Secondary cancer risk assessment in healthy organs following craniospinal irradiation.

INTRODUCTION: Medulloblastoma is a central nerves tumor that often occurs in pediatrics. The main radiotherapy technique for this tumor type is craniospinal irradiation (CSI), through which the whole brain and spinal cord are exposed to radiation. Due to the immaturity of healthy organs in pediatrics, radiogenic side effects such as second cancer are more severe. Accordingly, the current study aimed to evaluate the risk of secondary cancer development in healthy organs following CSI. MATERIALS AND METHODS: Seven organs at risk (OARs) including skin, eye lens, thyroid, lung, liver, stomach, bladder, colon, and gonads were considered and the dose received by each OAR during CSI was measured inside an anthropomorphic RANDO phantom by TLDs. Then, the mean obtained dose for each organ was used to estimate the probability of secondary malignancy development according to the recommended cancer risk coefficients for specific organs. RESULTS: The results demonstrated that the stomach and colon are at high risk of secondary malignancy occurrence, while the skin has the lowest probability of secondary cancer development. The total received dose after the treatment course by all considered organs was lower than the corresponding tolerable dose levels. CONCLUSIONS: From the results, it can be concluded that some OARs during CSI are highly at risk of secondary cancer development. This issue may be of concern due to organ immaturity in pediatrics which can intensify the radiogenic effects of radiation exposure. Accordingly, strict shielding the OARs during craniospinal radiotherapy and/or sparing them from the radiation field through modern techniques such as hadron therapy is highly recommended.

Exposure to volatile organic compounds in offices and in residential and educational buildings in the European Union between 2010 and 2023: A systematic review and health risk assessment.

Chronic exposure to indoor volatile organic compounds (VOCs) can result in several adverse effects including cancers. We review reports of levels of VOCs in offices and in residential and educational buildings in the member states of the European Union (EU) published between 2010 and 2023. We use these data to assess the risk to population health by estimating lifetime exposure to indoor VOCs and resulting non-cancer and cancer risks and, from that, the burden of cancer attributable to VOC exposure and associated economic losses. Our systematic review identified 1783 articles, of which 184 were examined in detail, with 58 yielding relevant data. After combining data on VOC concentrations separately for EU countries and building types, non-cancer and cancer risks were assessed in terms of hazard quotient and lifetime excess cancer risk (LECR) using probabilistic Monte Carlo Simulations. The LECR was used to estimate disability adjusted life years (DALYs) from VOC-related cancers and associated costs. We find that the LECR associated with formaldehyde exposure was above the acceptable risk level (ARL) in France and Germany and that of from exposure to benzene was also above the ARL in Spanish females. The sum of DALYs and related costs/1,000,000 population/year from exposure to acetaldehyde, benzene, formaldehyde, tetrachloroethylene, and trichloroethylene were 4.02 and €41,010, respectively, in France, those from exposure to acetaldehyde, benzene, carbon tetrachloride, formaldehyde, and trichloroethylene were 3.91 and €39,590 in Germany, and those from exposure to benzene were 0.1 and €1030 in Spain. Taken as a whole, these findings show that indoor exposure to VOCs remains a public health concern in the EU. Although the EU has set limits for certain VOCs, further measures are needed to restrict the use of these chemicals in consumer products.

Risk assessment of Benzene, Toluene, Ethyl benzene, and Xylene (BTEX) in the atmospheric air around the world: A review.

Volatile organic compounds, such as BTEX, have been the subject of numerous debates due to their detrimental effects on the environment and human health. Human beings have had a significant role in the emergence of this situation. Even though US EPA, WHO, and other health-related organizations have set standard limits as unhazardous levels, it has been observed that within or even below these limits, constant exposure to these toxic chemicals results in negative consequences as well. According to these facts, various studies have been carried out all over the world - 160 of which are collected within this review article, so that experts and governors may come up with effective solutions to manage and control these toxic chemicals. The outcome of this study will serve the society to evaluate and handle the risks of being exposed to BTEX. In this review article, the attempt was to collect the most accessible studies relevant to risk assessment of BTEX in the atmosphere, and for the article to contain least bias, it was reviewed and re-evaluated by all authors, who are from different institutions and backgrounds, so that the insights of the article remain unbiased. There may be some limitations to consistency or precision in some points due to the original sources, however the attempt was to minimize them as much as possible.

Predictive modeling and web-based tool for cervical cancer risk assessment: A comparative study of machine learning models.

In today's digital era, the rapid growth of databases presents significant challenges in data management. In order to address this, we have developed and designed CHAMP (Cervical Health Assessment using machine learning for Prediction), which is a user interface tool that can effectively and efficiently handle cervical cancer databases to detect patterns for future prediction diagnosis. CHAMP employs various machine learning algorithms which include XGBoost, SVM, Naive Bayes, AdaBoost, Decision Tree, and K-Nearest Neighbors in order to predict cervical cancer accurately. Moreover, this tool also designates to evaluate and optimize processes, to retrieve the significantly augmented algorithm for predicting cervical cancer. Although, the developed user interface tool was implemented in Python 3.9.0 using Flask, which provides a personalized and intuitive platform for pattern detection. The current study approach contributes to the accurate prediction and early detection of cervical cancer by leveraging the power of machine learning algorithms and comprehensive validation tools, which aim to provide learned decision-making.•CHAMP is a user interface tool which is designed for the detection of patterns for future diagnosis and prognosis of cervical cancer.•Various machine learning algorithms are employed for accurate prediction.•This tool provides personalized and intuitive data analysis which enables informed decision-making in healthcare.

Retrospective chart analysis to determine the impact of a patient-facing digital risk stratification tool combined with a clinical screener for hereditary cancer genetic risk assessment triage in a community oncology clinic.

The purpose of this study was to evaluate the utility of adding a clinical screener to the patient-facing digital risk stratification tool triage process for the identification of patients eligible for a genetic risk assessment for hereditary cancer. Digital risk stratification entries were retrospectively reviewed to determine the overall number of patients eligible for genetic risk assessment. These were also analyzed to determine how many patients were re-contacted by the clinical screener, and how many of those recontacted patients met criteria after their personal and family history was revised by the clinical screener. There was an 89.9% digital risk stratification triage tool completion rate, with 22.6% requiring contact from the clinical screener. Of the 640 patients who completed the digital tool, 5.9% met criteria for testing after their personal and/or family history was revised by the clinical screener. Overall, 51.1% of patients met criteria for a genetic risk assessment. The addition of a clinical screener further increased identification of patients eligible for genetic risk assessment. About half of patients who met criteria after being contacted by the clinical screener met criteria based on their personal diagnosis of cancer alone. Incorporation of a clinical screener to the digital screening process may serve to reduce barriers to patient completion of the tool and increase rates of patient identification for cancer genetic services.

Development of a framework for risk assessment of dietary carcinogens.

Although there are a number of guidance documents and frameworks for evaluation of carcinogenicity, none of the current methods fully reflects the state of the science. Common limitations include the absence of dose-response assessment and not considering the impact of differing exposure patterns (e.g., intermittent, high peaks vs. lower, continuous exposures). To address these issues, we have developed a framework for risk assessment of dietary carcinogens. This framework includes an enhanced approach for weight of evidence (WOE) evaluation for genetic toxicology data, with a focus on evaluating studies based on the most recent testing guidance to determine whether a chemical is a mutagen. Included alongside our framework is a discussion of resources for evaluating tissue dose and the temporal pattern of internal dose, taking into account the chemical's toxicokinetics. The framework then integrates the mode of action (MOA) and associated dose metric category with the exposure data to identify the appropriate approach(es) to low-dose extrapolation and level of concern associated with the exposure scenario. This framework provides risk managers with additional flexibility in risk management and risk communication options, beyond the binary choice of linear low-dose extrapolation vs. application of uncertainty factors.

Muller mistakes: The linear no-threshold (LNT) dose response and US EPA's cancer risk assessment policies and practices.

This paper identifies the occurrence of six major conceptual scientific errors of Hermann Muller and describes how these errors led to the creation of the linear no-threshold (LNT) dose response historically used worldwide for cancer risk assessments for chemical carcinogens and ionizing radiation. The paper demonstrates the significant role that Muller played in the environmental movement, affecting risk assessment policies and practices that are in force even now a half century following his death. This paper lends support to contemporary research that shows significant limitations of the LNT model for cancer risk assessment.

Error-corrected next generation sequencing - Promises and challenges for genotoxicity and cancer risk assessment.

Error-corrected Next Generation Sequencing (ecNGS) is rapidly emerging as a valuable, highly sensitive and accurate method for detecting and characterizing mutations in any cell type, tissue or organism from which DNA can be isolated. Recent mutagenicity and carcinogenicity studies have used ecNGS to quantify drug-/chemical-induced mutations and mutational spectra associated with cancer risk. ecNGS has potential applications in genotoxicity assessment as a new readout for traditional models, for mutagenesis studies in 3D organotypic cultures, and for detecting off-target effects of gene editing tools. Additionally, early data suggest that ecNGS can measure clonal expansion of mutations as a mechanism-agnostic early marker of carcinogenic potential and can evaluate mutational load directly in human biomonitoring studies. In this review, we discuss promising applications, challenges, limitations, and key data initiatives needed to enable regulatory testing and adoption of ecNGS - including for advancing safety assessment, augmenting weight-of-evidence for mutagenicity and carcinogenicity mechanisms, identifying early biomarkers of cancer risk, and managing human health risk from chemical exposures.

Breast Cancer Risk Assessment and Screening Practices Reported Via an Online Survey.

BACKGROUND: Breast cancer screening guidelines differ between organizations, and significant variations in practice patterns exist. Previous evidence suggests that provider-level factors are the greatest contributors to risk assessment and screening practice variability. This study aimed to characterize provider factors associated with breast cancer risk assessment and screening practice patterns, and to assess perceived barriers to providing risk assessment. METHODS: An online survey was distributed to providers at a single academic institution and to providers publicly via social media (January to August 2022). Respondents in the United States who care for adult women at risk for the development of breast cancer were included. RESULTS: Most of the respondents in the 143 completed surveys were white/Caucasian (79%) females (90%) age 50 years or younger (79%), and whereas 97% discuss breast cancer screening with their patients, only 90% order screening mammograms. Risk factor assessment was common (93%), typically performed at the first visit (51%). Additional training in genetics or risk assessment was uncommon (17%), although the majority were interested but did not have the time or resources (55%). Although most (64%) did not perceive barriers to providing risk assessment or appropriate screening, the most common barriers were time (77%) and education (55%). Barriers were more common among family practice or obstetrics and gynecology (OB/GYN) providers and those who worked in an academic setting (all p < 0.05). CONCLUSIONS: Breast cancer risk assessment and screening practices are highly variable. Although time is the major barrier to providing risk assessment, providers also need education. Primary care organizations could partner with breast cancer-focused societies for additional resources.

How self-interest and deception led to the adoption of the linear non-threshold dose response (LNT) model for cancer risk assessment.

This paper clarifies scientific contributions and deceptive/self-serving decisions of William L. Russell and Liane Russell that led to the adoption of the linear non-threshold (LNT) model for cancer risk assessment by the US EPA. By deliberately failing to report an extremely large cluster of mutations in the control group of their first experiment, and thereby greatly suppressing its mutation rate, the Russells incorrectly claimed that the male mouse was 15-fold more susceptible to ionizing-radiation-induced gene mutations as compared with fruit flies. This self-serving error not only propelled their research program into one of great prominence, but it also promoted the LNT-based doubling dose (DD) concept in radiation genetics/cancer risk assessment, by the US National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Genetics Panel (1956). The DD concept became a central element in their recommendation that regulatory agencies switch from a threshold to an LNT model. This error occurred because of a decision by W. Russell not to report that a large cluster of control group mutations found in an experiment for which preliminary results were reported in 1951. This failure to report that cluster and similar clusters continued throughout the careers of the Russells, resulting in massive overestimation of low dose radiation risks supporting the LNT. The Russell database and the repeated claim that those data show that there is no threshold dose rate for mutation in irradiated mouse stem-cell spermatogonia, have provided mechanistic validation supporting the epidemiological LNT hypothesis for radiation-induced leukemias and cancers. This reanalysis supports the threshold model for both males and females, thereby rebutting epidemiological extrapolations from the NAS and EPA claiming support for the LNT hypothesis for cancer risk assessment. The implications of the Russell errors/deceptions, how/why they occurred, and their impact upon society are enormous and need to be addressed by scientific/regulatory agencies, affecting regulatory and litigation activities.

Beyond the cancer slope factor: Broad application of Bayesian and probabilistic approaches for cancer dose-response assessment.

Traditional cancer slope factors derived from linear low-dose extrapolation give little consideration to uncertainties in dose-response model choice, interspecies extrapolation, and human variability. As noted previously by the National Academies, probabilistic methods can address these limitations, but have only been demonstrated in a few case studies. Here, we applied probabilistic approaches for Bayesian Model Averaging (BMA), interspecies extrapolation, and human variability distributions to 255 animal cancer bioassay datasets previously used by governmental agencies. We then derived predictions for both population cancer incidence and individual cancer risk. For model uncertainty, we found that lower confidence limits from BMA and from U.S. Environmental Protection Agency (EPA)'s Benchmark Dose Software (BMDS) correlated highly, with 86% differing by <10-fold. Incorporating other uncertainties and human variability, the lower confidence limits of the probabilistic risk-specific dose (RSD) at 10-6 population incidence were typically 3- to 30-fold lower than traditional slope factors. However, in a small (<7%) number of cases of highly non-linear experimental dose-response, the probabilistic RSDs were >10-fold less stringent. Probabilistic RSDs were also protective of individual risks of 10-4 in >99% of the population. We conclude that implementing Bayesian and probabilistic methods provides a more scientifically rigorous basis for cancer dose-response assessment and thereby improves overall cancer risk characterization.

Highly Sensitive Microsatellite Instability and Immunohistochemistry Assessment in Endometrial Aspirates as a Tool for Cancer Risk Individualization in Lynch Syndrome.

Women with Lynch syndrome (LS) are at increased risk of endometrial cancer (EC), among other tumors, and are characterized by mismatch repair (MMR) deficiency and microsatellite instability (MSI). While risk-reducing gynecologic surgeries effectively decrease EC incidence, doubts arise regarding the appropriate timing of the surgery. We explored the usefulness of highly sensitive MSI (hs-MSI) assessment in endometrial aspirates for individualizing gynecologic surveillance in LS carriers. Ninety-three women with LS, 25 sporadic EC patients (9 MMR-proficient and 16 MMR-deficient), and 30 women with benign gynecologic disease were included in this study. hs-MSI was assessed in prospectively collected endometrial aspirates in 67 LS carriers, EC cases, and controls. MMR, PTEN, ARID1A, and PAX2 protein expression patterns were evaluated in the LS samples. Follow-up aspirates from 8 LS carriers were also analyzed. Elevated hs-MSI scores were detected in all aspirates from MMR-deficient EC cases (3 LS and 16 sporadic) and negative in aspirates from controls and MMR-proficient EC cases. Positive hs-MSI scores were also detected in all 4 LS aspirates reported as complex hyperplasia. High hs-MSI was also present in 10 of 49 aspirates (20%) from LS carriers presenting a morphologically normal endometrium, where MMR protein expression loss was detected in 69% of the samples. Interestingly, the hs-MSI score was positively correlated with MMR-deficient gland density and the presence of MMR-deficient clusters, colocalizing PTEN and ARID1A expression loss. High hs-MSI scores and clonality were evidenced in 2 samples collected up to 4 months before EC diagnosis; hs-MSI scores increased over time in 5 LS carriers, whereas they decreased in a patient with endometrial hyperplasia after progestin therapy. In LS carriers, elevated hs-MSI scores were detected in aspirates from premalignant and malignant lesions and normal endometrium, correlating with MMR protein loss. hs-MSI assessment and MMR immunohistochemistry may help individualize EC risk assessment in women with LS.

Carcinogenic Activity and Risk Assessment of PAHs in Ambient Air: PM10 Particle Fraction and Bulk Deposition.

This paper present seasonal variation in the equivalent concentration (BaPeq) of PAHs in order to assess the potential cancer risk for two different groups of residents via ingestion, dermal contact and inhalation pathways. The possible ecological risk caused by PAH atmospheric deposition based on risk quotient was also estimated. A bulk (total, wet and dry) deposition and PM10 particle fraction (particles with an equivalent aerodynamic diameter < 10 µm) were collected from June 2020 to May 2021 at an urban residential location in the northern part of Zagreb, Croatia. The monthly average of total equivalent BaPeq mass concentrations of PM10 varied from 0.057 ng m-3 in July to 3.656 ng m-3 in December; the annul ∑BaPeq average was 1.348 ng m-3. In bulk deposition, ∑BaPeq mass concentrations varied from 1.94 to 57.60 ng L-1. In both investigated media, BaP had the highest contribution in carcinogenic activity. For PM10 media, dermal absorption implied the greatest potential cancer risk, followed by ingestion and inhalation. For bulk media, a moderate ecological risk for BaA, BbF and BaP was observed according to the risk quotient approach.

Colorectal Cancer Risk Assessment and Precision Approaches to Screening: Brave New World or Worlds Apart?

Current colorectal cancer (CRC) screening recommendations take a "one-size-fits-all" approach using age as the major criterion to initiate screening. Precision screening that incorporates factors beyond age to risk stratify individuals could improve on current approaches and optimally use available resources with benefits for patients, providers, and health care systems. Prediction models could identify high-risk groups who would benefit from more intensive screening, while low-risk groups could be recommended less intensive screening incorporating noninvasive screening modalities. In addition to age, prediction models incorporate well-established risk factors such as genetics (eg, family CRC history, germline, and polygenic risk scores), lifestyle (eg, smoking, alcohol, diet, and physical inactivity), sex, and race and ethnicity among others. Although several risk prediction models have been validated, few have been systematically studied for risk-adapted population CRC screening. In order to envisage clinical implementation of precision screening in the future, it will be critical to develop reliable and accurate prediction models that apply to all individuals in a population; prospectively study risk-adapted CRC screening on the population level; garner acceptance from patients and providers; and assess feasibility, resources, cost, and cost-effectiveness of these new paradigms. This review evaluates the current state of risk prediction modeling and provides a roadmap for future implementation of precision CRC screening.

A reflex testing protocol using two multivariate index assays improves the risk assessment for ovarian cancer in patients with an adnexal mass.

OBJECTIVES: Patients with adnexal masses suspicious for malignancy benefit from referral to oncology specialists during presurgical assessment of the mass. OVA1 is a multivariate assay using a five-biomarker panel which offers high overall and early-stage sensitivity. However, OVA1 has a high false-positive rate for benign masses. Overa, a second-generation multivariate index assay was developed to reduce the false-positive rate. The aim of the present study was to use Overa as a reflex for OVA1 and increase specificity. METHODS: OVA1 cut-off scores were established to place patients into three categories: low, intermediate, and high cancer risk. Samples with intermediate-risk OVA1 scores were reflexed to the Overa and defined as high or low risk. This protocol was tested with 1035 prospectively collected serum samples and validated with an independent prospectively collected sample set (N = 207). RESULTS: Thirty-five per cent (359) of samples had intermediate OVA1 scores. Reflexing these to Overa eliminated 58% of the false-positives and improved the overall specificity from 50% to 72%. This finding was confirmed in the independent dataset, in which the specificity increased from 56% to 73%. CONCLUSIONS: Reflexing samples with intermediate OVA1 scores significantly decreases the false-positive rate, thereby reducing unnecessary surgical referrals.

Cancer risk assessment and source apportionment of the gas- and particulate-phase of the polycyclic aromatic hydrocarbons in a metropolitan region in Brazil.

A risk assessment and a source apportionment of the particulate- and gas-phase PAHs were conducted in a high vehicular traffic and industrialized region in southeastern Brazil. Higher concentrations of PAHs were found during summer, being likely driven by the contributions of PAHs in the vapor phase caused by fire outbreaks during this period. Isomer ratio diagnostic and Principal Component Analysis (PCA) identified four potential sources in the region, in which the Positive Matrix Factorization (PMF) model confirmed and apportioned as gasoline-related (31.8%), diesel-related (25.1%), biomass burning (23.4%), and mixed sources (19.6%). The overall cancer risk had a tolerable value, with ∑CR = 4.6 × 10-5, being ingestion the major via of exposure (64% of the ∑CR), followed by dermal contact (33% of the ∑CR) and inhalation (3%). Mixed sources contributed up to 45% of the overall cancer risk (∑CR), followed by gasoline-related (up to 35%), diesel-related (up to 15%), and biomass burning (up to 10%). The risk assessment for individual PAH species allowed identifying higher CR associated with BaP, DBA, BbF, BaA, and BkF, species associated with gasoline-related and industrial sources. Higher risks were associated with PM2.5-bound PAHs exposure, mainly via ingestion and dermal contact, highlighting the need for measures of mitigation and control of PM2.5 in the region.

Study Protocol for Radiation Exposure and Cancer Risk Assessment: The Taiwan Nuclear Power Plants and Epidemiology Cohort Study (TNPECS).

BACKGROUND: This cohort was established to evaluate whether 38-year radiation exposure (since the start of nuclear reactor operations) is related to cancer risk in residents near three nuclear power plants (NPPs). METHODS: This cohort study enrolled all residents who lived within 8 km of any of the three NPPs in Taiwan from 1978 to 2016 (n = 214,502; person-years = 4,660,189). The control population (n = 257,475; person-years = 6,282,390) from three towns comprised all residents having lived more than 15 km from all three NPPs. Radiation exposure will be assessed via computer programs GASPAR-II and LADTAP-II by following methodologies provided in the United States Nuclear Regulatory Commission regulatory guides. We calculated the cumulative individual tissue organ equivalent dose and cumulative effective dose for each resident. This study presents the number of new cancer cases and prevalence in the residence-nearest NPP group and control group in the 38-year research observation period. CONCLUSION: TNPECS provides a valuable platform for research and opens unique possibilities for testing whether radiation exposure since the start of operations of nuclear reactors will affect health across the life course. The release of radioactive nuclear species caused by the operation of NPPs caused residents to have an effective dose between 10-7 and 10-3 mSv/year. The mean cumulative medical radiation exposure dose between the residence-nearest NPP group and the control group was not different (7.69; standard deviation, 18.39 mSv and 7.61; standard deviation, 19.17 mSv; P = 0.114).

Optimization of Cancer Risk Assessment Models for PM2.5-Bound PAHs: Application in Jingzhong, Shanxi, China.

The accurate evaluation of the carcinogenic risk of PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) is crucial because of the teratogenic, carcinogenic, and mutagenic effects of PAHs. The best model out of six models was selected across three highly used categories in recent years, including the USEPA-recommended inhalation risk (Model I), inhalation carcinogen unit risk (Models IIA-IID), and three exposure pathways (inhalation, dermal, and oral) (Model III). Model I was found to be superior to the other models, and its predicted risk values were in accordance with the thresholds of PM2.5 and benzo[a]pyrene in ambient-air-quality standards. Models IIA and III overestimated the risk of cancer compared to the actual cancer incidence in the local population. Model IID can replace Models IIB and IIC as these models exhibited no statistically significant differences between each other. Furthermore, the exposure parameters were optimized for Model I and significant differences were observed with respect to country and age. However, the gender difference was not statistically significant. In conclusion, Model I is recommended as the more suitable model, but in assessing cancer risk in the future, the exposure parameters must be appropriate for each country.

Assessment of Pb and Ni and potential health risks associated with the consumption of vegetables grown on the roadside soils in District Swat, Khyber Pakhtunkhwa, Pakistan.

Vegetables cultivated near roads absorb toxic metals from polluted soil, which enter the human body through the food chain and cause serious health problems to humans. The present study investigated the concentration of lead (Pb) and nickel (Ni) in soils and vegetables grown along the roadside of District Swat, Pakistan, and the health risks associated with the consumption of the tested vegetables. In results, Pb concentration was higher in plants located at the distance between 0-10 m away from the roadside than the WHO permissible limit. In such plants, Pb concentration was higher than Ni. Rumex dentatus contained the highest concentration of Pb (75.63 mg kg-1 DW) among the tested vegetables while Ni concentration (27.57 mg kg-1 DW) was highest in Trachyspermum ammi as compared to other plants. Concentration and accumulation of both the metals decreased in soil and plants with increasing distance from the road. Similarly, target hazard quotient values noted for Pb (up to 3.37) were greater than unity, which shows that there is a potential risk associated with the consumption of tested vegetables near the road. Moreover, the values of target cancer risk (up to 0.8413) were greater than 0.0001, which shows that there is a risk of cancer with the consumption of tested vegetables. In conclusion, the consumption of tested vegetables was very dangerous as it may lead to higher risks of cancer. Strict regulatory control is recommended on the cultivation of these vegetables along the roadside to avoid any contamination due to roadside exhaust.

Evolution frames the dose response for all endpoints including application to cancer risk assessment: Time for a mid-course correction.

An underappreciated perspective is that the quantitative features of the dose-response in the low dose zone are a genetically based biological characteristic with a highly conserved evolutionary basis. Failure to recognize and take this into account has been a major failing of toxicology and radiation biology, affecting regulatory agencies worldwide. The present perspective clarifies the historical foundations of this misstep and calls for a mid- course correction that replaces the public health based Precautionary Principle for risk assessment with one based on the principles of evolutionary biology.