Transcript Spread of drugs in the environment

Ecopharmacovigilance:
why?
Giampaolo Velo
Clinical Pharmacology Unit
Regional Pharmacovigilance Centre
WHO Reference Centre
University of Verona
Italy
Moving beyond Kyoto
New York Times, July 1 2007
by Al
Gore
WE — the human species — have arrived at a moment
of decision. It is unprecedented and even laughable for
us to imagine that we could actually make a conscious
choice as a species, but that is nevertheless the
challenge that is before us.
Our home — Earth — is in danger. What is at risk of
being destroyed is not the planet itself, but the
conditions that have made it hospitable for human
beings.
Workshop
ECOPHARMACOLOGY
June 9-10, 2006
“Sala Terzian”, Rettorato
University of Verona, Italy
Klaus Kümmerer
Giampaolo Velo
The “Little” Water Cycle
Workshop Ecopharmcology, Verona 2006
Prozac in the Thames….
British Environment Agency, UK
Cocaine in the Po river…
Istituto Mario Negri, Italy
Antidepressants, antiepileptics and statins
in Niagara river and Ontario lake…..
Water Quality Centre, University of Ontario, Canada
Spread of drugs in the environment
The largest flow of drugs into the environment
comes from people who are under medical
treatment. Drugs are eliminated from the body
either in unchanged form or as metabolites in
faeces and urine and find their way to sewage
treatment plants (STP).
Spread of drugs in the environment
How drugs later behave in the environment and what
happens in the long term will depend on their
chemical and physical properties.
Drugs and their metabolites may be
divided roughly into three groups:
Spread of drugs in the acqueous face
Drugs that break down rapidly will be found close to their
sources and only if they have been released in large amounts.
Acetylsalicylic acid is an example of such a drug.
Drugs that are both water-soluble and stable will pass
through a treatment plant more or less unchanged and be
dispersed in the surrounding watercourse. Bezafibrate and
other lipid-lowering drugs are examples of drugs of this kind.
Drugs that are fat-soluble and stable will adsorb to a
considerable extent to sludge particles through the sewage
treatment process. Fluoroquinolones (a group of antibiotics)
are examples of such drugs.
Spread of drugs in the drinking water
The first pharmaceutical substance detected in drinking water
was clofibric acid, found by a German research group in Berlin
ten years ago (Stan, 1994). Since then several drugs (such as
bezafibrate, phenazone and carbamazepine) have been found
in drinking water in Germany (Ternes, 2001).
Various types of antibiotics have also been detected in the USA
(Ye et al., 2004).
Drugs in drinking water
Compound
Therapeutic
group
Maximum
conc. (ng l -1)
Country
Reference
Bezafibrate
Lipid regulator
27
Germany
Stumpf, 1996
Bleomycin
Anti -neoplastic
13
UK
Aherne, 1990
Clofibric acid
Lipid regulator
+
UK
Fielding, 1981
70
Germany
Stumpf, 1996
165
Germany
Stan, 1994
270
Germany
Heberer, 1997
5
Italy
Zuccato, 2000
24
Canada
Tauber, 2003
258
USA
Stachelberg, 2004
10
UK
Waggot, 1981
23
Italy
Zuccato, 2000
Carbamazepine
Diazepam
Anti -epileptic
Anxiolytic
Diclofenac
NSAID
6
Germany
Stumpf, 1996
Gemfibrozil
Lipid regulator
70
Canada
Tauber, 2003
Ibuprofen
NSAID
3
Germany
Stumpf, 1996
Phenazone
NSAID
250
Germany
Zuhlke, 2004
400
Germany
Reddersen, 2002
80
Germany
Zuhlke, 2004
120
Germany
Reddersen, 2002
1.7
Italy
Zuccato, 2000
Propyphenazone
Tylosin
NSAID
Antibiotic
Spread of drugs in the watercourses
The majority of studies have been carried out in Europe and
the amounts in the watercourses are about one-tenth of those
found in treated sewage, i.e. 1–100 ng/L (Daughton and
Ternes, 1999, Debska et al., 2004).
Spread of drugs in the watercourses
The following classes of drugs have been found:
- Analgesic/anti-inflammatory agents (acetylsalicylic acid (and its
metabolites), diclofenac, ibuprofen (and its metabolites), indometacin,
ketoprofen, naproxen and phenazone)
- Antibiotics (chloramphenicol, erythromycin, lincomycin, roxithromycin,
fluoroquinolones, tetracyclines, sulphonamides and trimethoprim)
- Hormone preparations (estradiol-17alfa, estradiol-17beta,
ethinylestradiol, mestranol, 19-noretisterone, progesterone, testosterone
and estriol)
- Antihypertensive agents (beta-blockers: atenolol, metoprolol….)
The city's sewers each day soaks up its citizens' routines,
taking in a steady stream of products. Toothpaste and shampoo
may be harmless enough, but the waste also collects a wide
array of medicines people take. Most drugs are poorly
absorbed and metabolized by the body, so it is not unusual that
the majority of a drug would end up intact in the urine. Because
all water goes through toilets at some point, these artificial
compounds, some quite difficult to break down, can eventually
find their way into the city's water supply—even bottled water.
Nature Medicine 12, 376 - 377 (2006)
Drugs down the drain
Alan Dove
Traces of prescription heart medications and
caffeine have even found their way into the
Atlantic Ocean.
Nature Medicine 12, 376 - 377 (2006)
Drugs down the drain
Alan Dove
When medicines are used or misused
there can be some serious and
damaging consequences to our global
environment and ecosystem.
The pharmaceutical chemicals in the
environment can also affect man
chronically, causing many unwanted
interactions, compromising human
responses to medicines, contributing
to drug resistance
More rational drug use could be
very helpful for the patient
and for the ecosystem
Rational drug use
no consumerism!
Rational drug use
sometimes rational drug use means…
“no use”
Drugs can pollute our environment,
water, animals, soil and plant life and can
also have ongoing effects in humans,
causing adverse effects and/or unwanted
and unknowing consumption of
unnecessary drugs
Drug environmental concentrations
are well below therapeutic levels,….
…we do not know the significance in
humans of interactions between
multiple drugs at low concentrations
ingested over the whole lifespan….
…we must think and act on a
precautionary basis.
Precautionary principle
We should not deny risks simply
because they are less than certain. On
the contrary we should ensure that we
know in advance the possible damages
to human health and the environment,
so that we can prevent them.
Precautionary principle
We should consider special
populations, like infants and children,
pregnant women….
type B reactions are
dose/concentration independent….
Ecopharmacovigilance?
Ecopharmacovigilance concerns the
adverse events related to drugs
within the ecosystem with all
consequences in humans and other
organisms in the environment
ECOPHARMACOVIGILANCE
It is a world in which we are all swimming
but of which we know very little.
For a better and safer use of drugs?
Environmental contamination pathways
(Pharmaceuticals for human use)
ADMINISTRATION to patients
(treatment/prevention diseases)
Excretion in urine/stool
(parent compound, metabolites)
Industrial pollution
SEWAGE TREATMENT
PLANT
Treated water
(containing pharmaceuticals)
Rivers, Lakes
E. Zuccato, ISOP 2007
Improper disposal
Industrial pollution
Sludge
(containing pharmaceuticals)
Ground water
Pharmacology and Eco-Pharmacology
Pharmacology
(humans)
one or only a few
compounds at the same
time
stable
Eco-pharmacology
(environment)
an unknown cocktail of
different compounds
administration
aimed, on demand,
controlled
wanted effects/
side effects
active, wanted effects,
side effects
metabolism/
biotransformation/
affected organisms
one type of organism
diffuse i.e. emissions of
medical care units and the
community
wanted effects in humans
are often most important
„side effects“ in the
environment
various types of
organisms of different
trophic levels
number of compounds
administered
desirable physico-chemical
properties
readily (bio) degradable
Kümmerer (Ed) Pharmaceuticals in the Environment, 2nd Ed. 2004, Kümmerer K & Velo G, Drug Safety, 2006
Some Data
• Approx. 100,000 chemicals on the market in the EU
• World wide: several 100,000 tons of pharmaceuticals
used: anti-inflammatory, lipid lowering agents, pain
killers, antibiotics, anti-depressants, anti-inflammatory,
anti-neoplastics, …
Doctors fear drug pollution poses risk
to fish, people
Jim Ritter, Suntimes Chicago
The Americal Medical Association is considering
resolutions calling on the Environmental Protection
Agency to conduct comprehensive studies on the topic
“It is a huge , huge issue for us in the future…”
AMA, from Chicago Meeting, June 12, 2006
The Swedish Government commission the
MPA (Medical Products Agency) to:
• investigate environmental effects of pharmaceuticals.
• present proposals on measures to reduce environmental
effects of the products, nationally as well as within the EU.
• investigate how information about content and
quantities of chemical substances in these products can
be improved and made more easily available.
• investigate the possibilities to introduce environmental
classification of pharmaceutical products on a national
basis.
MPA
Environmental hazard
and risk assessment
• 27 drugs were selected
Selected drugs
Atenolol (β1-Adrenergic blocking)
Cyclofosfamide (Antineoplastic)
Dextropropoxyphene (Analgesic)
Diazepam (Tranquilizer)
Diclofenac (Analgesic, Antiinflammatory, Antipyretic)
Enalapril (ACE-inhibitor,
Antihypertensive)
Ethinyloestradiol (Oestrogen)
Furosemid (Diuretic)
Hydrochlorothiazide (Diuretic)
Ibuprofen (Analgesic, Antiinflammatory, Antipyretic)
Ifosfamide (Antineoplastic)
Ketoprofen (Analgesic, Antiinflammatory, Antipyretic)
Metformin (Antidiabetic)
Metoprolol (β1-Adrenergic blocking)
Naproxen (Analgesic, Antiinflammatory, Antipyretic)
Norethisterone (Progestin)
Oestradiol (Oestrogen)
Oestriol (Oestrogen)
Oxazepam (Tranquilizer)
Oxytetracycline (Antibiotic)
Paracetamol (Analgesic, Antipyretic)
Ranitidin (Gastric secretory inhibitor,
H2-receptor antagonist)
Salbutamol (Bronchodilator, β2Sympathomimetic)
Simvastatin (Antihyperlipidemic)
Terbutalin (Antiasthmatic, β2Sympathomimetic)
Tetracycline (Antibiotic)
Warfarin (Anticoagulant)
Conclusions of the swedish study
• The risk for acute toxic effects in the environment is
unlikely
• Chronic environmental toxic effects cannot be excluded
due to the lack of chronic ecotoxicity data
• Reduction of potential environmental impact should be
based on knowledge on chronic ecotoxic effects
• The environmental impact of drugs should be further
studied and more attention is needed
Directive 2004/27/EC of the European Parliament
and of the Council of the European Union
Environmental risk assessment
as part of a marketing
authorization application.
Directive 2004/27/EC of the European Parliament
and of the Council of the European Union
Article 8 (3):
(ca) Evaluation of the potential environmental risks
posed by the medicinal product. This impact shall be
assessed and, on a case-by-case basis, specific
arrangements to limit it shall be envisaged;
(g) Reasons for any precautionary and safety measures
to be taken for the storage of the medicinal product, its
administration to patients and for the disposal of waste
products, together with an indication of potential risks
presented by medicinal product for the environment”.
Different approaches for the reduction of the
pharmaceuticals in the environment
Short term approach:
effluent treatment
Fate of pharmaceuticals in treatment plants (STPs)
Removal efficiencies in the STPs analyzed
39%
Total loads (g/d/1000 inhabitants)
5,0
64%
31%
4,5
4,0
3,5
0%
0%
3,0
STPs influent
STPs effluent
2,5
2,0
16%
31%
1,5
1,0
0,5
0,0
Naples
Latina
Cagliari
Cuneo
Varese
Lago
STPs analyzed
E. Zuccato, ISOP 2007
Va Olona
winter
Va Olona
summer
Fate of pharmaceuticals in treatment plants (STPs)
Amoxycillin
Ciprofloxacin
Enalapril
Ibuprofen
Ofloxacin
Carbamazepine
Clarithromycin
Erythromycin
Estrone
Lincomycin
Spiramycin
Removal rate:
30-60%
Atenolol
Bezafibrate
Clofibric acid
Furosemide
Diazepam
Removal rate;
10-30%
Removal rate: 0%
E. Zuccato, ISOP 2007
Hydrochlorothiazide
Ranitidine
Sulphamethoxazole
Removal rate:
variable
Pharmaceuticals in effluents of urban sewage
treatment plants in Italy (Median values of 9 STPs)
E. Zuccato, ISOP 2007
Pharmaceuticals in effluents of sewage treatment plants (nine
plants), River Po (median and maximum, seven site),
and River Lambro (ng/L)
ng/L
STPs
Lambro River
Ofloxacin
Furosemide
Atenolol
Hydrochlorothiazide
Carbamazepine
Ranitidine
Ciprofloxacin
Sulphamethoxazole
Ibuprofen
Spiramycin
Bezafibrate
Erythromycin
Lincomycin
Clarithromycin
Salbutamol
Amoxycillin
Cyclophosphamide
Diazepam
Enalapril
Ethinylestradiol
Methotrexate
Omeprazole
Median
600.0
585.0
466.0
439.1
291.1
288.2
251.0
127.2
121.2
75.0
54.8
47.4
30.5
18.1
8.7
4.7
0.6
0.0
0.0
0.0
0.0
0.0
306.1
254.7
241.0
255.8
175.3
38.5
14.4
Nd
20.0
74.2
57.2
4.5
24.4
8.3
2.5
Nd
Nd
Nd
0.5
Nd
Nd
Nd
Po River
Maximum
37.0
67.2
41.7
24.4
34.2
4
26.2
Nd
17.4
43.8
2.7
15.9
248.9
20.3
1.7
Nd
Nd
Nd
0.1
Nd
Nd
Nd
Median
33.1
3.5
17.2
4.6
23.1
1.3
Nd
Nd
13.0
9.8
1.9
3.2
32.6
1.6
1.1
Nd
Nd
Nd
0.1
Nd
Nd
Nd
Refined list of
priority pharmaceuticals
for monitoring
ecotoxicology and
removal studies
Zuccato et al, ESPR 2006
Pharmaceuticals : concentrations in
the environment
•
•
•
•
•
Wastewater : 100-1000 ng/L
Sewage : 100-1000 ng/kg
Surface water (rivers, lakes) : 10-100 ng/L
Drinking water : 1-10 ng/L
Sea water : 0.1-1 ng/L
Different approaches for the reduction of the
pharmaceuticals in the environment
Mid term approach:
education training and creating public awareness.
Rational drug use could be an important issue
Mid-term Risk Management:
Information, Training, and Education
• Education and training (staff)
• Information of all involved people
(pharmacists, doctors, patients,…)
Pharmacovigilance
has tohas
inform
and pharmacists!
even Santa Claus
todoctors
train his
staff
Different approaches for the reduction of the
pharmaceuticals in the environment
Long term approach:
green pharmacy
Green Drugs
Readily degradable in the Environment
No Exposition
No Effects, no Risk !
What is Green Chemistry?
• Green chemistry is the design of chemical
products and processes that reduce or
eliminate the use and generation of hazardous
substances
• Discovery and application of new chemistry/
technology leading to prevention/reduction of
environmental, health and safety impacts at
source
Long Term Risk Management:
Green Pharmacy
New compounds are effective, efficient, and
readily degradable in the environment
identification (sub)structures essential for
• efficacy
• (bio)degradability
Modification of Structure
Changes Properties
OH
Benzene:
not biodegradable
cancergenic,
not bactericidal
Phenol:
readily biodgradable
not concerogenic
bactericidal
Green Chemistry
for a healthier
environment
GP Velo, 7th ISoP Annual Meeting
Bye-bye
Au revoir
(zai jian)
Ciao