ReviewBiphasic dose responses in biology, toxicology and medicine: Accounting for their generalizability and quantitative features
Introduction
Hormesis is a biphasic dose response phenomenon characterized by a low dose stimulation and a high dose inhibition. The shape of the dose response is typically graphed as either an inverted U- or a J-shape depending on the endpoint measured. In the case of the inverted U-shape this is seen with endpoints such as growth, longevity, and cognitive function; in the case of the J-shape this is seen with endpoints relating to disease incidence such as birth defects, mutation, cancer and cardiovascular disease (Fig. 1). Hormesis is commonly reported in the toxicological and pharmacological literature having quantitative features of the dose response that are strikingly consistent and independent of biological model, level of biological organization, endpoint, chemical/physical stressor, and mechanism (Fig. 2). The most distinctive features of the hormesis dose response are that it is contiguous with the no observed (adverse) effect level (NO(A)EL) of the threshold dose–response model and displays a modest stimulatory response below the threshold dose with a maximum stimulatory response typically reaching about 30–60% above control values (Calabrese, 2001, Calabrese, 2004, Calabrese and Baldwin, 1997). This modest stimulation can make the hormetic response difficult to differentiate from background variability without using more rigorous study designs and enhanced statistical power along with stronger efforts to replicate findings. While the dosage width of the hormetic stimulatory response is typically modest being only about 10–20-fold, it can be quite variable with a small proportion of cases reliably exceeding a factor of 1000 (Calabrese and Blain, 2005, Calabrese and Blain, 2011). The variability in the dosage width of the hormetic response may be explained, at least in part, by genetic heterogeneity; nonetheless, an explanation for the consistency of the magnitude (i.e., 30–60%) of the stimulatory response across so diverse a range of experimental protocols and biological models has not been forthcoming.
Hormetic-like biphasic dose response relationships have been explained in the pharmacological literature by the presence of two receptor subtypes mediating opposite effects, one with high agonist affinity and the other with low agonist affinity (Szabadi, 1977). While this is a general mechanism concept for which there are many specific examples in the literature for various tissues and endpoints (Calabrese, 2008, Calabrese and Baldwin, 2001), it does not address the magnitude of the stimulatory response nor the quantitative consistency across biological test systems.
Calabrese (1999) previously hypothesized that the modest stimulation may be due to an overcompensation (i.e., rebound or overshoot) response to chemical/physical stressor agents which cause disruptions in homeostasis based on a cybernetic feed-back model (Stebbing, 2000, Stebbing, 2003, Stebbing, 2009). This over-compensatory response might be expected to result in modest (i.e., percentile) stimulatory responses, that is, ensuring that affected biological systems return to their respective homeostatic conditions without excessive allocation of resources (Calabrese and Baldwin, 2001). The following paper proposes a general explanation for biphasic-hormetic stimulatory responses of both a direct stimulatory or overcompensation type and their occurrence within biological systems based on biological scaling.
Section snippets
Biological scaling and physiological functions-background
The principal question confronting this paper is whether there is a general mechanism that integrates hormetic responses within an organism that may account for its generalizability. While there have been about 500 hormetic dose responses that have been reported to be mediated via specific receptor and/or cell signaling pathways (Calabrese, 2013), these findings do not explain the consistency of the quantitative features of the hormetic dose response throughout the plant, microbe and animal
Allometrical assessment of hormetic dose responses
The biological scaling phenomenon has direct relevance to the hormetic dose response relationship. This judgment is based on the substantial observations that the maximum hormetic response range, as normalized to control group values, is quantitatively consistent across biological models (e.g. broad range of species and body weights), regardless of endpoint measured and chemical/physical stressor studied. This consistent maximum hormetic response range, regardless of biological model, infers
Conclusions
Given the above information the following explanation is proposed to account for the principal quantitative features of the hormetic dose response.
- 1.
Biological scaling is typically demonstrated by comparing large numbers of species for a particular trait and assessing whether it varies as a function of some common trait such as body size.
- 2.
There are large numbers of biological parameters (e.g., organ weights, hematological parameters, renal functions, organ enzyme activities) that are mathematical
Conflict of interest
The author declares no conflict of interest.
Acknowledgments
Effort sponsored by the Air Force Office of Scientific Research, Air Force Material Command, USAF, under grant number FA9550-13-1-0047. The U.S. Government is authorized to reproduce and distribute for governmental purposes notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsement, either expressed or implied, of the Air Force Office of
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