Science-based Risk Assessment Research Articles

Modernizing and harmonizing regulatory data requirements for genetically modified crops-perspectives from a workshop.

Genetically modified (GM) crops that have been engineered to express transgenes have been in commercial use since 1995 and are annually grown on 200 million hectares globally. These crops have provided documented benefits to food security, rural economies, and the environment, with no substantiated case of food, feed, or environmental harm attributable to cultivation or consumption. Despite this extensive history of advantages and safety, the level of regulatory scrutiny has continually increased, placing undue burdens on regulators, developers, and society, while reinforcing consumer distrust of the technology. CropLife International held a workshop at the 16th International Society of Biosafety Research (ISBR) Symposium to examine the scientific basis for modernizing global regulatory frameworks for GM crops. Participants represented a spectrum of global stakeholders, including academic researchers, GM crop developers, regulatory consultants, and regulators. Concurrently examining the considerations of food and feed safety, along with environmental safety, for GM crops, the workshop presented recommendations for a core set of data that should always be considered, and supplementary (i.e., conditional) data that would be warranted only on a case-by-case basis to address specific plausible hypotheses of harm. Then, using a case-study involving a hypothetical GM maize event expressing two familiar traits (insect protection and herbicide tolerance), participants were asked to consider these recommendations and discuss if any additional data might be warranted to support a science-based risk assessment or for regulatory decision-making. The discussions during the workshop highlighted that the set of data to address the food, feed, and environmental safety of the hypothetical GM maize, in relation to a conventional comparator, could be modernized compared to current global regulatory requirements. If these scientific approaches to modernize data packages for GM crop regulation were adopted globally, GM crops could be commercialized in a more timely manner, thereby enabling development of more diverse GM traits to benefit growers, consumers, and the environment.

Translational Insights into Molecular Mechanisms of Chemical Hepatocarcinogenesis for Improved Human Risk Assessment

Background: Hepatocellular carcinoma (HCC) is a prevalent liver cancer with major risk factors being hepatitis viral infections, alcohol, non-alcoholic fatty liver disease, and aflatoxin exposure. Both genotoxic and non-genotoxic agents can induce HCC through mechanisms involving DNA damage, oxidative stress, chronic inflammation, and disrupted signaling pathways like MAPK/ERK, PI3K/AKT, WNT/β-catenin and PPARα. While rodent assays are utilized to detect potential chemical hepatocarcinogens, species differences in pathways like PPARα and CAR/PXR activation impact human risk assessment. Purpose: This analysis provides an updated, critical examination of species concordance in mechanisms of hepatic carcinogenesis to inform human safety assessment of rodent liver tumor findings. Main Body: Rodent assays including 2-year bioassays, transgenic models, and short-term studies detect liver tumors through lifetime exposure or early biomarkers. However, rodent-specific PPARα and CAR/PXR activation, along with human risk factors like hepatitis, highlight key interspecies differences. Determining mode of action relevance requires evaluating mechanistic validity and pivotal key events leading to tumors across species. Non-genotoxic compounds eliciting rodent liver tumors can activate PPARα, CAR/PXR, and other pathways triggering increased cell replication; but downstream signaling may differ in human liver. Understanding applicability of these mechanisms in humans as well as incorporating human risk factors into experimental models is critical for accurate risk assessment. Conclusion: In summary, elucidating conserved versus divergent molecular mechanisms of hepatic carcinogenesis between rodents and humans is essential for appropriately interpreting rodent findings and safeguarding human health through science-based risk assessment frameworks and regulatory decision-making processes around potential chemical hazards.

The World Health Organization endeavours to put forward Integrated Approaches to Food and Diet Risk-Benefit Assessment

Abstract WHO has identified five pathways that outline how food systems can impact health, including unhealthy diets and food insecurity, zoonotic pathogens and antimicrobial resistance, unsafe and adulterated foods, environmental contamination and degradation, and occupational hazards. The WHO carried out studies on the global burden of foodborne illnesses in 2015, indicating that vulnerable people, particularly those in developing nations, are the most concerned. Unhealthy diet and malnutrition remain at the top ten of the identified risk factors for the global diseased burden. WHO provides science-based food safety risk assessments and evidence-based guidelines on foodborne hazards and nutrient requirements throughout life stages. WHO is currently developing food-based guidelines, covering meat, dairy, and fish intake, as well as scientific opinions on food processing levels. However, the issue of how to combine all of the guidelines into global recommendations for a healthy and sustainable diet remains unanswered. There is a need to develop a more integrated approach to risk and benefit that takes into account the wide range of the populations concerned as well as the new and future foods and food production systems. In this regard, WHO is focusing on developing integrated methodologies and frameworks based on the most recent advances in the risk-benefit assessment for foods and diets, as well as other advancements in decision-making and communication models.

154 Toward a General Approach to Risk Assessment of Naturally Occurring Asbestos and Asbestos-Like Minerals: the case of Fibrous Antigorite

Abstract The natural occurrence of asbestos and asbestos-like minerals (NOA) poses a risk to the environment and human health, notably when natural processes and anthropic activities promote fibre dispersion. Hundreds of potentially hazardous elongated mineral particles (EMPs, NIOSH 2011 definition) exist, and their toxicological profile is often unknown. We aim here to define a general approach, from field analysis to nano-structural investigation, to assess whether a fibrous mineral occurring in a specific site could pose a risk to human health. To evaluate the hazard associated with NOA, a multi-scale and multi-analytical integrated approach was adopted. Specifically, the geological factors that control the occurrence and distribution of NOA on site, and the mechanisms of formation and liberation of airborne fibres were investigated. In parallel, we explored the key bulk and surface properties of several natural mineral fibres and defined crystallographic, chemical, and morphological aspects that should be considered during hazard assessment. Also, the effect of standardized mechanical stress was used to simulate variation on morphometric parameters of investigated minerals and allowed us to quantitatively evaluate the potency to generate inhalable fibres. This property was connected with the mineral characteristic and the rock fabric. Isolated fibre specimens were used to assess solubility in simulated body fluids, surface reactivity, and toxicological endpoints in vitro and in vivo. Taken together, these findings allowed us to build a multidimensional description of the hazard parameters of a mineral fibre and paved the way for a science-based risk assessment in an unexplored NOA site.

Transcriptomic Profiling the Effects of Airway Exposure of Zinc Oxide and Silver Nanoparticles in Mouse Lungs

Consumers and manufacturers are exposed to nanosized zinc oxide (nZnO) and silver particles (nAg) via airways, but their biological effects are still not fully elucidated. To understand the immune effects, we exposed mice to 2, 10, or 50 μg of nZnO or nAg by oropharyngeal aspiration and analyzed the global gene expression profiles and immunopathological changes in the lungs after 1, 7, or 28 days. Our results show that the kinetics of responses varied in the lungs. Exposure to nZnO resulted in the highest accumulation of F4/80- and CD3-positive cells, and the largest number of differentially expressed genes (DEGs) were identified after day 1, while exposure to nAg caused peak responses at day 7. Additionally, nZnO mainly activated the innate immune responses leading to acute inflammation, whereas the nAg activated both innate and adaptive immune pathways, with long-lasting effects. This kinetic-profiling study provides an important data source to understand the cellular and molecular processes underlying nZnO- and nAg-induced transcriptomic changes, which lead to the characterization of the corresponding biological and toxicological effects of nZnO and nAg in the lungs. These findings could improve science-based hazard and risk assessment and the development of safe applications of engineered nanomaterials (ENMs), e.g., in biomedical applications.

Performance of early warning signals for disease re-emergence: A case study on COVID-19 data.

Developing measures for rapid and early detection of disease re-emergence is important to perform science-based risk assessment of epidemic threats. In the past few years, several early warning signals (EWS) from complex systems theory have been introduced to detect impending critical transitions and extend the set of indicators. However, it is still debated whether they are generically applicable or potentially sensitive to some dynamical characteristics such as system noise and rates of approach to critical parameter values. Moreover, testing on empirical data has, so far, been limited. Hence, verifying EWS performance remains a challenge. In this study, we tackle this question by analyzing the performance of common EWS, such as increasing variance and autocorrelation, in detecting the emergence of COVID-19 outbreaks in various countries. Our work illustrates that these EWS might be successful in detecting disease emergence when some basic assumptions are satisfied: a slow forcing through the transitions and not-fat-tailed noise. In uncertain cases, we observe that noise properties or commensurable time scales may obscure the expected early warning signals. Overall, our results suggest that EWS can be useful for active monitoring of epidemic dynamics, but that their performance is sensitive to certain features of the underlying dynamics. Our findings thus pave a connection between theoretical and empirical studies, constituting a further step towards the application of EWS indicators for informing public health policies.

Utility of the avian sub-acute dietary toxicity test in ecological risk assessment and a path forward to reduce animal use.

The United States Environmental Protection Agency (USEPA) has long required both avian sub-acute dietary and acute oral studies to inform risk assessments for pesticides. Recently, the USEPA collaborated with People for the Ethical Treatment of Animals to determine whether the results of the acute oral avian toxicity test or the sub-acute dietary toxicity test consistently generated the greatest risk predictions in USEPA tier 1 assessments for pesticides first registered between 1998 and 2017. Their study concluded that in 99% of the cases, risk conclusions were driven by the acute oral study (OPPTS 850.2100, OCSPP 850.2100, or similar) because using these data results in higher risk quotients than sub-acute dietary data. Shortly after publishing these results, the USEPA released a formal memorandum providing guidance for waiving the sub-acute dietary study for most pesticides. The USEPA will, however, retain the option to require sub-acute dietary studies for pesticides with certain chemical properties. However, as the avian sub-acute dietary study has an exposure regimen that is often more representative of how birds are exposed to pesticides under actual use conditions than does the acute oral study (i.e., as part of a dietary item eaten over the course of a day and not a bolus dose), this study can provide useful context for risk assessment on a case-by-case basis. Decision criteria are needed to determine a path forward that both minimizes vertebrate animal testing and positions the avian sub-acute dietary data as an option for risk refinement. Decision criteria are proposed here with recommendations for refining the design of avian sub-acute dietary studies to ensure that the data generated are optimized to support a science-based acute avian risk assessment, supported by a case study demonstrating when and how sub-acute dietary studies may be used in a higher-tier risk assessment. Integr Environ Assess Manag 2022;18:1629-1638. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Molecular Dosimetry of DNA Adducts in Rats Exposed to Vinyl Acetate Monomer.

Vinyl acetate monomer (VAM) is heavily used to synthesize polymers. Previous studies have shown that inhaled VAM, being metabolized to acetaldehyde, may form DNA adducts including N2-ethylidene-deoxyguanosine (N2-EtD-dG), which may subsequently cause mutations and contribute to its carcinogenesis. Currently, there is little knowledge on the molecular dosimetry between VAM exposure and DNA adducts under dosages relevant to human exposure. In this study, 0.02, 0.1, 1, 10, 50, 200, and 600 ppm VAM were exposed to rats by inhalation for 14 days (6 h/day). The use of [13C2]-VAM allows unambiguous differentiation and quantification of the exogenous and endogenous N2-EtD-dG by highly sensitive LC-MS/MS. Our data indicate that VAM-induced exogenous DNA adducts were formed in a non-linear manner. Exogenous DNA adducts were only detected in the nasal epithelium of rats exposed to 10, 50, 200, and 600 ppm VAM, whereas endogenous adducts were found in all nasal and other tissues analyzed. In addition, ratios of exogenous/endogenous DNA adducts were less than 1 with the dose up to 50 ppm, indicating that endogenous DNA adducts are predominant at low VAM concentrations. Moreover, differential dose-response in terms of exogenous DNA adduct formation were observed between nasal respiratory and olfactory epithelium. Furthermore, the lack of exogenous DNA adducts in distant tissues, including peripheral blood mononuclear cells, liver, brain, and bone marrow, indicates that VAM and/or its metabolite do not distribute systemically to cause DNA damage in distant tissues. Together, these results provided new molecular dosimetry to improve science-based cancer risk assessments of VAM.

Socio-Economic Considerations and Potential Implications for Gene-Edited Crops

Regulatory clarity and efficiency are increasingly important for the successful commercialization of technologies resulting from public and private R&D investments. This article examines recent developments in the movement away from mostly science-based risk assessment regulatory and variety approval systems focusing on human and animal health and environmental safety to hybrid systems that include assessment of socio-economic considerations allowed for under the auspices of the Cartagena Protocol on Biosafety. We propose that socio-economic consideration assessments can be grouped into three methodological categories: empirically based, legally grounded and consensus approaches. Our exploration of developments in the three categories reveals gaps in data, consistency and methodology rigor, that must be addressed for efficient and reliable socio-economic consideration assessment. We assess the potential impacts of these gaps on the regulation of gene-edited crop varieties, concluding that if gene-edited crops are regulated as genetically modified crops, they will endure the same fate, that is, lengthy regulatory approval processes and failure to be commercialized. The end result being that the regulatory burdens in potential adopting and food insecure countries will prevent important new crop varieties from reaching farmers and producers for their use. https://doi.org/10.21423/jrs-v09i2ludlow

Digitalization in the meat chain

The meat supply chain should be regularly monitored to ensure the safety of products. Recent developments in Artificial Intelligence, Internet of Things and blockchain technologies will have a tremendous and disruptive effect on the meat supply chain system in terms of improving the monitoring and surveillance of hazards at multiple points along the meat chain (pre-harvest, harvest, post-harvest), in the farm-to-retail continuum, as well as providing better quality of information to consumers for informed decisions regarding food purchase. The farm-to-fork food chain continuum should be managed to provide an appropriate level of consumer protection (ALOP). This can be achieved by science-based risk assessment, which includes information about the prevalence and concentration of major public health hazards (epidemiological indicators) of zoonotic origin (Salmonella, Campylobacter, Listeria monocytogenes, Yersinia, Shiga toxin-producing Escherichia coli/STEC) in all modules along the food (meat) chain: farm - transport - slaughterhouse - meat processing - distribution - retail - consumers. The integration of digital technologies to the Food (Meat) Safety Management System or Meat Safety Assurance System will enhance the integration of Food Chain Information and Harmonized Epidemiological Indicators along the meat chain, from farm to retail (bottom-up) and vice versa from retail to farm (top-down). Meat chain digitalization will also increase the transparency and visibility of all actors involved in meat production, processing, distribution and retail (farmers, meat business operators, competent authorities, retailers), and provide the basis for benchmarking producers and retail chains, as well as pro-active consumer participation in defining future food policies at the national and global level.

Increasing Engagement in Regulatory Science: Reflections from the Field of Risk Assessment

While the demands for greater engagement in science in general and regulatory science in particular have been steadily increasing, we still face limited understanding of the empirical resonance of these demands. Against this context, this paper presents findings from a recent study of a potential participatory opening of the German Federal Institute for Risk Assessment (“Bundesinstitut für Riskobewertung” [BfR]), a prominent regulatory scientific organization in the field of risk governance. Drawing upon quantitative surveys of the public and selected professional experts as well as in-depth qualitative expert interviews, we identify a general support for greater engagement in science-based risk assessment. However, we also find significant contestation concerning its potential enactment and its normative and strategic merit. Underlying these contestations, we identify the persistence of a normal view of science and decisionist understanding of risk assessment, which create conflicting legitimacy demands for BfR and other regulatory scientific organizations. Together with concerns about imbalances in the power to participate, especially in highly specialized engagement processes, these pose significant challenges for the institutionalization of more participatory practices.

How institutional biosafety committees contribute to safety, capacity and regulatory approvals in cell and gene therapy trials

Background & Aim In Australia clinical trials of viral vector gene therapies or gene modified (GM) viruses are required to be licenced by the Office of the Gene Technology Regulator (OGTR). Institutional Biosafety Committees (IBCs) play a crucial role by reviewing applications before they go to the OGTR for decision. IBCs also advise on cell therapy trials that do not require a licence and on laboratory research. Their advice covers safety, compliance and governance to meet the objective of the Australian Gene Technology Act 2000, which ‘is to protect the health and safety of people, and to protect the environment, by identifying risks posed by or as a result of gene technology, and by managing those risks through regulating certain dealings with GMOs [Genetically Modified Organisms]’. Methods, Results & Conclusion Royal Prince Alfred Hospital (RPAH) IBC contributes to cell and gene therapy capacity building within Sydney Local Health District. Since 2008 it has advised on over 22 clinical trials; 14 of which required an OGTR licence. It has reviewed 6 licence applications and local risk management for 7 licences obtained via other IBCs. The number of trials advised on is increasing (5 in 2008-2015, 9 in 2016-2019 and 4 as at March 2020). They cover adeno-associated viral vectors for haemophilia, adenoviral vectors for mesothelioma, oncolytic GM human HSV-1 for melanoma and squamous cell carcinoma, oncolytic GM vaccinia virus vaccine strain for liver and kidney cancer, autologous cells transduced ex vivo with lentiviral vectors for beta-thalassemia (CD34+ cells) and adult diffuse large B-cell lymphoma (chimeric antigen receptor T cells targeting CD19) and allogeneic CRISPR Cas-9 engineered T-cells for B cell malignancies. The IBC conducts science-based risk assessments, facility inspections, assists organisations to prepare for cell and gene therapy clinical trials and contributes to policy and national reviews. It assists applicants and liaises with the OGTR. It has answered infection control queries, educated sponsors, developed a GMO-waste management training program with environmental services; ensured eye-wash, autoclave maintenance and spills management training are provided; assisted with corrective actions; and provided risk prevention advice. The members are scientists, researchers, health professionals, engineers and lay persons. The committee has processes for managing confidential information and dualities of interest and assesses new technologies, policies and regulations as they emerge.

Risk Assessment Considerations for Genetically Modified RNAi Plants: EFSA's Activities and Perspective.

Genetically modified plants (GMPs) intended for market release can be designed to induce “gene silencing” through RNA interference (RNAi). The European Food Safety Authority (EFSA) and other international risk assessment bodies/regulatory agencies have taken several actions to determine whether the existing risk assessment approaches for GMPs are appropriate for the risk assessment of RNAi-based GMPs or require complementary or alternative approaches. To our knowledge, at the international level, no dedicated guidelines have been developed for the risk assessment and regulation of RNAi-based GMPs, confirming that existing science-based risk assessment approaches for GMPs are generally considered suitable for RNAi-based GMPs. However, some specificities have been identified for the risk assessment of RNAi-based GMPs. Here, we report on some of these specificities as identified and addressed by the EFSA GMO Panel for the molecular characterisation, food/feed safety assessment and environmental risk assessment of RNAi-based GMPs, using the DvSnf7 dsRNA-expressing maize MON87411 as a case study.

Upholding science-based risk assessment under a weakened Endangered Species Act

Upholding science-based risk assessment under a weakened <i>Endangered Species Act</i>

Science communication is needed to inform risk perception and action of stakeholders

Stakeholders are critical environmental managers in human-dominated landscapes. In some contexts, stakeholders can be forced to personally act following their own observations and risk perception instead of science recommendation. In particular, biological invasions need rapid control actions to reduce potential socio-ecological impacts, while science-based risk assessments are rather complex and time-delayed. Although they can lead to important detrimental effects on biodiversity, potential time-delayed disconnections between stakeholders' action and science recommendations are rarely studied. Using the case study of western European beekeepers controlling the invasive Asian hornet Vespa velutina nigrithorax for its suspected impact on honey bee colonies, we analysed mechanisms underlying personal actions of stakeholders and how they evolved in science disconnection. Personal actions of stakeholders were causal-effect linked with their risk observation but disconnected to time-delayed science predictions and recommendations. Unfortunately, these science-disconnected actions also led to dramatic impacts on numerous species of the local entomofauna. These results highlight the need to improve mutual risk communication between science and action in the early-stages of management plans to improve the sustainably of stakeholders’ practices.

Regulatory Control and Management of Public Health Pesticides in South Africa

Pesticides used in residential settings may have harmful health effects. There are reports about pesticide poisoning in South Africa, especially among children under the age of five years. The Department of Agriculture, Forestry and Fisheries and the Department of Health use the Fertilizers, Farm Feeds, Agricultural Remedies and Stock Remedies Act (Act No. 36) to ensure that pesticides are only registered after a rigorous science-based risk assessment. The Act 36 was designed primarily for agricultural pesticides. Therefore, guidelines have recently been developed to facilitate registration of PHPs. However, these guidelines do not provide guidance on acceptable methods for estimating residential exposures. Furthermore, inadequate monitoring and regulation of pesticides have resulted in the use of highly toxic pesticides in residential and commercial settings. Responsible government agencies and independent poisoning information centres (PICs) appear to lack the capacity routinely to report and investigate all pesticide-poisoning incidents adequately and comprehensively. Therefore, there is need to strengthen the capacity of responsible agencies as well as to conduct a revision of Act 36 in order to address critical gaps with regards to the registration, monitoring and surveillance of PHPs.

Soil contamination in China: Current priorities, defining background levels and standards for heavy metals

The Chinese Government is working to establish an effective framework in managing soil contamination. Heavy metal contamination is key to the discussion about soil quality, health and remediation in China. Soil heavy metal contamination in China is briefly reviewed and the concepts of background values and standards discussed. The importance of contaminated land and its management for China food security and urbanization are discussed. Priorities for China's next steps in developing an effective research and management regime are presented. We propose that critically important to the science-based risk assessment of contaminants in soils is the incorporation of speciation and bioavailability into the measurement and evaluation criteria. Consideration of soil biology/ecological endpoints will be necessary to protect ecosystem health. National and regional/local scenarios of land use type/usage will address residential/urban re-use of industrial land as well as varying agricultural scenarios.

Precision livestock farming in the context of meat safety assurance system

The food chain continuum `from farm to fork` should be managed to provide the appropriate level of consumer protection. Healthy animals are the essential precondition for obtaining a safe food supply. A science-based risk assessment includes the information about prevalence and concentration of major public health hazards of zoonotic origin (Salmonella, Campylobacter, Listeria monocytogenes, Yersinia, Verotoxin-producing E. coli/VTEC) and chemical contaminants (residues of veterinary drugs, dioxins, mycotoxins) in all modules along the food (meat) chain: farm-transport-slaughterhouse-meat processing-distribution-retailconsumers. The effective monitoring of biological or behavioural symptoms related to animal health and welfare can be achieved by Precision Livestock Farming (PLF). PLF emerged as a farm management approach based on information and communication technology (ICT). It can enable the early disease detection system using electronic information transfer from biosensors, in optimising animal health, production and management processes on farm. PLF can deliver added value to the integrated meat safety assurance system (MSAS) by providing real-time evidence of animal health and welfare status. This will strengthen understanding of all three major aspects of MSAS that must be monitored: biological hazards (farm-slaughterhouse continuum), animal health and welfare (Food Chain Information (FCI) quality and flow), and contaminants (prioritisation in monitoring based on FCI information).

Global status of the regulation of genome editing technologies.

Abstract Innovations affect societies in various ways. For example, the latest innovations in cell phones and electronics are readily adopted without hesitation. However, many innovations regarding the breeding of plants, the production of food crops and the processing of food products, can be met with fear and trepidation by some societies. Europe, the foundation of the Industrial Revolution, has developed strong adversity to agricultural innovations that involve innovative genome editing methods in general and to genetically modified (GM) crops in particular. While much of the industrial world models their regulatory frameworks for plant agriculture on the science-based risk assessment framework developed through the efforts of the Organisation for Economic Cooperation and Development, the European Union's regulatory framework for GM crops is based on the precautionary principle, approving but a single GM crop variety for production in the twenty-first century. As any field of science and technology advances, so has the breeding of GM crops. GM crop varieties were developed through the insertion of a gene or genes from a different species, such as the insertion of the trait for insect resistance in plants that originally came from a soil bacterium. Crop varieties are now being developed through a group of targeted, site-directed mutation technologies, known as genome editing, where some of this group of technologies results in no foreign genes being transferred into new varieties. While technologically viewed as a significant advancement in the development of new plant varieties, some jurisdictions have chosen to regulate genome editing as equivalent to GM crops, thereby establishing a de facto ban on the application of the technology. Yet other jurisdictions have chosen to embrace the technology, announcing that some applications of genome editing will face no regulatory oversight. This paper provides a global overview of the various regulatory frameworks for genome editing.

Predicting the effect of ozone on vegetation via linear non-threshold (LNT), threshold and hormetic dose-response models

The nature of the dose-response relationship in the low dose zone and how this concept may be used by regulatory agencies for science-based policy guidance and risk assessment practices are addressed here by using the effects of surface ozone (O3) on plants as a key example for dynamic ecosystems sustainability. This paper evaluates the current use of the linear non-threshold (LNT) dose-response model for O3. The LNT model has been typically applied in limited field studies which measured damage from high exposures, and used to estimate responses to lower concentrations. This risk assessment strategy ignores the possibility of biological acclimation to low doses of stressor agents. The upregulation of adaptive responses by low O3 concentrations typically yields pleiotropic responses, with some induced endpoints displaying hormetic-like biphasic dose-response relationships. Such observations recognize the need for risk assessment flexibility depending upon the endpoints measured, background responses, as well as possible dose-time compensatory responses. Regulatory modeling strategies would be significantly improved by the adoption of the hormetic dose response as a formal/routine risk assessment option based on its substantial support within the literature, capacity to describe the entire dose-response continuum, documented explanatory dose-dependent mechanisms, and flexibility to default to a threshold feature when background responses preclude application of biphasic dose responses. CapsuleThe processes of ozone hazard and risk assessment can be enhanced by incorporating hormesis into their principles and practices.