Pharmaceuticals in the environment

Specific hazards posed by substances

For the regulatory environmental risk assessment (EMA, 2024), a PBT (Persistent, Bioaccumulative and Toxic) assessment is performed within the hazard assessment. In other regulatory frameworks, a PMT (Persistent, Mobile and Toxic) assessment may also be required. 

Pharmaceuticals that meet PBT criteria or are very persistent and very bioaccumulative (vPvB) do not easily break down in the environment and accumulate in living organisms across the food web. They represents an environmental concern because their environmental exposure is difficult to reverse and the long-term effects of this accumulation cannot be easily predicted. 

PMT and vPvM substances are highly persistent and highly mobile. As such, once they enter the aquatic environment, they can spread over long distances. Many of these chemicals cannot be fully removed by wastewater treatment processes, and they may leach from soils and surfacewater into groundwater, ending up in drinking water sources, which makes them a concern.

Generally, to classify an Active Pharmaceutical Ingredient (API) as PBT/PMT, a tiered testing strategy should be followed. Detailed information on which criteria are used to perform a PBT or PMT assessment are described in the ECHA Guidance on Information Requirements and Chemical Safety Assessment (for PBT or vPvB substances) and in the Classification, Labelling and Packaging (CLP) of substances and mixtures EU regulation for PMT or vPvM substances.

Certain groups of pharmaceuticals need more attention or a tailored risk assessment approach (EMA, 2024). Some of these groups are discussed below.

"Forever chemicals"

Fluorine atoms are fairly ubiquitous in small molecule APIs (Inoue et al., 2020). The addition of fluorine increases drug stability and tunes the interactions of the API with biological receptors to optimise efficacy (O'Hagan and Young, 2023). Fluorine is synonymous with 'forever chemicals', of which 'per- and poly fluoroalkyl substances' (PFAS) are a prime example. Usually there is not enough fluorine atoms in a API to meet the PFAS definition, and the parent compound is like to degrade at least partially. However, its transformation products, will retain fluorine, at which point may not degrade further. 

Antibiotics

Antibiotics in the environment is a concern because of the creation of antibiotic resistance in bacteria. This mostly applies to antimicrobial substances, but also antifungal and antiparasitic substances have been shown to cause resistance in the organisms they combat. Following the European Medicines agency guidelines (EMA, 2024), testing fish is not needed for the market authorisation of antibacterials, as fish are not the most sensitive species to these compounds. For antiparasitics, specific environmental risk assessment requirements have been issued because of their known toxicity at very low concentrations (EMA, 2024). 

Endocrine active substances 

Some APIs are designed to interact with the endocrine system (hormone producing organs and glands), or they do so unintentionally (e.g. as a side effect). These substances may also affect the reproduction or development of organisms in the environment concentrations below the standard regulatory trigger value of 0.01 µg/L (EMA, 2024). Kidd et al. (2007) have shown the collapse of a whole fish population in a Canadian lake due to exposure to 5-6 ng/L of ethinylestradiol (a birth control medication). Thus, for endocrine active substances, environmental risk assessment is always needed regardless of the predicted environmental concentration.

Psychoactive substances

Psychoactive substances have been shown to affect organisms at environmentally relevant concentrations (Ford and Fong, 2016). They may influence the behaviour of fish, spawning of mussels, and detachment of snails. This is not part of regulatory risk assessment, because validated and standardised test methods are lacking.