Degradability of Pharmaceuticals in the Aquatic EnvironmentProf. Dr. Klaus Kümmerer*
Institute for Environmental Medicine and Hospital Epidemiology,
Breisacherstraße 115b, D-79106 Freiburg, Germany

Chemicals are part of modern life. They are part of all spheres of human life. They
are used as pharmaceuticals, pesticides, detergents, fertilizers, dyes, pints, finish,preservatives, food additives and others. They contribute to our well being, highexpectancy of life and economical prosperity. There is also a back side of thissuccess story. If chemicals are not used in closed loops they can enter into theenvironment. Especially if they are used in everyday life and if they are constituentsand ingredients of consumer products they are emitted into the environment by nonpoint sources. After administration pharmaceutical substances are excreted by thepatients into waste water.

Outdated medicaments or reminders are sometimes

disposed in drains in households, presumably 20-40 % in Germany. Therefore,
pharmaceutical substances enter municipal sewage and sewage treatment plants. Ifthey are not eliminated during sewage treatment they are emitted into surface waterand can reach drinking water. This makes it difficult to hold them back efficiently.
A long half live in the environment results in a big temporal and spatial range.
Therefore, for persistent chemicals, a risk assessment is not possible. With bigger
scales involved uncertainty increases time and possible effects cannot be tested inlab trials. Persistency is therefore one of the most important criteria for theenvironmental assessment of chemicals. For persistent organic pollutants (POPs) theStockholm*convention(http://www.pops.int/documents/context/corresponding
author:phone:
Klaus.kuemmerer@uniklinik-freiburg.de*761/270-5464,- 397 -fax:

convtext_en.pdf)+761/270-8235;

e-mail:came into force. Until now only 12 organo-halogen compounds the so called dirty
dozen are regulated under this convention among them polychlorinated biphenyls(PCBs), a classical example of persistent pollutants. PCBs have been synthesized forthe first time in 1877. In 1899 severe health problems (chloracne) associated with thehandling of PCBs had been reported. Throughout the years the poisoning of rice oilby these compounds and neurotoxic effects as carcinogenicity has been described indetail. Despite this knowledge it took until 1999 to ban PCBs fully within the EU – 100years after the first reports of its severe toxicity! This example demonstrates that it is
not only the time scales of the chemicals itself and the environmental processes
impacted by them but also the time scales of economical and political systems.
Additionally, the use of persistent chemicals is often associated with high costs in thelong run – at least for the general public.
In the Stockholm convention a half life of more than 50 days in water is set as acriterion for POPs.

Recent research show that other chemicals that are lesspersistent and have higher polarity then the dirty dozen are distributed globally andcan accumulate in humans. A statistical correlation between the persistency ofchemicals and the prevalence of the presence of chemicals in the environment that
can initiate cancer has been reported only recently.
The potential for chemicals to undergo biotransformation is an important aspect ofassessing the environmental fate and risk of chemicals. Several different non-biotic
processes can result in the removal of chemicals from sewage, surface waters,
ground waters, drinking water processing, and soil. Biologically mediated processes(i.e. biotransformation) and non biotic processes can result in the full transformation
or mineralization of chemicals in the aquatic environment. In rare cases chemicals
are fully broken down to water, carbon dioxide and inorganic salts. Very oftentransformation is incomplete and unknown transformation products are formed.
- 398 -Since the nineteen-eighties pharmaceuticals from different groups have been
detected in the environment (e.g. Kümmerer 2004). Only few data is currently
available concerning the biodegradability of antibiotic compounds in STPs andsurface water. It has been found that most pharmaceuticals are not biodegraded fully
in sewage treatment and in the environment. It has been found that in the case ofpharmaceuticals total degradation does take place only rarely and the process isstopped before total mineralization. These intermediates (i.e. stable metabolites or socalled transformation products) of (bio)transformation can be even more stable thanthe parent compounds. They often also differ in terms of toxicity and have a different
potential for accumulation compared to the parent compound. This also holds true fordrugs which are excreted as conjugates after they have been hydroxylated ortransformed for instance into sulfates, glycosides and others. If at all, these products
are usually less active than the parent compound. They can also be regained by
microbial activity in the environment or in STPs.
If the parent compounds are degraded only partially resulting transformation productswith high stability under environmental conditions will remain in the environment too.
They can also be toxic against humans and environmental organisms. In this casethe situation may be worse as we have usually much less knowledge on the stabletransformation products and their fate and effects in the environment than on theparent compounds. Furthermore, if the input rate is higher than the rate ofdegradation or mineralization of chemicals they will nevertheless be present atconstant levels in the environment. This can be called persistency of second order orpseudo persistency.
Kümmerer 2004: Pharmaceuticals in the Environment, 2nd Ed., Springer, Heidelberg New York Tokyo,
2004, 3rd Ed. In praparation- 399 -- 400 0 - 20%

0 -100%0 - 50%0 - 50%0 - 50%20 - 80%

0 -100%

0 -100%10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

K. Kümmerer
3Hirsch et al. 1999, Ternes 1998ff, Heberer 1996ff, Richardson und Bowron 1985, ….

…., Golet et al. 2002, Färber et al. 2002, Kolpin et al. 2002, Sacher et al. 2001, Kümmerer et al. 2001, Zuccato et al. 2001,

Diagnostics(x-ray, MRI):•Pain killers•

AntidepressentsStatines•

Disinfectants:

Hormones:••Zytostatics:••

Antibiotics:•Elimination of Pharmaceuticals
in Sewage Treatment Plants

K. Kümmerer
210th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

K. Kümmerer
4

What Does Elimination Mean?

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th…, Färber et al. 2002, Kolpin et al. 2002, Sacher et al. 2001, Kümmerer et al. 2001, Hamscher et al. 2002, Zuccato et al.
2001, Hirsch et al. 1999, Ternes 1998ff, Kümmerer et al. 1996, 1997 Heberer 1996ff ,...

pseudo persistence!

• continuous emission into the environment:Klaus.Kuemmerer@uniklinik-freiburg.dephone: ++761-270-8235• in soil: antibiotics, growth promoters (up to 300 µg/kg, higher in manure)(also: diagnostics, disinfectants e.g. QACs)• from all therapeutical groups as far as studied up to now

water, drinking water in the ng/L-µg/L range• in hospital effluent, waste water, rivers, ground

A, AUS, BRA, CDN, CH, D, DK, GB, F, I, J, NL, S, USA, …

Reports from:

Detection of Pharmaceuticals
in the EnvironmentProf. Dr. Klaus Kümmerer

Berlin, October 9th-10th 2006

10th Japanese-German Workshop on Water Technology

Degradability of Pharmaceuticals
in the Aquatic Environment

FNNSOOHOON-NHNOOOSO-N+H3C

H3CClOOO

H3 CClOOOO

H3 CO

CH3OH

CH3O

OO

HOO

H3 CO

OH

OH

O

H3C-O-CH2ClOOH

Cl

H3 C

CH3O

O-CH3O

OO

Cl

O

ClO

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11thK. Kümmerer
7O

O
OH

CH3O O

Avilamycin A

CH3O

Ceftazidime Species as Function of pHK. Kümmerer
5ONHzwitterionic!

O+N
Ciprofloxacin

Ceftazidime HO

H2 NONOH

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11thHN

CH3K. Kümmerer
6Zulaufinfluent

Ablaufeffluent

Belebtsludge
schlamm10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

020406080100

K. Kümmerer
8sludgeÜberschusssurplusschlamm

Alexy, Sacher, Wenz, Kümmerer, submitted

020406080100

Clarithromycin

effluent
AblaufsludgeBelebtschlamm

NOCH2OC2H5OCH3influent
ZulaufRoxithromycin

surplusÜberschussschlammsludge

Elimination of Antibiotics in a STP:
Impact of Structure

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

Konzentration[ng/l] oder
ConcentrationTS]d.m.)(ng/L;[µg/kgµg/kg“Designed“ for bioactivity and stability, complex
molecules with several, often different functionalgroups!

Ciprofloxacin as Zwitterion (pH 6.5-8.0)

Concentration

Pharmaceuticals are Special!

Konzentration [ng/l] oder(ng/L;µg/kg[µg/kgTS]d.m.)- 401 -051015

202530I

H 2NO

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11thIOINH 2OHK. Kümmerer
11IOCH3• No elimination in STP(OECD 303A)• Toxicity ?

2 fold deacetylation

NHNHOHIOI

A. Haiß, K. Kümmerer, Chemosphere, 62 (2006) 294–302

Diaminotrizioc acid(metabolite B)
Confirmed by MS, 1-H-NMR, IR

H3C

51015

0

5

10

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

Trautwein & Kümmerer, submitted

-20

020

40

60

80

100

120

202520K. Kümmerer
12day

152530DOC-Elimination ofVerapamil-HCl in the ZWTday0ATZA

Met-Bof production

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

0200400

sample day 23 Zahn-Wellens test

Sampling

Met-Adiamino trizoic acid,(intermediatein production
an intermediate

Transformation
product B

K. Kümmerer
10Significance of Metabolites andTransformation Products?

Amidotrizoic acid (ATZA)

Transformation

600 product A

800

1.000

1.200

1.400

1.600

1.800

2.000

3002

46810

12

14

16

1820

Verapamil-HCl
neg. control
Negativkontrolle

Verapamil-HCl 2

Verapamil-HCl 1

pos.
control
Positivkontrolle

Elimination of ATZA in the ZahnWellens Test (OECD 302B)

dayATZA concentration in mg/lK. Kümmerer
900

42ATZA

6200400600

Met-B

101.000
8121.200

Met-A

141.400800

161.600

2018Sampling

1.800

2.000

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

Peak area (metabolites, rel. units)

Elimination of ATZA in the ZahnWellens Test (OECD 302B)
Peak area (metabolites, rel. units)

D O C -E lim in a tio n [% ]- 402 -ATZA concentration in mg/l

Trautwein & Kümmerer, in preparationprecursor ionday 1TIC and specific masses

01020K. Kümmerer
15Abbautagday

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

Kümmerer et al., submitted

020406080100

K. Kümmerer
13

product ion

product ion

product ion

30control

Piperacilin
Negativkontrolle
Piperacilin
HPLC, HPLC

Piperacilin
HPLCHPLC
Mittelw ert
Piperacilin

Piperacilin
Negativkontrolle
DOC
Piperacilin
DOC, control

Piperacilin
DOCDOC
Mittelw ert
Piperacilin

Elimination of Piperacilin:
DOC vs. HPLC-UV/Vis

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

Elimination
Elimination bezogen
auf Kohlenstoff[%]

Elimionation (%)

product ion

K. Kümmerer
14oxidized verapamil?

product ion

01247911 14 17 22 25 28 30

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

Kümmerer et al., submitted

01000000

K. Kümmerer
16day

60
3000000

100

90

80

70

50
4000000

2000000

40

5000000

30

20

107000000
6000000

08000000

DOC

16.5

16.9

17.4

19Retention time

Transformation Products ofPiperacilin (HPLC-UV/Vis)

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

Trautwein & Kümmerer, submitted

product ion

dead end transformation productday 30Elimination of Verapamil in the ZWT(LC-MS/MS)

Peak Area (rel. Units)

Primary Elimination of Verapamil inthe ZWT (LC-MS/MS)

Elimination DOC [%]- 403 -O

HNO

HN

NHO

SOH+H2O

0.0

0.5

1.0

1.5

2.0

2.5

O

N

m/z=536
m/z
537

N

SC

K. Kümmerer
19Sample
Probe05 ANOVA mit Dunnett's Post-hoc-Test,
p < 0,05 - 0,01

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

Corrected
Korrigierteabsorption
Absorption (Mw ± SD)

OO
H
NO

O

HNOH

H

NHSO

15

Decreasing Estrogenic Activity
by Advanced Oxidation

K. Kümmerer
17

confirmed by LC-MS/MSO

Kümmerer et al., submittedNO

m/z 519m/z=518

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11thNO

Hydrolysis of Piperacilin LC-MS/MS

OH

N

M=376

O

O

O
H
N

O

O

HN

O

OH

M=159

O

O

H
N

O

HN

S

N
H

M=491

N

M=491

N

O

O

N

N

O

O

O

O

bacteria

OH

H

O

H
N

H
N

Bakterielle Umsetzung-CO2O

M=536

K. Kümmerer
18N

O

HN

O

HNO

O

OH

OH

HH

NHS

N
H

SOH

detected byLC-MS/MS

M=393O

M=349

SC

K. Kümmerer
20Sample
Probe0 ANOVA mit Dunnett's
Post-hoc-Test, p < 0,01

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

5

15



Increasing Androgenic Activity
by Advanced Oxidation

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11thNSOHN

Decarboxylation of Piperacilin
LC-MS/MS

Kümmerer et al., in preparation

NCorrected
Korrigierteabsorption
Absorption (Mw ± SD)- 404 -

- 405 -K. Kümmerer21

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th• Reaction by-products?

K. Kümmerer
23• Infiltration of the ground before STP?

• Storm water?

• Costs?

• Antibiotics: Resistance and bio-membrane (enrichment,residence time)• Efficiency may depend strongly on the type of compound.

• Advanced filtration technologies (reversed osmosis,membrane filtration, nanofiltration), and (photo)oxidation
technologies are emerging.

Advanced Effluent Treatment (1)10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

Which compound to what degree!

Elimination?

12

3

4
Slow sandfiltration

4Effluent:“without”
trace
contaminants

Other advanced
reatment

5K. Kümmerer
22

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

K. Kümmerer
24• Not compatible with green chemistry.

• Not possible in less developed countries• Effective for new compounds?

Advanced Effluent Treatment (2)10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th• Adsorption (coal)• Membrane (bio-, membrane filtration, ultra-filtration, …)• Advanced Oxidation (ozone, fenton-, photo-, …)• Slow sand filtration

Influent:
sewagewith tracecontaminants„classical treatment“

Advanced Effluent Treatment- the Solution?

NH

FF

HO5-FUZWT 28 days

CBT 45 days

CBT 28 days

NH

O

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th-10

1030

50

70

90

O

O

HN

HN C

C

O

OH

O

F

F
H

N

K. Kümmerer
27

Gemcitabin

Log P: -0,9Henry's Law: 13,56

C9H11F2N3O4
Mol. Wt.: 263,2

H

H

O

NNH2HOOH

O

Cytarabin

HHO

NHOH
HN

NH2Kümmerer & Ahmad,Acta Hydrochim.
Hydrobiol., 25, 166-172
1997

of Structurally Related Cytotoxics

Different Biodegradability

Na+O-K. Kümmerer
26

OSO-Na+O

ß-D-Glc-IPM („Glufosfamide“)

Ifosfamide:
not biodegradable (0%)

P

K. Kümmerer
28

well biodegradable (< 70%), improved
resorption in the gut; clinical trial phase III
10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11thCl

Kümmerer et al. Chemosphere, 40, 767 (2000)

ClCl

keeping the active moiety

PCl

Improving Biodegradability:
The Cytotoxics Ifosfamide and Glufosfamide

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

HOOH
OH

K. Kümmerer
25

LAS: readily biodegradable

O

HO

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11thSO

New legislation for surfactants 1962

TPS: not biodegradable

OO

1955

O

Improving Biodegradability:
Surfactants

NH

NH

O

Not Biodegradable TPS …

N

O

Biodgradation in %NH

- 406 -- 407 -K. Kümmerer
29

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

K. Kümmerer
31

Freiburg im Breisgau

Thank you!

10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

Kümmerer, Green Chemistry, submitted; www.start-project.deidentification (sub)structures essential for• efficacy• (bio)degradability

readily degradable in the environment

New compounds are effective, efficient, andLong Term Risk Management:
Green Chemistry & Pharmacy

K. Kümmerer
30

See also: Daughton C. G. (2003): Cradle-to-Cradle Stewardship of Drugs for Minimizing
Their Environmental Disposition While Promoting Human Health. I. Rationale for andAvenues toward a Green Pharmacy. Environ. Health Perspect. 111, 757•10th Japanese-German Workshop on Water
Technology, Berlin, October 8th-11th

Big Green Chemistry initiative by the U.S. Environmental
Protection Agency

In the middle and in the long run there will be an increase ofinnovation and economical advantages for healthy andenvironmental friendly products. (German Advisory Boardfor Environment 2003)••… within a generation chemicals should be produced andapplied that do not have any impact on the environment.
(EU Parliament and EU-Commission 2002)•

Economical and Other Aspects