2. ecotoxicological characterisation of pharmaceuticals during regulatory assessments state of the art, options for improvement -
Thomas Backhaus
University of Gothenburg

3. Three issues Additional issues, e.g. The Action Limit
Grouping for hazard and risk assessment
The substitution principle
Additional issues, e.g.
It does not make any scientific sense to distinguish between “existing” and “new” pharmaceuticals.
Transparency, i.e. public availability of risk assessment reports and their underlying datasets.

4. The Action Limit
Allows for the exposure-based waiving of risk assessment
Conceptually similar to the (eco)toxicological threshold of concern.
Action Limit for human pharmaceuticals: PNEC < 0.01 µg/L (water)
Action Limit for veterinary pharmaceuticals: EIA < 1 µg/L (water), EIA < 100 µg/kg (soil)
Unless specific hazard criteria fulfilled

5. The Action Limit
Action Limit is unique for chemicals that require market authorization
Tier 0 assessment
Must minimize the risk of false-negative results
Requires a reliable, publically available ecotoxicity database that is an unbiased representation of all relevant modes of action and chemical classes currently on the market
Requires constant update

6. The Action Limit
However, the action limit for veterinary drugs is based on an evaluation of the US market from only.
Neither the underlying reports nor the underlying data are available for scrutiny or amendment.

7. The Action Limit
No explicit justificiation for the 0.01 µg/L action limit for human pharmaceuticals given.
"The present action limit is based mainly on acute toxicity data and may therefore be revised in future versions of the guideline when a sufficient amount of chronic data is available".

8. The Action Limit - Conclusions
Potentially powerful shortcut to avoid unnecessary testing.
Currently unreliable due the outlined limitations of the underlying data (outdated, US-centric, not available for scrutiny and amendment).
Either modernize it – or scrap it.

9. The Substitution Principle
"If risks to the environment and human health and safety can be reduced by replacing a chemical substance or product either by another substance or by some non-chemical technology, then this replacement should take place."
(Swedish Chemicals Agency, 2007).

10. The Substitution Principle
Incentives phasing out compounds and products with particularly problematic characteristics.
However, even problematic compounds remain on the market (or are even gaining market approval), if no alternatives are available.
Goes beyond chemical substitution
Includes the protection of human health and the environment

11. The Substitution Principle
For industrial chemicals in REACH (EC/1907/2006 )
For biocides in the Biocide Product Regulation (EU/528/2012)
For pesticides, in the Regulation on Plant Protection Products (EC/1107/2009)

12. The Substitution Principle
Implementing a strategy for substitution can be either /or
hazard based – focus on the active substance
risk based – focus on the formulated product
Two critical issues
Identifying candidates for substitution
Comparative hazard and risk assessment

13. The Substitution Principle
Pass
Phase I
Fail
Fail
Fail
No Authorisation
Authorisation
Phase II
Benefit Risk Evaluation
Pass
Pass
Pass
Evaluation of SHEC criteria
Evaluation of SHEC criteria
Fail
Pass
Fail
Substitution
Candidates
Class 2
Class 1
Class 3
hazard
risk
hazard risk
Yes
Better Alternative available? No
Limited Authorisation
Veterinary Pharmaceuticals

14. The Substitution Principle
Hazard driven or risk driven
Identifying a compound as a candidate for substitution does NOT imply the compound cannot be marketed
However, authorization should be time-limited
Depends on the availability of alternatives
Incentives to develop alternatives, if none are available

15. The Substitution Principle
Criteria for Substances of High Environmental Concern
PBT criteria
Properties as endocrine disrupting compounds in non-target organisms
Compounds that impair resistance management
Risk of groundwater contamination

16. The Substitution Principle
Alternatives Assessment
Substitution takes place only if a suitable alternative is available
Characteristics of a suitable alternative
Comparable therapeutic profile and efficacy
No increased risk of resistance development
Alternative needs to be authorized itself (although perhaps not for the same application)
No increased hazards / risks for human health (worker safety, residue in the produce)
No significant practical and economic disadvantages
Significantly better environmental profile

17. The Substitution Principle - Conclusions
Applying the substitution principle introduces incentives to limit the use of particularly problematic compounds to the absolute minimum.
Applied already for other chemical classes, there is no reason why it should not be applicable also to pharmaceuticals.
Just to avoid misunderstandings: patient safety, consumer protections, efficacy take priority. Acknowledging the substitution principle does NOT imply that critical pharmaceuticals are taken of the market before viable alternatives are available.

18. Grouping for hazard & risk assessment
2 Rationales
To develop specific assessment strategies
To account for the joint action of pharmaceuticals

19. Effects of a fungicide on algae
Clotrimazole is a common antimycotic pharmaceutical
Tested in natural marine algal biofilms
Porsbring, T., Blanck, H., Tjellström, H. and Backhaus, T., Toxicity of the pharmaceutical clotrimazole to marine microalgal communities. Aquatic Toxicology, 91(3), pp

20. Effects of an anti-anxiety drug on fish behaviour
Oxazepam
Tested concentrations: 1.8 and 910 µg/L
Surface water concentrations: max µg/L (Sadezky et al., 2008)
Brodin, T., Fick, J., Jonsson, M. and Klaminder, J., Dilute concentrations of a psychiatric drug alter behavior of fish from natural populations. Science, 339(6121), pp

21. Effects of Chlortetracycline to natural lake bacterial communities
Measured surfacewater concentrations
Brosché, Backhaus, (2010): Toxicity of five protein synthesis inhibiting antibiotics and their mixture to limnic bacterial communities, Aquatic Toxicology, 99(4),

22. Grouping for hazard & risk assessment
“Pharmaceuticals” are not a chemically or pharmacologically well defined group.
Specific hazard assessment approaches might be needed for chemically or pharmacologically defined groups.

23. Biocide Regulation
Also has to cover vastly different chemicals and formulated products.
Uses so-called “product types”, in order to allow for specific approaches that follow a common strategy.

24. Grouping for hazard & risk assessment
“Pharmaceuticals” are not a chemically or biologically well defined group.
Specific hazard assessment approaches might be needed for chemically or pharmacologically defined groups.
Suggestion: follow the rational of the biocide Regulation and define “product types”, which undergo a common assessment strategy.
Core dataset
Specific dataset
Specific dataset
Specific dataset

25. Mixture toxicity of pharmaceuticals

26. Grouping for hazard & risk assessment
Pharmaceuticals with the same mode of action act concentration-additively.
A substance-by-substance assessment is insufficient.
Group-level assessments needed.
Default approach: each member of a group is only allowed a risk quotient (PEC/PNEC) of 1/n, with n being the number of group members.
Alternative: full mixture assessment, based on Concentration Addition.

27. Grouping - conclusions
Grouping allows to develop consistent, yet specific, assessment approaches – which are needed, given the enormous chemical and functional heterogeneity of pharmaceuticals.
Single substance assessment underestimates the actual impact of a pharmaceutical group.
CA-compliant assessements needed instead.

28. Take home messages…
The Action Limit – potentially powerful to avoid unnecessary testing, but needs update
The substitution principle – provides an incentive to develop & use compounds with acceptable environmental profiles
Grouping – improves practicality and realism of environmental hazard and risk assessments.

29. ecotoxicological characterisation of pharmaceuticals during regulatory assessments state of the art, options for improvement -
Thomas Backhaus
University of Gothenburg