Experiences gained through the Environmental Classification System for Pharmaceuticals Andreas Woldegiorgis, Ph. D

Experiences gained through the Environmental Classification System for Pharmaceuticals

Andreas Woldegiorgis, Ph. D.

Conference on Sustainable Development and Pharmaceuticals,Uppsala 10-11/11, 2009

www.ivl.seWoldegiorgis, Uppsala 10/11 2009

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OverviewBackgroundThe PEC/PNEC relationship

PEC and human metabolism

PEC and STP-removal

PNEC data in the fass.se system

The role of the system reviewer

A case study from the fass.se system

Conclusions


3Background;Effects in the environment (and in the media..)

Frogs, fish and pharmaceuticals a troubling brewProzac, other drugs detected in streams and their inhabitantsBy Marsha Walton CNNFriday, November 14, 2003 Posted: 9:14 AM EST (1414 GMT)

Two tapdpoles after 57 days of development in the lab. The one on the right, which has yet to sprout limbs, was exposed to fluoxetine, also known as Prozac.

(CNN) -- A number of aquatic and amphibian species are being exposed to small amounts of everything from Prozac to perfume to birth control pills that make their way into U.S. rivers and streams. And scientists now have evidence that this "cocktail" of pharmaceuticals, in high enough quantities, can lead to problems that may be serious enough to prevent wildlife from reproducing. It's not yet clear how the buildup over time could affect the species. In 2002, 80 percent of streams sampled by the U.S. Geological Survey showed evidence of drugs, hormones, steroids and personal care products such as soaps and perfumes. The U.S.G.S. tested 139 rivers in 30 states.


4

0

5

10

15

20

25

Prop

ortio

n of

arti

cles

(%)

Approximatively 550 peer-reviewed articles published on the issue"pharmaceuticals in the environment" between 1991-2008.

...~ 65 % published rather recently, 2006 and onwards...

Or;


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Thus;Any classification system of the environmental risks ofpharmaceuticals implemented 2005 must be considered as a'living' system in which improvements and newmethodology can easily be implemented.


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Basic principles of Environmental Risk Assessment (ERA)

PEC / PNEC

Predicted Environmental Concentration

Predicted No Effect Concentration

Predicted concentration of the substance in the environment is related to the toxicity of the substance towards organisms living in the environment.


7

)100(105.110200)/(

109

10036510010)/( 6

69

RAdilutionDdaylVP

DVPRAlgPEC

Estimation of the Surface water PEC in µg/l

"A" ; sold amount annually [kg]

Consumption in kgPEC =

Nr of liters of water that the Swedish population uses annually

Thus, the system requires an exact estimation of the soldamount of any given pharmaceutical!!!

Or, in a simplified way...


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Refinement (reduction...) of the PEC-value possible;

Metabolism in the human body;from the fass.se-guideline; "...Identification of the metabolites, including specification ofconjugates, which may de-conjugate to the parent compound in a sewage treatment plant....Pharmacological activity (or eco-toxicity, if known) of the metabolites compared with theparent compound."

Fate of the pharmaceutical upon passage of the waste water treatment plant;

If no eco-toxicological data on the main metabolite canbe found, PEC should NOT be reduced based on metabolism!

PEC-reduction should be based on either the SimpleTreat-model, OECD 303-experiments,or extensive measurements!SimpleTreat(Strujis J, 1996, TGD (Ref. 4), Part II, Chapter 3, Appendix II) "R" = f (OECD301/302-data, logH and logKow)


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The PNEC data in the fass.se system;

Data should reflect tests performed on 3 trophic levels; algae, crustaceans and fish.

In order to ensure acceptable safety margin when going from lab tests on x individualsto an entire population in the environment; a safety factor (AF) is applied. Thus;

AFLCEC

PNEC 5050 /

If only short term acute data available then AF = 1000...

If chronic long-term data are available from all 3 trophic levels, then AF = 10


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PNEC data in the fass.se-system are mostly;

1) provided by the companies from standard tests performed during the ERA process.

2) reflecting acute and short-term testing conditions (thus seldom chronic data)

3) mostly data not taking the specific mode-of-action of the pharmaceutical intoconsideration

4) never 'calculated' or estimated based on structure-activity relationships (SARs/QSARs)

Consequently, PNEC data currently used leave room for improvements when moreappropriate data becomes available!!


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One important remark before we continue....

PEC and PNEC data on all available substances are transparently displayed at the fass.se website (for anybody to check/audit)

(along with data on biodegradation and bioaccumulation).

The transparency (and availability) renders the system attractive to anybody interested;(authorities, stake holders, other companies).

Which other environmental classification systems possesses this property?


12The role of IVL Swedish Environmental Research Institute in the fass.se-project

To scientifically review the environmental risk-and hazard data supplied by the pharmarceutical companies.

To comment the supplied risk assessments submitted and recommend improvements to ensure;1. compatibility with the fass.se guideline,2. that data chosen seem appropriate with respect to methodology used,3. that the overall traceability of the data meets the guideline requirements.

To suggest improvements of the guideline to the environmental committée of LIF.

To summarize the data accumulated on fass.se to some general and overall synthese, beneficial to the stakeholders (at the end of the project).


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Important considerations of the reviewing process

No direct contact between IVL-reviewers and pharmaceutical companies, all communication and data iteration through the LIF office.

A self-declaration system where the pharmaceutical companies "owns" their respective data. IVL does not 'police' the published material beyond the reviewing process.

The system is a classification system with a broad perspective, hence sometimes difficult to implement latest scientific findings from the research frontier.


14Case study; Fass.se-data may not always be enough to make environmentally good choices!

Sertraline and Citalopram considered equally good on some indications of depression (therapeutic effect of treatment).

PNEC (Sertraline) = 0.056 µg/l PNEC (Citalopram) =4.9 µg/l ("Sertraline 88 times more "toxic"..) Both "have the potential to bioaccumulate" (log Kow > 3) Sertraline; "slowly degraded" Citalopram; "potentially persistent" (due to lack of data) PEC/PNEC (Sertraline) = 6.6 PEC/PNEC (Citalopram) = 0.05 Sertraline poses a 132 times higher environmental risk, nationally... Best 'choice' would be Citalopram, right?


15IVL Screening data on STP effluents

Concentration (ng/l)

Gällivare

Luleå

Piteå

Mora

Falun

Borlänge

Avesta

Ludvika

Säter

Stockholm B

Stockholm H

Stockholm K2

Stockholm K4

Stockholm K6

Stockholm

Karlstad

Kristinehamn

Strängnäs M

Strängnäs S

Eskilstuna W

Eskilstuna

Flen

Katrineholm

Trosa

Trosa W

Visby

Olofström

Ronneby

Karlshamn S

Karlshamn M

Karlskrona

Sölvesborg

Risperidone Zolpidem Fluoxetine Paroxetin Citalopram oxazepam propofol

after wetland

after wetland

Zoplicone-n-oxid 7-aminoflunitrazepam nordiazepam Caffein

Citalopramdetected in allSTP effluents;1-120 ng/l

Sertraline neverdetected in any ofthe 28 effluents


16Fate of Sertraline ?

concentration ng/g dw

0 100 200 300 400 500 600

Eslöv

Sölvesborg

Karlskrona

Karlshamn S

Karlshamn M

Ronneby

Olofström

Borås

Bollebygd

Alingsås

Floda

Göteborg

Stockholm B

Stockholm H

Stockholm Sj1

Stockholm SJ2

Stockholm K5

Stockholm K6

Stockholm K7

Stockholm K8

Trosa

Katrineholm

Flen

Eskilstuna

Strängnäs M

Strängnäs S

Säffle

Karlstad

Kristinehamn

Arvika

Avesta

Borlänge

Umeå

Lycksele

Skellefteå

Luleå

Dextropropoxyphen Clozapine Zolpidem Sertraline Oxazepam Citalopram Propofol Caffein vs City

Detected in all digestedsludge samples;1.6 – 310 ng/g DWIn Stockholm;

Citalopram easily reaches thethe archipelago throughthe effluent discharge in Saltsjönwhile Sertraline-contaminatedsludge is transported 2000 kmto Lapponia where it is used aslandfill!

Which is the more favourable choice for the environment?

IVL Screening data on digested sludge


17Conclusions Scientific reviewing of the fass.se-data should safeguard

that data and methods are in accd. with guidelines (fass.se and TGD) and that the interpretation of data is in accd. with the precautionary principle.

Scientific reviewing of the fass.se-data not always straightforward, many "special cases" not entirely covered by guidelines". The guideline is thus a 'living' document.

Fass.se-data can perferably be combined with occurence data and some kind of scientific rationale, fass.se is not a "bible" for ERA!

The total transparency of the fass.se system makes it unique as a classification system.

The system can be transferred to other countries!

Documents

Experiences gained through the Environmental Classification System for Pharmaceuticals Andreas Woldegiorgis, Ph. D