A tiered secondary poisoning risk assessment approach to prevent unnecessary fish bioaccumulation testing of pharmaceuticals

The European Medicines Agency (EMA) guideline on environmental risk assessment of pharmaceuticals requires a fish bioaccumulation study for substances that enter phase II assessment and have a log Dow ≥3, to determine if the measured bioconcentration factor in fish (BCF FISH ) triggers a secondary poisoning risk assessment. This approach could be modified to leverage available relevant data and determine whether a fish bioaccumulation study is necessary. In a preliminary step, a worst-case secondary poisoning risk quotient (RQ) could be calculated using available (sub)chronic mammalian toxicity data, the estimated concentration of the pharmaceutical in surface waters, and replacing the experimental BCF FISH value with a conservatively estimated BCF FISH (log Dow range-specific and evidence-based). If the outcome of this preliminary assessment is a RQ below 1, conducting a fish bioaccumulation study would not be justified; whereas a preliminary RQ ≥1 would indicate that a substance-specific BCF FISH value is warranted. Experimental data for 44 pharmaceuticals was compiled to evaluate this approach. Thirty-one of these substances did not indicate a potential secondary poisoning risk in the preliminary assessment step. A considerable amount of fish testing could be concluded to be unnecessary. We propose that this two-step approach is implemented in the EMA guideline for environmental risk assessment of human pharmaceuticals.