The hormetic response of heart rate of fish embryos to contaminants - Implications for research and policy.

Evidence of contaminant-induced hormesis is rapidly accumulating, while the underlying mechanisms of hormesis are becoming increasingly understood. Recent developments in this research area, and especially the emergence of the nuclear factor-erythroid factor 2-related factor 2 (Nrf2) as the master mechanism, suggest that contaminants can induce cardiac hormetic responses. This paper collates significant evidence of hormetic response of the heart rate of fish embryos to contaminants, in particular antibiotics, microplastics, and herbicides, characterized by a low-dose increase (tachycardia) and a high-dose decrease (bradycardia). The increase often occurs at doses about 100-800 times smaller than the no-observed-adverse-effect-level (NOAEL). There are also indications for even triphasic responses, which include a sub-hormetic decrease of the heart rate by doses over 106 times smaller than the NOAEL. Such sub-NOAEL effects cannot be captured by linear-no-threshold (LNT) and threshold models, raising concerns about environmental health and highlighting the pressing need to consider hormetic responses in the ecological risk assessment. A visionary way forward is proposed, but addressing this research bottleneck would require improved research designs with enhanced ability and statistical power to study diphasic and triphasic responses of heart rate.