How do you explain a 'medium dose' eliciting the least effects instead of either the lowest dose or highest dose? I was thinking hormesis but it does not really apply when the lowest and highest doses are both eliciting the best responses. Any ideas?
Hello Sylvia,
If I understood well you're talking about a non-monotonic response right? Quoting my Master thesis:
"It has been argued that the shape of the dose-response curve,particularly for chemicals with hormonal activity, is very different at high concentrations than the one obtained at low concentrations, BPA often exhibits a lack of linear dose-dependent relationship, showing instead U-shaped or inverted U-shaped curves. Consequently, extrapolation from an action or lack of action, of BPA at high doses to its presumed bioactivity at low doses is unwarranted (Naciff and Daston, 2004;Hugo et al, 2008). For many years, when assessing the effects of possible endocrine disruptors, toxicologists have relied on the principle that “the dose makes the poison,” implying that higher doses were expected to cause greater harm. Thus, effects that are not seen at high doses are not expected at low doses. In contrast, multiple studies have found that neither the threshold nor the linear non-threshold models are applicable to the responses of hormones in which biphasic dose responses have been observed for many different endpoints at many levels of organization. These U-shaped and inverted Ushaped dose response curves are considered “non monotonic” and are used as evidence that very low doses of natural and synthetic hormones can affect endpoints such as cell proliferation and organ development (Vandenberg et al 2009; Schug et al, 2011). Non monotonic dose–response curves result from multiple mechanisms. Hormones and hormone-mimicking chemicals act through receptors in target cells. Very low doses can stimulate the production of more receptors (receptor up-regulation), resulting in an increase in responses, whereas higher doses (within the typical toxicological range of chemical testing) can inhibit receptors (receptor down-regulation), resulting in a decrease in responses (Myers et al, 2009). Despite the controversy surrounding the “low dose” concept, there are several reasons why dose response curves to toxicants may be non-monotonic, the induction of metabolizing enzymes, conjugation of substrates, down regulation of receptors at higher hormone levels and also the integration of two or more monotonic dose response curves that occur through different pathways affecting a common endpoint with opposing effects. Additionally, adaptive responses through complex cell signalling pathways and feedback mechanisms could cause non-monotonic effects that are inconsistent with traditional dose-response curves (Schug et al, 2011)."
If you find it interesting/important please take a look, it's entitled:
"The role of endocrine disruption in the regulation of pancreatic beta cell activity: a toxicogenomical approach"
Kind regards,
Paulo Almeida
How many data points? Three, low, medium, and high? Not enough information.
Dear Paulo,
Thank you for your prompt reply. Your response gave me better search terms like ‘non-monotonic dose response’ and ‘biphasic dose response’ which I inputted into google that led me to find some interesting papers for instance those written by Dr Caleberese. I also read your thesis and your results were intriguing; congratulations.
I am still not completely sure I can explain why 2 out of 3 doses will elicit similar effects, while the medium dose elicits the least effect. If the medium dose were to elicit the best effects (by the way, I am referring to a medicinal substance not a toxic one) giving rise to an inverted U-shaped curve, then one can explain this by saying that the low dose elicits some effects, while the medium dose elicits better effects since the amount of the available drug is higher (cascade effect), but the highest dose becomes toxic probably because of a negative feedback reaction where the high number of drug molecules available end up inhibiting some of the receptors, thus lowering the effect.
But what is the possible explanation when the medium dose elicits the least response (giving rise to a U-shaped curve)? I look forward to your reply.
Cheers,
Sylvia
Hello Joseph,
Thank you for your prompt reply. Yes there were three doses in the experiment: a low dose, a medium dose and a high dose. were you saying an experiment featuring three doses is not enough for a dose-response study, or were you saying that the information I supplied was not enough?
Cheers,
Sylvia
Three doses are not enough. Classification as to low, medium, and high is not enough. Actual values are needed, dose values, response values. How was dose response determined? How many subjects? What is the variance of the response at each dose value?
Hello Sylvia,
It's hard for me to suggest you any kind of mecanism, with the information available, especially if it's a medicinal substance. But you can consider 3 distinct effects. Low -just you just have 1 pathway envolved, medium - after the saturation of the first receptors a different pathway; High - The third type of receptors can trigger a response similar to the first that counters the "medium".
This is a shot in the dark, since as Joseph said, there is very little information available.
Good luck!
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