-chem texts and can't find the synthetic steroid. Does anyone know of a site that would have projections of the compounds to compare?

I'm also a cyclist, good banter Phunny.
JUST RIDE!

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98. Shelley on August 6, 2006 2:55 PM writes...

Could synthetic testosterone have been added to Landis' urine sample?

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99. Realist on August 7, 2006 2:53 AM writes...

Guilty!

I rest my case.

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100. David McCune on August 7, 2006 10:38 AM writes...

I'm still intrigued by the possibility that the synthetic cortisone was converted by his body into a "natural" testosterone that would test artificial by the isotope test. The liver does recycle the steroid hormones, so it is possible. In theory, an isotope test on earlier samples would also be positive. While this would not eliminate the possibility that Landis was cheating all along, it would refute the idea that he took a one-time injection before stage 17. Conversely, if only the stage 17 test showed altered isotopes, that would eliminate a pure natural variant, and leave only cheating and tampering as explanations.

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101. brenda on August 7, 2006 11:13 AM writes...

So the french are out to get the Americans. I'm so grateful Lance Armstrong led us all to this truth. Forget all of the millions of dollars, fame, status that goes along with winning the Tour De France. Floyd Landis tested positive; perhaps he got desperate at the last minute, who knows. I'm sick of hearing all of these people defending him just because, "he's my hero and he would never lie" Why wouldn't he lie? just because he's your big, bad cycling hero? News Flash-people lie!! especially to cover their trail. I'm sure we could fill volumes with the names of honest looking people that told lies. Lets all stick to the facts and quit with the "hero worship".

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102. David Reed on August 7, 2006 11:42 AM writes...

According to Brooks JR etal 2002 "the delta13C of European beers indicated mostly C3 plant carbon". How rapidly is testosterone metabolized? How variable is its isotopic ratio content in relation to diet over time? Does human metabolism discriminate carbon for testosterone production (like photosynthesis metabolisms) in preference to a common ratio? If the incorporation of carbon into testosterone is slow versus rapid, then the day of the synthetic testosterone addition would be bounded by those samples when the C3 signature appeared.

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103. The Analyzer on August 7, 2006 11:56 AM writes...

Maybe it's not really Landis's fault. This article offers a different viewpoint.

The Floyd Landis Conspiracy

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104. Bob Eastley on August 7, 2006 12:33 PM writes...

I just listened to two interviews related to the Landis case. First, results of the "A" test were not supposed to be made public until he had a chance to react to them. When asked why they were relased, the gentleman who got the lab results and released the information to the media gave some lame excuse about how he wanted to get it out there before someone leaked it. So it's OK if HE leaked it? When questioned again, he ducked the issue. Next, a doctor was questioned about the fact that the RATIO was high, but the testosterone level was not. The interviewer specifically asked if an athlete would gain any benefit by having a high ratio if the testosterone level was not high. Again the interviewee ducked the question. Floyd Landis may be guilty, but people VERY close to the issue are not following due process. If they aren't honest enough to give him a fair chance to defend himself, why should we believe their lab results?

RCE

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105. Brad Sherman on August 7, 2006 4:38 PM writes...

In response to David Reed's (102) question, the RACI paper (see Mim #85) suggests diet is unlikely to be responsible. The study presented there showed diet-related changes of deltaC13 in the testosterone metabolites that are tested ranged from around -23.6 for the highest C3 diet (Italy) to -19.5 for the highest C4 diet (Mexico). Short term impact of taking the synthetic hormone Adione (deltaC13 = -35) was to reduce deltaC13 inthe metabolites to -28 or below for 3 to 4 days.

I'd be interested to learn how testosterone is metabolised when under great stress as Landis was the day before when he cracked going up the last climb. Is it possible to deplete C13 more rapidly than C12 even though C13 is heavier and less reactive?

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106. Phunny Pharm on August 7, 2006 7:21 PM writes...

Yippee for Realist (#99)! You've single handedly made the world of cycling a better sport because YOU called it. You've won YOUR case. Now you can go to France or Spain or wherever and pick up your prize. By the way, what did you win? What was it that excited you so much about the worlds greatest stage race being tainted by the current evidence, hhmmm? Oh, it does'nt matter, as long as YOU won! I'd say however that the rest of the cycling world lost...bigtime. Perhaps you can sleep better now.

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107. jdb13 on August 7, 2006 10:16 PM writes...

I too, wonder about how Cortisone is metabolized. Here is a PDF article I found. Can one of you chemists tell me if it relates to this discussion?

http://doi.wiley.com/10.1002/bms.1200170502

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108. Strixwood on August 8, 2006 9:51 AM writes...

As a (retired) chemist with eons of experience in clinical analyses, I'm curious as to the actual numbers involved in these tests -- especially the expected accuracy and precision. It seems to me that the situation requires some rather complex number crunching to get at the naturally produced vs. "synthetic" content in the samples, and I would love to play around with it as an intellectual exercise strictly for my own amusement/amazement.

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109. frank gattoni on August 8, 2006 3:20 PM writes...

the way to resolve the issue as to whether floyd landis has taken testosterone or whether the results reflect an inherent metabolic anomaly that he has is to repeat that race section (or simuluate it) taking appropiate precautions to prevent illicit administration of testosterone and to then repeat the analysis.they may also wish to use some of the epitheal cells in the urine specemin to confirm that they match his dna

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110. J on August 8, 2006 5:33 PM writes...

I believe the heads of the doping committees for the Olympics has publicly stated that a professional athlete familiar with performance enhancing drugs knows that taking drugs the night before a race would not provide any benefit. So why do you have a rider who has been tested 4 other times so far in the race, sets out to win the Stage(all stage winners are tested) knowing he will be tested if he wins and then proceeds to pass three more drug test for the remainder of the race.

How do you pass 7 and fail 1 in the middle of a few weeks. Don't forget this is the same rider that has won many other races and passed many drug tests. I am skeptical of all pro riders but it seems fishy in the sense that he would slip up during the biggest race of his life.

This French Lab is notorious for breaking rules and not following protocol, why is it so odd that a technician would taint the sample.

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111. rt on August 8, 2006 9:18 PM writes...

One thing no one has addressed is isotope levels in the subsequant samples. Testosterone has a half-life of several days. The synthetic T should also have shown up in those later sdamples.

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112. bob on August 9, 2006 3:17 AM writes...

The paper cited in #84 is indeed interesting, and it suggests two simple ways in which WADA could reinforce the persuasiveness of its argument.
(1) It shows that for a reasonable-sized sample, people eating US or Mediterranean diets produce T with a isotope ratio of around -23 average, with a standard deviation of around 1.2 or so. Thus, the 3-sigma limit of the sample is around -26.6, and the "cutoff value" recommended in the paper is -27. It also shows that for the precursor they tested, the actual ratios were below -28, and stayed there for 100 hours or so. So, what were the measured values in Landis's samples? Maybe this has been released, but I haven't seen it. If they were -31, probably case closed. If they were -27.1, maybe a little more review is needed.

(2) The same paper and others indicate that the reduced carbon ratio remains detectable for 100 hours or more. Wasn't Landis tested again a couple more times after Stage 17? For that matter, what did his results look like from his earlier tests?

My point is that while the mass spec work has been well documented with respect to repeatability and accuracy, the LIMITS appear to have been set pretty tight: about 1 or 2 non-dopers out of 1000 could be expected to marginally fail the -27% ratio cutoff; and as many as 10 or 15 out of 1000 might naturally fail the 4:1 screening for T/E.

Because of this, the convincing way to present the evidence is to show that (1) Landis exceeded the normal range on the tests by a large margin; and (2) that it was an aberration -- he was normal before and normal after (and maybe even normal now), but abnormal during Stage 17; and maybe (3) that at the immediately next following test he was still a little abnormal.

It wouldn't be that hard to show the data, instead of just having Dick Pound say "The science is good".

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113. brad sherman on August 9, 2006 11:17 AM writes...

Following on from Bob's comments, the -27 ppt (not %) ratio suggested as the target in the RACI paper (#85) is 3 standard deviations from the mean, i.e. for Landis to get below this, i.e. -30 or so, there's a 3 in 1000 chance of it's being natural variability based on the samples of the 1120 atheletes sampled to determine the 'accepted' range of natural variability. Although the plot in the paper shows about a 100 h effect I believe the authors claim that one can only reliably expect the effect to last for 40 hours. That said, I believe Landis would have samples taken every day that he wore the yellow jersey.

Bearing in mind the absence of actual published test results to fuel any of this speculation, I expect it will be some weeks as the other samples are analysed. I assume he must have been sampled after the last two stages as wearer of the maillot jaune, but not necessarily after stage 18. Does anyone know who is required to provide samples at the end of each stage apart from the stage winner? Landis didn't win any stages after #17. If he wasn't sampled in 19 and 20 it would be hard to prove innocence as I would guess he'd need a clear test for samples taken within 24 - and maybe 48 - hours of the stage 17 sample.

Seems a shame that in the world of sport, one is no longer presumed innocent until proven guilty after due process. For some perverse reason I don't understand, society prefers to assume top athletes are all cheaters rather than gifted humans. My personal assumption is the converse - call me naive. I reckon none of this should have been made public until all tests and appeals had been completed. It's not fair on the athlete.

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114. jdb13 on August 9, 2006 12:57 PM writes...

Tested each day are the stage winner, the current yellow jersey holder and several other iders at random. So, Landis would have been tested after Stage 19 and 20.

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115. anonymous on August 9, 2006 2:36 PM writes...

If cyclists are held to a 2 year ban for infractions of the code, why isn't the testing lab held to a similar high standard? They made a mess of the Olympic tests, and are clearly not impartial. Why aren't there multiple labs and random selection of which samples go to which labs. Why is it a French-Canadian in charge of WADA and a French lab calling all the shots.

Mr Pound has a long history of being judge and jury without a shred of scientific data, while trying to represent an organization that is suppose to uphold science and morals at the highest standard. These atrocities including unfounded comments about NHL athletes, Armstrong, etc which have all gone unproven and false.

In early June of 2006 Armstrong wrote a letter to the IOC asking that Mr Pound, be removed for his behavior. Now we get to the end of July and you have to ask the question if there is a hidden agenda for Mr Pound to strike back at America.

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116. Mr. Smith on August 9, 2006 6:09 PM writes...

the one thing I don't get is, Testosterone is a steroide that would build mass over time. I dont see the advantige of taking it DURING a race. Also Why did he not just mask it with epi. I dont know why but i smell a coverup. I have no evidence for it but after the way they tried to get armstrong... I wonder... or could they have screwed up the test and to save face used sample A again inplace of B... or worse yet added testosterone to the sample to make the "american look bad."


I want to see the method of testing, What type of machine, (LCMS, GCMS, UV?) What model, what year, when the machine was last calibrated. The reagents used during the test, The lot numbers of the reagents, Experiation dates, I would also like the samples tested by independent labs. Also did they use a strandard? What standard. From an analytical chemist point of view i have a bunch of questions. Speaking of chemist was this guy a pro or was he a rookie fresh.

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117. EHF on August 9, 2006 9:51 PM writes...

How long does synthetic testosterone stay in the system? Landis was tested 3 or 4 times after the 17th stage, all were negative. How could his testosterone ratio be 2-1/2 times the permisable ratio after the 17th stage, but ok a day or two later?

By all accounts, synthetic testosterone takes weeks not hours to provide any performance enhancement. Why would Landis take a banded subtance following the 16th stage that would provide no benifit for weeks?

It just doesn't make sense, he takes one hit of testosterone during the tour with no positives before or after?

Some have suggested that Landis must have been slipped a mickey. But after the 16th stage, he was not considered a threat to win the tour by anyone. Why would conspiring powers slip him a banded substance when he was no longer a threat to win the tour?

The positive sample was taken after the 17th stage, but testing was not performed and results released until after what some have called the greatest comeback in tour history. So we have the wrong drug to bolster near-term performance sandwiched between numerous clean tests before and after the 17th stage.

In my opinion, everything points to a tampered urine sample. At some point after the 17th stage comeback, but before the labratory testing, synthetic testosterone was added to his urine sample. I would take a long, hard look at chain-of-custody proceedures for that sample, who handled it, or had access to it prior to testing?

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118. proofread on August 9, 2006 11:06 PM writes...

Landis' urine, not blood, was tested. Proof read.

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119. Isotope Man on August 10, 2006 2:29 AM writes...

To me this dopping alligation is not clear. While plants fractionate isotopes, animals in general do not. For animals, you are what you eat, isotopically speaking. Therefore, I see at least two possible paths for this alleged synthetic testosterone. One, that is was injected (it is unlikely that testosterone taken orally would actually be used in the body without modification). The other possible reason would be that he had two very different diets (isotopically speaking) so that he had two different compositions of testosterone in his body at the same time. This would seem like it might have alot of merit because you would assume that the diet in training differes drastically with the race diet. The things that stick out are the training drinks and gu. What is gu isotopically? It most likely comes from some sort of natual sugar (perhaps corn, a C4 plant). The best question to ask is what is the variation of the isotopic composition of testosterone in cyclist, my bet is that there is not study to back up this method of testing!

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120. weekend warrior on August 10, 2006 3:52 AM writes...

If the news reports are right, that's what Landis's blood samples have shown. And if they have, there seems only one unfortunate conclusion to be drawn.

a) You don't even know what substance was tested.
b) You have a very limited imagination if you think there's one possible conclusion. I sure hope none of your work is in a critical area.

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121. TEC on August 10, 2006 10:11 PM writes...

I do not know exactly which isotope test they used on the urine. I worked at the UCLA Olympic doping lab and published two peer reviewed papers with validated methods. These have been adopted by the sports authorities. At UCLA we ran lots of controls each time we ran samples. T/E ratio is one thing our Clin Chem paper was cited in the cyclingnews.com web site. here it was used to indicate the T/E was high but isotopic data was clean. However with Landis the lab went onto use the isotope method and that was positive too. Contamination/tampering could be an issue, BUT these labs have such strict chain of custodies and samples are not identified with any name that this would be difficult to do. The isotope test involves extraction of steroids from urine, chemical treatment to make them stable in the gas chromatograph, this "peak" which is separated from other steroids it is then combusted (on-line to carbon dioxide) and goes into an IRMS (isotope ratio mass spectrometer). It analyses masses 44, 45 and 46. Then the ratio 13C/12C is calculated. The instrument is calibrated against an international standard. At UCLA we also ran a number of control positive and negative urines with know 13C-levels, everytime we tested real samples.

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122. CanYouSayWitchHunt on August 11, 2006 12:17 PM writes...

I am glad to see that many of these posts are considering the possibility that Landis' urine sample was tampered with. Of all the possiblities this is the one that seems most likely to me.

Assuming that the French lab did the carbon isotope ratio test correctly, i.e. there actually was synthetic testosterone in Landis' urine, then we can discard all the arguments about drinking alcohol, "naturally high levels of T", etc.

(BTW, those who think that Landis "acts guilty" because of his multiple attempts at explaining the test results have not thought carefully about how an innocent man, especially one raised in a rural, religious society, would actually react if he were wrongly accused. Floyd is not "simple" or "stupid" in any way, but he may be a bit naive regarding the capacity for deceit and dishonesty present in much of humanity...)

This leaves few possibilities: 1) Landis took a one-time dose of testosterone, 2) someone "dosed" him unknowingly with same, 3) the lab "inadvertantly" screwed up, somehow "contaminating" both the A and B sample, or 4) same as (3) except "purposely" and "tampered with" replacing the corresponding phrases.

We can discount (1) because Landis and the Phonak team doctors & trainers are not stupid. Testosterone does nothing helpful for an athlete overnight, and they KNEW he would be tested if he won the stage and/or the yellow jersey. (2) seems vanishlingly unlikely since everything Landis consumes during a race is carefully controlled by the team - this scenario would require a "traitor" on Phonak. (3) is conceivable but just barely; how on earth would an "accredited" drug-testing lab make a mistake of such a gross nature, and ONLY on THE SINGLE MOST IMPORTANT TEST THEY WILL MAKE ALL YEAR?

No my friends, (4) is the answer. Why use testosterone and not some other more plausible banned substance? (Testosterone is not "plausible" because everyone knows there is no benefit to using just once, overnight.) Here I am out of my league (I'm a physicist, not a chemist) but I know that many drug tests look not for the banned substance itself, but for the metabolic byproducts thereof. However all I have read about the test for testosterone seems to indicate that the testosterone molecule itself passes unaltered into the urine - can any of you chemists/biochemists/endochrinologists out there confirm or deny this supposition? It seems to me that it would be very difficult to "spike" a urine sample with just the right amounts of say amphetamine metabolic products, but very easy to do so with synthetic testosterone.

It smacks very much of a not-well-thought-out-but-who-cares last minute attempt to discredit one of the greatest athletic performances in history. When it became apparent that Landis would win stage 17 and place himself clearly back in contention, it is not hard to imagine someone who could not abide Yet Another American winning the Tour de France for an 8th consecutive year. It would be sufficient to plant any convenient banned substance in Landis' urine sample - vastly easier than figuring out how to actually get it into his body. Whether or not the substance chosen "made sense" is immaterial. Since the "war on doping" is nothing more than bureacratic histrionics and posing, an athlete is presumed guilty until proven innocent. The anti-doping rules do not require "motive" for a conviction. In fact, conviction is automatic; it is exoneration that takes work.

Landis' only possible defense at this point rests on the dynamics of how testosterone is eliminated from the body. Again, I am out of my league here but I think it might be possible to show that it is IMPOSSIBLE for a human to have ingested as much testosterone as Landi