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

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 D_OW≥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 D_OW 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.