A global environmental health perspective and optimisation of stress

Journal Pre-proofs Review A Global Environmental Health Perspective and Optimisation of Stress Evgenios Agathokleous, Edward J. Calabrese PII: DOI: Reference:

S0048-9697(19)35255-6 https://doi.org/10.1016/j.scitotenv.2019.135263 STOTEN 135263

To appear in:

Science of the Total Environment

Received Date: Revised Date: Accepted Date:

22 August 2019 21 October 2019 27 October 2019

Please cite this article as: E. Agathokleous, E.J. Calabrese, A Global Environmental Health Perspective and Optimisation of Stress, Science of the Total Environment (2019), doi: https://doi.org/10.1016/j.scitotenv. 2019.135263

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Review

A Global Environmental Health Perspective and Optimisation of Stress Evgenios Agathokleous1* and Edward J. Calabrese2 1Ph.D.;

Professor; Institute of Ecology, School of Applied Meteorology; High-End Talent Workstation, W406;

Nanjing University of Information Science and Technology (NUIST); Ningliu Rd. 219; Nanjing, Jiangsu 210044, China. 2Ph.D.;

Professor of Toxicology; Department of Environmental Health Sciences; Morrill I, N344; University

of Massachusetts; Amherst MA 01003 USA.

*Correspondence and requests for materials should be addressed to E.A. ([email protected]). ORCID: 0000-0002-0058-4857

Abstract: The phrase “what doesn’t kill us makes us stronger” suggests the possibility that living systems have evolved a spectrum of adaptive mechanisms resulting in a biological stress response strategy that enhances resilience in a targeted quantifiable manner for amplitude and duration. If so, what are its evolutionary foundations and impact on biological diversity? Substantial research demonstrates that numerous agents enhance biological performance and resilience at low doses in a manner described by the hormetic dose response, being inhibitory and/or harmful at higher doses. This Review assesses how environmental changes impact the spectrum and intensity of biological stresses, how they affect health, and how such knowledge may improve strategies in confronting global environmental change.

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Keywords: contamination; dose-response relationship; environmental pollution; global environmental change; hormesis; stress biology

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1 Introduction Global environmental change exerts pressure on humans and other organisms that may challenge their capacity to cope and/or thrive under stressful conditions (Adger et al. 2010; Fischer 2019). In the recognition of the threat that excessive stress may pose to human health, biota, communities, ecosystems, and various sectors such as agriculture, water resources, and terrestrial and marine productivity (Feng et al. 2019; Fleming et al. 2018; Hitz and Smith 2004; Malek et al. 2018; Sicard et al. 2017; Springmann et al. 2018), environmental regulatory policies reflect significant efforts to understand and mitigate excessive environmental stress effects to protect planetary health (Lu et al. 2018; Makri 2018). As Heraclitus stated, 'change is the only constant in life', and the Earth has been subject to environmental change throughout its geological history (Hochella et al. 2019; Körner 2006). However, a contemporary core problem are massive and novel anthropogenic impacts on the environment, including land use practices, vast chemical and pharmaceutical synthesis and discharge, and energy related fossil fuel emissions (Ekins et al. 2019). For example, while nanomaterials are not a new input into the environment, human activity has transformed them into an important environmental issue (Hochella et al. 2019). In a similar fashion atmospheric CO2 is not a novel area of study but has become a significant environmental issue in debates over climate change and global warming (Körner 2006). A prominent issue therefore, is how living entities at multiple levels of organisation cope with change. Hence, an important consideration should concern not only how organisms can adapt to a broad spectrum of environmental stressors, but also how organisms can biologically anticipate challenges via prior adaptation that can be harmful and/or life threatening.

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The last 20 years have marked a new era in the field of dose-response that addresses these critical adaptation related challenges (dose refers to either intake dose or exposure hereafter). Extensive assessments of the scientific literature have revealed the widespread and frequent occurrence of hormetic-like biphasic dose responses across the broad spectrum of life such as animals, bacteria, fungi and plants (Calabrese 2017a; Calabrese et al. 2019; Calabrese and Mattson 2017). Hormesis may be defined as a biphasic dose-response relationship (Fig. 1) with low doses inducing stimulatory effects by activating adaptive mechanisms that enhance resilience, while higher doses may induce inhibitory responses that at even higher doses often become toxic (Agathokleous et al. 2019a,b). Many natural and anthropogenic environmental change factors induce hormesis as well (Agathokleous et al. 2019b,c,d), providing an opportunity to examine the implications of such hormetic effects for global sustainability. This paper evaluates recent advances in mechanism-based dose response research to examine how natural and anthropogenic environmental changes in the form of low dose biological stressors may affect the sustainability of life on Earth, and provide future directions for research and regulatory options with the goal of improving the process of assessing human and ecological health and biosphere sustainability on a changing planet. To this end, this Review documents the widespread and highly generalisable occurrence of hormesis induced by copious environmental change agents, occurring at scales ranging from local to global, within various temporal frameworks. Environmental effects on organisms may occur at levels of stress often lower than is currently appreciated or even considered within regulatory evaluation, suggesting that current global regulatory standards demand more novel research and assessment approaches. The study of the ecological effects of low-level stress is still in its relative infancy, and collaborative actions within and among the environmental, social, engineering and policy

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dimensions of sustainability are needed to advance current understandings and increase the likelihood of enhancing sustainability on the planet.

2. Hormesis in a changing world The first scientific evidence for this biphasic dose-response phenomenon was published in the waning decades of the 19th century, with the term hormesis being applied in the early 1940s (Calabrese and Baldwin 1999, 2000a; Stebbing 1982). Nevertheless, the biphasic dose response in biology had a rocky start as it got dragged into the long-standing debate between what is now called traditional medicine and the medical practice of homeopathy. This debate not only led to marginalisation of the concept of hormesis but had a profoundly negative effect on research to explore potential low-dose effects and societal and regulatory applications

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However, the area of biphasic dose responses has experienced a striking resurgence within the biological and biomedical communities over the past several decades (Agathokleous and Calabrese 2019a; Calabrese 2004, 2017b). Evidence for hormesis induced by chemicals, pharmaceuticals, and radiation in a vast array of organisms has been extensively documented throughout the last century (Calabrese and Baldwin 2000a,b,c). Of significance to the current resurgence of hormesis in the environmental domain was the research of Stebbing in the late 1970s on marine toxicology (Stebbing 1976, 1982), along with his integrative assessment of a vast body of previously unrelated biphasic dose response findings and the foundation of a cybernetic basis for hormetic dose responses. In 1981, Laughlin et al. also reported that petroleum hydrocarbons induced hormesis in the megalopal weight of zoeal mud crabs (Laughlin et al. 1981). While there were numerous other reports for such biphasic dose responses to “pollutants” (Agathokleous et al. 2019c), lack of a common terminology, as well as lack of a general understanding of the quantitative features of the 5

hormetic dose response, its generality and no broadly accepted molecular mechanistic basis greatly impacted its acceptance and progress. Consequently, extensive evidence for hormesis induced by environmental change factors, including environmental pollutants and emerging contaminants, has only recently been brought to light (Agathokleous et al. 2019b,c; VázquezHernández et al. 2019). Among the plethora of agents found to induce hormesis are heavy metals, nanomaterials, rare earth elements, antibiotics, pesticides, human and veterinary pharmaceuticals,

ground-level

ozone,

other

atmospheric

pollutants,

and

temperature

(Agathokleous et al. 2018, 2019b,c,d; Poschenrieder et al. 2013). Hormesis has been induced in plants, animals, and microorganisms by numerous environmental change factors based on many thousands of dose responses (Fig. 2) (Supplementary Materials). Low doses of toxic substances and other environmental change factors have the capacity to enhance highly conserved physiological mechanisms for coping with stress, repairing tissue damage/enhancing wound healing, increasing growth and productivity, fecundity, extending lifespan, and enhancing organismic health overall, reflecting a fundamental evolutionary strategy (Supplementary Materials). These findings reveal that hormesis is a general phenomenon with widespread implications for all phases of biology. Changes in space weather, and particularly cosmic rays and geomagnetic activity, may affect biota on the Earth (Galata et al. 2017; Hajnorouzi et al. 2011; Maffei 2014; Vale 2018; Van Huizen et al. 2019). Novel findings indicate that low electric and magnetic fields can stimulate organismic performance (Hajnorouzi et al. 2011; Li et al. 2019; Maffei 2014; Vale 2018; Van Huizen et al. 2019), suggesting that the low-level stress can be generated not only by factors occurring at the surface of the Earth but also by space conditions such as solar wind and Sun-emanating charged particles [or other geological and other poorly understood physical

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factors (Aubert and Finlay 2019; Miller and Yunes 2019; Witze 2019)]. In fact, nulling of geomagnetic fields can have detrimental effects on plants, and ceasing (e.g. during reversal of the magnetic pole) may relate to mass extinctions (Maffei 2014). Likewise, subtracting (i.e., blocking) background radiation can deteriorate organismic health (Agathokleous et al. 2018; Castillo and Smith 2017). These findings suggest that low radiation and geomagnetic fields became functionally integrated within biological systems early in evolutionary processes. If lowlevel terrestrial/cosmic rays and geomagnetic fields enhance organismic performance or are necessary for sustaining life on Earth, it may be postulated that the evolution on Earth has been influenced by space forces (Fig. 3), such as solar wind and Sun-emanating charged particles, a hypothesis requiring further examinations. While these new developments have contributed important insights into the role of reactive oxygen species in central biological processes, background radiation on earth is sufficiently low as to have little impact on background mutagenicity which is principally the result of oxidative metabolism (Muller and Altenburg 1930).

3. Biological understanding Studies in the last 20 years demonstrate that hormesis is a highly generalisable biological phenomenon appearing in organisms across the universal tree of life and having quantitative characteristics that are independent of underpinning biological mechanisms, taxonomical classification, cell type, endpoint, and types of inducing agent and agent potency (Agathokleous et al. 2019b; Calabrese et al. 2019; Calabrese and Blain 2011; Calabrese and Mattson 2017). These research advancements have also revealed the quantitative characteristics of hormesis: the maximum stimulatory response is commonly 130-160% and rarely >200% of the control response (Calabrese et al. 2019; Calabrese and Blain 2011; Calabrese and Mattson 2017). While 7

the range of the maximum stimulatory response has been generally within 130%-160%, a recent study shows that the detection of the stimulatory magnitude is affected by the number of doses in the low-dose zone (Fig. 1), suggesting that the hormetic maxima may approach 100% (i.e. two fold) (Calabrese et al. 2019). These dose response features describe cellular and organismal phenotypic plasticity and the ability and limits of organisms to adapt to stress, achieving enhanced resilience (Agathokleous et al. 2019b; Costantini and Borremans 2019; Leak et al. 2018).The width of the stimulatory zone is usually <10-fold, commonly <100-fold, and rarely >1000-fold (Fig. 1) (Calabrese and Blain 2011). These highly generalised and conserved quantitative characteristics permits organisms to integratively modulate functional adaptations within a homeodynamic state. The biological mechanisms underpinning the low-dose response are becoming better understood having been documented in numerous cases at the level of receptor and cell signalling pathway for numerous biological models (Agathokleous et al. 2018, 2019b; Calabrese and Agathokleous 2019; Ferrarelli 2017; Kourtis et al. 2012; Leak et al. 2018; Poschenrieder et al. 2013; Tang and Loke 2015; Vaiserman 2011; Vázquez-Hernández et al. 2019). These mechanisms have involved genetic recombination, gene expression, non-lethal mutations, and activity of transposable elements (Costantini 2019). Intermittent fasting, caloric/nutrient restriction, physical exercise, intellectual and psychological challenges, and environmental stimuli can all induce hormesis in aquatic and terrestrial organisms via the upregulation of adaptive responses by low-level stimuli (Agathokleous et al. 2018; Calabrese and Agathokleous 2019; Calabrese and Mattson 2017; Ferrarelli 2017; Kishimoto et al. 2017; Kumsta et al. 2017; Leak et al. 2018; Moore et al. 2015). Such adaptive responses activate defence and repair mechanisms which stimulate numerous

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independent cellular functions (including autophagic removal of damaged proteins) that often act via a preconditioning mode to not only protect organisms from subsequent health/life threatening agents/events (Calabrese and Mattson 2017; Cramer et al. 2019; Kourtis et al. 2012; Moore et al. 2015), but also to enhance biological performance in areas such as learning, memory, fecundity, and others (Agathokleous et al. 2018; Calabrese and Agathokleous 2019; Calabrese and Mattson 2017; Ferrarelli 2017; Kishimoto et al. 2017; Kumsta et al. 2017; Leak et al. 2018). Among hundreds of preconditioning examples is that brief anoxia or low-level hypoxia induce adaptive responses which protect against subsequent adverse environmental challenges and increase survival within a hormetic dose response framework (López-Martínez et al. 2016b; LópezMartínez and Hahn 2014). This preconditioning mode would demand expenditure of energy resources (Sthijns et al. 2016), affecting the relation between energy flow versus energy capital at any given time (Malea et al. 2019; Nunn et al. 2017). If the demands are high and the capital low but the flow strong, sufficient energy can be generated if the available time suffices. If both the demands and capital are high but the flow is weak, the needed energy would be beyond the system capacity. However, although preconditioning requires expenditure of energy, energy (perhaps more) may likely be saved if severely challenged after preconditioning, with less damage and potentially more favourable energy use. Hormesis is also challenging to study since it requires substantial statistical power, which is affected by sample size and variability in response by both treatment groups and controls. Furthermore, it is also influenced by temporal and compensatory factors which are best captured within a dose-time relationship (Agathokleous and Calabrese 2019b; Leak et al. 2018). Hormesis is not always observed due to many possible factors such as inadequate number of doses, lack of

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statistical power, improper dose spacing, lack of temporal considerations, background disease incidence amongst others. Furthermore, hormetic responses can be differential among endpoints/functions on a given system, i.e. some endpoints/functions may exhibit positive or negative effects, and some others being apparently unresponsive or clinically/practically insignificant (Lefcort et al. 2008; Shetty et al. 2016; Tang et al. 2019a).

4. Ecological and evolutionary relevance A notable advancement is the recognition that natural occurring environmental stress (among others radiation, anoxia or hypoxia, starvation, and heat) can induce transgenerational effects in animals as well as in plants in an hormetic fashion, with low-level exposure of F0 ancestors which can lead to descendant survival advantages within harsh environments, with enhanced tolerance to stress and/or extended longevity via epigenetic processes (Kishimoto et al. 2017; Kumsta et al. 2017; López-Martínez et al. 2016a; Margus et al. 2019; Rahavi et al. 2011; Rechavi et al. 2014; Shephard et al. 2018; Shetty et al. 2016; Tang et al. 2019a; Webster et al. 2018). While such observations were commonly noted in F1-F3 generations (Rechavi et al. 2014), there is also evidence that gene expression can persist for more than 10 generations in C. elegans nematodes (Klosin et al. 2017). In a complimentary manner, within-lifespan epigenetic hormetic changes (effects of early life challenges to later stages of life) (Costantini et al. 2014; Cramer et al. 2019, 2015, López-Martínez and Hahn 2012, 2014; Shephard et al. 2018; Shetty et al. 2016) suggest that low-level challenges experienced at the fetal stage may have health-transforming effects and stress resilience throughout adulthood. Such hormesis based trans- and intergenerational developments may provide a means to manipulate stress to enhance productivity in agricultural and animal husbandry systems, and even to protect human health in both normal and

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high risk situations, although this remains speculative and at the level of non-human animal model study and epidemiologic investigation. Potential negative trans-generational effects may occur for some traits or particular generations (Emborski and Mikheyev 2018; Tang et al. 2019a; Webster et al. 2018; Yan et al. 2016). These may indicate trade-offs between epigenetic memory and plasticity, with some stages investing more on reproduction while others on defence, or fluctuating responses across several generations that would otherwise be compensatory responses. Such effects may be due to a) non-variable environment for descendants, b) mismatch between ancestral environmental prediction for descendant environments, and c) excessive costs for the epigenetic memory (transgenerational effect) (Webster et al. 2018). However, trade-offs may be seen as a central, evolutionary based optimisation strategy permitting organisms to allocate, utilise, invest and store resources, enhance performance and survival. That is, some traits/functions that are needed to “get ready” for coming threats may be enhanced whereas other functions that are non-essential for the new environment may be suppressed. This type of trade-off represents a survival enhancing biological “balancing act”, even if there is a mismatch between the predicted and the actual environment (Bennett and Lenski 2007). Evolutionary rescue (Oziolor et al. 2019) and phenotypic plasticity are paradigms that illustrate the role of hormesis as a fundamental evolutionary mechanism (Costantini 2019; Costantini and Borremans 2019). While low-level stress induced hormetic processes are a fundamental mechanism of evolution, they also can affect evolution in an indirect manner by enhancing reproduction, competitiveness, and resistance (Belz 2018; Schreck 2010). Since lowlevel doses inducing stimulatory effects can differ by several orders magnitude between sensitive and resistance genotypes, differences in the reproductive fitness between them may exert

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pressure for selection (Belz 2018), suggesting the potential of mankind to affect evolutionary patterns (explained in following sections). The post-2000s progress in the field of dose-response also suggests that hormesis can be also proactively applied (i.e., anticipatory as in the case of preconditioning), in addition to regularly occurring adaptive responses. Therefore, hormetic lowdose stress may affect evolution (Fig 4), especially in situations where humans can manipulate or intervene with low-dose stress in sectors such as agriculture, public health, and medicine. Hormetic processes have been present in all species preceding the occurrence of humans on Earth and its consequent anthropogenic pollution, pharmaceuticals, and other agents. There would be multiple natural sources of stress, such as forest fires (e.g. from lightning), volcanic eruptions, heat, drought, lack of oxygen, presence of toxic metals in crustal earth, solar radiation and vast chemical products produced as defensive/protection agents (i.e., natural pesticides). Strong evidence exist that hormesis can be induced by each of these general environmental stress areas, such as by forest fires which may enhance regeneration and establishment of trees at moderate severities but devastate plants at high severities (Romeo et al. 2019) (Supplementary Materials). Since ecological systems are highly complex, it is difficult to predict their responses to low-level environmental stress (Agathokleous et al. 2019a). One example is the bystander effect (Ji et al. 2019; Tang and Loke 2015; Vaiserman 2011) where low-dose environmental stress may affect directly exposed cells or organisms, which in turn communicate stress signals and thereby affect cells (cell-to-cell communication) or other organisms (individual-to-individual communication) that were not exposed directly to the stress (Agathokleous et al. 2019b; Choi et al. 2012). This was seen in multiple cases (Havaki et al. 2015) including fish, and mammals(Choi et al. 2012) and in plant-emitted leaf volatile organic compounds (used for plant-

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plant and plant-herbivore communication) (Agathokleous et al. 2019b). Bystander effects can be detrimental (e.g. in the case of genetic changes in animals) or protective (Vaiserman 2011). The bystander effect suggests that low-level stress can have prolonged and potentially significant implications to complex biological processes and levels of organisation beyond the individual and remains to be more fully explored (Agathokleous 2018; Belz 2018; Belz et al. 2018; Costantini and Borremans 2019; Sugai et al. 2018). The bystander effect also can be mediated by hormetic processes. For example, low levels of cAMP (10-18 M-lowest concentration tested) have the capacity to affect immune activation (i.e., macrophage phagocytosis) in a biphasic manner. At the lowest concentration evaluated (10-18) one molecule of cAMP upregulated yeast cell phagocytosis by 40% per 3300 macrophage cells. This hormetically driven intercellular bystander broadcasting effect represents an adaptive strategy at extremely low concentrations. Furthermore, such hormetic stimulating effects were blocked by receptor antagonists (Choi et al. 2012). Among the non-linear responses that higher levels of organisations show are the unimodal ones. In particular, hormetic-like perturbation-response relationships at community or ecosystem levels are shown in ecology, often with other names such as humped-back model, intermediate disturbance hypothesis, and subsidy-stress gradient (Agathokleous 2018; Chapman 2002). Communities or ecosystems may be stimulated by low-level/moderate perturbations and suppressed by high/very high level perturbations. These suggest that some degree of perturbation may enhance productivity for higher levels of biological organisation; however, there are myriads of factors to account for, and ecological time scales are needed to assess its integrated effects. For example, even if low-level environmental perturbation can increase above- or belowground biodiversity, what may this mean qualitatively? Low-level environmental perturbation

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can stimulate ecological systems for long durations, ultimately returning to a homeostatic condition (Koike et al. 2018). While we agree that the evaluation of such complex processes may be speculative they would profit from being framed within a hormetic context. Numerous emerging contaminants induce hormesis (Supplementary Materials); however, does this mean it is ecologically “good” or “bad” to have dynamically changing low loads of contaminants in the environment? Even if low levels of contaminants can mediate positive effects on individual organisms, the ecological effects at higher levels of biological organisation are hard to reliably predict (Mater et al. 2014; Solís et al. 2011). For example, human and veterinary pharmaceuticals, urea, and other agents can induce hormesis in soil nitrification or denitrification (Calabrese and Baldwin 2000b; DeVries et al. 2015; Yang et al. 2013), N2O (DeVries et al. 2015) and CO2 (Geng et al. 2017) efflux, and CH4 uptake (Geng et al. 2017; Peng et al. 2019), suggesting indirect effects on the atmospheric composition. Such effects are unknown if they are transient or long term and if they are positive, negative, or both. However, cells seem to commonly require more than 104 atoms/molecules per cell, and often more than 106 – 107 molecules per cell, to induce biological effects (Dinman 1972; Jukes 1983). This suggests that indirect impacts of low-level stress (by changes in atmospheric composition via soil and vegetation fluxes) have the potential to be below hormetic thresholds, within the hormetic zone, or possibly higher than the hormetic zone depending on local conditions.

5. Human and policy dimensions

5.1 LNT is biologically invalid The current scientific literature is dominated by researches where the effects of stress are studied after applying few and often only excessive doses/exposures of stress (Agathokleous et al. 2019a; Calabrese 2018a; Calabrese and Baldwin 2003a). Hence, worldwide regulatory 14

agencies have often based the risk assessment process on inappropriately high doses to extrapolate the effects to low doses of stress, often assuming that adverse effects are proportional to dose/exposure (Fig. 5) (Agathokleous et al. 2019a; Calabrese 2018a; Calabrese and Baldwin 2003a). This high dose treatment methodology fails to consider possible low dose adaptive/preconditioning responses (Agathokleous et al. 2019b; Calabrese and Mattson 2017; Leak et al. 2018; Shibamoto et al. 2018; Stark 2012; Stranahan and Mattson 2012). Contemporary genetics and epigenetics have demonstrated that, among others, DNA is efficiently repaired, mutations can be non-lethal, the acquired information can be transferred to the next generation (heritable small RNAs), and “use and disuse of organs” can occur (Fig 6) (Costantini 2019; Costantini and Borremans 2019; Cramer et al. 2019; Kishimoto et al. 2017; Klosin et al. 2017; Kumsta et al. 2017; Rechavi et al. 2014; Veigl 2017). It was also recently shown that evolutionary rescue from high environmental pollution can be enabled by adaptive introgressive hybridisation (interspecific movement of genes) (Oziolor et al. 2019), suggesting that life has evolved complex ways permitting individuals to avoid or cope with high stress, thus, further restricting the utility of high to low dose extrapolation. In fact, if the proportionality rule were valid, the evolution on Earth may well have been impossible (Costantini and Borremans 2019). Therefore, the current ecological and human risk-assessment process suffers from high uncertainty regarding the risk estimates based on unrealistic high doses and the critical levels and loads set for regulated environmental agents (Agathokleous et al. 2019a; Jargin 2018; Sacks and Siegel 2017). Since adaptive and maladaptive responses can occur, especially in highly complex ecological systems, at levels of stress much lower than is currently appreciated or considered within regulatory evaluation (Fig. 1) (Calabrese and Blain 2011; Tafoya-Razo et al. 2019; Supplementary Materials), important questions are raised as to

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whether current global regulatory standards (Agathokleous et al. 2019a) are properly framed within a scientific context to accurately estimate human and ecological health responses.

5.2 Why should hormesis be on the regulators view screen? Regulatory agencies, such as the US EPA, have deliberately rejected the incorporation of hormesis (and low-dose induced adaptive response) in the risk assessment practices (Agathokleous et al. 2019a). If there is an “optimal” stress zone and low levels of stress can “prime” organisms as reflected in increased temporal resilience, then why has the risk assessment process not been more conceptually holistic, ignoring such low dose effects? While low-level stress can be controlled and applied effectively in the medical and agricultural practice (Agathokleous et al. 2019b; Agathokleous and Calabrese 2019b; Calabrese and Agathokleous 2019; Calabrese and Mattson 2017; Gressel and Dodds 2013), this is not the norm for the natural world with changing environments (Agathokleous et al. 2019a). Hence, the risk assessment process should not have deliberately ignored the concept of adaptation, but should have incorporated information on the entire dose-response continuum. Consideration of hormesis into the risk assessment process would enhance the scientific basis to better inform risk assessment and risk management judgments, rather than being guided by vague precautionary, philosophical, and/or ideological perspectives as is currently often the case [Bogen 2016; Bus 2017; Calabrese 2017c, 2019; Golden et al. 2019; Hanekamp and Bast 2007; Kesavan 2014; counterviews are cited in Agathokleous et al. 2019a]. In addition to the scientific basis explained earlier in the text, which suggests the scientific irrelevance of the regulatory use of the LNT, it is noteworthy to showcase that the ethical stance of nonperturbation of species, including Homo sapiens L., might dictate a “zero tolerance” of sorts of chemicals and other anthropogenic agents (Hanekamp and Bast 2007). This “zero tolerance” is incorrectly understood as “zero concentration or dose”, something that has led to a regulatory 16

impasse with a “zero tolerance” goal that is based on precaution rather than on risk (Hanekamp and Bast 2007). Strikingly, the Second Law of Thermodynamics (SLT) nullifies “zero-tolerance” policies because “zero-concentration” implied by “zero tolerance” is physicochemically unrealistic (Hanekamp and Bast 2007); thermodynamics theory does not support the concept of harm (Chukova 2018). The SLT holds that entropy increases; however, in isolated systems, but not in dynamically interactive systems in the nature (Brandão et al. 2015; Schreiber and Gimbei 2010) where living systems are subjected to a constant flow of information in the form of environmental perturbation (Nunn et al. 2017). The evolutionary theory is in line with the SLT (Luisi 2006; Schreiber and Gimbei 2010): Primary producers convert high energy light directed from the Sun (low entropy) to dispersed low-energy infrared light (high entropy) to produce and store energy products, with the entire process leading to a thermodynamically-promoted natural selection and evolution of complex multicellular form of life (Schreiber and Gimbei 2010). Hormesis

is

supported

by

quantum

thermodynamics

because

it

describes

the

adaptive/conditioning response to stress [see Nunn et al. (2017) for brain and Chukova (2018) for α, β and γ radiation], highlighting a need for a more inclusive risk assessment/management strategy that will incorporate hormesis in its practices. By incorporating the entire dose-response continuum in risk assessment practices, the risks and benefits can be better identified and predictive because: i) Maladaptive effects (Costantini et al. 2014) that can occur at low levels of stress (e.g., some types of endocrine disruption) and their dose-response quantitative features (i.e., width of the stimulation zone) cannot be identified or predicted by the LNT and threshold models. ii) The effect of low-level stress seems to depend on the life history, as for example if organisms come from populations being subjected to environmental contamination for decades or centuries

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(Lefcort et al. 2008), showing different effects across populations. This would have further implications to organisms or populations moving to different environments throughout their life; some may experience adaptive while others maladaptive responses. The current research base and regulatory capabilities cannot yet account for this but consideration would provide a valuable first step. iii) Not all species, organisms, communities, and ecosystems are equally vulnerable to changing environments (Pinsky et al. 2019; Solís et al. 2011; Zhang et al. 2019). Thus, failure to incorporate low-level stress effects may affect necessary understandings of ecological processes and structure of organisational levels beyond the individual. iv) In natural, uncontrolled systems complex mixtures rather than single environmental agents exist, and, they may have antagonistic, additive, or synergistic effects when occurring together (Kortenkamp and Faust 2016). Hormesis occurs in response to mixtures of agents (e.g., complex industrial waste water effluents) (Agathokleous et al. 2019a). However, little information exists for the action of the myriads of possible mixtures that can occur, and such effects cannot be predicted (the current regulatory process even excludes them (Agathokleous et al. 2019a; Kortenkamp and Faust 2016)). While the issue of the mixtures arises from research limitations (lack of studies with mixtures), biological systems have evolved in the presence of mixtures of stressors/agents with hormesis being commonly observed. This suggests that hormesis has evolved to work in the presence of mixtures (references in Supplementary Materials). v) Toxicological estimates can be improved (Agathokleous et al. 2019a) (see also earlier sections). In addition to what is already explained, hormesis holds a central role in and can mediate risks arising from incorrect application of hormesis-based interventions (Agathokleous and

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Calabrese 2019b). Hormesis induced by agrochemicals can act as a driver of resistance evolution in weeds (Belz 2018; Farooq et al. 2019) and agricultural insects (Campos et al. 2019; Guedes et al. 2019). At the same time, low doses of agrochemicals can also enhance the virulence of phytopathogens within a hormetic mode (Agathokleous and Calabrese 2019b; Cong et al. 2019). Not only may these have further consequences at ecosystem levels by changes in competition among different types of species or organisms, but it can impede the achievement of the United Nations and Food and Agriculture Organisation of the United Nations goals for sustainable development of food systems (Agathokleous and Calabrese 2019b; Springmann et al. 2018) (Supplementary Materials). Another example of this phenomena is seen with low doses of antibiotics inducing adaptive responses for potential bacterial competitors (Liu et al. 2018). Antimicrobial-induced hormesis in microbes (Liu et al. 2018; Mathieu et al. 2016), suggests that resistance is facilitated by preconditioning processes (Davies 2006). Antimicrobial resistance is one of the most important threats for health and economic sustainability (Zhu et al. 2019a; World Bank Group 2017). The misuse of antibiotics at doses below the therapeutic may have ecological and potential dangerous effects by generating strains of bacteria multi-resistant to diverse antibiotics, thus, becoming one of the biggest health problems to be faced by the humanity in the coming decades (World Bank Group 2017). Hence, regulatory consideration of hormesis may have benefits within the regulatory framework as well, because extreme economic costs related to regulatory actions against antibiotic resistance can be prevented. Even if hormesis imposes resource demands on regulatory agencies, for acquisition of adequate dose-response data and reviewing and applying data in the regulatory decision (Marchant 2002), these costs may be proved far below the benefits of preventing microbial, insect and weed resistance.

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5.3 Relevance to belief systems The concept of hormesis has become important for the evaluation of anthropogenic impacts on the environment. Some synthetic chemicals were banned by governmental authorities (e.g. dichloro-diphenyl-trichloroethane, DDT, PCBs, and dioxins), and their levels in the environment are decreasing over time (e.g. https://www.epa.gov/ingredients-used-pesticideproducts/ddt-brief-history-and-status). These synthetic chemicals induce hormesis for multiple endpoints, in multiple experimental models (Supplementary Materials), creating the need to better understand the biological implications of biphasic dose responses on the individual and population within appropriate environmental and biological contexts (Iavicoli et al. 2006). Synthetic chemicals may be relevant as harmful examples of hormesis as in endocrine disruptors or they may have some low-dose positive effects. At low doses, they may also induce positive effects on plant defence mechanisms, invertebrate fecundity, and other endpoints (Iriti and Faoro 2009; Savvides et al. 2016; Shahali and Dadar 2018; Shine and Xiao 2019) (Supplementary Materials). Similar concerns also have been raised concerning atmospheric contaminants such as nitrogen oxides, ground-level ozone, particulate matter, and large numbers of complex chemical mixtures. While society and regulatory agencies have been concerned about dietary synthetic chemicals, most of the chemicals entering the food systems are naturally occurring. For instance, more than 99.99% of the weight of pesticides occurring in the diet of US citizens in the late 1990s were plant-produced pesticides, i.e. defensive chemicals that plants produce against environmental threats (Ames et al. 1990). Synthetic toxins may not differ qualitatively from natural toxins in their toxicology, and considering that the vast majority of toxins that humans ingest via food are of natural origin, natural chemicals may not be safer than synthetics (Ames and Gold 1997, 2000; Swirsky Gold et al. 1997). Since the production of “toxins” by plants can 20

be largely driven by environmental stress (Iriti and Faoro 2009; Savvides et al. 2016; Shahali and Dadar 2018; Shine and Xiao 2019), human-mediated environmental change may lead to changes in the natural toxins entering the food systems, with a potential to induce qualitatively different low-dose or high-dose effects on consuming animals. The events that led to the development of the LNT dose-response model and its adoption by leading regulatory agencies for risk assessment throughout the last century (Fig. 5) had a major impact on society, effecting regulatory philosophy, legislative proposals, environmental exposure standards, and belief systems concerning what is safe and what is unsafe (Oakley and Harrison 2018). Regardless of whether carcinogens are being regulated via the LNT or threshold model, the regulatory mentality is that lower exposure is always better. This paper challenges this most fundamental belief by demonstrating that lower is not always better. In contrast to the LNT perspective, “stress” should not be feared, but understood in order to both avoid harm and maximise benefit.

5.4 Further regulatory considerations The enormous growth of research body in the recent years, denoting the generality of hormesis and its underpinning biological mechanisms (Agathokleous and Calabrese 2019a, and this paper), suggests that hormesis cannot be overlooked by risk assessors, especially when leading regulatory authorities are set to base their practices upon the most up to date science (Agathokleous et al. 2019a). But how may the acceptance of hormesis affect the hazard and risk assessment and cost-benefit framework, and, what may it mean to the regulator? Regulatory standards are based on balancing between costs and benefits, as in the case of the Toxic Substances Control Act (Marchant 2002). If the regulatory agencies accept hormesis, its incorporation into the hazard and risk assessment will be challenging because of the resourceintensive requirements of hormesis. The today understandings of hormesis suggest that 21

incorporation of hormesis is resource-demanding and complex, which may puzzle regulators (Table 1). Among others, underlying experimental studies, doses incorporated in the assessments, statistical power issues, dose-time responses, and replication issues would demand higher time and economic costs (Table 1). However, most, if not all, of the increases in demands/costs could be ruled out if hormesis becomes a default assumption. In fact, the practice of default assumptions has been the hitherto classical practice of regulatory agencies, and it is with the same policy that the LNT model was adopted (Calabrese and Baldwin 2003b; Hanekamp and Bast 2007). Assuming the occurrence of hormesis, the costs may significantly decrease since experimental testing would only be required to provide an estimate of a threshold. In the case of the LNT, it was adopted assuming that is real by default, with no extensive testing or proof (Calabrese 2017c,2018a,2019; Calabrese and Baldwin 2003b; Hanekamp and Bast 2007). However, in the case of hormesis, there is a massive documentation across forms of life and endpoints, an advanced mechanistic understanding for numerous stress-inducing agents, and a growing body of literature demonstrating its ecological and evolutionary underpinning theory. Hence, regulatory agencies should examine the possibility that hormesis becomes a default assumption. The hormetic perspective is of considerable value because it requires an evaluation of the entire dose response continuum. This information is needed by regulatory agencies in their hazard assessment evaluation. Prior to the hormetic viewpoint, the risk assessment has been dominated by very few doses administered at very high and unrealistic levels of exposures in most instances. This is no longer adequate for society. The role of the dose response is to help provide the most relevant information to risk managers in their overall decision making processes that consider issues such as data base uncertainties, limitations in extrapolation

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confidence, cost-benefit, societal values, and political considerations. Thus, the dose-response information, whether affected by hormesis or other dose response models, plays an important but understandably limited role in the overall decision making process.

6. Conclusions This study indicates that an “optimal” low level stress response strategy is a highly conserved feature of all organisms. Life, from bacteria to man, evolved a plethora of complementary and partially overlapping adaptive mechanisms that mediate both immediate and possible life threatening challenges within a limited time window of several days out to about two weeks. Such enhanced acquired resilience/adaptive homeostasis is constrained by the limits of plasticity and is described by the quantitative features of the hormetic dose response. Organisms respond to toxic agents and other stressors in a dynamic manner, upregulating integrative adaptive response patterns that modestly overcompensates, not only repairing nearly all induced and some measure of background damage, but also resulting in an acquired resistance that protects against acute life threatening damage should it occur within the above noted limited time window. For plants, this life threatening event may be extreme heat or drought while for people it may be seen as a severe heart attack, stroke, or shock event from an acute loss of blood. Being “primed” or preconditioned means being protected within a hormetic dose response context. While hormesis can be induced by environmental change agents from local to global scales, not only individuals are exposed to low-dose stress but also holobionts, communities, and populations, on which the understanding of low-dose effects is at its infancy. To better understand and predict the effects on complex systems and ecosystems, the research should be moved from the dominating reductionist approach to holistic approaches where complex 23

interactions will be accounted at levels of biological organisation higher than the individual (e.g. communities, populations, ecosystems). At the center of the stress-mediated dynamic evolutionary process is the concept of hormesis with its application to all organisms and levels of biological organisation. While hormesis was essentially excluded from scientific and societal attention through most of the 20th century, the past 20 years of research has revealed hormesis to be central to biology, public health, medicine, and ecology. It needs to be better understood in order to have a transformative effect in protecting and enhancing performance in humans and in ensuring environmental sustainability. Hormesis can enhance the quality of hazard and risk assessment processes along with other dose-response models.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. E.A. acknowledges multi-year support from the National Natural Science Foundation of China (NSFC) (Grant No. 31950410547) and The Startup Foundation for Introducing Talent of Nanjing University of Information Science & Technology (NUIST), Nanjing, China (Grant No. 003080). E.J.C. acknowledges longtime support from the US Air Force (Grant No. AFOSR FA9550-13-1-0047) and ExxonMobil Foundation (Grant No. S18200000000256). 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 policies or endorsement, either expressed or implied. Sponsors had no involvement

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in study design, collection, analysis, interpretation, writing and decision to and where to submit for publication consideration.

Competing Interests The authors declare no competing interests. In agreement with Pech and Oakley, “the authors argue strongly against the use of hormetic effects if it means deliberately exposing people to any form of physical, moral, or psychological risk”, and policies should be implemented to protect the public from risks that arise with incorrect application of hormesis in any means (Pech and Oakley 2005). The Peach and Oakley report represents a good avenue for avoiding incorrect exploitation by decision makers.

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Fig. 1

Fig. 1. A hypothetical, illustrative example of hormetic dose/exposure-response relationship. The asterisk represents the no-observed-adverse-effect-level (NOAEL), aka toxicological threshold, which separates the low-dose zone (left) from the high-dose zone (right). Stimulatory effects occur in the low-dose zone, however, there may be adaptive or maladaptive responses. Adverse toxicity starts appearing after the NOAEL and increases as the level of challenge increases. The distance from NOAEL to the maximum response in the low-dose zone is commonly 10fold. The hormetic dose-response relationship may have reverse shape (U shape), depending on the endpoint

45

(response indicator).

Fig. 2

46

Fig. 2. Examples of hormesis-inducing environmental change factors. Hormesis was induced in terrestrial and aquatic organisms across the universal tree of life. The inducing agents include classically seen environmental “pollutants” and emerging “contaminants” as well as physical agents that are influenced by factors beyond Earth (space). Heavy metals include metals of public health concern (e.g. cadmium, copper, lead, selenium, zinc). Active human and veterinary pharmaceutical ingredients include several classes and types such as anti-inflammatory, antibiotics, sex and steroid hormones and induced hormesis not only in animals and microorganisms but also in plants. Agrochemicals include fungicides, herbicides, insecticides and other growth control substances with evidence for hormesis in plants, animals, microorganisms. Ozone refers to tropospheric ozone or liquid ozonation. The references are provided in Supplementary Materials. The figure was created by E. Agathokleous and has not been published previously.

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Fig. 3

Fig. 3. Evolution of life on Earth under continuous environmental perturbations. Life on Earth can be influenced by organismic responses to mixtures of non-human-induced (e.g. space influence and wind) and human-induced environmental changes at local to global scales. Planetary-scale perturbations can be influenced by solar system objects around the solar system and the space weather but also by other non-human- and human-induced changes. These perturbations can induce either positive or negative effects on biota, depending on their magnitude, frequency and duration as well as numerous other factors such as random events, geospatial characteristics, local environmental conditions, and genetic base. Life on Earth has evolved with continuous environmental perturbations which are needed for sustaining life on Earth. Note: a well-documented non-human phenomenon is thigmomorphogenesis where plants display adaptive responses to mechanical stimuli such as wind, raindrops and animal touch (Johnson et al. 2003). The figure was created with the help of Biorender (credits: E. Agathokleous).

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Fig. 4

Fig. 4. Hormesis-mediated evolution. Three examples of hormesis-mediated evolution may be antimicrobial resistance in microbes, herbicide resistance in weeds, and insecticide resistance in insects (see section “3. Human and policy dimensions”). The figure was created with the help of Biorender (credits: E. Agathokleous).

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Fig. 5

Fig. 5. How the linear non-threshold (LNT) dose-response model became default. The most significant events that marked the initial process of adopting the LNT model are presented. For further details and the later history, the readers may refer to previous papers (Calabrese 2018a).

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Fig. 6

Fig. 6. Research advancements suggesting the linear non-threshold (LNT) dose-response model is invalid. The figure was created with the help of Biorender (credits: E. Agathokleous).

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Table 1 Table 1. What incorporation of hormesis would mean to the regulators. Demands indicate expected demands for resources, time, economic costs, relative to the current practices. Note: more details on how hormesis may affect the hazard and risk assessment process can be found elsewhere (Calabrese 2018b; Calabrese and Baldwin 2003b; Hanekamp and Bast 2007). A/A 1 2

Action for consideration Dissolve carcinogen and non-carcinogen assessment (Lave 2001). Select experimental models (Agathokleous et al. 2019e; Calabrese 2018b; Calabrese and Baldwin 2003b).

3

Select study endpoints (Agathokleous and Calabrese 2019b; Agathokleous et al. 2019a,d,e; Calabrese and Baldwin 2003b).

4

Use enhanced biostatistical models (Belz and Piepho 2015; Di Veroli et al. 2015; Li and Xiao 2019; Liu et al. 2011; Tang et al. 2019b; Qu et al. 2019a,b; Zhu et al. 2019b).

5

Select experimental studies (Agathokleous et al. 2019d,e; Calabrese and Blain 2011).

6

Increase the number of doses in the low-dose zone (Calabrese et al. 2019; Varret et al. 2018).

7

Increase the number of time points (Agathokleous et al.

Details Both types of assessment will be treated in a similar fashion.

Demands of the action Decrease

Selection of experimental models would be affected, especially due to its relevance to background disease incidence. Hormesis evaluations are largely based on selected endpoints from chronic assays where the background incidence is high; in contrast to the utilisation of experimental models that are susceptible to develop disease while having a low background incidence. Not all endpoints display hormesis, and hormesis in some endpoints does not necessarily mean hormesis for each endpoint. The selection of endpoints could rely on endpoints seen as beneficial at the level of communities/populations, such as extended lifespan, decreased incidence of diseases, infections and illnesses and enhanced productivity and reproduction. The biostatistical models used should be able to detect hormesis and derive estimates in the low-dose zone.

Increase

The underlying experimental studies should be selected by assessing the experimental design quality (if the study was capable to detect low-dose effects). More doses would be needed in the low-dose zone. This would also facilitate the required hazard assessment below the traditional NOAEL.

Increase

More time points would be needed to account for temporal variability.

Increase

Increase

Neutral (exist)

Increase

52

2019a,d).

8

Consider reproducibility (Calabrese and Baldwin 2003b; Calabrese and Blain 2011; Varret et al. 2018).

9

Enhance statistical power (Agathokleous et al. 2019e; Casero-Alonso et al. 2018).

10

Consider in vitro versus in vivo and chamber versus open-field results

Reproducibility of hormesis in the same system should be considered to ensure its unambiguous occurrence.

Increase

The modest low-dose responses would demand enhanced experimental design with more replicates for enhanced statistical power. It should be confirmed that in vitro results do not differ from in vivo results. Same applies to chamber versus open-field experimentation with plants.

Increase

(Agathokleous et al. 2019e; Calabrese et al. 2019; Feng et al. 2018).

11

Select dose metrics (Agathokleous et al. 2019f; Calabrese and Baldwin 2003b; Nascarella and Calabrese 2012).

12 13

Confirm transgenerational health (Agathokleous et al. 2019a and this paper). Examine the possibility of setting hormesis as the default assumption

Dose metrics (response predictor) should be selected based on the ability to sufficiently depict hormesis. Cumulative dose metrics based upon integrated concentration thresholds (e.g. the accumulated ozone exposure above the threshold of 40 ppb, AOT40, used for vegetation) are biologically irrelevant. Confirmation would be needed that beneficial effects in one generation would not associate with harmful effects in following generations. The linear-non-threshold model became default with way less evidence than what exists for hormesis nowadays. Hormesis can be considered as default.

Neutral (current practices do not account for; regulatory assessment for plant studies did not reveal significant differences in adverse effects on plants between chamber and open-field experiments, yet recent analyses showcased significant difference) Increase

Neutral (current practices do not account for) Decrease

(Calabrese and Baldwin 2003b; Hanekamp and Bast 2007).

53

    

Global environmental change agents induce biphasic organismic responses (hormesis). The most fundamental belief that the less the stress, the better, is incorrect. Stress should not be feared, but understood to both avoid harm and enhance health. Ecological effects of low-level stress must be better understood. Hormesis can enhance the quality of hazard/risk assessment processes along with other dose-response models.

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Author contributions Each author was fully involved in all aspects of the study and takes responsibility for the integrity and the accuracy of the study concept and work product. Initial drafting of the manuscript was done by E.A. Critical revision of the manuscript for important intellectual content was performed by E.J.C. Each author has read and approved the final manuscript.

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