Introduction to pharmaceuticals and illicit drugs

1

SCARCE course. Valencia. February 7-8, 2011

PHARMACEUTICALSand

ILLICIT DRUGS

Department of Environmental ChemistryIDAEA-CSICBarcelona

Spain

Miren López de Alda


OUTLINE

IntroductionEmerging contaminants

Pharmaceuticals and illicit drugs:General characteristicsUseSourcesRemoval in sewage treatment plants

(STPs)FateEnvironmental levelsTransformation products (TPs)EffectsLegislation

Conclusions

2


Emerging contaminants = newly identified or previouslyunrecognized contaminants

New and more sensitive analytical and biological methods

PriorityPriority vsvs EmergingEmerging ContaminantContaminantss

...........Not regulated...........

Little or not investigatedScarcity or lack ofenvironmental data

and analytical methods

Priority (= regulated) contaminants


EmergingEmerging contaminantscontaminants: : pharmaceuticalspharmaceuticals

• Due to their physico-chemical properties (high water solubility, low volatility, and often poor degradability) they are able topenetrate through all natural filtration steps and man-made treatments

• Low elimination in WWTP• Potential risk for drinking water supply- Large volume production/high fluxes in the environment (e.g.

pharmaceuticals, surfactants, pesticides)- They do not need to be persistent in the environment to cause

negative effects due to continuous introduction: pseudo-persistent chemicals

3


PharmaceuticalsPharmaceuticals

• Pharmaceuticals are often large, complex, ionic and hydrophilic compounds; these properties influence their environmental fate.

• Most pharmaceuticals enter the environment daily through patient use.

• Sources are geographically diffuse and may be influenced by regional use patterns.

• Pharmaceuticals in the environment may be parent, metabolites orconjugates.

• Pharmaceuticals vary in their potency; in general, highly potentcompounds will be used at lower volumes resulting in lower environmental concentrations.

• Some more potent compounds may be of environmental concern at lower concentrations (ex. estrogens).

• Designed to be biologically active


Pharmaceuticals as environmental contaminants

1970s: clofibric acid in wastewater (USA)1980s: ----1990-present: studies

0

20

40

60

80

100

Estim

ated

Ann

ual p

resc

ribed

am

ount

s / to

ns

Am

oxic

illin

Am

pici

llin

Peni

cilli

n G

Sulfa

met

hoxa

zole

Trim

etho

prim

Eryt

rom

ycin

Rox

itrom

ycin

Cla

rithr

omyc

in

Min

ocyc

line

Dox

ycyc

line

Ben

zafib

rate

Clo

fibric

aci

d

Gem

fibro

zil

Dic

lofe

nac

Ibup

rofe

n

Indo

met

acin

e

Met

opro

lol

Prop

anol

ol

Car

bam

azep

ine

consumedunchangedglucuronidesother metabolites

Source: “Pharmaceuticals and Personal Care Products in the Environment-Scientific and regulatory issues” CG Daughton, TL Jones-Lepp, Ed. ACS Simposium Series 791. American Chemical Society 2001.

4


Source: IMS Health(Global source for pharmaceutical market intelligence)

Pharmaceutical market

Top ten markets (2007)

56.4

36.2

33.7

22.2

21.3

17.8

16

12

9.1

283.3

0 50 100 150 200 250 300

USA

Japan

France

Germany

UK

Italy

Spain

Canada

China

Brasil

sales ($ billions)

02468

1012141618

World (10key

markets)

Usa Europe (5main

markets)

Spain China Brasil Japan

Ann

ual g

row

th 2

007

(%)

Annual growth (2007)


Leading Therapy Classes by Global Prescribed Pharmac. Sales (2007)

Source: IMS Health

37.5

34.2

26.5

24.6

22.6

20.2

19.3

17.8

14

13.9

0 5 10 15 20 25 30 35 40

oncologics

cholesterol and lipid regulators

respiratory agents

acid pump inhibitors

antidiabetics

antidepressants

antipsychotics

angiotensins-II antagonists

antiepileptics

erythropoietins

global sale ($ billions)

Pharmaceuticals owe their origins in the environment to their worldwide, frequent, and highly dispersed but cumulative usage by multitudes of individuals.

5


0

4000000

8000000

12000000

16000000

Nol

otil

Effe

ralg

an

Gel

ocat

il

Adi

ro 1

00

Aug

men

tine

Orfi

dal

Dia

nben

Neo

bruf

en

Term

algi

n

Lexa

tin

Nº u

nida

des

vend

idas

The top-selling drugs in pharmacies in Spain (2007)

Dipyrone(metamizole)

Acetaminophen(paracetamol)

Acetylsalycilicacid

Amoxicillin

Lorazepam

Metformin

Ibuprofen

Bromazepam


Illicit drugs. Consumption

-World Drug Report 2008 of the United Nations:- 208 million people use illicit drugs annually worldwide- 994 tonnes of cocaine = global cocaine production in 2007

-Annual Report 2008 of the EMCDDA :

Spain presents thehighest prevalenceamong adults (15 to 64 years) of cannabis andcocaine use in Europe

Cocaine

Cannabis

Trends on Illicit drug use have stabilized in the last years; however:

6


Illicit drugs. Consumption

World Drug Report 2008 of the United Nations


The problem of drug abuse in Europe

7

Run off

Drinkingwater

Sludge Surface waters

Domestic wasteSewage

LandfillTreatment plant

Human Medicine

overflow leaks

excretion disposal

Groundwaters Food chain

Agricultural soils

Manure

Aquaculture Livestock Poultry

excretion excretion

VeterinaryMedicine

Sea

Ways to theenvironment:


Factors affecting environmental fate

* Source (industrial, urban, agriculture, etc.)

* Physical-chemical properties- Water solubility- Polarity (Kow)- Volatility (Henry’s constant, vapor pressure)- Acid-base properties- ...

* Environmental conditions- Temperature, Altitude, Latitude, Wind, Rainfall,

pH, Organic matter, Flow rate...

* Persistence/degradation- Photo-, chemical-, and bio-degradation

8

Run off

Drinkingwater

Sludge Surface waters

Domestic wasteSewage

LandfillTreatment plant

Human Medicine

overflow leaks

excretion disposal

Groundwaters Food chain

Agricultural soils

Manure

Aquaculture Livestock Poultry

excretion excretion

VeterinaryMedicine

Sea

Removal pathways____________________________________________________________________________________________________________________________________________________

Sludge disposal

inletoutlet

Primary settling

Biological compartment

Volatilization air stripping

Biodegradation BiodegradationSorption Sorption

Dissolvedsorbed

Physico-chemical properties of the compound (Henry costant, Kow)

Process design and operating conditions of the treatment system

(HRT, SRT, AFR Air Flow Rate)

Sorption

Log Kow < 2.0 volatilization

Log Kow 3-4 adsorption

Log Kow 1.5 – 4 biodegr. has a role

9


Elimination in Sewage Treatment Plants (STP)(conventional activated sludge treatment)

10-39%Diclofenac (anti-inflammatory)

> 90% Note: hydroxy and carboxy

metabolites found in effluents)

Ibuprofen (anti-inflammatory)

60%Fluoroquinolones (antibiotics)

42-92%Naproxen (anti-inflammatory)

43-71%Gemfibrozil (lipid regulator)

50% Methoxazole

< 10 % (no removal)Carbamezapine (anti-epileptic drug)Atenolol, Metoprolol (b-blockers)Trimethoprim (antibiotic)

RemovalCompound

• Removal efficiency is a function of the drug’s structure and treatment technology employed; the conjugates can be hydrolyzed back to the free parent drug. Source: REMPHARMAWATER final report


Deconjugation of glucuronide and sulfate metabolites of pharmaceuticals

in sewers and STPs

OS

H

H

H

O

OO

O Na+ OH

H

HH

O

Estrone(↑ activity)

Estrone-sulfate(↓ activity)

10

SCARCE course. Valencia. February 7-8, 2011Fent et al. Aquatic Toxicology 76 (2006) 122.

STP effluents: point-source contaminationConc. of pharmaceuticals in treated sewage and surface water


Atenolol Gemfibrozil Diclofenac Naproxen Ibuprofen Carbamazepine

0

2000

4000

6000

8000

10000

12000

WWTP1 WWTP2 WWTP3 WWTP5 WWTP6 WWTP7

Con

cent

ratio

n(ng

/L)

0

2000

4000

6000

8000

10000

12000

WWTP4

0

50

100

150

200

250

300

350

400

RW donwns.WWTP1

RW donwns.WWTP2

RW downs.WWTP3

RW downs.WWTP5

RW downs.WWTP6

RW downs.WWTP7

Con

cent

ratio

n(ng

/L)

0

500

1000

1500

2000

2500

RW downs.WWTP4

Atenolol Gemfibrozil Diclofenac Naproxen Ibuprofen CarbamazepineAtenolol Gemfibrozil Diclofenac Naproxen Ibuprofen Carbamazepine

0

2000

4000

6000

8000


Con

cent

ratio

n(ng

0

2000

4000

6000

8000

WWTP4

0

50

100

150

200

250

300

350

400

RW donwns.WWTP1

RW donwns.WWTP2

RW downs.WWTP3

RW downs.WWTP5

RW downs.WWTP6

RW downs.WWTP7

Con

cent

ratio

n(ng

/L)

0

500

1000

1500

2000

2500

RW downs.WWTP4

Atenolol Gemfibrozil Diclofenac Naproxen Ibuprofen Carbamazepine

0

2000

4000

6000

8000

10000

12000


Con

cent

ratio

n(ng

/L)

0

2000

4000

6000

8000

10000

12000

WWTP4

0

50

100

150

200

250

300

350

400

RW donwns.WWTP1

RW donwns.WWTP2

RW downs.WWTP3

RW downs.WWTP5

RW downs.WWTP6

RW downs.WWTP7

Con

cent

ratio

n(ng

/L)

0

500

1000

1500

2000

2500

RW downs.WWTP4

Atenolol Gemfibrozil Diclofenac Naproxen Ibuprofen CarbamazepineAtenolol Gemfibrozil Diclofenac Naproxen Ibuprofen Carbamazepine

0

2000

4000

6000

8000

10000

12000


Con

cent

ratio

n(ng

/L)

0

2000

4000

6000

8000

10000

12000

WWTP4

0

50

100

150

200

250

300

350

400

RW donwns.WWTP1

RW donwns.WWTP2

RW downs.WWTP3

RW downs.WWTP5

RW downs.WWTP6

RW downs.WWTP7

Con

cent

ratio

n(ng

/L)

0

2000

4000

6000

8000

10000

12000


Con

cent

ratio

n(ng

/L)

0

2000

4000

6000

8000

10000

12000

WWTP4

0

50

100

150

200

250

300

350

400

RW donwns.WWTP1

RW donwns.WWTP2

RW downs.WWTP3

RW downs.WWTP5

RW downs.WWTP6

RW downs.WWTP7

Con

cent

ratio

n(ng

/L)

0

500

1000

1500

2000

2500

RW downs.WWTP4

Concentrations of the most ubiquitous anti-inflammatories, lipidregulators, psychiatric drugs and ß-blockers detected in (A)

wastewater effluent and (B) river water downstream the WWTP monitored

11


Analgesics/antiinflamatories: paracetamol, acetylsalicylic acid, ibuprofen, diclofenacAntibiotics:

- Macrolides: clarithromicine, dehydroeritromicine, roxitromicine, lincomicine- Sulfamides: sulfametoxazol, sulfadimetoxin, sulfametazine, sulfatiazol- Fluoroquinolones: ciprofloxacine, norfloxacin, enrofloxacin- Tetracyclines: clortetracycline, oxytetracycline, tetracycline... chloranfenicol, tylosin, trimethoprim

Antiepileptics: carbamazepine, primidoneβ-Blockers: metoprolol, propanolol, bisoprolol, betaxolol, nadolol, sotalolLipid regulators: clofibric acid, bezafibrate, gemfibrozil, fenofibric acidX-ray contrast media: diatrizoate, iohexol, iopamidol, iopromide, iomeprolCitostatics (chemotherapy): ifosfamide, ciclofosfamideOral contraceptives: ethynyl estradiol, mestranolSteroids: coprostanol, estradiol, progesterone, testosterone.Tranquilizers, antihistaminics, barbiturates, ...

Pharmaceuticals detected in the aquatic environment

LEVELS: ng-μg/L; μg-g/KgFrom: Heberer T (2002) Toxicol. Lett. 131, 5-17.


1Heberer T (2002) Toxicol. Lett. 131, 5-17.2 Thiele-Bruhn S (2003) J. Plant Nutr. Soil Sci. 166, 145-167.3 http://www.epa.gov/OGWDW/ccl/cclfs.html

Most problematic/less studiedpharmaceuticals1

Oral contraceptives:Estrogenic effects at ∼ 1ng/LSea, sediments and sludge

Antibiotics2:Bacterial resistance

- 2/3 in human medicine: 3rd position.- 1/3 in veterinary medicina: 70%

X-ray contrast media:Persistence

Poor STP removalGroundwater

Metabolites

Cytostatics:Carcinogenic prop.

Poor STP removallevels, fate, and risks

12


Removal of illicit drugs and metabolites

99 99 97

80

99

43

61

45

87

75

88

73

42

9

0

20

40

60

80

100

120C

OC BE CE

EPH

AM

MD

MA

MA

LSD

O-H

-LSD

nor-

LSD

HER

MO

R

6AC

M

OH

-TH

C

nor-

THC

THC

%

0

25

50

75

100

Barcelo

na

Valenc

ia

Benica

ssim

Gandía

Miranda

Logro

ño

Pamplo

na

Tudela

Zarago

zaLle

ida

Tortos

a

%

Average drug removal in ≠ STPs

57‐85 %

Some compoundse.g. THC‐COOH and MDMA are occasionally not removed.(Higher levels in effluentscompared to influents)

El Prat STP


Occurrence of illicit drugs in surface waters

010

2030

405060

7080

90100

MOR(1)

6ACM(2)

EDDP(1)

METH(1)

THC-COOH(1)

BE(2)

BE(3)

CO(2)

CO(3)CE(2

)

EPH(2)

MDMA(2)

MDMA(3)

AM(3)

METH(3)

MDA(3)

Con

cent

ratio

n (n

g/L)

(1) M.R. Boleda, M.T. Galcerán, F. Ventura (2009). Water Res. 43(4): 1126‐1136.(2) C. Postigo, M.J. Lopez de Alda, D. Barceló. Unpublished data.(3) M. Huerta‐Fontela, M.T. Galcerán, F. Ventura (2008) Environ. Sci. Technol. 42 (18): 6809‐6816.

150Llobregat River

13


DBPs and TPs may be more active and more persistent than parent compounds

Transformation products (TPs)/disinfection byproducts (DBPs)

- Estrogens DBPs:

5 min.

NaClO4-ClEE + 2,4-diClEEEthynyl estradiol

retention time [min]

Scan

Time3.00 3.10 3.20 3.30 3.40 3.50 3.60 3.70 3.80 3.90 4.00 4.10 4.20 4.30 4.40 4.50 4.60 4.70 4.80 4.90 5.00 5.10 5.20 5.30 5.40 5.50

%

2

707 Scan neg Bio DCF t 239 low temp 1: TOF MS ES- 294.008

8.49e34.46

rel.

inte

nsit y

[%]

4.30 (M340)

4.46 (DCF)

4.13 (M324)

3.90 (M190)

(-) XIC 294m/z

(-) XIC m/z 323

(-) XIC m/z 339

(-) XIC 189m/z

(-) TIC ( 100-500)m/z

(+) TIC ( 100-500)m/z

M324 M340M190

3.00 4.00 5.00 5.504.503.50

M190

M324

M340

• Degradación lenta de DCF, el día 6 se ha eliminado

un 60%

• Formación de tres nuevos productos de degradación:

M324, M190 y M340

NH

Cl

Cl

O

O

NO

M324

Cl

Cl

O

HO

M190

NH

Cl

Cl

O

OH

NO2

M340

NH

Cl

Cl

O

OHDiclofenac

0 1 2 3 4 5 6 70,0

0,5

1,0

1,5

2,0

4

6

8

10

Conc

entra

tion

[mg/

L]

Time [days]

DCF M190 M324 M340

B

retention time [min]

Scan

Time3.00 3.10 3.20 3.30 3.40 3.50 3.60 3.70 3.80 3.90 4.00 4.10 4.20 4.30 4.40 4.50 4.60 4.70 4.80 4.90 5.00 5.10 5.20 5.30 5.40 5.50

%

2

707 Scan neg Bio DCF t 239 low temp 1: TOF MS ES- 294.008

8.49e34.46

rel.

inte

nsit y

[%]

4.30 (M340)

4.46 (DCF)

4.13 (M324)

3.90 (M190)

(-) XIC 294m/z

(-) XIC m/z 323

(-) XIC m/z 339

(-) XIC 189m/z

(-) TIC ( 100-500)m/z

(+) TIC ( 100-500)m/z

M324 M340M190

3.00 4.00 5.00 5.504.503.50

M190

M324

M340

• Degradación lenta de DCF, el día 6 se ha eliminado

un 60%

• Formación de tres nuevos productos de degradación:

M324, M190 y M340

NH

Cl

Cl

O

O

NO

M324

Cl

Cl

O

HO

M190

NH

Cl

Cl

O

OH

NO2

M340

NH

Cl

Cl

O

OHDiclofenac

0 1 2 3 4 5 6 70,0

0,5

1,0

1,5

2,0

4

6

8

10

Conc

entra

tion

[mg/

L]

Time [days]

DCF M190 M324 M340

B

0 1 2 3 4 5 6 70,0

0,5

1,0

1,5

2,0

4

6

8

10

Conc

entra

tion

[mg/

L]

Time [days]

DCF M190 M324 M340

B

-Biodegradation ofdiclofenac in wastewaterand comparison of CAS and MBR:

S. Perez, D. Barceló. Anal. Chem. 80, 8135–8145, 2008


Subtle (currently unrecognized) effects:

some examples:

• Profound effects on development, spawning, and wide array of other behaviors in shellfish, ciliates, and other aquatic organisms by tricyclicantidepressants.

• Dramatic inhibition of sperm activity in certain aquatic organisms bycalcium-channel blockers.

• Antiepileptic drugs (e.g., phenytoin, valproate, carbamazepine) have potential as human neuroteratogens, triggering extensive apoptosis in the developing brain neurodegeneration.

• ppm and sub-ppm levels of various drugs (NSAIDS, glucocorticoids, anti-fibrotics) affect collagen metabolism in teleost fish, leading to defective/blocked fin regeneration

• Decline of Gyps spp. Vultures (study in India and Pakistan) – Possible link with Diclofenac used for cattle, whose carcasses are a major food source for Gyps

Source: Christian G. Daughton, Emerging Pollutants Workshop, August 2003, Chicago, USA

Potential impact in the aquatic environment

14


Environmental Effects of Antibiotics

• Antibiotics are designed to affect microorganisms and bacteria found in humansand animals. This, therefore makes them potentially hazardous to other suchorganisms found in the environment.

• Excreted antibiotics (up to 90% of one dose in urine and 75% in feces) partiallyinhibit methogenesis in anaerobic waste-storage facilities, thus decreasing therate at which bacteria metabolize animal waste products.

• The frequent use of antibiotics has promote the rise of populations of newstrains of bacteria resistant to antibiotics. Some studies evidenced up to70% increase in resistance to certain antibiotics when manure from a farmwas applied to a garden soil.

• On release into the environment through manure/sluge application, antibioticsmay end up on agricultural soils and can be taken up by plants, affecting thegrowth and development.

• In general, toxic levels of antibiotics for microorganisms, bacteria and micro-algae are 2-3 orders of magnitud below the toxic values for higher trophiclevels.


• Decreased fertility & growth• Sex alteration• Poor hatching/egg shell thinning• Abnormal thyroid function

Well-documented effects of EDCs (estrogens) in wildlife

Some examples include:

•reproductive effects in Baltic seals, •eggshell thinning in birds of prey, •decline in the alligator population in polluted lakes, •general declines in frog populations, •effects on the reproduction and development of fish, •development of male sex organs in female marine organisms.

Aquatic animals, especially carnivores, are the most affectedbecause they are at the top of the "food chain".

EDC definition: “An exogenous substance that causes adverse health effects in an intact organism, or its progeny, consequent to changes in endocrine function”

15


Suspected effects of EDCs (estrogens) in humans

• Malformations of newborns • Undescended testicles• Abnormal sperm• Low sperm counts• Abnormal thyroid function• Possible breast, testicular,

prostate cancer• Other effects


Legislation

USEPA - Contaminants Canditate List (CCL)

• Estrogens: 17α-estradiol, 17β-estradiol, estriol, estrone, ethinilestradiol, mestranol, equilenín and equilín• Antibiótics: erythromycin

UE - Substances subject to review for possible identification as priority substances (draft of Directive 2008/105/EC)

• X-ray contrast media: Amidotrizoate and iopamidol• Antiepileptics: carbamazepine• Fungicides: clotrimazole• Analgesics-antiinflamatories: diclofenac• Fragances: tonalid

16


- investigating the environmental occurrence of pharmaceuticals and illicit drugs,

- producing integrated data on levels and effects- developing both biological and chemical analytical methods- identifying new, still unknown, contaminants and

transformation products (TIE, EDA) - studying the removal efficiency of current and advanced

wastewater treatment methods (bioreactors, nanofiltration, etc.),

- searching for substitutive, less harmful chemicals,- performing epidemiological studies for human risk

assessment-…

Future research needs

To continue…


- establishment of maximum allowable concentrations for compounds not yet regulated, such as estrogens,

- increment of the number of STPs,

- incorporation of terciary or more advanced water treatmentprocesses in STPs,

- application of source-point, specific water treatments in industries.

Recommended actions

to diminish the presence and effects of emerging contaminants in the aquatic environment

Documents

Introduction to pharmaceuticals and illicit drugs