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The pharmaceutical industry gives high priority to animal welfare in the process of drug discovery and safety assessment. In the context of environmental assessments of active pharmaceutical ingredients (APIs), existing U.S. Food and Drug Administration and draft European regulations may require testing of APIs for acute ecotoxicity to algae, daphnids, and fish (base-set ecotoxicity data used to derive the predicted no-effect concentration [PNECwater] from the most sensitive of three species). Subject to regulatory approval, it is proposed that testing can be moved from fish median lethal concentration (LC50) testing (typically using > or = 42 fish/API) to acute threshold tests using fewer fish (typically 10 fish/API). To support this strategy, we have collated base-set ecotoxicity data from regulatory studies of 91 APIs (names coded for commercial reasons). For 73 of the 91 APIs, the algal median effect concentration (EC50) and daphnid EC50 values were lower than or equal to the fish LC50 data. Thus, for approximately 80% of these APIs, algal and daphnid acute EC50 data could have been used in the absence of fish LC50 data to derive PNECwater values. For the other 18 APIs, use of an acute threshold test with a step-down factor of 3.2 is predicted to give comparable PNECwater outcomes. Based on this preliminary scenario of 91 APIs, this approach is predicted to reduce the total number of fish used from 3,822 to 1,025 (approximately 73%). The present study, although preliminary, suggests that the current regulatory requirement for fish LC50 data regarding APIs should be succeeded by fish acute threshold (step-down) test data, thereby achieving significant animal welfare benefits with no loss of data for PNECwater estimates.

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The majority of testing for the effects of chemicals on fish has, historically, been designed to provide continuous exposure to constant concentrations. However, in the environment, fish are typically exposed intermittently or to fluctuating levels of contaminants, due to their mobility between polluted and clean waters and to variations in effluent discharge concentrations. The effects of such intermittent exposure of fish to estrogenic substances are unknown. Therefore, male fathead minnows (Pimephales promelas) were exposed to nominal concentrations of 17-β estradiol (an endogenous and environmental estrogen) at 30, 60, or 120 ng L -1 dosed continuously, or 120 ng estradiol L -1 dosed intermittently, for 21 or 42 days. The estrogenic effects of these dosing regimes were evaluated by determination of plasma vitellogenin concentrations and changes in gonad weight. Intermittent exposure resulted in plasma vitellogenin concentrations approximately equal to those in response to continuous exposure to the same concentration and significantly higher than continuous exposure to the equivalent time-weighted average concentration. Thus, the response to the intermittent regime was greater than would be expected from a simple integration of concentration and time. Changes in gonadosomatic index were less sensitive to the dosing regimes. Exposed fish were also allowed to depurate to determine the rate at which the estrogenic response disappeared after removal of the stimulus. After a 21 day depuration, the elevated plasma vitellogenin concentrations remained high, suggesting that this estrogenic effect would be sustained in the fish for long periods after transient estrogenic exposure.