Suggestions for Toxicological Risk Assessment reforms in respect of pharmaceuticals



PharmaceuticalsFor many years, the environmental effects of agrochemicals and industrial chemicals were subjects of public concern, increasing regulation and toxicological risk assessment, while the environmental effects of pharmaceuticals were largely neglected. It was only in the 1990s that regulators turned their attention towards pharmaceuticals, which resulted in the European Medicines Agency producing its ?Guideline?on the environmental risk assessment of medicinal products for human use, which came into force in 2006. The current regulations only apply to ?new? authorisations for medicines (i.e. from 2006), so medicinal substances already licensed for use in the EU before that date are not covered.


Excreted pharmaceuticals can have significant adverse effects in the environment; for example, hormonal pharmaceuticals used in oral contraceptives and HRT can seriously affect the reproduction of fish and amphibians. The presence of antibiotics in the environment can encourage the development of antibiotic-resistant strains of bacteria. According to the non-governmental organisation CHEM Trust, typically 30-90% of an ingested active pharmaceutical ingredient is excreted, and may subsequently reach the environment via sewage treatment works. The spreading of sewage sludge on the land can lead to terrestrial pollution by pharmaceuticals.


The toxicological risk assessment is carried out in a number of stages. Firstly, for some categories of medicine, namely vitamins, vaccines, herbal medicines, electrolytes, amino acids, peptides, proteins, carbohydrates and lipids, the risk assessment?merely consists of a justification showing that further testing is not required, since these classes of medicine are not normally expected to cause environmental problems. All other new medicines have to go on to the first phase of the assessment. Those judged to have a potentially significant risk on the first phase go on to the second phase of the?risk assessment, which is split into two tiers.


In phase one of the toxicological risk assessment, the likely exposure of the environment to the drug substance is assessed. The Predicted Environmental Concentration (PEC) is estimated by considering the average dose and expected market share. The initial calculation assumes that the drug passes through the patient and the sewage treatment plant unchanged (a ?worst case scenario?). The PEC for surface water, PECSURFACEWATER, is then calculated, following the procedure in the guidelines. If PECSURFACEWATER SURFFACEWATER ?0.01 ?g / litre, or there are other environmental concerns which may make this limit inappropriate, the substance has to undergo phase two of the TRA. In addition to the above calculation, if the logkow (octanol water partition coefficient) is > 4.5 (i.e. the compound is unusually lipophilic), then a risk assessment needs to carried out to determine if the compound should be classed as PBT (Persistent, Bioaccumulative and Toxic).


In phase two tier A of the TRA, tests must be carried out to determine the adhesion to sewage sludge, and also on biodegradation. Tests on fish (early life stage), algae and Daphnia magna (water flea) are also required. Predicted no-effect concentrations (PNEC) are calculated for water and groundwater. For antimicrobial compounds, the effects on sewage sludge microbial activity are also determined. Depending on the values calculated in tier A of phase 2, further environmental and toxicological studies may be required in tier B of phase 2. If significant adhesion to sewage sludge is present, terrestrial studies, such as earthworm toxicity tests, are required.


The outcome of the TRA may result in particular measures to limit the impact of an active pharmaceutical ingredient on the environment. For example, these may include labelling that advises the user on the disposal of unused medication. A medicine cannot be banned solely because of an adverse TRA.



Suggested reforms to Toxicological?Risk Assessment for medicines


Despite the European legislation, the environmental regulations for pharmaceuticals are less stringent than those that apply to agrochemicals and industrial chemicals. For example, there is no requirement for a toxicological risk assessment (TRA) on older pharmaceuticals, while risk assessments are now required for all agrochemicals and industrial chemicals used in significant amounts within the EU. A recent scientific paper, ?gerstrand M. et al, by UK and Swedish academics, outlined potential improvements to the medicinal environmental risk assessment regime. The following changes were suggested:


  • Require TRA?to be carried out on all pharmaceuticals, rather than just the newer ones.For antibiotics, add requirements to examine the potential for the spread of antibiotic resistance as part of a?risk assessment.
  • Avoid duplication by carrying out only one risk assessmentper active pharmaceutical ingredient. Currently, each firm applying for permission to market a new formulation will require a new TRA, even if the active ingredient is already approved.
  • Add data from the drug discovery work, such as pharmacological and toxicological data, to the tiered TRA system.
  • Perform mixture toxicological risk assessment tests on groups of similar pharmaceuticals with the same mode of action, such as mixtures of oestrogenic hormonal compounds.
  • All reliable and relevant ecotoxicity studies should be considered in the TRA, not just those produced to standardised guidelines. The authors note that the current approach of standardised tests is more applicable to industrial chemicals, rather than pharmaceuticals, since in the latter case the general toxicity is usually fairly low, but specific non-lethal effects (for example on the reproductive or nervous system) may still be important.
  • Include environmental risks in the risk benefit analysis required before authorisation. This would give companies an incentive to complete the TRA speedily.
    Require regular review of a toxicological risk assessment.
  • When reviews are carried out on TRAs of existing products, the TRA should include data on discharges from manufacturing sites.
  • Increase transparency by making all TRAs and discharge data from manufacturing sites publicly available.


The authors of the paper believe that these changes would make the regulatory regime regarding the environmental effects of pharmaceuticals more effective. However, the authors admit that their recommendations would lead to increased regulatory costs. There is likely to be resistance from pharmaceutical companies to the financial implications of increased testing, and to making details of their waste streams, and hence their manufacturing processes (often a closely-guarded secret), publically available.



Political implications of toxicological risk assessment reform


In order to protect the environment, it?s important that the environmental risks of pharmaceuticals are properly assessed and mitigated. There seems no logic in banning agrochemicals or industrial chemicals for damaging the environment, if pharmaceuticals with similar potential impacts are not subject to these controls. In reality, pharmaceuticals are not like other chemicals. Obviously, some medicines are life-saving, so their benefits would outweigh environmental risks. However, significant political problems might still arise from increased regulation, since even when pharmaceuticals are not life-saving, any ban could still be controversial. Which politician would dare to permit officials to ban oral contraceptives or HRT drugs on environmental grounds? Although current regulations are undoubtedly in need of reform, it is likely that governments will not hasten to strengthen them significantly.










Useful links

Lyons G. (CHEM Trust), ?Pharmaceuticals in the environment: a growing threat to our tap water and wildlife?, (2014).

?gerstrand M. et al, ?Improving environmental risk assessment of human pharmaceuticals?, Environmental Science & Technology, (2015), 49, 5336-5345.

De Roode D.F., ?Assessing environmental risks of pharmaceuticals?, Pharmtech website (2010).



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