Similarities between the Yin/Yang Doctrine and Hormesis in Toxicology and Pharmacology

Abstract

Hormesis is a generalizable dose-response relationship characterized by low-dose stimulation and high-dose inhibition. Despite debate over this biphasic dose-response curve, hormesis is challenging central beliefs in the evaluation of chemicals or drugs and has influenced biological model selection, concentration range, study design, and hypothesis testing. We integrate the traditional Chinese philosophy - Yin/Yang doctrine - into the representation of the Western hormetic dose-response relationship and review the Yin/Yang historical philosophy contained in the hormesis concept, aiming to promote general acceptance and wider applications of hormesis. We suggest that the Yin/Yang doctrine embodies the hormetic dose-response, including the relationship between the opposing components, curve shape, and time-dependence, and may afford insights that clarify the hormetic dose-response relationship in toxicology and pharmacology.

Keywords: Yin/Yang doctrine; dose–response relationship; hormesis; pharmacology; toxicology.

Figure 1

Consistency between Hormetic Dose–Response and '4C' (Containment, Consanguinity, Counterpoise, and Conversion) Laws in Yin/Yang Doctrine. (A) The typical J-shaped and inverted U-shaped hormetic dose–response curve. (B) The classical symbol for Yin/Yang. (C) Four types of relationships between Yin and Yang in Yin/Yang doctrine (4C laws): Yin/Yang containment is used to describe how Yin and Yang restrain and suppress each other to form everything in the universe; Yin/Yang consanguinity means that Yin and Yang originate from the same root and represent the same object in different ways, and neither can exist in the absence of its counterpart; Yin/Yang counterpoise indicates that Yin and Yang move or change in opposite directions to generate a dynamic equilibrium; Yin/Yang conversion clarifies that Yin can transform into Yang under some circumstances, and vice versa, and this change into the reverse qualitatively starts from the aforementioned quantitative movements (Yin/Yang counterpoise), and thus generates the diversity of the whole world.

Figure I

Time-Dependent Hormetic Effects of Sulfapyridine (SPY) on the Bioluminescence of A. fischeri over a 24 h Period [55], and Correspondence to the 4C Laws of the Yin/Yang Relationship. In each scatter diagram, the x axis represents the logarithm of SPY concentration, and the y axis represents SPY-mediated inhibition of bioluminescence. P₁, P₂, and P₃ represent the inhibitory effects of SPY (9.63 × 10⁻⁶ M) on bioluminescence at 9, 17, and 21 h.

Figure 2

Similarities between the Yin/Yang Symbol and the Hormetic Curve. (A) Rotated through 90° clockwise or anticlockwise, the Yin/Yang demarcation curve can be envisaged as depicting the J-shaped hormetic dose–response curve. (B) Likewise, similarities can be drawn between the Yin/Yang demarcation curve and a hormetic dose–response curve. In the Ying/Yang symbol, A and B represent the areas of the first and the second regions delineated by the Yin/Yang demarcation line and the x axis, m and n are the widths of areas A and B respectively, and p and q are the heights of areas A and B, respectively. These parameters can also have corresponding meanings in the hormetic dose–response curve where A and B represent stimulatory and inhibitory areas, respectively; m and n denote the stimulatory and inhibitory concentration ranges, respectively; and p and q denote the maximum stimulatory and maximum inhibitory rates, respectively. (C) When the test endpoint reflects complex biological activities, and the organism is exposed to a wide dose range of agent (theoretically extending to infinite dose), the hormetic dose–response relationship can be presented as a wave-like increasing curve that is composed of several successive Yin/Yang demarcation curves.

Figure 3

The 'Yin/Yang Doctrine' Contained in Hormesis. (A) The graph shows the fitting model for hormetic dose–response curve (in black) with seven specific and significant points on the curve (A–G). These points are detailed in the accompanying key. S represents the maximum stimulation and I represents the maximum inhibition. The S-shaped dose–response relationship (blue dashed line) represents inhibition, and the inverted S-shaped dose–response relationship (yellow dashed line) refers to stimulation. (B) The swinging seesaw model: stimulation (S) and inhibition (I) at each end generate the seesaw; the downward force of the stimulatory end of the curve (K_S) equals the absolute value of the gradient of the virtual stimulatory curve and represents the increasing rate of stimulatory effects, whereas the downward force at the inhibitory end of the curve (K_I) equals the absolute value of the gradient of the virtual inhibitory curve and represents the increasing rate of inhibitory effects; when the incline of the seesaw is at the stimulatory end, S > I; when the seesaw is in balance, S = I; and when the seesaw is at the inhibitory end, S < I. (C) The schematic shows how the seesaw swings regularly between the stimulatory and inhibitory ends from point A to point G in a hormetic dose–response curve.

Figure I

Components of the Hormetic Dose–Response Curve. (A) Schematic of a typical hormetic dose–response curve showing the classical parameters used to quantitatively describe it, where SCR is the stimulatory concentration range, NEP is the no-effect point, EC_m is the effective concentration at maximum stimulation, E_m is the effect at maximum stimulation, ZEP is the zero equivalence point, and EC₅₀ is the concentration at 50% inhibition. (B) Two different dose–response curves (depicted in orange and blue) that have the same E_m values but different SCRs (SCR₁ and SCR₂). (C) Two different dose–response curves (depicted in orange and blue) that have the same SCR but different E_m values (E_m1 and E_m2).