Hi,

Yes, such studies are known, see the paper:

Article Hormesis controversy

It's possible that in the case of different dose levels test substance may induce a contradictory toxicodynamic/pharmacodynamic effect. Such effects could be mechanistically different but have still a common physiological denominator and in the effect inverse/opposite hormesis.

An example could be some therapeutic monoclonal antibodies (mAb). It's a known fact that mAbs induce immune response and production of anti-drug antibodies (ADA). Especially after many doses (boosting effect). Raising concentrations of ADA (if they have a high affinity for mAb) may provide for high mAb clearance and this way hinder therapy.

But in some cases with subsequent doses, on one hand, the immune system starts production of ADA but on the second hand with rising immunosuppression related to the mechanism of action of the drug immune response measured by ADA is decreasing. Consequently higher exposure (numerous doses) provides for a decreasing concentration of ADA because the drug suppresses its production with the rising number of doses.

Best regards

Tomasz

I see this quite often. Depending on what the cause of the effect is, one can certainly see compensatory processes that offset a direct effect, and for some toxins those kinds of relationships have been identified. My understanding is that if the effective threshold for the outcome is below the compensatory threshold, doses that fall in-between will show an effect that is unique. An alternative way of looking at it is with toxins that have multiple mechanisms of action (which is most of them). If those mechanisms have different thresholds and shift the outcome in opposite directions, you will expect a bi-phasic or otherwise non-monotonic curve. Without a lot of data to pull from, it may be hypothetical, but in some cases you may be able to identify specific relationships like that.

A couple of things worth reading:

Beausoleil, C., Ormsby, J. N., Gies, A., Hass, U., Heindel, J. J., Holmer, M. L., ... & Schoenfelder, G. (2013). Low dose effects and non-monotonic dose responses for endocrine active chemicals: science to practice workshop: workshop summary. Chemosphere, 93(6), 847-856.

Vandenberg, L. N. (2014). Non-monotonic dose responses in studies of endocrine disrupting chemicals: bisphenol a as a case study. Dose-response, 12(2), dose-response.

Thanks Tomasz and Andrew for giving me something to think about! Andrew, I think what you're discussing is closer to what I'm observing, thanks for the references, I appreciate it!

Fluoride may cause inhibitory/stimulatory effects at low/high doses - it depends not only on dose but also on exposure duration, the presence of other signaling molecules, and on the downstream pathways activated. It's related to G protein activation.