Using the fish plasma model for comparative hazard identification for pharmaceuticals in the environment by extrapolation from human therapeutic data

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★ We studied a model using human drug data to extrapolate long-term fish toxicity. ★ We found structurally and functionally conserved drug targets in fish. ★ Since many drugs do dissociate, KOW-based accumulation model may yield poor results. ★ For worst case scenarios, hazards are indicated for one third of the selected drugs. ★ The model is useful to indicate drugs for which long-term evidence seem necessary.

Thousands of drugs are currently in use, but only for a few of them experimental chronic fish data exist. Therefore, Huggett et al. (Human Ecol Risk Assess 2003; 9:1789–1799) proposed the fish plasma model (FPM) to extrapolate the potential of unintended long-term effects in fish. The FPM compares human therapeutic plasma concentrations (HPCT) with estimated fish steady-state concentrations (FPCss), under the assumption that biological drug targets may be conserved across the species. In this study, the influence of using different input parameters on the model result was characterised for 42 drugs. The existence of structurally and functionally conserved protein targets in zebrafish could not be refuted. Thus, the FPM model application was not in contradiction to its basic assumption. Further, dissociation of drugs was shown to be important in determining the output and model robustness. As the proposed model for FPCss estimation was considered to predict accurate values for neutral and lipophilic chemicals only, a modified bioconcentration model was used with DOW as predictor. Using reasonable worst case assumptions, a hazard was indicated for one third of the selected drugs. Our results support the notion that this approach might help to prioritise among in use drugs to identify compounds where follow up evidence should be considered.

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