Drugs in drinking water?
what should we think of it?

ORIGIN OF THE PROBLEM

The drugs we consume are not designed to be metabolized by the human body. An important part of the absorbed drug is excreted in the faeces and urie and ends up in the environment through sewage. Sewage Treatment Processes have little effect on drug substances.

They are not designed to have a low life expectancy once they are released into the environment, mainly dissolved in water: groundwater, rivers, lakes.

How contamination occurs?
  • As previously mentioned: human waste – sewage – spreading of sludge and waste water.
  • Path similar for drugs for animals by spreading of liquid manure (but often without going through a treatment plant which, anyway, would have very limited effectiveness).
  • Still shortest path in the case of aquaculture.
  • Disposal of unused medications in the bathroom or any other inappropriate means.

CURRENT SITUATION

SUBSTANCES DETECTED – MWRA

The most frequently found substances following MWRA (Massachusetts Water Resources Authority) 2011.

Drugs:
  • Acetaminophen
  • Caffeine
  • Carbamazepine
  • Fluoxetine
  • Gemfibrozil
  • Ibuprofen
  • Iopromide
  • Sulfamethoxazole
  • Trimethoprim
HORMONES:
  • Estradiol
  • Estrone
  • Ethinylestradiol
  • Progesterone
  • Testosterone
Molecules found in water of 24 major cities in the USA
Source : Associated Press, Jeff Donn et al., Drugs found in drinkig water, 2008.

Molecule (En) Molécule (Fr) Frequence
caffeine Caféine 9
meprobamate méprobamate 7
phenytoin phénytoïn 7
carbamazepine carbamazépine 6
codeine codéine 4
sulfamethoxazole sulfaméthoxazole 4
cotinine cotinine 3
ibuprofen ibuprofène 3
acetaminophen acétaminophène 2
azithromycin azithromycine 2
dehydronifedipine dehydronifédipine 2
naproxen naproxène 2
amoxicillin amoxicilline 1
clofibric clofibrique (acide) 1
diclofenac diclofénac 1
diphenhydramine diphénhydramine 1
estradiol estradiol 1
estrone estrone 1
monensin monensine 1
prednisone prednisone 1
roxithromycin roxithromycine 1
sulfathiazole sulfathiazole 1
tetracycline tétracycline 1
tylosin tylosine 1
virginiamycin virginiamycine 1

It should be noted that these lists are highly dependent on the precision of the analysis and, of course, of substances analyzed.
This makes them a moderate interest.

REGULATIONS FOR DRINKING WATER

The official considers that the health impact of drugs in the water is low or uncertain and that it is therefore premature to set standards.
To our knowledge, there are no regulations on concentrations of drug molecules either in drinking water or sewage effluent [with the exception of the Australia]. (New Republic, This New Study Found More Drugs in Our Drinking Water Than Anybody Knew, 2013)

This is not unlike the case of asbestos: the first harmful effects have been detected as early as 1898 in the United Kingdom and 1906 in France but it took until 1998, that is to say a century to get to a ban on all forms of asbestos (COMEST world commission on the ethics of knowledge scientific technology and the precautionary principle, 2005)

Regulation for New Drug Approval

In the United States, when a pharmaceutical company requires a New Drug approval, it must determine an estimate of the future concentration of this drug in the environment. This takes into account the estimated number of consumers, amounts released by the body of it degrades in the environment. If the concentration in the environment (in water) is greater than 1 ppb FDA (Food & Drug Administration) can ask for further study. Source: Dawn Fallik, This New Study Found More Drugs in Our Drinking Water Than Anybody Knew, 2013

FISH AND ESTROGEN

The impact of the drug molecules on marine animals, and especially the fish, is a topic that is more discussed. The substances involved are, first, estrogen causing a feminization of male fish to the point that males can produce eggs. It is not sure that only estrogens are responsible for, more and more researchers think a cocktail of substances is responsible for these disturbances (Futura Sciences, feminization of fish in rivers: new products at issue, 2009).
The problem was detected in the Potomac River flowing through Washington, in 2002. Nearly 42% of individuals from a variety of perch (small mouth perch , Micropterus dolomieu) male had both testicular and ovarian tissue. Another study found sexual anomalies for nearly 80 percent fish of the same species.
Source: National Geographic News, Cocke W, Male Fish Producing Eggs in Potomac River, 2004.

FISH AND ANTI-DEPRESSANTS

Researchers from the University of Wisconsin-Milwaukee were interested in the behavior of male minnows (Phoxinus phoxinus, species commonly used by the laboratories of Biology) exposed to fluoxetine, marketed as Prozac.
At 1ppb, frequent concentration in sewage water, important disorders of libido were observed. When the dose is increased, the behavior of the males becomes aggressive up to kill females.
Cf. Environmental Health News, Bienkowski B., Fish we Prozac: Anxious, anti-social, aggressive, 2013.
More details in USGS, Intersex fish Endocrine disruption in smallmouth bass.

PROSTATE CANCER

A study published in 2011 in BMJ Open (Maine, Fleshner, Oral contraceptive use is associated with prostate cancer: year ecological study, 2011 has highlighted a strong correlation between female oral contraceptive use and frequency of prostate cancers. This correlation does not exist for other forms of contraception.
Certainly, a single correlation does not allow to conclude a causal relationship but only a suspicion of causal relationship.

ANTIBIOTICS

The use of antibiotics is not limited to human medicine. They are also widely used in veterinary medicine. Princeton University researchers have discovered that pigs could consume on average in OECD countries, 172 mg of antibiotics per kilogram of animal, 148 for chickens and 45 mg for cattle.
Cf. Princeton Environmental Institute, White A., Antibiotic effectiveness buried as use in livestock expected to increase 67 percent by 2030, 2015.
See Resel C. et al. Pharmaceutical residues and other emerging substances in the effluent of sewage treatment plants, 2015.

POINT OF VIEW OF SCIENTISTS

First, it should be noted that if many articles address this problem, little scientific work are available to form an opinion as objective as possible. Of course, pharmaceutical companies must be reluctant to fund this kind of research!

WHO

As we lack of regulations for these substances, it makes sense to ask the question: how to determine acceptable levels?
WHO deals with this topic and made a synthesis in the WHO document, Pharmaceuticals in Drinking-water, 2011 :
“For human pharmaceuticals, the health end-point was a surrogate ADI, which was derived by dividing the lowest daily therapeutic dose by safety factors ranging from 1000 to 10 000. The use of the lowest daily therapeutic dose as a starting point for deriving guideline values or assessing risk has been adopted by others (Webb et al., 2003; Schwab et al., 2005; DWI, 2007; Versteegh et al., 2007; Bull et al., 2011). With respect to pharmaceutical metabolites in source waters, it was considered that the activity of metabolites is generally lower than that of the parent compound, and application of safety factors in the range of 1000–10 000 should provide a safety buffer that is sufficiently conservative.”
In short, the lowest therapeutic daily dose should be divided by a factor of 1 000 to 10 000 depending on whether it is a basic molecule or a metabolite.

The values of the safety coefficients to use differ slightly according to different sources. This topic is widely discussed in Australian Government, National Health and Medical Research Council, Australian Guidelines for Water Recycling, 2008, which also has a range of values ranging from 1,000 to 10,000 but applied differently:
It is standard practice to apply safety (or uncertainty) factors to derive guideline values from base data for threshold chemicals (in this case lowest recommended therapeutic doses) that are designed to be protective of human health. […] the following safety factors have been applied:
  • all pharmaceuticals — a safety factor of 1000 is applied, comprising
    • 10 for differences in response between humans (intraspecies variation taking into account responses from sensitive individuals)
    • 10 for protection of sensitive subgroups including children and infants
    • 10 for the lowest daily therapeutic dose not being a NOEL
  • cytotoxic drugs — an additional safety factor of 10 is applied due to the higher level of toxicity associated with these compounds
  • endogenous and synthetic hormones —an additional safety factor of 10 is applied on the grounds that the potential effects of these chemicals on hormonal function and fertility are strong (eg contraception) and are unwanted in those not being treated.

VARIOUS STUDIES

FRANCE
A study conducted in the Northwest of the France showed that “Psychostimulants, non-steroidal anti-inflammatory drugs, iodinated contrast media and anxiolytic drugs were the main therapeutic classes of human pharmaceutical compounds detected in the surface water and drinking water.”
Article in Journal of Environmental Monitoring, September 2011:
“Contamination levels of human pharmaceutical compounds in French surface and drinking water.”
Waiting for the full text asked the 26/01/2016.

CHINA
Chinese researchers have analyzed the drinking water of vile large 13 of the countries (Beijing, Yancheng, Nanjing, Hangzhou, Shanghai, Wuhan, Changsha, Xiamen, Guangzhou, Zhuhai, Macau, Shenzhen and Hong Kong). They carried out 113 samples and searched 32 molecules of pharmaceutical products.
Here is the summary of the results of these analyses:
“We detected 17 pharmaceuticals in 89% of samples, with most detectable concentrations (92%) at Source: Ho Wing Leung and al., Pharmaceuticals in Tap Water: Human Health Risk Assessment and Proposed Monitoring Framework in China, 2013.

ACCEPTABLE CONCENTRATIONS

METHOD OF DETERMINATION OF THE ACCEPTABLE CONCENTRATIONS

Here we apply the method proposed by the WHO with a safety factor k1 = 10 000 for the base molecules and k2 = 1 000 for metabolites.
It should be noted that such factors of safety are in line with practices in toxicology as they take into account:
  • several molecules can have similar effects (for example several antidepressants)
  • the duration of use (a few weeks for a medical prescription, sometimes years when the molecule is in drinking water)
  • intraspecies variability
  • individuals at risk.

Example for fluoxetine (Prozac)
Indication: episodes of major depression, OCD.
The minimum therapeutic dose is 20 mg/day.
We may absorb on a daily basis, through drinking water, only 20 mg / k1 = 2µg
Assuming that an adult consuming 2 L of water per day, the concentration of fluoxetine may not exceed 1 µg/L = 1 ppb.

Example for estradiol (Oestrodose)
Indication: hormone replacement therapy (HRT) of the deficit in oestrogen in postmenopausal women, prevention of osteoporosis.
The minimum therapeutic dose is 0.75 mg/day.
We may absorb on a daily basis, through drinking water, that 750µg / k1 = 0.075µg
Assuming that an adult consuming 2 L of water per day, the estradiol concentration must not exceed 0.038 µg/L = 0.038 Sch = 38 ppt.

Example for ethinylestradiol (EE2)
Indication: it is the most used orally active estrogen in the world.
The minimum therapeutic dose is 20 µg/day.
We may absorb on a daily basis, through drinking water, that 20µg / k1 = 2ng
Assuming that an adult consuming 2 L of water per day, ethinylestradiol concentration may not exceed 1 ng/L = 1 ppt.

ACCURACY REQUIRED FOR MEASUREMENT

We have just seen, through the previous examples, that the acceptable concentrations are highly variable according to the molecule: from 1ppb to 1ppt in these examples.
It follows that the required accuracy for analysis is a function of the molecules.
The water framework Directive (WFD) 2009/90/EC of 31 July 2009 defines the notions of limit of detection (LOD) and limit of quantification (LOQ).

detection limit: the output signal or the value of concentration beyond which it is permissible to say with a degree of confidence that a sample is different from a sample does not contain the relevant analyte.

limit of quantification: a multiple given the limit of detection for concentration of the analyte that can reasonably be determined with a degree of accuracy and acceptable accuracy. The quantification limit can be calculated using a stallion or a proper sample, and can be obtained from the lowest point on the calibration curve, excluding the witness.

This is supplemented by article 4 “performance criteria minimum for analytical methods”:
. Member States shall ensure that the minimum performance criteria of all analytical methods used should be based on a lower measurement uncertainty or equal to 50% (k = 2), estimated at the level of standards and applicable environmental quality on a quantification limit lower or equal to a value of 30% of the standards appropriate environmental quality.
In the absence of environmental quality standard appropriate for a given parameter or in the absence of method analysis meets the minimum performance criteria referred to in paragraph 1, Member States shall ensure that the monitoring is done using the best available techniques not excessive costs.

The decree to the methods of analysis of water samples and their performance characteristics DGS/SD7A/30-07-2003, meanwhile, sets:

The detection limit is:
  • is three times the standard deviation within a batch of a natural sample containing a low concentration of the parameter,
  • is five times the standard deviation within a batch of a virgin sample.
The limit of quantification is the smallest value from which there is a result of measure with sufficient fidelity. It must be calculated according to paragraph 5.1.3.3 the French standard XP T 90-210 of December 1999.

It should be noted that this Decree states, in addition, for each substance, the LOD and the LOQ without indicating what rule has been specifically applied to set them.
It is nevertheless clear that LOD and LOQ are relaxed with the increase of the analytical difficulty, which is understandable.
For instance, for a comparable analytical difficulty (100ng/L or 100ppt), most pesticides have a LOD set at 25% of the parametric value and a LOQ at 5%. These two values are supplemented by “goal value” note.

METHODS OF ANALYSIS

The research of molecules in water at concentrations of the order of the ppt requires particularly performant analytical techniques.
In the following document, the authors claim a LOD of the order of the ppt for antibiotics.
Article in Environmental Science and Pollution Research, Qiang Xue and al., Ultra-high performance liquid chromatography-electrospray tandem mass spectrometry for the analysis of antibiotic residues in environmental waters, June 2015.