lysosomes (Gulde et al. 2018; Heikkinen et al. 2009). Such an increased freely
dissolved concentration in some parts of an organism can, of course, also result in
increased membrane concentration in adjacent membranes and thus an increased
toxic effect as compared to the aqueous exposure concentration (Neuwoehner and
Escher 2011). This might explain observed pH effects on toxicity that cannot be
explained otherwise (e.g., (Bittner et al. 2018; Boström and Berglund 2015;
Neuwoehner and Escher 2011)).
Some hydrophobic anions possess a membrane permeability that – although still
much smaller than that of their neutral corresponding species – can still be important.
At mitochondrial membranes that keep up a proton gradient for the generation of
ATP, acids with relatively permeable anionic species will act as proton shuttles and
destroy the natural proton gradient – an effect known as uncoupling (LeBlanc 1971;
McLaughlin and Dilger 1980). This toxic effect is observed for many chloro- and
nitrophenols, for example, and it is pH-dependent (Escher et al. 1999). In a recent
paper, a series of systematic measurements for the membrane permeability of a
diverse set of organic anions ranging over 10 orders of magnitude is presented which
is the first data set of that kind (Ebert et al. 2018). These anionic permeabilities nicely
correlate with the predicted hexadecane–water partition coefficient of the respective
anions which should provide a promising opportunity for predicting toxic effects by
uncoupling (Ebert et al. 2018).
Besides these effects on equilibrium sorption and toxicity there are also direct
kinetic effects: The total membrane permeability of an acid or base results from the
parallel transport of neutral and ionic species. Neutral species are usually limited in
their permeability by the aqueous boundary layer, which is always present adjacent
to both sides of a membrane. Ionic species are usually limited by the membrane itself
and not by the aqueous boundary layer (ABL). Thus, if both species travel in parallel
(i.e., speciation is about 50/50) and are quickly interchangeable by acid–base
reactions, then they can readily pass any combination of ABL and membrane. If
one species prevails, then the respective dominating permeability barrier becomes
more and more important (Avdeef 2012). The latter situation becomes extreme for
permanent ions. This means that cells (either in a cellular toxicity assay or as part of
an organism) may have to be exposed for quite a long time to some ions and
ionizable chemicals before they reach a steady-state internal concentration, provided
that the chemical is not taken up by active transport. In this case a toxicity assay that
is run for only 24 h might not show any effect (because the steady-state concentration is not yet reached within the cells) although the compound might eventually turn
out to be toxic if enough time for equilibration is provided. Fischer et al. (2018)
studied this situation for 7 ionizable chemicals and one permanently charged cation
and found delayed but still substantial cellular uptake after 24 h. This could be
explained by the high intrinsic permeability of the remaining neutral species of the
ionizable chemicals. For the permanently charged cation the authors concluded that
permeation as an ion pair or via ion channels or active transport must be responsible
for this finding. More experimental work in this direction is needed.
Organic ions may also pass membranes by active transport through transporter
proteins (König et al. 2013). While this is a well-studied topic in pharmaceutical
Environmental Sorption Behavior of Ionic and Ionizable Organic Chemicals
55
dissolved concentration in some parts of an organism can, of course, also result in
increased membrane concentration in adjacent membranes and thus an increased
toxic effect as compared to the aqueous exposure concentration (Neuwoehner and
Escher 2011). This might explain observed pH effects on toxicity that cannot be
explained otherwise (e.g., (Bittner et al. 2018; Boström and Berglund 2015;
Neuwoehner and Escher 2011)).
Some hydrophobic anions possess a membrane permeability that – although still
much smaller than that of their neutral corresponding species – can still be important.
At mitochondrial membranes that keep up a proton gradient for the generation of
ATP, acids with relatively permeable anionic species will act as proton shuttles and
destroy the natural proton gradient – an effect known as uncoupling (LeBlanc 1971;
McLaughlin and Dilger 1980). This toxic effect is observed for many chloro- and
nitrophenols, for example, and it is pH-dependent (Escher et al. 1999). In a recent
paper, a series of systematic measurements for the membrane permeability of a
diverse set of organic anions ranging over 10 orders of magnitude is presented which
is the first data set of that kind (Ebert et al. 2018). These anionic permeabilities nicely
correlate with the predicted hexadecane–water partition coefficient of the respective
anions which should provide a promising opportunity for predicting toxic effects by
uncoupling (Ebert et al. 2018).
Besides these effects on equilibrium sorption and toxicity there are also direct
kinetic effects: The total membrane permeability of an acid or base results from the
parallel transport of neutral and ionic species. Neutral species are usually limited in
their permeability by the aqueous boundary layer, which is always present adjacent
to both sides of a membrane. Ionic species are usually limited by the membrane itself
and not by the aqueous boundary layer (ABL). Thus, if both species travel in parallel
(i.e., speciation is about 50/50) and are quickly interchangeable by acid–base
reactions, then they can readily pass any combination of ABL and membrane. If
one species prevails, then the respective dominating permeability barrier becomes
more and more important (Avdeef 2012). The latter situation becomes extreme for
permanent ions. This means that cells (either in a cellular toxicity assay or as part of
an organism) may have to be exposed for quite a long time to some ions and
ionizable chemicals before they reach a steady-state internal concentration, provided
that the chemical is not taken up by active transport. In this case a toxicity assay that
is run for only 24 h might not show any effect (because the steady-state concentration is not yet reached within the cells) although the compound might eventually turn
out to be toxic if enough time for equilibration is provided. Fischer et al. (2018)
studied this situation for 7 ionizable chemicals and one permanently charged cation
and found delayed but still substantial cellular uptake after 24 h. This could be
explained by the high intrinsic permeability of the remaining neutral species of the
ionizable chemicals. For the permanently charged cation the authors concluded that
permeation as an ion pair or via ion channels or active transport must be responsible
for this finding. More experimental work in this direction is needed.
Organic ions may also pass membranes by active transport through transporter
proteins (König et al. 2013). While this is a well-studied topic in pharmaceutical
Environmental Sorption Behavior of Ionic and Ionizable Organic Chemicals
55