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Observed and modeled effects of pH on bioconcentration of diphenhydramine, a weakly basic pharmaceutical, by fathead minnows
Citation:
Nichols, J., B. Du, R. Erickson, A. Hoffman, J. Berninger, C. Chambliss, K. Connors, AND B. Brooks. Observed and modeled effects of pH on bioconcentration of diphenhydramine, a weakly basic pharmaceutical, by fathead minnows. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 34(6):1425-1435, (2015).
Impact/Purpose:
A substantial number of compounds evaluated by U.S. EPA ionize at environmentally relevant pH values. Included among these are pharmaceuticals which, due to their discharge in municipal effluents, can be detected in the environment. Until recently, little attention was given to predicting the accumulation of ionizable compounds in aquatic biota because the likelihood of substantial accumulation was thought to be low. This situation is changing due to the demonstrated accumulation of several ionized compounds (e.g., PFOS and several ionic surfactants) and the fact that even low levels of accumulation may pose a significant hazard if the compound is biologically active at low dose levels (e.g., for pharmaceuticals). In the present study we used an existing model for branchial uptake of ionizable chemicals by fish to predict the accumulation of diphenhydramine (DPH), a weakly basic pharmaceutical, in fathead minnows. The model was originally developed to describe the uptake of acidic phenolic compounds by trout. In principal, however, it can be used to predict the uptake of basic compounds by appropriate specification of chemical attributes such as the dissociation constant (pKa) and plasma binding of the ionized form. Importantly, this model accounts for the acidification of the gill surface which occurs due to branchial elimination of metabolically-derived acid. The model was evaluated by measuring the accumulation of DPH in fathead minnows at three ambient pH levels (6.7, 7.7, and 8.7). Model predictions were then compared to observed levels of accumulation. The results show that the full gill model accurately describes pH effects on DPH uptake by fathead minnows while models that ignore pH changes at fish gills do not. The results of this effort substantially increase current our understanding of the mechanisms by which ionized chemicals are accumulated by fish, and provide a validated tool which can be used to predict the extent of this accumulation for compounds of interest.
Description:
Understanding the influence of pH on uptake and accumulation of ionizable pharmaceuticals by fish was recently identified as a major research need. In the present study, fathead minnows were exposed to diphenhydramine (DPH), a weakly basic pharmaceutical (pKa = 9.1). Fish were exposed to 10 µg/L DPH in water for up to 96 h at three nominal pH levels: 6.7, 7.7, and 8.7. In each case, an apparent steady-state was reached by 24 h allowing for direct determination of the bioconcentration factor (BCF), blood/water partitioning value (total chemical basis; PBW,TOT), and apparent volume of distribution (VD; approximated from the whole-body/plasma concentration ratio). BCFs and measured PBW,TOT values increased in a non-linear manner with pH while the VD remained constant, averaging 3.0 ± 0.08 kg/L. The data were then simulated using a model which accounts for acidification of the gill surface due to elimination of metabolically-derived acid. Good agreement between model simulations and measured data was obtained for all three tests by assuming that plasma binding of ionized DPH is approximately 14% that of the neutral form. This finding is consistent with measured binding of DPH in humans. A simpler model, which ignores elimination of metabolically-derived acid, performed much less well. These findings suggest that pH effects on accumulation of ionizable compounds by fish are best described using a model that accounts for acidification of the gill surface. Moreover, measured plasma binding and VD data for humans, determined as part of the drug development process, may have considerable value for predicting the accumulation of pharmaceuticals in fish.
