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

1. Experiences gained through the Environmental Classification System for PharmaceuticalsAndreas Woldegiorgis, Ph. D. Conference on Sustainable Development and Pharmaceuticals, Uppsala 10-11/11, 2009

2. Overview Background The 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

3. Frogs, fish and pharmaceuticals a troubling brew Prozac, other drugs detected in streams and their inhabitants By 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. Background; Effects in the environment (and in the media..)

4. Or; Approximatively 550 peer-reviewed articles published on the issue "pharmaceuticals in the environment" between 1991-2008. ...~ 65 % published rather recently, 2006 and onwards...

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

6. Predicted No Effect Concentration Predicted Environmental Concentration Basic principles of Environmental Risk Assessment (ERA) Predicted concentration of the substance in the environment is related to the toxicity of the substance towards organisms living in the environment. PEC / PNEC

7. Estimation of the Surface water PEC in µg/l "A" ; sold amount annually [kg] Or, in a simplified way... Consumption in kg PEC = Nr of liters of water that the Swedish population uses annually Thus, the system requires an exact estimation of the sold amount of any given pharmaceutical!!!

8. Refinement (reduction...) of the PEC-value possible; Metabolism in the human body; from the fass.se-guideline;"...Identification of the metabolites, including specification of conjugates, 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 the parent compound." Fate of the pharmaceutical upon passage of the waste water treatment plant; If no eco-toxicological data on the main metabolite can be 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)

9. 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 individuals to an entire population in the environment; a safety factor (AF) is applied. Thus; 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

10. 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 into consideration 4) never 'calculated' or estimated based on structure-activity relationships (SARs/QSARs) Consequently, PNEC data currently used leave room for improvements when more appropriate data becomes available!!

11. 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?

12. The 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; • compatibility with the fass.se guideline, • that data chosen seem appropriate with respect to methodology used, • 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).

13. 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.

14. Case 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?

15. IVL Screening data on STP effluents Citalopram detected in all STP effluents; 1-120 ng/l Sertraline never detected in any of the 28 effluents

16. IVL Screening data on digested sludge Detected in all digested sludge samples; 1.6 – 310 ng/g DW Fate of Sertraline ? In Stockholm; Citalopram easily reaches the the archipelago through the effluent discharge in Saltsjön while Sertraline-contaminated sludge is transported 2000 km to Lapponia where it is used as landfill! Which is the more favourable choice for the environment?

17. Conclusions • 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!