Linear Non-threshold Research Articles

First report of X-ray induced somatic mutation by Muller's department chair fails to support Muller's linearity hypothesis.

This paper reevaluates the first report of X-ray-induced somatic gene mutations. It was undertaken by John Patterson, Department Chair of Hermann Muller, using the same biological model, methods and equipment of Muller. Patterson reported X-ray induced mutation frequencies for X-chromosome-linked (sex-linked) recessive gene mutations in somatic cells of Drosophila melanogaster that resulted in color changes in the ommatidia of the eyes. Results were based on color changes detected in both male and female offspring irradiated while in egg, larval or pupal stages and for unirradiated controls. Patterson claimed that the observed dose response displayed linearity, with a clear implication that the linear response extended to background exposure levels of unirradiated controls. This reanalysis disputes Patterson's interpretation, showing that the dose response in the low-dose zone strongly supported a threshold model. The doses in the experiment, which were not clearly presented, were so high that it would preclude the assumption that the experiment provided any information of relevance to radiation exposures of humans at low doses, or even at high doses delivered at low-dose rates. Induced phenotypical changes that occurred at the higher doses, especially in female offspring, overwhelmingly resulted from X-ray-induced chromosome breaks instead of point mutations as initially expected by Patterson. The Patterson findings and linearity interpretations were an important contributory factor in the acceptance of the linear non-threshold (LNT) model during the formative time of concept consolidation. It is rather shocking now to see that the actual data provided no support for the LNT model.

The Linear Non-Threshold Hypothesis-A Failed Concept

The linear non-threshold (LNT) hypothesis is based on the premise that the smallest amount of ionizing radiation produces a biological detriment. It implies that exposure to low-dose radiation be minimized. The LNT approach causes fear and anxiety regarding the beneficial use of radiation and radioactive materials. Contrary to its intended goal of protecting workers and the public, the LNT premise causes physical and economic harm by encouraging radiophobia.

ОЦЕНКА РАДИАЦИОННЫХ РИСКОВ ЗАБОЛЕВАЕМОСТИ КАТАРАКТОЙ ЛИКВИДАТОРОВ ПОСЛЕДСТВИЙ АВАРИИ НА ЧЕРНОБЫЛЬСКОЙ АЭС С УЧЕТОМ ВЛИЯНИЯ СОПУТСТВУЮЩИХ БОЛЕЗНЕЙ

Purpose: To assess the radiation risk of cataracts among the Chernobyl clean-up workers (liquidators), considering the impact of concomitant diseases on this risk and to determine the dose threshold for the development of cataracts. Material and methods: Radiation risks of cataract incidence were studied in the cohort of liquidators of the consequences of the accident at the Chernobyl nuclear power plant, observed in the system of the National Radiation and Epidemiological Register (NRER) from 1986 to 2021. Among the 62,828 male liquidators, 9,461 new cases of cataracts were detected. The average age of the liquidators at the beginning of exposure was 34 years, the average absorbed dose of external gamma exposure of the whole body was 0.132 Gy, the maximum dose was 1.5 Gy, and the average duration of exposure was 2.5 months. To analyze the relationships of cataract incidence with other diseases and with the dose, a statistical method of link analysis, free from the type of distribution, as well as logistic regression models, were used. Results: The radiation risk of cataracts in the cohort of liquidators who did not have diagnoses of diabetes mellitus, hypoparathyroidism, malnutrition and myotonic disorders depends on the presence of concomitant diseases in the patient: glaucoma (ICD-10 H40–H42), hyperopia (H52.0), myopia (H52.1) or presbyopia (H52.4). For liquidators with comorbidities, radiation risk is statistically significant only 15 years after exposure, with an excess relative risk of ERR/Gy=0.46 with 90 % CI (0.06; 0.90). For liquidators without comorbidities, ERR/Gy decrease over time: from 4.42 with 90 % CI (0.72; 13.41) in the first 5 years, to zero risk 15 years after exposure. Nonparametric estimates of the relative risk (RR) of cataracts for the dose groups of liquidators are consistent with the estimates of ERR/Gy in the linear non-threshold (LNT) model. The determination of the dose threshold for cataracts according to the LNT model, in accordance with the recommendations of the ICRP, leads to estimates from 1.2 Gy to 13.3 Gy, depending on the presence or absence of cataract concomitant diseases in the liquidators. Conclusions: At present, there are no epidemiological evidence for reducing the equivalent dose limit for the lens of the eye for occupational exposure in planned exposure situations at the level of 150 mSv per year, previously established by the recommendations of the ICRP in 2007 and the current Russian radiation safety standards NRB-99/2009.

Radiation issue in clinical nuclear molecular imaging.

Radiation is ubiquitous in nature, and radiation is also widely used in various fields of medicine, agriculture, and industry. Current biological doses below 100 mSv are called low-dose radiation (LDR). Scientists have no consensus of effects on humans below this dose, so a variety of dose-response curve theories have been derived. This approach makes the public believe that even a small dose of radiation has adverse side effects, and overreact to refuse the related medical procedures for fear of radiation. The linear non-threshold (LNT) model has been used in radiation protection for over 40 years however, adverse effects from low dose, low-dose rate (LDDR) exposures are not detectable. Nuclear molecular imaging is LDR, using different radionuclides or combining with specific ligands (carries) to form "radiopharmaceuticals" for functional or pathological evaluations of diseases. As an integral part of patient care, nuclear medicine is used in the diagnosis, management, treatment, follow-up, and prevention of diseases. Therefore, this paper discusses literature review and provides appropriate scientific data and communication to help the peers and the public understand its advantage and disadvantage.

The Gofman-Tamplin Cancer Risk Controversy and Its Impact on the Creation of BEIR I and the Acceptance of LNT.

The major public dispute between John Gofman and his colleague Arthur Tamplin and the United States (US) Atomic Energy Commission (AEC) at the end of the 1960s and during the early 1970s significantly impacted the course of cancer risk assessment in the US and worldwide. The challenging and provocative testimony of Gofman to the US Senate in early 1970 lead to the formation of the US National Academy of Sciences (NAS) Biological Effects of Ionizing Radiation (BEIR) I Committee in order to evaluate the accuracy of claims by Gofman and Tamplin that emissions from nuclear power plants would significantly increase the occurrence of genetic defects and cancers. BEIR I recommended the adoption of the linear non-threshold (LNT) dose response model for the assessment of cancer risks from radiation exposures. The US EPA adopted this recommendation and generalized it to incorporate chemical carcinogens, thereby affecting cancer risk assessments over the next decades. Despite the scientific limitations and ideological framework of their perspectives, Gofman and Tamplin are of considerable historical importance since they had essential roles in affecting the adoption of LNT by regulatory agencies.

Low-Dose Radiation Risks of Lymphohematopoietic Cancer Mortality in U.S. Shipyard Workers.

The linear, non-threshold (LNT) hypothesis of cancer induction derived from studies of populations exposed to moderate-to-high acute radiation doses may not be indicative of cancer risks associated with lifetime radiation exposures less than 100 mSv. The objective of this study was to examine risks and dose-response patterns of lymphohematopoietic cancer (LHC) and its types associated with low radiation exposure while adjusting for possible confounding factors. A retrospective cohort of 437,937 U.S. nuclear shipyard workers (153,930 radiation and 284,007 non-radiation workers) was followed from 1957 to 2011, with 3,699 LHC deaths observed. The risk of LHC in radiation workers was initially compared to the risk in non-radiation workers. Time dependent accumulated radiation dose, lagged 2 years, was used in categorical and continuous dose analysis among radiation workers to examine the LHC risks and possible dose-response relationships based on Poisson regression models. These analyses controlled for sex, race, time dependent age, calendar time, socioeconomic status, solvent-related last job, and age at first hire. The median lifetime radiation dose for the radiation worker population was 0.82 mSv and the 95th percentile dose was 83.63 mSv. The study shows: 1. LHC mortality for radiation workers was significantly lower than non-radiation workers relative risk: 0.927; 95% confidence intervals (95% CI): 0.865, 0.992; P = 0.030]. Among LHC types, the risks for lymphoid leukemia and lymphomas in radiation workers were lower than the risk in non-radiation workers with statistical significance, while the risk for the rest of LHC types did not show any statistically significant difference. 2. In categorical dose analysis among radiation workers, sample size weighted linear trend of relative risk (RRs) for LHC and its types in five dose categories (>0-<25, 25-<50, 50-<100, 100-<200, and > = 200 mSv) vs. 0 mSv were not statistically significant, although there was an elevation of RR for chronic myeloid leukemia only in the 50-<100 mSv category (RR: 2.746; 95% CI: 1.002, 7.521; P = 0.049) vs. 0 mSv. 3. The Poisson regression analyses among radiation workers using the time dependent radiation dose as a continuous variable showed an excess relative risk (ERR) for LHC at 100 mSv of 0.094 (95% CI: -0.037, 0.225; P = 0.158) and leukemia less chronic lymphoid leukemia, of 0.178 (95% CI: -0.085, 0.440; P = 0.440) vs. 0 mSv. The ERRs and their linear trend for all other types were not statistically significant.

Key historical study findings questioned in debate over threshold versus linear non-threshold for cancer risk assessment

This paper demonstrates that the dissertation research of Ray-Chaudhuri (1939, 1944) that was used by Hermann Muller to support his radiation induced gene mutation hypothesis and linear non-threshold (LNT) dose response model during his Nobel Prize Lecture is “uninterpretable” with respect to these issues. The research failed to include essential research design information, resulting in reporting flaws that have never been previously identified. These observations are historically important because this dissertation was used to blunt powerful criticism of Muller's gene mutation research and strongly promoted his advocacy of the LNT model in radiation risk assessment.

Reflections on effects of low doses and risk inference based on the UNSCEAR 2021 report on ‘biological mechanisms relevant for the inference of cancer risks from low-dose and low-dose-rate radiation’

The 2021 United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) report summarises the knowledge on biological mechanisms of radiation action at low doses where, due to low statistical power of epidemiological investigations, the level of cancer risk must be inferred. It is the fourth UNSCEAR report since 1994 that looks into biological effects following low dose exposure with the aim of examining whether they support the assumption of the linear non-threshold (LNT) dose response for radiation-induced cancers. The conclusions of all four reports are affirmative. The new aspect of the 2021 report is that it focuses on the process of cancer risk inference. The aim of this article is to discuss the consequences of the conclusions regarding LNT and the possibilities of inferring risks from biological studies.

Valid versus invalid radiation cancer risk assessment methods illustrated using Swiss population data

After the nuclear accident in Fukushima, the public interest in radiation related cancer-risk assessment increased. However, interpretations of results from epidemiological studies and comprehension of cancer risk assessment methods can be unclear and involve questions about correctness and validity of the approaches. To shed some light on this potential lack of clarity, valid versus invalid radiation cancer risk assessments methods are illustrated here using Swiss population data. This involves a comparison of the cancer risk assessment method based on collective dose and the cumulative risk assessment method, where the latter is recommended with regard to uncertainties and risk of misinterpretation. Further, risk assessment in different dose ranges is discussed and it is concluded that below 100 mSv it cannot be appropriately stated that an adequate strength of evidence of a causal relationship between cancer and radiation is provided, because of the large uncertainties in this dose range. However, the linear non-threshold (LNT) model can be used to model the dose response, because it represents a prudent and parsimonious model, that fits the data well and lies within the given uncertainties. Additionally, treatments of uncertainties in the risk models are illustrated. The EU-project CONFIDENCE software is applied here to obtain example radiation related lifetime cancer risks for exposures of 20 mSv and 5 mSv. Furthermore, the impact of different dosimetry errors on the uncertainties in the cancer lifetime risk calculation is analysed, by including different standard deviations (SD) and by comparing the sampling of the doses from a normal and a lognormal distribution. Using the normal distribution, for females exposed to 20 mSv, the 95% confidence interval (CI) on the cancer lifetime risk increases, when compared to using a SD of 4 mSv, by a factor of 1.5 using a SD of 8 mSv and by a factor of 1.7 using a SD of 10 mSv. The corresponding factors for males for the same exposure are 1.3 and 1.5 respectively. For exposure to 5 mSv, the 95% CIs on the risk increase by a factor of 1.2 for females and 1.4 for men for a SD of 2 mSv using the normal distribution compared to the lognormal distribution and by a factor of 1.5 and 1.8 for a SD of 3 mSv compared to a SD of 1 mSv respectively. Furthermore, differences in the resulting 95% CI on the risk, using different distributions for the dose sampling are visible.

Оценка радиационных рисков неонкологических заболеваний среди российских участников ликвидации последствий аварии на Чернобыльской АЭС

In the absence of man-made sources of ionizing radiation health risks are related primarily to non-malignant diseases, particularly circulation diseases. However, risks of radiation-induced non-cancer diseases can make a notable contribution to the overall radiation-associated detri-mental effects to the human health. The impacts of harm caused by radiation induced non-cancer and cancer diseases are comparable. That is why the study of risks of non-cancer diseas-es for health of the Chernobyl cleanup workers is actual scientific problem, it is also essential for radiation protection. The aim of the study is to estimate radiation risks of incidence and mortality from non-cancer diseases identified in the Russian cohort of the Chernobyl liquidators during the follow-up period. All considered non-communicable diseases have proven diagnoses identified according to ICD-10 chapters and code sets. The data for the study are available in the system of the National Radiation Epidemiological Registry (NRER). For estimating risks of low radiation doses the linear non-threshold (LNT) model was used. For 9 of 19 disease diagnosis codes in-vestigated for statistical significance of associations between excess incidence of a disease and radiation dose received by liquidators can be considered as significant code sets. These are the following diseases: 1) Diseases of the blood and blood-forming organs and certain disorders in-volving the immune mechanism (D50-D89); 2) Diseases of the endocrine system, nutritional dis-orders and disorders of metabolism (E00-E90); 3) Mental and behavioural disorders (F00-F99); 4) Diseases of the nervous system (G00-G99); 5) Diseases of the circulatory system (I00-I99); 6) Diseases of the respiratory system (J00-J99); 7) Diseases of the digestive system (K00-K93); 8) Diseases of the musculoskeletal system and connective tissue (M00-M99); 9) Diseases of the genitourinary system (N00-N99). Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism (D50-D89); diseases of the circulatory system (I00-I99); blood diseases (D50-D89) are characterized by the highest radiation risk coefficients (ERR/Gy). The estimates are ERR/Gy=0.55 and ERR/Gy=0.57, respectively. To date, epidemiolog-ical studies provide sufficient evidence for the existence of statistically significant radiation risks of the circulatory system diseases (I00-I99). For estimating contribution of non-cancer diseases to the overall radiation detriment further research is required.

WAM to SeeSaw model for cancer therapy – overcoming LQM difficulties –

Purpose The assessment of biological effects caused by radiation exposure has been currently carried out with the linear-quadratic (LQ) model as an extension of the linear non-threshold (LNT) model. In this study, we suggest a new mathematical model named as SeaSaw (SS) model, which describes proliferation and cell death effects by taking account of Bergonie-Tribondeau’s law in terms of a differential equation in time. We show how this model overcomes the long-standing difficulties of the LQ model. Materials and methods We construct the SS model as an extended Wack-A-Mole (WAM) model by using a differential equation with respect to time in order to express the dynamics of the proliferation effect. A large number of accumulated data of such parameters as α and β in the LQ based models provide us with valuable pieces of information on the corresponding parameter and the maximum volume of the SS model. The dose rate and the notion of active cell can explain the present data without introduction of β, which is obtained by comparing the SS model with not only the cancer therapy data but also with in vitro experimental data. Numerical calculations are presented to grasp the global features of the SS model. Results The SS model predicts the time dependence of the number of active- and inactive-cells. The SS model clarifies how the effect of radiation depends on the cancer stage at the starting time in the treatment. Further, the time dependence of the tumor volume is calculated by changing individual dose strength, which results in the change of the irradiation duration for the same effect. We can consider continuous irradiation in the SS model with interesting outcome on the time dependence of the tumor volume for various dose rates. Especially by choosing the value of the dose rate to be balanced with the total growth rate, the tumor volume is kept constant. Conclusions The SS model gives a simple equation to study the situation of clinical radiation therapy and risk estimation of radiation. The radiation parameter extracted from the cancer therapy is close to the value obtained from animal experiment in vitro and in vivo. We expect the SS model leads us to a unified description of radiation therapy and protection and provides a great development in cancer-therapy clinical-planning.

Bayesian approaches for radiation dose-response estimation

Many people are exposed to radiation from frequently receiving X-rays or CT scans at the hospital. Exposure at low dose does not give an immediate response to the body. However, it is well known that the risk of cancer incidence rate is increasing over time. Therefore, in order to accurately quantify the risk of radiation exposure, many studies have been actively conducted. However, the Bayesian approach has not been rarely applied as a way to quantify radiation exposure risk. In this paper, the Bayesian approaches were introduced for several dose-response models to estimate the risk of radiation exposure, and the proposed model was applied to Life Span Study (LSS) solid cancer incidence data obtained from atomic bomb survivors (1958-2009). It was confirmed that the dose-response model of Linear nonthreshold (LNT), Quadratic, Linear-Quadratic, and Threshold showed similar results to those without the Bayesian analysis method. In the case of the piecewise linear dose-response model, the changes in slope associated with radiation exposure were found to vary with the dose ranges.

Epidemiological Support of the Linear Nonthreshold Model in Radiological Protection: Implications of the National Council on Radiation Protection and Measurements Commentary 27 for the Radiologist.

Epidemiological Support of the Linear Nonthreshold Model in Radiological Protection: Implications of the National Council on Radiation Protection and Measurements Commentary 27 for the Radiologist.

The significance of the failed historical foundation of linear non-threshold model for cancer risk assessment

The linear non-threshold (LNT) single-hit (SH) dose response model for cancer risk assessment is assessed with respect to its historical foundations. This paper examines and summarises how mistakes, ideological biases, and scientific misconduct by key scientists affected the acceptance, validity, and application of the LNT single-hit model for cancer risk assessment. This analysis concludes that the LNT single-hit model was inappropriately adopted for governmental risk assessment, regulatory policy and practices, and for risk communication.

The significance of the failed historical foundation of linear non-threshold model for cancer risk assessment

The linear non-threshold (LNT) single-hit (SH) dose response model for cancer risk assessment is assessed with respect to its historical foundations. This paper examines and summarises how mistakes, ideological biases, and scientific misconduct by key scientists affected the acceptance, validity, and application of the LNT single-hit model for cancer risk assessment. This analysis concludes that the LNT single-hit model was inappropriately adopted for governmental risk assessment, regulatory policy and practices, and for risk communication.

Stress response and population dynamics: Is Allee effect hormesis?

Hormesis is a fundamental notion in ecotoxicology while competition between organisms is an essential notion in population ecology and species adaptation and evolution. Both sub-disciplines of ecology deal with the response of organisms to abiotic and biotic stresses. In ecotoxicology, the Linear-non-Threshold (LNT), Threshold and Hormetic models are used to describe the dominant responses of a plethora of endpoints to abiotic stress. In population ecology, the logistic, theta-logistic and the Allee effect models are used to describe the growth of populations under different responses to (biotic) stress induced by population density. The per capita rate of population increase (r) measures species fitness. When it is used as endpoint, the responses to population density seem to perfectly correspond to LNT, Threshold and Hormetic responses to abiotic stress, respectively. Our analysis suggests the Allee effect is a hormetic-like response of r to population density, an ultimate biotic stress. This biphasic dose-response model appears across different systems and situations (from molecules to tumor growth to population dynamics), is highly supported by ecological and evolutionary theory, and has important implications in most sub-disciplines of biology as well as in environmental and earth sciences. Joined multi-disciplinary efforts would facilitate the development and application of advanced research approaches for better understanding potential planetary-scale implications.

EPA transparency proposal: testimony of Edward J. Calabrese, Ph.D, October 3, 2018.

The historical foundations of cancer risk assessment and its adoption by the US EPA in the mid 1970s were based on the discovery of X-ray-induced gene mutations by Hermann J. Muller, its transformation into the linear nonthreshold (LNT) single-hit theory and the recommendations of the model by the US National Academy of Sciences, Biological Effects of Atomic/Ionizing Radiation, Genetics Panels in 1956 and 1972. This testimony summarizes substantial recent revelations which profoundly challenge the use of LNT as a default in cancer risk assessment, showing multiple significant scientific errors and incorrect interpretations, mixed with deliberate misrepresentation of the scientific record by leading ideologically motivated radiation geneticists. These novel historical and scientific findings demonstrate that the scientific foundations of the LNT single-hit model were seriously flawed and should not have been adopted for cancer risk assessment. The testimony supports the recommendation by the EPA to move away from the use of the LNT as a default in cancer risk assessment and to the formal consideration of alternative dose response models such as the threshold, hormetic and other non-linear modeling approaches.

Requirements for Transparency and Communicability of Regulatory Science.

This article presents the results of a study attempting to provide examples that implement transparency and communicability elements of Ethical Rules Principle of Best Available Regulatory Science (BARS) and Metrics for Evaluation of Regulatory Science Claims (MERSC). It starts with an overview of regulatory science and briefly summarizes principles of BARS and key pillars of MERSC. Subsequently, the BARS/MERSC system is used to evaluate the linear nonthreshold (LNT) process used in cancer assessments and the similar process used for evaluating in particulate matter (PM) exposure. The study identifies 3 parts in dose–response curves, where the first part is reproducible science and the second part includes uncertainties and often requires the application of precautionary principle. The primary reason for disagreements on LNT and PM is a lack of recognition that the third part is based on desire of regulators to be protective, a policy decision process. Two PM epidemiological examples are included in this study to demonstrate the point. The regulatory process would benefit from recognizing the distinction between science and policy and excluding policy from regulatory science. Furthermore, the society would greatly benefit from increased transparency in the regulatory process and compliance with the Jeffersonian communication principle

Implications of recent epidemiologic studies for the linear nonthreshold model and radiation protection

The recently published NCRP Commentary No. 27 evaluated the new information from epidemiologic studies as to their degree of support for applying the linear nonthreshold (LNT) model of carcinogenic effects for radiation protection purposes (NCRP 2018 Implications of Recent Epidemiologic Studies for the Linear Nonthreshold Model and Radiation Protection, Commentary No. 27 (Bethesda, MD: National Council on Radiation Protection and Measurements)). The aim was to determine whether recent epidemiologic studies of low-LET radiation, particularly those at low doses and/or low dose rates (LD/LDR), broadly support the LNT model of carcinogenic risk or, on the contrary, demonstrate sufficient evidence that the LNT model is inappropriate for the purposes of radiation protection. An updated review was needed because a considerable number of reports of radiation epidemiologic studies based on new or updated data have been published since other major reviews were conducted by national and international scientific committees. The Commentary provides a critical review of the LD/LDR studies that are most directly applicable to current occupational, environmental and medical radiation exposure circumstances. This Memorandum summarises several of the more important LD/LDR studies that incorporate radiation dose responses for solid cancer and leukemia that were reviewed in Commentary No. 27. In addition, an overview is provided of radiation studies of breast and thyroid cancers, and cancer after childhood exposures. Non-cancers are briefly touched upon such as ischemic heart disease, cataracts, and heritable genetic effects. To assess the applicability and utility of the LNT model for radiation protection, the Commentary evaluated 29 epidemiologic studies or groups of studies, primarily of total solid cancer, in terms of strengths and weaknesses in their epidemiologic methods, dosimetry approaches, and statistical modelling, and the degree to which they supported a LNT model for continued use in radiation protection. Recommendations for how to make epidemiologic radiation studies more informative are outlined. The NCRP Committee recognises that the risks from LD/LDR exposures are small and uncertain. The Committee judged that the available epidemiologic data were broadly supportive of the LNT model and that at this time no alternative dose-response relationship appears more pragmatic or prudent for radiation protection purposes.

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.