Environmental Risk Assessment of Pharmaceutical Mixtures:

-empirical knowledge, gaps and

regulatory options

Thomas Backhaus University of Gothenburg thomas.backhaus@gu.se

[T]here are known knowns; there are things we know that we know.

There are known unknowns; that is to say there are things that we now know we don't know.

But there are also unknown unknowns – there are things we do not know, we don't know.

Donald Rumsfeld, 2002

Background: Different mixture types

Type of mixture Comment

• Products:Compounds that co-occur in a specific product, i.e. the combination of active pharmaceutical ingredients (API) and excipients

Not relevant from an environmental perspective

• Emissions:Pharmaceutical mixtures that are emitted from a common process or emission source, e.g. in an STP stream from a pharmaceutical production facility

• Immissions / Multi-Pathway Exposure:

NOT intentionally produced complex mixtures, occurring in environmental media, in food or in humans as a result of release and emissions from numerous products and processes

Co-exposure with chemicals from other use categories

Prospective: In the context of an application for market approval

Retrospective: In the context of the Water Framework Directive or the Marine Strategy Framework Directive

Background: Environmental Risk Assessment (ERA)

Mixtures matter. They constitute the typical environmental exposure situation.

Mixtures are more toxic than each individual pharmaceutical at the concentration at which it is present, and they have an impact on biota at exposed sites.

Compliance with individual environmental quality targets does not necessarily safeguard against unwanted mixture effects.

Mixtures are not magic. Modeling approaches, based on Concentration Addition, Independent Action, provide mixture toxicity estimates with a sufficient precision and accuracy for regulation.

Known knowns of mixture ecotoxicology

Recent monitoring studies

STP effluents: in average 24 pharmaceuticals (Kostich et al. 2014)

STP sludge: 21-30 pharmaceuticals (Jelic, 2009)

Drinking water supply: 6-21 pharmaceuticals (Vulliet, 2011)

The typical exposure is towards pharmaceutical mixtures.

Known knowns: Mixtures matter

Known knowns: Mixtures are more toxic & individual thresholds do not safeguard

Backhaus, Blanck, Sumpter, 2008: “On the ecotoxicology of pharmaceutical mixtures“, Kümmerer (ed) Pharmaceuticals in the environment, Springer

Known knowns: Mixtures are more toxic & individual thresholds do not safeguard

Backhaus, Blanck, Sumpter, 2008: “On the ecotoxicology of pharmaceutical mixtures“, Kümmerer (ed) Pharmaceuticals in the environment, Springer

Direct testing of the mixture of concern Drawing conclusions from similar mixtures

Component-based approaches

Sidestep: Approaches for mixture testing and risk assessment

Depending on the specific context, mixture toxicities can be accounted for by

Sidestep: Mixture toxicity concepts

n

iiMix EE

1

)1(1

EMix = Effect of the mixture of n compounds

Ei = Effect of substance i, when applied singly

ci = Concentration of component i in the mixture

(i = 1...n)ECxi = Concentration of substance i provoking a

certain effect x when applied aloneECx(Mix) = Predicted total concentration of the mixture, that

provokes x% effect.pi = relative fraction of component i in the mixture

1

1)(

n

i i

iMix ECx

pECx

Similarly acting substances: Concentration Addition

Dissimilarly acting substances: Independent Action

Only option when the mixture cannot be tested in its entirety

Are applied in conjunction with whole mixture testing for TIE-studies for the identification of causative links.

Introduces an additional extrapolation step (uncertainty)

Sidestep: Component based approaches

CA and IA assume no interaction between the mixture components

CA and IA assume that each component in the mixture affects the endpoint of interest (i.e. all are toxic)

Sidestep: Limitations of component based approaches

Known knowns: Mixtures are more toxic & individual thresholds do not safeguard

Backhaus, Blanck, Sumpter, 2008: “On the ecotoxicology of pharmaceutical mixtures“, Kümmerer (ed) Pharmaceuticals in the environment, Springer

Known knowns: mixtures are not magic

Three independent replicates analyzing the predictive power of CA and IA in an ecological context

5 component mixture of antibiotics

………. CA - - - - - - IA

from: Brosche & Backhaus, 2010

Mixtures matter

Mixtures are more toxic

Individual environmental quality targets do not necessarily safeguard against unwanted mixture effects.

Mixtures are not magic Modeling approaches, based on Concentration Addition, Independent Action, provide mixture toxicity estimates with a sufficient precision and accuracy for regulation.

Known knowns of mixture ecotoxicology

Legal basis is article 8(3) of Directive 2001/83/EC

Details in EMA guideline EMEA/CHMP/SWP/4447/00 corr 1

Based on a classical tiered approach

Tier 0, the “Action Limit” is based solely on an exposure estimation

Prospective ERA of Pharmaceuticals

Mixtures not considered in the final EMA guidelines

Draft from 2005 for human pharmaceuticals states that "Existing information on synergistic effects in the environment should be included in the risk assessment."

The passage that was dropped in the final guideline

Regulatory ERA of pharmaceuticals lags behind

Regulatory ERA of pharmaceutial mixtures

Pesticide Regulation EC 1107/2009

Article 4(2) (approval criteria for active substances, residue levels) stipulates that:

“The residues of the plant protection products, […], shall meet the following requirements:

(a) they shall not have any harmful effects on human health, including that of vulnerable groups, or animal health, taking into account known cumulative and synergistic effects”

Mixture Risk Assessment in other Regulations

Biocide Regulation (EU) No 528/2012:

Article 19(2) states that that "the evaluation […] shall take into account the following factors: […] cumulative effects, synergistic effects."

Mixture Risk Assessment in other Regulations

Known unknowns: limited information on individual pharmaceuticals

MEC

max

/ PN

EC

Bergmann, Compilation of monitoringdata on pharmaceuticals, Report to the German Environment Agency, 2010

15 Risk Quotients were calculated using an assessment factor > 1 000 (Bergmann et al, 2010)

Indicates severe data gaps

Known unknowns: limited information on individual pharmaceuticals

Known unknowns: what are the drivers of mixture toxicity?

Backhaus et al. Water Research, 2014

The contributions of the different pharmaceuticals are different: ecotoxicological profile of an STP effluent from Gothenburg

Known unknowns: when and how often do synergisms and antagonisms occur?

Kortenkamp et al., 2009

Anti-androgenic effect of a mixture of - DEHP- Finasteride- Prochloraz- Vinclozolin

Known unknowns

Conclusions – Known knowns

Act on the available scientific knowledgeModernize regulatory frameworksFill in ecotoxicological data gaps Improve documentation of data

Conclusions – known unknowns

Which pharmaceuticals are “drivers of mixture toxicity”? Under which conditions? Improve exposure assessment Improve understanding of the

relevance of synergisms How important are

pharmaceuticals in comparison to other chemical groups?

Marine systems

Conclusions – Unknown unknowns

Improve Read Across and better integrate ERA & HRA Ecopharmacovigilance Incidence reporting Postmarket monitoring

Environmental Risk Assessment of Pharmaceutical Mixtures:

-empirical knowledge, gaps and

regulatory options

Thomas Backhaus University of Gothenburg thomas.backhaus@gu.se