Here’s a summary of the Froome case as I see it.
1. I think it’s quite unlikely he will be able to explain his high urine level of salbutamol as the result of inhaling the drug within the allowable limits. I have not seen a single study reporting a level that high, 2000 ng/ml., for any subject taking the maximum amount allowed, 1600 ug, within 24 hours. One study, discussed here, found a few subjects with amounts higher than this when the entire 1600 ug was inhaled at once, but since there’s also a limit of 800 ug in twelve hours, this would not be allowed. Other studies, in which the drug is taken over some period of time, report an occasional subject above the threshold of 1000 ng/level, but just barely. While I haven’t seen every study, and I’m not going to claim a level of 2000 ng/ml can never occur under allowable conditions, based on the data I have seen, which include mean levels and standard deviations for a pool of subjects, I’m fairly confident that a level as high as Froome’s would be exceptionally rare. And it should be. The WADA threshold is intentionally set at a level to minimize false positives, so it should be difficult for a rider inhaling the allowed amount to exceed it, let alone to produce a value double the threshold.
(Edit: I just started looking at the Sundby CAS case linked upthread. It turns out the athlete took nearly ten times the amount of allowed salbutamol, via a nebulizer. So hardly surprising that he exceeded the threshold. His argument apparently is that it was medically necessary, and that since it was administered orally, would not have been performance-enhancing. I also bring this up because it further supports my point, below, that it's possible to take a much larger than allowed dose and not exceed the threshold. This athlete's urine level was actually lower than Froome's, despite taking 15 mg of salbutamol in a period of just a few hours.)
There has been speculation that his level might have resulted from dehydration, which concentrates solutes in the urine. But I don’t think that explanation will work, either, for three reasons. First, even a study which attempted to maximize dehydration, by minimizing water intake of subjects during exercise, found urine levels of salbutamol as high as or higher than Froome’s only under conditions that exceed the allowable intake of the drug.
Second, during a race, riders of course attempt to remain fully hydrated, so while some dehydration is certainly likely, I don’t think it would be to the extreme reported in that study. Also, as will be discussed further below, Froome tested below the threshold literally more than a dozen times during the Vuelta. If dehydration could make that much difference in his values, surely he would have exceeded the threshold more than once.
Third, the WADA guidelines specify how much the threshold level and decision limit are to be raised if the specific gravity of the urine is higher than normal levels. So I assume that if Froome’s urine was concentrated as a result of dehydration, that correction would have been made. If it was, and the adjusted threshold and limit were now higher than Froome’s level, then he would not have an AAF, and we never would have heard about this.
(Edit: In that same CAS decision mentioned above, it's stated that "WADA do not allow a correction for SG down to 1020 for exogenous substances with a threshold such as Salbutamol." So apparently Froome's values could have been affected by dehydration without WADA doing anything about it. I now see further, from the passage that hog quotes below, that the reason WADA doesn't do anything is because they have an allowable range of urine SG values. If the athlete's urine SG falls within this range, they go ahead with the test. If it doesn't, they request another sample. As hog points out, since Froome's sample was actually analyzed, the SG must have fallen within the required range. Depending on how broad the range is, Froome's value at 1.020 might have been considerably lower, but probably not below the threshold, and even if were, this won't help him. All he can do in a further test is try to maximize dehydration to the point that it affects his urinary value, but does not take the SG out of the allowed range).
2. How did Froome come to have such a high level of salbutamol? This is puzzling, because he was tested before and after the one day, stage 18, in which this level was reported, without as far as we know having any other tests in which the level was above the allowed threshold. In fact, he wore the leader’s jersey in the Vuelta from stage 3 to the end of the race, which means, I believe, that he was tested fifteen times before stage 18, and three times after. Any explanation has to take this into account, and in particular, it seems to indicate he wasn’t intentionally taking large, unallowed doses of salbutamol throughout the race. But I will return to this point later.
There seem to be only two possible explanations. The first is that he took more than the allowed dose, either by accident or intentionally. The problem with this scenario is that he would have had to exceed the allowed dose by a very large amount. Since he wasn’t above the threshold of 1000 ng/ml following any of the other stages, the amount that he took on stage 18 appears to have been more than double what he normally took. (Note to hazaaran: the data fully back up the assumption of roughly linearity in this range). I think it’s unlikely that such a large difference would result from an accident or carelessness. In fact, based on the studies I’ve seen, he would have to take considerably more than the allowed amount just to get to the threshold. According to one typical study, an 8 mg oral dose might be expected to result in a peak urine level of roughly 2000 ng/ml. Thus about 4 mg would be needed to breach the threshold of 1000 ng/ml. These relationships are roughly the same for inhalation.
One might point out that Froome’s urinary level of salbutamol would depend not only on how much of the drug he took, but when. If he took much of the drug before the stage began, and urinated at some point during the stage, his level when tested at the end of the stage would be relatively low. Whereas if he took much of the drug during the stage, particularly late in the stage, and didn’t relieve himself, his levels would be much higher. The problem, though, is that even if we presume his stage 18 level occurred under something like the latter conditions, resulting in maximally high urine levels, this level is still far above what would be expected if he inhaled the maximum allowable. This is clear from the numbers I provided in the preceding paragraph. His level doesn’t make sense as the result of accidentally taking somewhat more than his usual dose, even if everything he did subsequently maximized the amount of drug found in the urine test.
3. However, there is another version of this explanation where these factors may become relevant. Suppose that Froome was in fact taking larger than allowed doses of salbutamol throughout the Vuelta. He would probably be doing this as an intentional doping program, but for our purposes, it doesn’t really matter why. The conventional thinking is that he couldn’t have been doing this, or he would have tested above the threshold on other stages besides 18. But this is not necessarily the case.
I already pointed out the CAS Sundby case, in which the athlete took 15 mg of salbutamol, and didn't exceed the threshold by that much, 1300 ng/ml. In fact, WADA stated in the decision that had Sundby took that amount over 24 hours (he actually took it within five hours), he probably would not have exceeded the threshold! I also noted that a study reported that a 4 mg oral dose resulted in a peak urine level right about at the threshold of 1000 ng/ml. So while taking that much might be pushing the envelope, Froome could probably take a somewhat lower dose, say 2 mg, without concern. That alone might give him some benefit that he thought made it worthwhile.
But he could take more if he was careful about the timing. About half of an oral dose of salbutamol is excreted within 3-4 hours after ingestion. Most stages are longer than this, of course, so if Froome were to take a very large dose before the stage, then urinate at some point before the end of the stage, he could reduce his urinary levels substantially. That 4 mg borderline dose might now become as much as 8 mg, and a safe dose now becomes perhaps 5-6 mg.
Now it becomes somewhat easier to understand how one stage could have an outlier value. Part of the reason could be because he took more than the usual dose before the stage began, either intentionally or by accident. Part of the reason could be because he didn’t pass urine before the end of the stage, or conversely, did so too soon after dosing. Part of the reason could be because in addition to an oral dose at the start of the stage, he also inhaled the drug during the stage, more so than he anticipated.
All of these factors, contributing together, make it somewhat easier to see how Froome might have greatly exceeded the limit. I’m not saying this is a completely satisfactory solution, the difference between stage 18 and other stages is still huge, but I think it’s more credible than the alternative version, in which he simply inhaled too much by accident. At the very least, I think it establishes that it would be possible to take fairly large doses of salbutamol, and generally remain under the threshold. And most important, this is a testable hypothesis; it might be supported by further data that should be available. This scenario predicts that Froome's urinary values on the other stages would be fairly high, > 500 ng/ml, probably higher than one would expect if he was just inhaling the allowed amount. WADA, of course, only cares if his values are below the threshold, but in theory, if Froome was taking large oral doses of salbutamol, there should be a disconnect between his claims of inhaled doses and his actual urinary levels. If this case gets as far as CAS, I can see that issue becoming important.
Also, someone help me out here. Are nature breaks common in GT stages? I know they happen sometimes, but would a rider usually stop at some point? Because with a relatively rapidly cleared drug like salbutamol, whether or not you stopped to piss before the end of the stage could be critical.
And while on this general subject, I asked earlier what evidence there was that Froome used salbutamol previously. All I got in response was that he used an inhaler in 2014. But that's after the great transformation! What about before? Again, this seems to me fairly critical.
4. The other explanation for his high level is that it was the result of a blood transfusion. He had salbutamol in his circulation—the result of intentional doping with probably oral dosing—when he withdrew blood, and when he then transfused this blood, during the Vuelta, the salbutamol of course went into his system as well, and resulted in exceeding the threshold. This explanation has the advantage of accounting for why Froome exceeded the threshold only once—he transfused before the stage—and of course, blood transfusion is a very well established means of performance enhancement, much better supported than simply using salbutamol. In this scenario, salbutamol would probably be a secondary means of doping, not the main factor, and he wasn't necessarily using it all during the Vuelta, except for inhaling it.
This explanation also has problems, though. First and foremost, in order for a transfusion to contain enough salbutamol to result in a urinary level exceeding the threshold, an extremely high dose would have to have been taken prior to blood withdrawal. How high? Pharmacokinetic studies of salbutamol, in which peak plasma concentrations of the drug are determined following an oral dose, indicate that a maximum as high as 120 ng/ml. might result from 4 mg. Since 500 ml of blood contains roughly 300 ml of plasma (the remainder is the hematocrit), this would contain about 36 ug of salbutamol, or roughly 1% of the oral dose.
As I pointed out above, an 8 mg oral dose is roughly the minimum one would have to take to result in a peak urinary level of salbutamol of 2000 ng./ml, the threshold concentration. From this it follows that for 500 ml of transfused blood to contain enough of the drug to reach this threshold, the dose preceding withdrawal would have to be about 800 mg, or nearly 1 g! This is a very rough estimate, and might be reduced somewhat by taking into account other considerations. For example, only about half of an oral dose gets into the circulation, whereas of course all of the drug contained in a blood transfusion goes into the circulation. Just based on this, we might reduce the amount to 400 mg.. We might knock this value down further by noting there will substantial individual variation. There is a great deal of uncertainty in this estimate.
But the bottom line is that a very high dose will be required. When we consider other problems—that the withdrawal-transfusion paradigm for blood doping would probably not be favored by someone like Froome, who could afford the centrifuge necessary to separate red cells from plasma, then freeze them—this explanation doesn’t look very likely to me. Based on what evidence I’ve seen so far, I think oral dosing is the best explanation. But I look forward to any new information that could affect this conclusion.
I thought there was a suggestion that transfusions don't take immediately. Like, maybe part of the reason for the bad day after a rest day thing is settling in to the effects of the transfusion? Similarly, I thought that was part of the potential explanation for Floyd, back in the day. Bad reaction to the transfusion, so boost the testosterone to improve it a bit, or something like that. The other thought is, do we know for sure they tested for salbutamol every day? I thought they sometimes don't test for some things? Admittedly that might be 10 year old methodology (or flawed recollection, whatever), and nowadays they might throw the book at every sample?
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