The anti-flu drugs could have consequences through wastewater

[Tonka]

http://cordis.europa.eu/fetch?CALLER=ES_NEWS&ACTION=D&SESSION=&RCN=33142

Spanish to English translation

The anti-flu drugs could have consequences through wastewater

[Date: 03/03/2011]

Many of the drugs used to prevent or treat influenza will remain active when released into the sewer and in the event of a pandemic, large quantities of these substances could end up in sewage treatment. In this case, could carry out its mission of these facilities? An international team of scientists funded in part by the European Union has studied this issue.

His work focused on analyzing the ecotoxicological risks posed by sanitary measures against a future pandemic of influenza, was backed by three European projects: DYNANETS ("Computing real-world phenomena through complex networks of dynamic change process), epiphora ("Complexity and predictability of epidemics: toward a computational infrastructure for epidemic forecasting) and EPIWORK (" Development of a framework for epidemic forecasting infrastructure).

In 2009, during the pandemic of H1N1 influenza, the public health sector was following developments closely and tried to mitigate its impact on society. However, only took into account the impact that could lead to environmental health intervention against the pandemic. The authors of the referred study explored the concentrations of antiviral drugs and antibiotics that could end up in wastewater.

Antivirals are used to prevent or treat the flu, while antibiotics can be given to remedy secondary bacterial infections such as pneumonia. The human body does not completely absorb this flow of drugs. Sooner or later, most of these are removed by the body and the potent blend of bioactive substances for goes directly to the course nearest wastewater. In the event of a pandemic, the usual trickle of these substances could become an entire stream.

To assess the risk this poses to the water supply network, the authors created a computer model that simulated the amount of drugs likely would be used in pandemics of varying severity based on a water quality model of the watershed of the Thames (United Kingdom). Thus the researchers issued forecasts of the expected concentrations of these substances in wastewater. Moreover another model was used to assess the potential impact on the area's rivers and sewage treatment.

A high concentration of antivirals and antibiotics in such waste water may inhibit the growth of microorganisms used in these facilities to remove harmful nutrients, thereby reducing the efficiency of purification. At least in theory, would therefore plausible contribution of inadequately treated sewage into rivers receptors. Depending on the severity of the problem, this could significantly affect the quality of drinking water and the environment (in the latter case, eutrophication and the loss of aquatic life).

The findings of this research team, published in Environmental Health Perspectives, indicate that probably the ecotoxicological implications of a mild pandemic would be negligible. In contrast, moderate or severe pandemic could lead to another disturbing consequences on the environment. The computer projections indicate that the threshold of inhibition of microbial growth would be exceeded in most treatment plants in the watershed of the Thames and this could affect the quality of water in between 5% and 40% of river.

The first author of the article, Andrew Singer, of the Centre for Ecology and Hydrology in the UK, also highlighted another issue: "The possible large-scale dispersion of antivirals and antibiotics in the environment could accelerate the development of resistant pathogens, which could affect human health both during and long after the final "formal" of the pandemic. "

That said, Dr. Singer also stressed the need to investigate further. "In order to reliably assess the risks posed by the health response to pandemic flu, should be obtained before a more precise understanding of the ecotoxicity in sewage treatment plants," he added.

Before a pandemic flu vaccine would greatly reduce the health risks to humans and the impact on society, and contribute to limit the potential damage from the environment. ?[...] Correct production and distribution of vaccines against influenza (pre-pandemic and pandemic phases) could greatly help to remedy all the problems for the environment and human health that we indicated in our article, it implies the important additional benefit of reducing morbidity and mortality among the British population. Vaccination probably poses the biggest challenge for society, "said Dr. Singer," but also constitute the most effective intervention. "

DYNANETS, epiphora and EPIWORK received funding amounting to 2.8 million, 684,000 and 4.9 million euros, respectively, through the Seventh Framework Programme (FP7). The EU contribution to DYNANETS and EPIWORK was conducted as part of FP7 support to research related to information technologies and communication technologies (ICTs). For its part, the funding for EPIPHORA came in the form of a grant to independent researchers who begin their careers (Starting Grants) of the European Research Council (ERC) under the Ideas Programme of FP7.

The study also involved researchers from the University of Indiana (United States), the Institute for Scientific Interchange (Italy), University of Sheffield (United Kingdom) and the University of Utrecht (Netherlands).

For more information, see:

Centre for Ecology & Hydrology (CEH):

http://www.ceh.ac.uk

[Shannon Bennett]

Re: The anti-flu drugs could have consequences through wastewater

This is an experiment that can be studied as we speak. If, as we suspect, there is a Tamiflu blanket being applied to a wide swath of Indonesia, scientists should be able to see for themselves what happens when the excreted medicine enters the treatment plants as well as local waterways.

[JJackson]

Re: The anti-flu drugs could have consequences through wastewater

See also the original paper. The Reveres posted on this and do not forget to read the comments as many good points were made by Revere, Andrew Singer (lead author), Marc Lipsitch and others.

This is a link to the original paper (full .pdf) and this is to the current abstract

My thoughts have not changed and are in the 2006 Effect Measure comments.

Shannon: The effects require massive (pandemic) quantities to be taken and are unlikely to be measurable as it is being used in too small quantities. There was a point early in the 2009 pandemic when the UK shifted from MD based flu diagnosis to a call center based system where answering question from a flow chart lead to over-the-phone Tamiflu prescription for self collection from designated local pickup points. As it became clear that the disease was relatively mild in most cases they stopped handing it out so freely. If there was a point where measurable quantities could have been detected in the water course it is likely to have been then. I do not know if Andrew and team looked.

[AlaskaDenise]

Re: The anti-flu drugs could have consequences through wastewater

A high concentration of antivirals and antibiotics in such waste water may inhibit the growth of microorganisms used in these facilities to remove harmful nutrients, thereby reducing the efficiency of purification

How does this compare to the currently existing presence of anti-bacterials from anti-bacterial hand soaps, counter wipes, etc.? Do the current residential-use anti-bacterials impact "friendly organisms" in the same way that anti-virals would, as far as the impact scope?

One may be able to estimate effects by comparing the total production volume of these everyday products, with an estimated volume of anti-virals in a pandemic.

.

[AlaskaDenise]

Re: The anti-flu drugs could have consequences through wastewater

Here's an interesting study about municipal treatment plants, that includes how they address antibiotic resistant bacteria. What I find especially interesting, is they found 11 strains of bacteria that are resistant to at least 4 different antibiotics, including cipro and several of those are shown to be capable of lateral gene exchange!

See: http://www.cura.umn.edu/reporter/06-...Para_et_al.pdf

.

[JJackson]

Re: The anti-flu drugs could have consequences through wastewater

<!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:Compatibility> <w:BreakWrappedTables/> <w:SnapToGridInCell/> <w:WrapTextWithPunct/> <w:UseAsianBreakRules/> </w:Compatibility> <w:BrowserLevel>MicrosoftInternetExplorer4</w:BrowserLevel> </w:WordDocument> </xml><![endif]--><!--[if !mso]><object classid="clsid:38481807-CA0E-42D2-BF39-B33AF135CC4D" id=ieooui></object> <style> st1\:*{behavior:url(#ieooui) } </style> <![endif]--><!--[if gte mso 10]> <style> /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman";} </style> <![endif]--> Darwin would be proud.

Create a novel environment and selection pressure will help something adapt to fill the niche.

[AlaskaDenise]

Re: The anti-flu drugs could have consequences through wastewater

Which type of organism adapts fastest (related to the normal replication rate) - pathogens, plants, animals, etc.? Given how nature strives to keep things "in balance", it may well be those organisms that can reduce a perceived oversupply, i.e., pathogens.

If SS RNA viruses are some of the faster adapators, does that imply that a massive influx of anti-virals could create even more varieties than those bacteria in municipal treatment facilities? I'd like to think it would be limited by the timespan of a pandemic, but then there would be all those new strains.....

That might explain why we have an innate immune system in addition to our humoral system. Gotta have those general all-hazard tools.

.

[andrewcsinger]

Re: The anti-flu drugs could have consequences through wastewater

As was previously noted, the amount of Tamiflu that is used during 'interpandemic' periods are relatively small compared with the amount that was/will be used during a pandemic. So the impact of interpandemic Tamiflu use is unlikely to be meaningful. However, it is really difficult to empirically test this question as there are few places in the world that use enough Tamiflu to allow for researchers to look at this question. Japan happens to be the one place that uses quite a lot of Tamiflu. There are publications on the amount of Tamiflu coming out of these sewage plants but there was no indication by the researchers whether the plant was working any less well during the seasonal flu period.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0006064

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831951/?tool=pubmed

The confounding factor is that the flu season is in the winter when sewage works are working at their worst owing to the cold temperatures--so this would indeed be a difficult problem to tease apart without doing experimental work (i.e. manipulations in the lab).

I can direct those who are interested to two pieces of work that lend some insight into the potential effects of pharma on sewage plants. Some relevant references are found in the original EHP paper being cited above...but the following is also relevant: http://www.citeulike.org/group/13135/article/8291710

and a poster presented at a conference this past year:
http://www.prepare.org.uk/news-links/ (top link on page)

The latter link shows the amount of Tamiflu and some antibiotics recovered from the Thames River in the UK during the last pandemic. The data from this study is still coming out as we have loads more datapoints still to be processed, but the peak period (or so we thought) were the ones we report in the poster. The concentration of Tamiflu is the highest reported concentration so far--but will be minor compared to a more severe pandemic as the amount of Tamiflu consumed declined as people realised that they will probably survive the pandemic without any drug use.

Have a look through the website:

http://www.prepare.org.uk/

as it addresses many of these questions.

As for the effect of antimicrobials from handsoaps, etc on bacteria--yes, this has been looked at and there are very clear signs that the bacteria have adapted to the presence of these chemicals in their environment through resistance genes--it's not clear whether it has made a bit of difference to the function of the 'system'--but the (increased) presence of resistance genes is a clear sign that it does matter that the chemicals are there.

Lastly, one needs to keep in mind that a flu virus will not adapt to the presence of antivirals unless it has infected a host and the antivirals are present during the replication of the virus. This can happen in the human at the time of infection and administering of the drug or in the environment as the wildfowl will drink riverwater containing antiviral which will also contain the influenza virus--both of which will be present at the site of infection (gut) and thus can select for antiviral resistance. This point is SO FAR a point of academic interest as it's not clear how relevant it is for human health that a bird influenza virus is resistant to Tamiflu (as the bird flu virus is unlikely to be able to infect humans).

I hope this helps answer some questions raised above!
Best,
Andrew Singer

[Laidback Al]

Re: The anti-flu drugs could have consequences through wastewater

Thanks for the informative post, Dr. Singer. Welcome to FluTrackers.

[sharon sanders]

Re: The anti-flu drugs could have consequences through wastewater

Welcome and thank you Dr. Singer.

[sharon sanders]

Re: The anti-flu drugs could have consequences through wastewater

hat tip Senior Moderator Michael Coston -

Pandemics & The Law Of Unintended Consequences





# 5348

A variation today on a theme we?ve touched on before.

What happens to the environment during a pandemic when large numbers of people in a community are taking ? and subsequently excreting in their urine & feces ? antivirals and antibiotics?

Many of the life-saving drugs used during a pandemic are excreted at some percentage from the human body unchanged or as a bioactive metabolite. Tamiflu, Erythromycin, and Moxifloxacin are almost 100% bio-actively intact at excretion.

Supplemental Table 4. Assessing the Ecotoxicologic Hazards of a Pandemic Influenza Medical Response. Environ Health Perspect :-. doi:10.1289/ehp.1002757

A little more than four years ago, the subject of what happens to Tamiflu once it is excreted by the human body first graced these pages.

The blog was called The Law of Unintended Consequences, and it looked a study conducted at the Centre for Ecology and Hydrology in Oxford, England.

Their findings were released in the January 2007 issue of Environmental Health Perspectives (EHP) in a report entitled, Potential Risks Associated with the Proposed Widespread Use of Tamiflu, that illustrated what might happen if millions of people simultaneously began taking Tamiflu and releasing it into our environment.

The upshot of the the study was that scientists believed enough of the metabolite OC (oseltamivir carboxylate)would be present in some rivers and streams, after sewage plant processing, to present a genuine risk to the environment.

The concern being that enough Tamiflu might persist after wastewater treatment and release to rivers and streams that it might speed the development of resistant influenza viruses in waterfowl.

Fast forward to October of 2009 and we saw another report (see Everything Old Is News Again), based on studies done the previous year in Kyoto, Japan ? that showed elevated levels of the OC Metabolite in wastewater discharge.

More recently, investigators looking at the levels chemicals in rivers downstream from a pharmaceutical manufacturing hub in India, found staggering amounts of antibiotics along with signs of resistant bacteria.

That story was recently well covered by Maryn McKenna on her Superbug Blog (see Drug residues and drug resistance in water: Not good).

Today, a new study appears in Environmental Health Perspectives that reports on another potential problem inherent in the massive distribution and consumption of antibiotics and antivirals during a pandemic.

WWTPs (Wastewater Treatment Plants) depend upon microbial activity in order to breakdown or `digest? sewage.

Antibiotics in the sewage ? at elevated levels such as might be seen during a pandemic ? could inhibit microbial activity, resulting in the failure of WWTPs and the discharge of under-treated wastewater into the environment.

First a link to the study, an excerpt from the abstract, and a link to the press release . . . then I?ll return with a little more.

Assessing the Ecotoxicologic Hazards of a Pandemic Influenza Medical Response
Andrew C. Singer, Vittoria Colizza, Heike Schmitt, Johanna Andrews, Duygu Balcan, Wei E. Huang, Virginie D. J. Keller, Alessandro Vespignani, Richard J. Williams

Background: The global public health community has closely monitored the unfolding of the 2009 H1N1 influenza pandemic to best mitigate its impact on society. However, little attention has been given to the impact of this response on the environment.

Antivirals and antibiotics prescribed to treat influenza are excreted into wastewater in a biologically-active form, which presents a new and potentially significant ecotoxicologic challenge to microorganisms responsible for wastewater nutrient removal in wastewater treatment plants (WWPTs) and receiving rivers.

<SNIP>

Conclusions: The current pandemic influenza medical response might result in the discharge of insufficiently treated wastewater into receiving rivers, thereby increasing the risk of eutrophication and contamination of drinking water abstraction points. Widespread drugs in the environment could hasten the generation of drug resistance. These results highlight the need for empirical data on the effects of antibiotics and antiviral medications on WWTP and freshwater ecotoxicity.
Supplemental Material

(1.8 MB) PDF.

The 48-page supplemental file provides a pretty good look at the assumptions used in this computational study.

A press release summarizes this study?s findings, portions of which follow:

Centre for Ecology & Hydrology
Public release date: 2-Mar-2011

Effectiveness of wastewater treatment may be damaged during a severe flu pandemic

Existing plans for antiviral and antibiotic use during a severe influenza pandemic could reduce wastewater treatment efficiency prior to discharge into receiving rivers, resulting in water quality deterioration at drinking water abstraction points.

These conclusions are published this week (2 March 2011) in a new paper in the journal Environmental Health Perspectives, which reports on a study designed to assess the ecotoxicologic risks of a pandemic influenza medical response.

<SNIP>

The research team concluded that, consistent with expectations, a mild pandemic (as in 2009) was projected to exhibit a negligible ecotoxicologic hazard. However in a moderate and severe pandemic nearly all WWTPs (80-100%) were projected to exceed the threshold for microbial growth inhibition, potentially reducing the capacity of the plant to treat wastewater.
In addition, a proportion (5-40%) of the River Thames was similarly projected to exceed key thresholds for environmental toxicity, resulting in potential contamination and eutrophication at drinking water abstraction points.
(Continue . . . )

As Professor Emeritus of Statistics at the University of Wisconsin George E. P. Box famously observed:

?All models are wrong, but some models are useful.?

Until we actually see a severe pandemic combated by modern pharmaceuticals, it is impossible to know just how big the environmental impact will be.

Computational models, such as the one above however, give us clues as to what might happen under various very specific scenarios.

And what this study, and others in the past, have shown us is that the impact could be multi-faceted and pose significant public health ramifications.

The solution, of course, isn?t to withhold life saving antibiotics or antivirals during a pandemic. It is to recognize potential problems before they occur, and to devise contingency plans now on how to deal with them.

Much like the more famous Murphy?s law, the Law of Unintended Consequences is not a scientifically recognized law, as is Boyle?s or Torricelli?s.

Nevertheless, they can almost always be counted on introduce new complications anytime you attempt to to `fix something?.

Whether it is the creation of newly resistant organisms or the discharge of dangerous partially treated effluent into the environment, studies such as these give us new insight into unexpected problems we might face during a severe pandemic.

[JJackson]

Re: The anti-flu drugs could have consequences through wastewater

Firstly let me add my welcome to Dr. Singer as participation by researchers is always especially appreciated, and thanks for the links. Also thanks to Mike for typically clear and well linked explanation.

If we cast our minds back to the beginning of the pandemic it started in April 2009 and the UK were in what the UK Health Protection Agency (HPA) designated the ‘containment phase’ in May and June (roughly calendar weeks 19 to 26), with Margaret Chan declaring phase 6 in mid June (cw24).

I am going to add a number of graphs and quote some other data all of which – unless otherwise specified – are taken from The HPA report ‘Epidemiological report of pandemic (H1N1) 2009 in the UK; April 2009 – May 2010’

From the first of the graphs we can see the dates and relative sizes of the summer and winter peaks. The second shows the HPA regions and that the two – London (LN) and South Central (SC) – which cover most of the Thames catchment are fairly average.

If we now consider Oseltamivir usage the UK initially ordered enough Tamiflu for one course for 25&#37; of the population and later increased this to 50%. The UK has a population of about 60 million and 50 million of these live in England with the Thames valley being one of the most densely populated regions. For scale you could probably drive across regions LN and SC in a couple of hours if it weren’t for the traffic. The next graph shows when and how much Tamiflu was doled out (Ignore the top graph and concentrate on the bottom half).


As I guessed, and Dr. Singer confirmed, it is not a good match for the summer and winter peak graphs which is due to a change in perception about virulence. In fact despite the government laying in Tamiflu stocks for two waves at a 25% attack rate the report states on page 45

Sixty-eight per cent of assessments through the NPFS (1,645,948 of 2,401,043) resulted in an authorisation for antiviral drugs being issued; of these 66% (1,079,179 [2.1% of the population]) were collected.

In my earlier post I referred to a switch to ‘over-the-phone Tamiflu prescription’ this was done by the National Pandemic Flu Service (NPFS) which operated from July 2009 to February 2010. The ~2% collected and , presumably used, would only equate to about 4% of the Tamiflu stockpile.The UK pandemic plan were conceived with HP H5N1 as the primary concern and had it, or anything else, caused a high virulence pandemic then I would assume this figure would have been far higher and a tenfold increase in OC concentrations at WWTP feasible.

One thing that did surprise me - form Dr. Singer's links - was the peak OC values were found in November rather than August which is what I had been expecting but I believe that Dr. Singer has a fair bit of unpublished data which will hopefully give a temporal OC concentration graph which we can compare with the prescribing graphs.

My lastly is the same as Dr. Singer’s in that it is important to remember in all this that Oseltamivir is a Neuraminidase inhibiter. Neuraminidase is a viral surface protein which prunes sialic acid residues from proteins which helps the new virions make a clean getaway and prevents clumping. As all viruses are obligate parasites and flu has a limited host range Oseltamivir can only work if it is present at the moment of budding when infected cells release new virus. For humans this in the respiratory tract but we are only susceptible to a few serotypes, birds, and waterfowl in particular, are flu’s reservoir species. For them flu is not a respiratory disease but has an oral/faecal transmission system which does allow for neuraminidase in river water to be at the site of budding in the gut. Bacteria which need not be parasitic can live unaided in treatment plants, and are in fact critical to their function, so can be subject to relatively low levels of continuous selection pressure over long periods of time while the virus in a mallards alimentary tract would, under normal circumstance, not receive a high enough concentration to provide significant selection pressure except at the height of a pandemic.

[andrewcsinger]

Re: The anti-flu drugs could have consequences through wastewater

...Oseltamivir can only work if it is present at the moment of budding when infected cells release new virus. For humans this in the respiratory tract but we are only susceptible to a few serotypes, birds, and waterfowl in particular, are flu’s reservoir species. For them flu is not a respiratory disease but has an oral/faecal transmission system which does allow for neuraminidase in river water to be at the site of budding in the gut. Bacteria which need not be parasitic can live unaided in treatment plants, and are in fact critical to their function, so can be subject to relatively low levels of continuous selection pressure over long periods of time while the virus in a mallards alimentary tract would, under normal circumstance, not receive a high enough concentration to provide significant selection pressure except at the height of a pandemic.

Thanks very much for your excellent comments...I just have one point of query. I've copied and pasted from the original paper on Tamiflu in the environment http://ehp03.niehs.nih.gov/article/f....1289/ehp.9574

"The avian species most commonly infected with AI are wildfowl of the order Anseriformes (e.g., ducks, geese, swans) (Alexander 2000). The AIA virus is believed to be transmitted between waterfowl by the fecal–oral route as they imbibe contaminated water, although in a recent report with one AIA strain, Normile (2006) demonstrated that the virus was shed far more heavily in the duck pharynx than through the feces. In birds, the virus replicates in the lower intestinal tract (small and large intestine) and in the lungs. In the gut it buds from the surface of mucosal cells into the lumen (Webster et al. 1978). In the event of widescale Tamiflu use, waterfowl would ingest large quantities of active OC together with virus in their daily water intake, ranging from 64 mL/kg/day in glaucous-winged gulls (Walter and Hughes 1978) to 200–300 mL/kg/day in duck species (Hughes 2003). Because of the poor bioavailability of OC relative to its prodrug, Tamiflu (Kim et al. 1997; Li et al. 1998), a high percentage of OC ingested by avian species will remain in the intestinal tract, the primary site of viral replication in Anseriformes. Waterfowl have been shown to reabsorb urine into the rectum, ileum, and/or ceca, amounting to as much as 40&#37; of a mallard duck’s daily water influx, thereby concentrating nontransported ions and molecules in the lumina (Hughes et al. 1999). Hence, the concentration of OC in the gut of waterfowl might be higher than that found in the riverwater. The published IC50 of the NA enzyme for OC varies widely depending on the assay method and AIA isolate, ranging from 0.01 to 114.0 nM OC (Ferraris et al. 2005; Hurt et al. 2004; Mendel et al. 1998; Roche 2004). Le et al. (2005) reported the IC50 for drug-resistant H5N1 virus (A/Hanoi/30408/2005) to be 90 nM."

I've not seen any evidence to date to suggest that the facts and assumptions made here are no longer true. If they remain true, then it is entirely possible that Tamiflu can enrich for resistance in avian influenza.

Thanks again for your insights!
Best,
Andrew

[JJackson]

Re: The anti-flu drugs could have consequences through wastewater

Thank you for that, I had either missed it first time around or, more likely, read and forgot it.
If ducks are concentrating the OC by selectively reabsorbing the water in their alimentary track then you will need to know how much higher the gut concentration is than that in the water the Mallard is dabbling in (assuming it is higher). This would require collection of gut fluids.

[andrewcsinger]

Re: The anti-flu drugs could have consequences through wastewater

By most measures of the inhibitory concentration of tamiflu (IC50), environmental concentrations should already be sufficient to inhibit virus replication in the wildfowl gut. The matter of further concentrating it by recycling urine in wildfowl just makes matters worse. In short, the conditions necessary to select for tamiflu resistance in avian influenza virus will be present in rivers even during as mild of a pandemic as the one we just had in 2009. Actual data on whether this has already happened or could realistically happen (i.e., laboratory studies), is out there--but not yet published (sorry but I dont yet know the results of this work).

Again, I don't quite know how significant of a result it might be--as the presence of antiviral resistance in wildfowl is really only of immediate concern to ducks with a drug habbit ;-) The real question is whether the resistance genes can become more embedded in the wild-type virus which would require the selection for compensatory mutations that allow the resistant virus to out-compete the sensitive virus. Lots and lots of "ifs" invovled.