The asthma medication salbutamol, which lies at the center of Chris Froome’s recent adverse analytical anti-doping test, presents challenges for anti-doping experts, says the United States Anti-Doping Agency’s chief scientist. Unlike more well-known doping substances like EPO or human growth hormone – which can trigger a positive test when found in an athlete’s system – inhaled salbutamol is defined as a threshold substance, not inherently banned, but only allowed up to a certain amount. That amount can be impacted by a wide range of factors, from environment and hydration levels to even an athletes’ very own genetics.
“We’re all different in the way that we process these drugs,” explains Matthew Fedoruk, Ph.D., Senior Managing Director of Science and Research at USADA. Fedoruk declined to comment on Froome’s case (Froome’s case lies outside of USADA’s purview). However, he said that a wide range of factors could explain why an athlete had an elevated level of salbutamol in his or her system—even if that athlete had taken a legal dose of the drug.
“Everything from hydration status to other medication use, for example, previous medication use,” Fedoruk said. “Was he using this medication multiple times in the days and the hours leading up to the test? Was the residual amount of medication in his system maybe below the limit and then he used an acute dose and was tested in such a way that now he’s over the limit? There’s a lot of these little details that I’m not privy to, but that’s the UCI’s job to work with the athlete’s medical team, as the results management authority, to piece together.”
Salbutamol, a drug that helps open the airways of asthmatics, is allowed by WADA code when inhaled (and only via inhalation) at a maximum dosage of 1,600 micrograms over 24 hours, not to exceed 800 micrograms every 12 hours. That amount is quantified by the presence of the drug in urine tests at an excess of 1,000 nanograms per milliliter.
Referencing recent studies, Fedoruk noted that there is evidence suggesting an athlete could return a test that exceeds the limit after having taken the legal dose of the drug.
A 2015 study conducted by scientists in Denmark and Norway, for instance, found that some athletes exceeded the WADA threshold for salbutamol even when inhaling 1,600 micrograms of the substance. Exercise and dehydration increased the likelihood of an adverse result. It’s important not to draw too many conclusions from a single study, but those conclusions nevertheless raise important questions for Froome’s case.
“The study that I referred to suggests that even if you are taking the maximum amount, up to the maximum amount, there are some individuals that can reach that threshold and go beyond that threshold,” Fedoruk said. “We’re all different in the way that we process these drugs. Depending on a bunch of different confounding factors it’s certainly possible that this particular athlete could have used this drug within the therapeutic regimen and now it’s up to figure out what did he exactly do and is it plausible scientifically.”
Froome registered his adverse analytical finding during an anti-doping control in September. A urine sample taken after stage 18 of the Vuelta a España revealed 2,000 nanograms per milliliter of salbutamol, putting him at double the threshold amount. To avoid a sanction, Froome must now provide an explanation for why a legal usage of salbutamol nevertheless exceeded the testing limit.
If he is unable to successfully make his case, he will face a ban. He would not be the first pro cyclist to receive a sanction for an elevated level of salbutamol. Both Alessandro Petacchi and Diego Ulissi received bans for the drug. Other riders, including Leonardo Piepoli, have successfully avoided sanctions despite registering test results exceeding the WADA threshold. According to the list of sanctions on the United States Anti-Doping agency’s website, the agency has yet to ban an athlete for salbutamol use. The agency has handed out three public warnings to three different track and field athletes.
Per WADA rules, Froome must undergo a pharmacokinetic study, which attempts to recreate the physical and environmental situations that occurred during his test, to prove that it is possible the salbutamol concentration in his urine was a result of a legal administration of the drug.
Fedoruk said that a laboratory will need to take into account a litany of factors in this test, due to the individual way in which the human body processes salbutamol.
“Absorption, distribution, metabolism, and excretion are the four parameters that need to be considered,” he said. “You need to understand from an absorption standpoint how the athlete took the medication and the circumstances behind that. When the athlete was tested in relation to the last dose of the medication is important as well because the sample is a snapshot in time of what was in the urine, in the bladder. Did he void six hours previously? What are the circumstances behind that?”
Froome is likely to explore every possible factor in his quest to explain the result. That said, the defending Tour champ faces several challenges if he hopes to prove a legal administration of salbutamol inadvertently led to his adverse analytical finding. His result was double the allowed amount, well beyond a built-in buffer zone in the testing process intended to take testing uncertainties into account.
“There’s both a threshold and there’s a decision limit,” Fedoruk said. “In this case, the threshold is 1,000 nanograms per milliliter. The decision limit, which it has to be over for the laboratory to report the adverse finding, is 1,200 nanograms per milliliter, because there is a measure of uncertainty.”
What’s more, although it is true that some individuals show high concentrations of the substance in their urine even after minimal doses, Froome maintains that he has relied on an inhaler to help with his asthma for years, raising the question of why he happened to return an adverse analytical finding this September.
“This athlete has been tested so many times and probably been using the drug fairly regularly, so I would have thought if that would have been the case, some kind of genetic difference, that he probably would have had multiple instances of this happening previously,” Fedoruk said.
The disparity in past cases and the findings of recent studies both speak to the nuances of anti-doping controls and Salbutamol. A pharmacokinetic study should shed more light on the situation, but it could be some time before the many unanswered questions of Froome’s case are addressed with clarity.