Pharmaceuticals in water –

including legislative aspects

Nicole Adler, Anette Küster,

Bettina Rechenberg

German Federal Environment Agency (UBA)

Copenhagen 6th of December 2010

Overview

1. Pharmaceuticals in the environment

2. Entry of human/veterinary pharmaceuticals into water

3. Disposal of pharmaceuticals

4. ERA in authorisation procedures

5. Problem of “old” substances

6. “Gaps” in regulation

7. Ecopharmacovigilanz

8. Production and consumption of pharmaceuticals

9. Monitoring of pharmaceuticals

10. Conclusions

120 different pharmaceutical active substances and metabolites detected in surface waters

German rivers: single substances > 0.5 µg/l

German ground water: single substances > 0.5 µg/l

Leachate from waste dump:single substances > 100 µg/l

Environmental loads into surface waters:

pharmaceuticals plant protection products

Source: BLAC report 2003

Foto: Simone LehmannFoto: Simone Lehmann

1. Pharmaceuticals in the environment – an arising problem?

EE2- hormone: effects < 1 ng/L fishes, measured

environmental concentrations sometimes exceed this value

Fluoxetin – anti-depressant: delay of development in fishes and frogs in concentrations that were measured in sewage

Avermectins – parasiticides: inhibition of dung fauna organisms; highly toxic to invertebrates

Diclofenac - antiphlogistic: damages in kidneys in fishes after a long exposure =1 µg/L*, concentrations in sewage and STP effluents sometimes exceed this value

*Schwaiger et al. 2004, Triebskorn et al. 2004

1. Pharmaceuticals in the environment – an arising problem?

2. Entry of human pharmaceuticals into water

excretionexcretion

surface water

ground waterground waterdrinking water

Incorrect disposalIncorrect disposal

waste/ sewage systemwaste/ sewage system

sewage sludge

soilproductionproduction

2. Entry of veterinary pharmaceuticals into water

direct entrydirect entry

entry via incorporation of slurry/manure

ground waterground water

productionproduction

drinking water

What can be done for reduction by authorities?

productionsetting quality standards for sewage, monitoring

excretion after ingestion, injection or infusionassessing potential environmental risk within authorization procedure, risk mitigation measures, risk triggered monitoring

disposal of unwanted or leftover pharmaceuticals

organizing safe disposal

2. Entry of pharmaceuticals into water

Incorrect disposal

waste/ sewage system

Improper disposal of unwanted and unused medications represents a significant source of pharmaceutical discharges into the environment

Sewage system is a main route of entry of unwanted or leftover pharmaceuticals

Disposal on household waste landfills without leachate collection represents a locally significant source

3. Disposal of pharmaceuticals

Incorrect disposal - Examples

UK (Bound and Voulvoulis 2005)63% of patients dispose pharmaceuticals via household waste

11% of patients empty them into sink or toilet

22% of patients return them to a pharmacy

Germany (START 2008 www.start-project.de) 15.7% of patients dispose tablets via the toilet (1% always)

43.7% of patients dispose liquid medicinal products via drain/toilet (10% always)

approximately 10-20% of unused HMPs enter household waste

Berlin: 100 t unused pharmaceuticals per year were collected in pharmacies (wiss. Institut AOK, 2006)

3. Disposal of pharmaceuticals

Incorrect disposal - Regulation

EC Directive 2004/27/EC – Article 127b requires:

“Member States shall ensure that appropriate collection systems are in place for medicinal products that are unused or have expired.”

Survey of the 27 EU member states and Norway in 2007

(Taylor and Poulmaire 2008, cited in Glassmeyer et al. 2009):

20 nations have established a pharmaceutical waste collection scheme

11 of which are pharmacy-based collection systems

3. Disposal of pharmaceuticals

ERA regulated by Directives 2001/83/EC and 2001/82/EC (as amended in 2004) for human and veterinary pharmaceuticals within EU

ERA carried out according to:

EU Human Guideline

Phase I und II - 2006

Veterinary Guideline

VICH Phase I 2001

and Phase II 2005

and supporting document 2007

4. ERA in authorisation procedures

Assess potential risk for the environment on product level

prospective risk assessment before marketing

Directives require mitigation measures in case of risk

for veterinary pharmaceuticals e.g. no access for treated animals to surface

waters

if no practicable mitigation measures available –

refusal of marketing authorisation possible after risk-benefit analysis

for human pharmaceuticals e.g. disposal advices

availability of the medicine must not be reduced, environmental risks not

included in risk/benefit analysis –

marketing authorisation cannot be denied

4. ERA in authorisation procedures

Estimation of Exposure (Phase I)non-experimentalcalculation of predicted environmentalconcentration, identification of substances of concern

Analysis of Fate (Phase II)experimental data on degradation, sorption and partitioning between octanol and water

Analysis of Effects (Phase II)experimental dataon effects on organisms in surface water, sediment,…(here only aquatic compartment)

4. ERA in authorisation procedures

EffectAssessment

PNECPredicted No

Effect Concentration

Exposureassessment

PECPredicted

Environmental Concentration

Riskquotient (RQ):

PEC

PNEC≥ 1 ?

1 Risk for Environmentgranting of marketing authorisation with risk mitigation measurements or refusal of marketing authorisation (only possible vor VMPs)

< 1 No risk for environment granting of marketing authorisation

4. ERA - Risk Characterisation

Assessment of the medicinal product

Pharmaceuticals (HMPs) with identified Environmental RiskUBA results 2008-2009

Same situation for VMPs

4. ERA - Risk Characterisation

Top 10 HMP - measured surface water concentrations in Germany 2001

BLAC-Report 2003

5. Problem of “old” substances

Active ingredientAnnual consumption (kg/a)

Max. measured Concentration

(µg/L)

Measured in Ground /

Drinking Water

Carbamazepine 87,604.9 1.81 +

Metoprolol 92,974.4 1.8 +

Iopamidol 42,994.4 1.0 +

Sotalol 26,649.2 0.95 +

Diatrizoic acid 60,686.8 0.95 +

Clarithromycin 7,159.1 0.95 +

Phenazone 24,843.2 0.84 +

Diclofenac 85,800.7 0.47 +

Sulfamethoxazole 53,600.3 0.38 +

Bezafibrate 33,475.6 0.35 +

Not a single ERA available!Same situation for VMPs

UBA proposes

a program for substances that are already on the marketfor years but have no environmental risk assessment:

Prioritization of substances of concern

Monographic system for „old“ HMPs and VMPs

Data Sharing (COM; EMA; EEA and Member States)

5. Problem of “old” substances

Example VMP - Toltrazuril

Coccidiostatic

Infection of protozoa (Coccidiosis)

NN

O

NO

OOSF

F

F

Environmental Risk Assessment

Broiler: PECgw = 1.33 µg/l (Focus)

Toltrazuril-sulfone = Metabolite = organohalogen compound

Risk for groundwater !Risk for groundwater !

because of the persistency (dt50 = 472d) and the mobility of Toltrazuril-sulfonebecause of the persistency (dt50 = 472d) and the mobility of Toltrazuril-sulfone

6. “Gaps” in regulation

ANNEX VIIIINDICATIVE LIST OF THE MAIN POLLUTANTS1. Organohalogen compounds and substances which may form such

compounds in the aquatic environment.2. Organophosphorous compounds.3. Organotin compounds…

DIRECTIVE 2000/60/EC establishing a framework for Community action in the field of water

policy

DIRECTIVE 2006/118/EC on the protection of groundwater against pollution and deterioration

Article 6 1.(a) all measures necessary to prevent inputs into groundwater of any hazardous substances… In identifying such substances, Member States shall in particular take account of hazardous substances belonging to the families or groups of pollutants referred to in points 1 to 6 of Annex VIII to Directive 2000/ 60/EC…

6. “Gaps” in regulation

“no input into groundwater” can be interpreted as input < 0.1 µg/l

DIRECTIVE 2006/118/EC on the protection of groundwater against pollution and deterioration

ANNEX IGROUNDWATER QUALITY STANDARDS

Pollutant Quality standards

Nitrates 50 mg/l

Active substances in pesticides, including their relevant 0.1 µg/lmetabolites, degradation and reaction products (1) 0.5 µg/l (total)

(2)

(1) ‘Pesticides’ means plant protection products and biocidal products as defined in Article 2 of Directive 91/414/EEC and in Article 2 of Directive 98/8/EC, respectively.

(2) ‘Total’ means the sum of all individual pesticides detected and quantified in the monitoring procedure, including their relevant metabolites, degradation and reaction products.

6. “Gaps” in regulation

Pharmaceuticals should be clearly mentioned

Decision of CVMP (EMEA):

Authorization without special measures(CVMP used ADI for ground water risk assessment )

UBA proposal:

• Monitoring of groundwater• New Environmental Risk Assessment after 5 years

Example VMP - Toltrazuril

6. “Gaps” in regulation

0.1 µg/l limit from veterinary ERA guideline not applied

Potential risk for human health through environmental pathway?

PHARMAS: detailed assessment of risks for ground and drinking water to be included in the ERA guidelines for HMPs and VMPs

EU Project PHARMAS starts in January 2011 “Ecological and human health risk assessments of antibiotics

and anticancer drugs found in the environment”

6. “Gaps” in regulation

Definition Ecopharmacovigilance:

Collection of unexpected side effects in environment after authorisation and monitoring of concentration in environment

VMPs: implemented in the legislation but not used in practice

HMPs: not implemented in the current legislation

7. Ecopharmacovigilanz

Revision of EU Directive and Regulation for human pharmaceuticals

- Released by the Commission in November 2008

Recital 2 a (new)

2a) The pollution of waters and soils with pharmaceutical residues is an emerging environmental problem and an emerging public health concern. Measures should be taken to monitor and evaluate adverse environmental effects of medicinal products, including those which impact on public health.

The Commission should, based on data received from the Agency, the Environment Agency, and Member States, produce a report on the scale of the problem, along with an assessment on whether amendments to EU legislation on medicinal products or other relevant EU legislation are required.

Results of the Pharmaceutical Package

EU Commission has to collect and evaluate

monitoring data and write a report on the results

7. Ecopharmacovigilanz

8. Production and consumption of pharmaceuticals

8. Production and consumption of pharmaceuticals

Production data:

Unknown for HMPs and VMPs (production is not regulated)

Consumption data:

Data for HMP are comercially available (IMS)

Nearly no data for VMP are exisiting for Europe (IFAH EU)

German government will start programm in 2011 to collect data for

the use of Antibiotics in animal production

Entry of pharmaceuticals through production is not regulated

Monitoring of surface waters:

Data from production, consumption and incorrect disposal:

Problem:

No standardized monitoring programs for pharmaceuticals in the EU Member States

Very few quality standards in WFD for pharmaceuticals

EU: Ibuprofen, Diclofenac, 17 alpha-Ethinylestradiol, 17 beta-Estradiol under discussion for list of priority substances

Germany: Carbamazepine, Diclofenac, Sulfamethoxazole under discussion for national quality standards

9. Monitoring of pharmaceuticals

9. Monitoring of pharmaceuticals

UBA proposes:

• Report of production data from industry

• Report of detailed sales/consumption data

• Monitoring of pharmaceuticals in surface waters – setting quality standards for pharmaceuticals in WFD

10. Conclusions

For the sustainable use of pharmaceuticals authorities should:

assess the potential environmental risk of existing (old) substancese.g. by Monographic systems, identify critical substances

find a harmonized approach for the assessment of hazardous pharmaceuticals entering ground and drinking water

establish systematic monitoring programs for pharmaceuticals and set quality standards for wastewater, surface water, drinking water, etc.

establish safe collection systems for unused pharmaceuticals

make “all” existent data available and evaluate it in order toprotect environmental and human health

development of a life-cycle-assessment for pharmaceuticals (production + consumption)

nicole.adler@uba.de

Any Questions?Any Questions?