1. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Assessment of the impact of selected steroid hormones on biodiversity Reinhard Laenge Experimental Toxicology Schering AG, Berlin International Environment Forum (IEF) Helsinki, Finland 8 -9 June 2006

2. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Content Introduction Pharmaceuticals and the environment: Current issues Steroid Hormones: Substance characteristics, applications Occurrence in the environment and ecotoxicological data Principles of environmental risk assessment Conclusion Policy issues

3. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Introduction What is the issue with pharmaceuticals in the environment? In the ’90 the discussion on “endocrine disruptors”, observation of gender bending in fish in UK rivers by hormones and hormone like compounds Recently, the mass mortality of vultures on the Indian subcontinent were correlated with diclofenac uptake

4. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Less spectacular findings of pharmaceuticals in low concentrations in effluents and rivers in Europe, US, Japan (examples): Antibiotics Antiepileptics Antianalgetics Betablockers Lipid lowering compounds Pharmaceuticals in the environment: Occurrence

5. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 How do pharmaceuticals reach the environment? Used medicines Unused medicines Waste water treatment

6. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Hormones reaching the environment Since millions of years animals and humans introduce hormones into the environment by natural excretion Additionally, hormones are introduced as a result of the use of hormone products (natural and synthetic steroids) since decades Is the introduction of hormones affecting biodiversity in the environment?

7. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 How the discussion began In the early ’90s feminization of fish populations particularly in English rivers were reported As causes steroid hormones and hormonally active chemicals were proposed Cause is probably combination of natural and synthetic estrogens; Contamination mainly caused by waste water effluents from densely populated areas and cattle Today we know that in the neighbourhood of waste water effluents fish populations have been influenced by estrogens and possibly, other hormonally active substances

8. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Some substance characteristics of steroidal estrogens natural estrogens: Estradiol, Estron, Estriol synthetic estrogens: Ethinylestradiol, Mestranol Mechanism by binding/activation on/of the estrogen receptors Influence on fertility, primary and secondary sex characteristics, hormone dependent physiological processes Excretion after metabolism to hydroxylated and conjugated compounds

9. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Occurrence of selected steroidal estrogens in the environment Measured concentrations (ng/L) [median values]: Estradiol: Raw effluent 2-20; treated effluent 0.2-10; Surface water <0.1-3 Estron: Raw effluent 2-50; treated effluent 0.3-10; Surface water <0.1-3 Ethinylestradiol: Raw effluent 2-12; treated effluent <0.1-5; Surface water <0.1

10. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Ecotoxicity of estrogenic homones Standard species (laboratory tests) Crustacean (Waterflea, copepods): NOEC/21d (reproduction) higher than 100 µg/L [estradiol, ethinylestradiol] Fish: NOEC/96d (growth, sexual development) 3-8 ng/L [estradiol ] NOEC/300d (growth, sex development, reproduction) 0.5-1 ng/L [ethinylestradiol ]

11. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Principles of the environmental risk assessment (ERA) PNEC Water Consumption & Drug Use Water Consumption & Drug Use Ecotoxicity Data Ecotoxicity Data PEC Metabolization Biodegradation Sorption & Dilution Metabolization Biodegradation Sorption & Dilution Assessment Factor Assessment Factor Risk Characterisation ExposureEffects

12. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Risk assessment (risk quotient approach) Ratio of PEC to PNEC: PEC/PNEC < 1: No risk expected PEC/PNEC  1: Risk expected Comparison of predicted (measured) environmental concentrations (PEC) with environmental no-effect-concentrations (laboratory tests, uncertainty factor)) (PNEC)

13. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Risk assessment of steroidal estrogens Concentration [ng/L] 0 123 Environm. Conc. EE2 Environm. Conc. E1, E2 PNEC EE2 PNEC E2

14. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Conclusion Synthetic and natural steroids are introduced into waste water treatment plants and traces reach surface waters like other pharmaceuticals Natural estrogens represent the bulk of the entire estrogenic hormones reaching the environment In general no risk indicated for the environment, but at hot-spots the estrogen concentrations can reach effect levels in fish Improved WW treatment technologies needed To date an environmental risk assessment of new medicines including hormones is part of the approval process

15. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Policy issues Regulatory situation globally: ERA for new drug marketing approval, most stringent in Europe ERA not part of risk benefit analysis, but information and labelling Policy options for pharma industry: - Active response to the public (“We take the issue serious”) - Provide information - Maintain high ethical image as providing benefit for mankind

16. Environmental impact assessment of steroid hormones R. Laenge, LGE 09 June 2006 Aspects of Scherings policy Proactive approach: - Research to develop a data base on potential impact (chronic ecotoxicity data, exposure assessment) for major pharmaceutical compound classes - networking with research scientists and regulators Future perspective: - Including of environmental aspects in development process of pharmaceuticals ERA part of product stewardship and responsibe care