ecotoxicological characterisation of pharmaceuticals during regulatory assessments state of the art, options for improvement - Thomas Backhaus University of Gothenburg thomas.backhaus@gu.se

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.

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

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

The Action Limit However, the action limit for veterinary drugs is based on an evaluation of the US market from 1973- 1997 only. Neither the underlying reports nor the underlying data are available for scrutiny or amendment.

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".

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 Currently unreliable due the outlined limitations of the underlying data (outdated, US-centric, not available for scrutiny and amendment).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.

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).

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

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)

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

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

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

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

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

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.

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

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., 2009. Toxicity of the pharmaceutical clotrimazole to marine microalgal communities. Aquatic Toxicology, 91(3), pp.203-211.

Effects of an anti-anxiety drug on fish behaviour Oxazepam Tested concentrations: 1.8 and 910 µg/L Surface water concentrations: max. 2.2. µg/L (Sadezky et al., 2008) Brodin, T., Fick, J., Jonsson, M. and Klaminder, J., 2013. Dilute concentrations of a psychiatric drug alter behavior of fish from natural populations. Science, 339(6121), pp.814-815.

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), 457-465

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.

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.

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

Mixture toxicity of pharmaceuticals

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.

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.

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.

ecotoxicological characterisation of pharmaceuticals during regulatory assessments state of the art, options for improvement - Thomas Backhaus University of Gothenburg thomas.backhaus@gu.se