Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants of global concern, yet substantial uncertainty remains regarding their health and ecological risks, particularly at low exposure levels. This paper provides the first extensive evaluation of PFAS-induced hormetic dose responses across a wide range of ecological models, from bacteria to vertebrates, and, where available, examines the underlying mechanisms. Hormesis, characterized by low-dose stimulation and high-dose inhibition, is shown to be a common and evolutionarily conserved response to PFAS exposure. Evidence across diverse taxa—including zebrafish, invertebrates, insects, amphibians, and microbial systems—demonstrates consistent biphasic dose-response relationships affecting endpoints such as locomotion, immune function, reproduction, growth, and survival. Quantitative features of these responses generally align with established hormetic patterns, with stimulatory effects often occurring well below toxic thresholds. Mechanistically, PFAS-induced hormesis appears to involve adaptive processes such as modulation of oxidative stress, immune activation, and metabolic reprogramming. The findings highlight the generality of hormesis across biological systems and suggest that low-dose PFAS exposures may elicit adaptive or beneficial responses under certain conditions. These results challenge traditional toxicological assumptions and underscore the importance of incorporating hormetic dose-response models into ecological risk assessment frameworks.

This paper provides the first critical review of the capacity of per- and polyfluoroalkyl substances (PFAS) agents to induce hormetic effects in mammalian toxicological and biomedical cellular and animal models. PFAS induced hormetic responses were reported in primary cells and cell lines from multiple organ systems (e.g., liver, lung, colon, breast, prostate, immune, brain) from animal models and humans. While more limited, PFAS induced hormetic dose responses in experimental animals for short-term and chronic studies. Hormetic effects were induced by long and shorter carbon length alternative PFAS agents, with hormesis dose-response features being similar. The PFAS-induced hormetic dose responses are consistent with quantitative features of hormetic responses of other chemical and physical agents, including PFAS effects on plants and ecological animal models. These findings suggest ways to optimize study designs to assess the nature of the dose response in the low-dose zone, including dose selection, number of doses and dose spacing strategies. The findings present challenges for interpretations concerning what is an adverse effect as some effects presented here may be desirable while others potentially harmful. The introduction of the hormesis concept into the hazard assessment process creates novel risk assessment considerations making the process more scientifically robust, creating a range of new regulatory options. These findings and those shown with plants and ecological animal models indicate that the hormetic concept should become a fundamental feature of ecological and human risk assessment principles and practices by regulatory agencies.

Persistent uncertainty regarding health risks associated with contaminated drinking water at Camp Lejeune reflects a broader limitation in toxicology: the difficulty of evaluating complex chemical mixtures in genetically heterogeneous populations. Historical assessments have relied on single-chemical paradigms, assumptions of dose additivity, and population-average susceptibility. These approaches are not well aligned with exposures involving multiple volatile organic compounds (VOCs) that share metabolic pathways and generate reactive intermediates. This Forum article advances the position that artificial intelligence (AI)-enabled computational toxicology can strengthen mixture risk assessment by integrating toxicokinetic, toxicodynamic, and toxicogenomic data into mechanistically coherent, testable models. Using the Camp Lejeune VOC mixture-trichloroethylene, tetrachloroethylene, benzene, and vinyl chloride-as a case study, we illustrate how AI-augmented approaches can identify plausible interaction mechanisms, quantify genotype-dependent variability in internal dose, and generate probabilistic estimates of risk. We argue that the principal unresolved issue at Camp Lejeune is whether chronic low-level exposure to interacting mixtures disproportionately affected susceptible subpopulations. AI-driven approaches provide a tractable framework to address this question and to clarify the interface between mechanistic toxicology and public health decision-making.

Aloe vera has an extensive history in traditional folk medicine. There is a robust scientific literature on Aloe vera extracts and several prominent chemical constituents, covering chemical characterization, biological/chemoprotective effects, and mechanisms. This paper provides the first integrative assessment of Aloe vera-induced hormetic dose responses. Aloe vera extract-induced hormetic responses acted as an immunostimulant in multiple fish species, enhancing development/growth and reducing adverse effects from environmental stressors. Aloe vera extract-induced hormetic effects are prominent in dermatological studies, improving keratinocyte- and fibroblast-related wound-healing processes. Aloe vera extracts induced hormetic-based neuroprotective endpoints for epileptic seizures, pain, in Alzheimer’s disease models, and for lifespan. This analysis includes the hormetic effects of specific chemical constituents of Aloe vera extracts (acemannan/aloin) on stem cells, cardiomyocytes, bone cells, and other cell types, and their mechanisms. These findings show that a complex range of Aloe vera extract mixtures/specific constituents induce hormetic dose responses. These findings also indicate that hormetic dose responses play a prominent role in mediating many biomedical and chemopreventive effects of Aloe vera extracts and their major chemical constituents. Recognition of these findings should assist in creating optimized hormetic-based study designs and improving biologically/mechanistically based interpretations of their dose-response findings with their clinical implications.

Food defense encompasses both the prevention of accidental contamination and the protection of food and water systems against deliberate adulteration. Within this framework, algal toxins deserve greater attention because they occupy a critical intersection of water security, seafood and drinking-water safety, environmental change, supply-chain continuity, and public health preparedness. The novelty of this review lies in reframing algal toxins from a primarily environmental, seafood-safety, or clinical-toxicology topic into an integrated food-and-water defense problem. This perspective brings together harmful algal bloom ecology, toxin toxicology, seafood safety, drinking-water protection, preparedness for intentional adulteration, climate-change risk, surveillance, and emergency response. Algal toxins can enter the human supply chain through multiple marine and freshwater pathways, are often undetectable by taste, odor, or appearance, may resist routine preparation measures, and can generate high-consequence disruptions even when contamination begins locally. The analysis further shows that prevention depends largely on upstream measures--including environmental surveillance, harvest-area restrictions, source-water protection, testing, supply-chain controls, and rapid public communication--rather than on consumer behavior. Framed in the context of the U.S. Food and Drug Administration’s Intentional Adulteration Rule under the Food Safety Modernization Act, this paper situates algal toxins within a preventive defense model that integrates monitoring, vulnerability reduction, and emergency preparedness. Although most harmful algal bloom events are naturally occurring, algal toxins warrant attention in food-defense planning because they can contaminate seafood and drinking-water systems, complicate detection and attribution, and expose vulnerabilities across interconnected food and water infrastructures.

This present paper provides the first integrative evaluation of the occurrence of emodin-induced hormetic-biphasic dose responses in the biological and biomedical literature, their study design and dose-response features, underlying adaptive and toxic mechanistic foundations, and generality across biological models, cell types, as well as across different levels of biological organization (i.e., cell, organ, and organism). Emodin-induced hormetic responses have been reported in numerous cellular experimental systems of broad biomedical interest, as well as in in vivo studies with fish and rodent models. Of particular interest was the generality of the in vivo findings across multiple commercial fish models, in which emodin enhanced growth and development and increased resistance to various physical and environmental stressors. While emodin induces hormetic effects via multiple molecular targets and pathways, a general mechanistic adaptive response strategy involves its capacity to activate peroxisome proliferator-activated receptor gamma and the AMPK/Nrf2 pathway.

Hermann J. Muller, Nobel Prize recipient for producing gene mutations, was the de facto leader of the radiation genetics community from the mid-1920s until he died in 1967. Muller had a major impact on US hereditary/cancer risk assessment policies/practices, and the course of the secondary school biological sciences curriculum development in the US and worldwide. Despite these accomplishments, Muller was at the center of provocative controversies. Within this context, this paper reports the discovery of a letter (April 4, 1956) from Muller to Warren Weaver, Chair of the BEAR I Genetics Panel, about a major controversy in which the radiation-induced hereditary damage estimates of Panelist Milisav Demerec were strikingly lower than those of others, especially Muller's. In this recently discovered letter, Muller attempted to reconcile these differences and unexpectedly claimed that Demerec's estimates were correct. However, Muller appears to have inexplicably confused the evaluation by switching his focus away from Demerec's data on radiation-induced mutation rates in bacteria to his old unresolved dispute with Demerec regarding fruit flies. He even suggested that Demerec was correct in that Muller's groundbreaking mutational research had induced mostly major chromosomal aberrations rather than gene mutations. Muller curiously suggested that he had thereby resolved the conflict amongst Demerec, himself, and other BEAR I Genetics Panel members. Yet, as noted, Demerec's data for the BEAR I Genetics Panel mutation risk estimates were based on his (i.e., Demerec's) more current research on bacteria, with Muller completely missing the entire point of the Panel's scientific conflict with the Demerec data. Thus, Muller never addressed the real issue. This transitory detachment from factual reality by Muller is obvious and acute. Finally, if Weaver had shared this letter from Muller with the BEAR I Genetics Panel, it seems possible that many members might have been so troubled by Muller's apparent detachment from reality (on such a consequential disagreement) that they would have questioned why they had allowed Muller to exert so much influence on their report.

This manuscript examines food safety through the lens of bioterrorism, emphasizing how deliberate contamination of food and water systems can cause not only illness and death, but also fear, economic disruption, and erosion of public trust. It reviews the public health and regulatory foundations of food defense, including preventive controls, vulnerability assessments, surveillance, and traceback systems, and situates mycotoxins within this broader security framework. Historical incidents of intentional contamination with microbial pathogens demonstrate that foodborne agents can be weaponized, while mycotoxins represent a distinct but credible concern because of their persistence, difficulty of detection, and capacity to contaminate widely distributed staple commodities. The manuscript synthesizes major mycotoxin classes, their exposure pathways, toxicologic mechanisms, analytical detection methods, and mitigation strategies, with attention to cross-cutting risk drivers such as climate, storage conditions, masked toxins, and co-contamination. Collectively, the evidence supports integrating microbial and mycotoxin hazards into food-defense planning and strengthening coordination among surveillance, laboratory, regulatory, and emergency- response systems to improve preparedness and resilience.

This paper provides the first comprehensive documentation and assessment of the capacity of per- and polyfluoroalkyl substances (PFAS) agents, including PFAS-based pesticides, to induce hormetic effects in plants, including agricultural crops, aquatic algae, seaweed and riparian species, as well as cyanobacteria and fungi. PFAS-induced-hormetic responses in plants were generally associated with their capacity to enhance growth processes, chlorophyll production and the upregulation of antioxidant enzymes to counter PFAS-induced oxidative stress. The findings show that PFAS induced-hormetic effects in highly diverse plant species is a reasonable biological expectation, showing considerable generality. Recognition that PFAS regularly induces hormetic effects in highly diverse plant species should help guide future PFAS research on plants with respect to study design strategies, dose selection, number of doses, dose spacing and temporal aspects of such studies.

Increasing research suggests that low-dose persistent organic pollutants (POPs) can elicit hormetic stimulatory effects on organisms, highlighting the need for a comprehensive synthesis of the literature to evaluate the prevalence, mechanisms, and implications of these non-linear responses. This review consolidates evidence supporting the hypothesis that hormesis describes a common and evolutionarily conserved adaptive strategy, consistently observed across a broad spectrum of POPs. The hormetic response of whole-organism endpoints such as growth is primarily driven by initial mild oxidative stress, which activates sophisticated adaptive signaling pathways, coordinated overexpression of defensive machinery, induction of antioxidant enzymes, and activation of detoxification pathways involving phase I/II enzymes. These responses are often transient and context-dependent, often influenced by exposure duration and other environmental factors, and thus may play a fundamental role as a dynamic survival strategy. The vast concentration range of stimulations, spanning several orders of magnitude (from nanograms to milligrams), suggests the broad environmental relevance of POP-induced hormesis. Hence, the widespread occurrence of POP-induced hormesis presents a significant challenge to conventional risk assessment frameworks, creating an urgent need to integrate these biphasic dose-response relationships into developing more accurate ecological and human health risks of POPs exposure.

Emerging evidence reveals low, environmental concentrations of contaminants trigger stimulatory-hormetic responses in animals, prompting this literature synthesis to explore broader patterns and implications of contaminant-induced developmental hormesis. Findings demonstrate consistent biphasic responses across fundamental developmental endpoints. Low-dose exposures enhance key traits such as embryonic survival, hatching success, and fertilization rates while reducing developmental deformities and mortality. Hormetic stimulation further manifests in morpho-anatomical traits, including altered growth and organ size and shape, and shifts in developmental timing across life stages. These phenotypic outcomes are mechanistically linked to physiological and molecular changes, such as modified gene expression in critical developmental pathways and altered energy allocation strategies, though molecular evidence is limited. Such responses often represent interconnected adjustments across anatomical, physiological, and temporal dimensions of development. However, apparent stimulations of specific endpoints at sub-lethal (but not true hormetic) doses often involve context-dependent trade-offs and may arise from indirect contaminant interactions rather than direct biological stimulation. Consequently, low-dose developmental stimulation does not necessarily confer net fitness benefits at organismal or population levels. Future research should clarify underlying mechanisms, quantify long-term fitness and ecological consequences across developmental stages and generations, and assess prevalence under realistic multi-stressor conditions to advance ecological risk assessment beyond linear models.

The present paper provides the first integrated assessment of the capacity of the flavonol, fisetin, to induce hormetic dose responses. Fisetin was shown to induce hormetic dose responses in cellular and in vivo animal model systems affecting a broad range of endpoints of potential therapeutic and public health significance across the entire lifespan. Fisetin was effective in slowing aging processes, acting as a senolytic agent in multiple organ systems, in an hormetic fashion. In addition, fisetin was broadly neuroprotective, including during fetal development, and preventing the toxicity of methylmercury. Since these findings indicate that fisetin may have the potential to induce multi-system chemoprotective effects, it indicates the need to better clarify the absorption and bioavailability of fisetin and ways to enhance its efficiency.

It has been said that "too much confidence cannot be placed on the lessons of history." We suggest that this declaration is particularly salient for the dynamic field of toxicology. The intersection of historical trends and technological developments within and outside the discipline is briefly considered as they have shaped what we study and what we do. Most importantly, perhaps, both individually and collectively, these elements also highlight cautions and define challenges that toxicology must embrace to continue to thrive and contribute to the scientific enterprise and public health.

Kaempferol is a polyphenol in various fruits and vegetables. It is also commercially developed and sold to consumers as a supplement. It has been extensively assessed in clinical trials for clinical utility based upon its numerous experimentally based chemopreventive properties. Kaempferol has been evaluated at the levels of molecule, cell, and individual animal, showing a broad spectrum of biological effects. Kaempferol-induced hormetic concentration responses are common, being reported in many cell types and biological models for numerous endpoints. While the hormetic effects of kaempferol are biologically diverse, there has been a strong focus on age-related endpoints affecting numerous organ systems and endpoints, indicating that kaempferol is a senolytic agent, showing similar properties as quercetin and fisetin. This paper offers the first integrated evaluation of kaempferol-induced hormetic dose responses, their quantitative characteristics, mechanistic explanations, extrapolative strengths or limitations, and related experimental design, biomedical, therapeutic, ageing, and public health, including ageing related applications.

The present paper provides a new perspective of previously published findings by Siwak (Food Chem 141:1227–1241, 2013) which showed that 15 structurally diverse flavonoids reduced toxicity (i.e., enhanced cell viability) from hypochlorite using the MTT assay within a pre-conditioning experimental protocol, with each agent showing a similar biphasic concentration response relationship. We use this Commentary to point out that each of the concentration response relationships are consistent with the hormetic dose response. The paper of Siwak (Food Chem 141:1227–1241, 2013) is unique in that it provides a comparison of a relatively large number of agents using the identical experimental protocol.

The present paper provides the first integrative assessment of the capacity of dietary, endogenous and other agents to induce hormetic dose responses in oocytes, their supportive cells such as granulosa cells, blastocyst formation and early stage embryo development with the goal of improving fertility and reproductive success. The analysis showed that numerous agents enhance oocyte maturation and blastocyst/embryonic development in an hormetic fashion. These findings indicate that numerous agents improve oocyte related biological functioning under normal conditions as well as enhancing its capacity to prevent damage from numerous chemical toxins and related stressor agents, including heat and age-related processes in pre-post conditioning and concurrent exposures. The present assessment suggests that hormetic based lifestyles and dietary interventions may offer the potential to enhance healthy reproductive performance with applications to animal husbandry and human biology. The present findings also significantly extend the generality of the hormesis dose response concept to multiple fundamental biological processes (i.e., oocyte maturation, fertilization and blastocyst/embryo development).

Caffeic acid is a common phenolic acid found in coffee and numerous fruits and vegetables. Known for its antioxidant properties, it is widely used as a dietary supplement as part of a polyphenol mixture or as an extract in the form of a capsule or powder. It is also available in liquid form as a homeopathic supplement. Caffeic acid phenethyl ester (CAPE) is an active component of propolis produced by honey bees. Propolis extract is used as a supplement and is available in various forms. The present paper is a comprehensive review of the biomedical literature, showing that caffeic acid effects are hormetic and occur in numerous biological models and cell types for a broad range of endpoints including many aging-related processes. Hormesis is a biphasic dose/concentration response displaying a low concentration/dose stimulation and a high concentration/dose inhibition. Complex alternative search strategies for caffeic acid were used since publications rarely used the terms hormesis or hormetic. Evaluation of the data provides the first assessment of caffeic acid-induced hormetic concentration/dose responses and their quantitative features. Their mechanistic foundations, extrapolative strengths/limitations, and their biomedical, clinical, and public health implications are discussed. Suggestions for future research are presented.

The present paper provides the first documentation and assessment of the capacity of chlorogenic acid to induce hormetic dose-response relationships. The findings suggest that chlorogenic acid may induce anabolic (i.e., growth) and catabolic (i.e., protective) hormetic dose responses in several cell types via a range of complementary and cross-talking pathways, affecting a spectrum of endpoints of biomedical and therapeutic importance. This paper also addresses the issue of whether the widely recognized beneficial effects of coffee consumption, as reported in multiple epidemiological studies, may be related to the hormetic effects of chlorogenic acid and its metabolites and their interactions. The present analysis suggests that some beneficial effects of coffee consumption may be due to the effects of chlorogenic acid and/or its metabolites on the gastrointestinal tract via their capacity to impact gastrointestinal integrity, structure, and functionality. These effects collectively contribute to the attenuation of the gastrointestinal tract and concurrent systemic oxidative stress, positively affecting a range of organ-specific effects.

Quercetin is a polyphenol present in numerous fruits and vegetables and therefore widely consumed by humans with average daily dietary intakes of 10–20 mg/day. It is also a popular dietary supplement of 250-1000 mg/day. However, despite the widespread consumer interest in quercetin, due to its possible chemopreventive properties, the extensively studied quercetin presents a highly diverse and complex array of biological effects. Consequently, the present paper provides the first assessment of quercetin-induced hormetic concentration/dose responses, their quantitative features and mechanistic foundations, and their biological, biomedical, clinical, and public health implications. The findings indicate that quercetin-induced hormetic dose responses are widespread, being independent of biological model, cell type, and endpoint. These findings have the potential to enlighten future experimental studies with quercetin especially with respect to study design parameters and may also affect the appraisal of possible public health benefits and risks associated with highly diverse consumer consumption practices.