Since the World Health Organization's first warning of an avian flu pandemic two years ago, nations worldwide have been stockpiling Tamiflu for treatment and outbreak prevention. The drug, which minimizes flu symptoms and duration, inhibits the movement of the influenza virus from the cells it infects, and also helps uninfected people avoid contracting the flu. However, Tamiflu's active agent, the metabolite oseltamivir carboxylate (OC) would be excreted into sewers for several weeks during a pandemic and is expected to withstand biodegradation. According to the researchers in the current study, once birds drink OC-laced water from catchments receiving treated wastewater, they could produce Tamiflu-resistant strains and pass them on to other birds who share the same waters.

The investigators analyzed 11 waterway catchments in the United States and 5 in England using a metabolic pathway prediction system to determine the potential biodegradability of OC. They also measured wastewater discharges into the catchments. They estimated the number of clinically infected people in each catchment area treated with a full 5-day course of Tamiflu with 100% compliance, assuming that 80% of the ingested Tamiflu was released into sewer systems as OC and that all of the OC entering each catchment was flushed out in one day.

Their estimates showed a maximum concentration well above that required for development of resistance in vitro for 62 consecutive days in the arid Lower Colorado River catchment area. Overall, the researchers say that because of the lower population density for many of the U.S. catchments, peak concentrations of OC in a pandemic would be approximately 10 times less than the concentrations in British rivers. All but one of the American catchments studied are larger than those in Britain and, with the exception of the Lower Colorado River flow area, have more available dilution per person in each given population. There were no specific ecotoxicological risks from Tamiflu identified at the time the drug was submitted for approval to the European Medicines Agency. The authors, however, suggest that the ecotoxicological risk associated with Tamiflu use needs to be reassessed in light of the hundreds of millions of courses that would be consumed globally during a pandemic.

The authors warn that, with the release of the uniquely structured, biochemically resistant OC antiviral into river water, "the range of OC concentrations predicted . . . will have uncharacterized ecotoxicological consequences." They call for more detailed water contamination modeling, especially in high-risk areas of the world such as Southeast Asian countries, where there is more frequent human-to-waterfowl contact and where future use of Tamiflu would be significant. They also recommend development of methods to minimize the release of OC into wastewater systems, such as biological and chemical pretreatment in the toilet.

The lead author of the study was Andrew C. Singer. Other authors included Miles A. Nunn, Ernest A. Gould, and Andrew C. Johnson. The article is available free of charge here.

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Centre for Ecology and Hydrology in Oxford