Toxic Mixtures in TimeThe Sequence Makes the Poison

“The
dose makes the poison”. This principle assumes that once a
chemical is cleared out of the organism (toxicokinetic recovery),
it no longer has any effect. However, it overlooks the other process
of re-establishing homeostasis, toxicodynamic recovery, which can
be fast or slow depending on the chemical. Therefore, when organisms
are exposed to two toxicants in sequence, the toxicity can differ
if their order is reversed. We test this hypothesis with the freshwater
crustacean Gammarus pulex and four toxicants that
act on different targets (diazinon, propiconazole, 4,6-dinitro-o-cresol, 4-nitrobenzyl chloride). We found clearly different
toxicity when the exposure order of two toxicants was reversed, while
maintaining the same dose. Slow toxicodynamic recovery caused carry-over
toxicity in subsequent exposures, thereby resulting in a sequence
effect–but only when toxicodynamic recovery was slow relative
to the interval between exposures. This suggests that carry-over toxicity
is a useful proxy for organism fitness and that risk assessment methods
should be revised as they currently could underestimate risk. We provide
the first evidence that carry-over toxicity occurs among chemicals
acting on different targets and when exposure is several days apart.
It is therefore not only the dose that makes the poison but also the
exposure sequence.