Experimental comparison of cylindrical and plane parallel ionization chambers for reference dosimetry in continuous and pulsed scanned proton beams.

Objective. In this experimental work we compared the determination of absorbed dose to water using four ionization chambers (ICs), a PTW-34045 Advanced Markus, a PTW-34001 Roos, an IBA-PPC05 and a PTW-30012 Farmer, irradiated under the same conditions in one continuous- and in two pulsed-scanned proton beams.Approach. The ICs were positioned at 2 cm depth in a water phantom in four square-field single-energy scanned-proton beams with nominal energies between 80 and 220 MeV and in the middle of 10 × 10 × 10 cm3dose cubes centered at 10 cm or 12.5 cm depth in water. The water-equivalent thickness (WET) of the entrance window and the effective point of measurement was considered when positioning the plane parallel (PP) ICs and the cylindrical ICs, respectively. To reduce uncertainties, all ICs were calibrated at the same primary standards laboratory. We used the beam quality (kQ) correction factors for the ICs under investigation from IAEA TRS-398, the newly calculated Monte Carlo (MC) values and the anticipated IAEA TRS-398 updated recommendations.Main results. Dose differences among the four ICs ranged between 1.5% and 3.7% using both the TRS-398 and the newly recommendedkQvalues. The spread among the chambers is reduced with the newlykQvalues. The largest differences were observed between the rest of the ICs and the IBA-PPC05 IC, obtaining lower dose with the IBA-PPC05.Significance. We provide experimental data comparing different types of chambers in different proton beam qualities. The observed dose differences between the ICs appear to be related to inconsistencies in the determination of thekQvalues. For PP ICs, MC studies account for the physical thickness of the entrance window rather than the WET. The additional energy loss that the wall material invokes is not negligible for the IBA-PPC05 and might partially explain the lowkQvalues determined for this IC. To resolve this inconsistency and to benchmark MC values,kQvalues measured using calorimetry are needed.

A Comparison of In Vitro Points of Departure with Human Blood Levels for Per- and Polyfluoroalkyl Substances (PFAS).

Per- and polyfluoroalkyl substances (PFAS) are widely used, and their fluorinated state contributes to unique uses and stability but also long half-lives in the environment and humans. PFAS have been shown to be toxic, leading to immunosuppression, cancer, and other adverse health outcomes. Only a small fraction of the PFAS in commerce have been evaluated for toxicity using in vivo tests, which leads to a need to prioritize which compounds to examine further. Here, we demonstrate a prioritization approach that combines human biomonitoring data (blood concentrations) with bioactivity data (concentrations at which bioactivity is observed in vitro) for 31 PFAS. The in vitro data are taken from a battery of cell-based assays, mostly run on human cells. The result is a Bioactive Concentration to Blood Concentration Ratio (BCBCR), similar to a margin of exposure (MoE). Chemicals with low BCBCR values could then be prioritized for further risk assessment. Using this method, two of the PFAS, PFOA (Perfluorooctanoic Acid) and PFOS (Perfluorooctane Sulfonic Acid), have BCBCR values < 1 for some populations. An additional 9 PFAS have BCBCR values < 100 for some populations. This study shows a promising approach to screening level risk assessments of compounds such as PFAS that are long-lived in humans and other species.

60 Years of the 3Rs symposium: Lessons learned and the road ahead.

When The Principles of Humane Experimental Technique was published in 1959, authors William Russell and Rex Burch had a modest goal: to make researchers think about what they were doing in the laboratory - and to do it more humanely. Sixty years later, their groundbreaking book was celebrated for inspiring a revolution in science and launching a new field: The 3Rs of alternatives to animal experimentation. On November 22, 2019, some pioneering and leading scientists and researchers in the field gathered at the Johns Hopkins Bloomberg School of Public Health in Bal-timore for the 60 Years of the 3Rs Symposium: Lessons Learned and the Road Ahead. The event was sponsored by the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the Foundation for Chemistry Research and Initiatives, the Alternative Research & Development Foundation (ARDF), the American Cleaning Institute (ACI), the International Fragrance Association (IFRA), the Institute for In Vitro Sciences (IIVS), John "Jack" R. Fowle III, and the Society of Toxicology (SoT). Fourteen pres-entations shared the history behind the groundbreaking publication, international efforts to achieve its aims, stumbling blocks to progress, as well as remarkable achievements. The day was a tribute to Russell and Burch, and a testament to what is possible when people from many walks of life - science, government, and industry - work toward a common goal.

William Russell and Rex Burch published their book The Principles of Humane Experimental Technique in 1959. The book encouraged researchers to replace animal experiments where it was possible, to refine experiments with animals in order to reduce their suffering, and to reduce the number of animals that had to be used for experiments to the minimum. Sixty years later, a group of pioneering and leading scientists and researchers in the field gathered to share how the publi­cation came about and how the vision inspired international collaborations and successes on many different levels including new laws. The paper includes an overview of important milestones in the history of alternatives to animal experimentation.

Dermal absorption of high molecular weight parent and alkylated polycyclic aromatic hydrocarbons from manufactured gas plant soils using in vitro assessment.

An enhanced in vitro human dermal bioavailability method was developed to measure the release of twenty parent and seven alkylated high molecular weight (HMW) polycyclic aromatic hydrocarbons (PAHs) from contaminated soils collected from five former manufactured Gas Plants (MGP) in England. GC-MS/MS was used to quantify HMW PAHs in soil, Strat-M artificial membrane representing skin, and synthetic receptor solution (RS) representing systemic circulation at 1-h, 10-h, and 24-h timesteps. Fluoranthene and pyrene exhibited the highest fluxes from soils to membrane (ranging from 9.5 - 281 ng/cm2/h) and soil to RS (

Adverse effects in traditional and alternative toxicity tests.

Chemical safety assessment begins with defining the lowest level of chemical that alters one or more measured endpoints. This critical effect level, along with factors to account for uncertainty, is used to derive limits for human exposure. In the absence of data regarding the specific mechanisms or biological pathways affected, non-specific endpoints such as body weight and non-target organ weight changes are used to set critical effect levels. Specific apical endpoints such as impaired reproductive function or altered neurodevelopment have also been used to set chemical safety limits; however, in test guidelines designed for specific apical effect(s), concurrently measured non-specific endpoints may be equally or more sensitive than specific endpoints. This means that rather than predicting a specific toxicological response, animal data are often used to develop protective critical effect levels, without assuming the same change would be observed in humans. This manuscript is intended to encourage a rethinking of how adverse chemical effects are interpreted: non-specific endpoints from in vivo toxicological studies data are often used to derive points of departure for use with safety assessment factors to create recommended exposure levels that are broadly protective but not necessarily target-specific.

Technical evaluation and standardization of the human thyroid microtissue assay.

The success and sustainability of U.S. EPA efforts to reduce, refine, and replace in vivo animal testing depends on the ability to translate toxicokinetic and toxicodynamic data from in vitro and in silico new approach methods (NAMs) to human-relevant exposures and health outcomes. Organotypic culture models employing primary human cells enable consideration of human health effects and inter-individual variability but present significant challenges for test method standardization, transferability, and validation. Increasing confidence in the information provided by these in vitro NAMs requires setting appropriate performance standards and benchmarks, defined by the context of use, to consider human biology and mechanistic relevance without animal data. The human thyroid microtissue (hTMT) assay utilizes primary human thyrocytes to reproduce structural and functional features of the thyroid gland that enable testing for potential thyroid-disrupting chemicals. As a variable-donor assay platform, conventional principles for assay performance standardization need to be balanced with the ability to predict a range of human responses. The objectives of this study were to (1) define the technical parameters for optimal donor procurement, primary thyrocyte qualification, and performance in the hTMT assay, and (2) set benchmark ranges for reference chemical responses. Thyrocytes derived from a cohort of 32 demographically diverse euthyroid donors were characterized across a battery of endpoints to evaluate morphological and functional variability. Reference chemical responses were profiled to evaluate the range and chemical-specific variability of donor-dependent effects within the cohort. The data-informed minimum acceptance criteria for donor qualification and set benchmark parameters for method transfer proficiency testing and validation of assay performance.

High-Throughput Transcriptomics of Water Extracts Detects Reductions in Biological Activity with Water Treatment Processes.

The presence of numerous chemical contaminants from industrial, agricultural, and pharmaceutical sources in water supplies poses a potential risk to human and ecological health. Current chemical analyses suffer from limitations, including chemical coverage and high cost, and broad-coverage in vitro assays such as transcriptomics may further improve water quality monitoring by assessing a large range of possible effects. Here, we used high-throughput transcriptomics to assess the activity induced by field-derived water extracts in MCF7 breast carcinoma cells. Wastewater and surface water extracts induced the largest changes in expression among cell proliferation-related genes and neurological, estrogenic, and antibiotic pathways, whereas drinking and reclaimed water extracts that underwent advanced treatment showed substantially reduced bioactivity on both gene and pathway levels. Importantly, reclaimed water extracts induced fewer changes in gene expression than laboratory blanks, which reinforces previous conclusions based on targeted assays and improves confidence in bioassay-based monitoring of water quality.

High-Throughput Screening to Advance In Vitro Toxicology: Accomplishments, Challenges, and Future Directions.

Traditionally, chemical toxicity is determined by in vivo animal studies, which are low throughput, expensive, and sometimes fail to predict compound toxicity in humans. Due to the increasing number of chemicals in use and the high rate of drug candidate failure due to toxicity, it is imperative to develop in vitro, high-throughput screening methods to determine toxicity. The Tox21 program, a unique research consortium of federal public health agencies, was established to address and identify toxicity concerns in a high-throughput, concentration-responsive manner using a battery of in vitro assays. In this article, we review the advancements in high-throughput robotic screening methodology and informatics processes to enable the generation of toxicological data, and their impact on the field; further, we discuss the future of assessing environmental toxicity utilizing efficient and scalable methods that better represent the corresponding biological and toxicodynamic processes in humans.

Monte Carlo modelling of a prototype small-body portable graphite calorimeter for ultra-high dose rate proton beams.

Background and purpose: Accurate dosimetry in Ultra-High Dose Rate (UHDR) beams is challenging because high levels of ion recombination occur within ionisation chambers used as reference dosimeters. A Small-body Portable Graphite Calorimeter (SPGC) exhibiting a dose-rate independent response was built to offer reduced uncertainty on secondary standard dosimetry in UHDR regimes. The aim of this study was to quantify the effect of the geometry and material properties of the device on the dose measurement. Materials and methods: A detailed model of the SPGC was built in the Monte Carlo code TOPAS (v3.6.1) to derive the impurity and gap correction factors, kimp and kgap. A dose conversion factor, DwMC/DgMC, was also calculated using FLUKA (v2021.2.0). These factors convert the average dose to its graphite core to the dose-to-water for a 249.7 MeV mono-energetic spot-scanned clinical proton beam. The effect of the surrounding Styrofoam on the dose measurement was examined in the simulations by substituting it for graphite. Results: The kimp and kgap correction factors were 0.9993 ± 0.0002 and 1.0000 ± 0.0001, respectively when the Styrofoam was not substituted, and 1.0037 ± 0.0002 and 0.9999 ± 0.0001, respectively when substituted for graphite. The dose conversion factor was calculated to be 1.0806 ± 0.0001. All uncertainties are Type A. Conclusions: Impurity and gap correction factors, and the dose conversion factor were calculated for the SPGC in a FLASH proton beam. Separating out the effect of scatter from Styrofoam insulation showed this as the dominating correction factor, amounting to 1.0043 ± 0.0002.

Reproducibility of organ-level effects in repeat dose animal studies.

This work estimates benchmarks for new approach method (NAM) performance in predicting organ-level effects in repeat dose studies of adult animals based on variability in replicate animal studies. Treatment-related effect values from the Toxicity Reference database (v2.1) for weight, gross, or histopathological changes in the adrenal gland, liver, kidney, spleen, stomach, and thyroid were used. Rates of chemical concordance among organ-level findings in replicate studies, defined by repeated chemical only, chemical and species, or chemical and study type, were calculated. Concordance was 39 - 88%, depending on organ, and was highest within species. Variance in treatment-related effect values, including lowest effect level (LEL) values and benchmark dose (BMD) values when available, was calculated by organ. Multilinear regression modeling, using study descriptors of organ-level effect values as covariates, was used to estimate total variance, mean square error (MSE), and root residual mean square error (RMSE). MSE values, interpreted as estimates of unexplained variance, suggest study descriptors accounted for 52-69% of total variance in organ-level LELs. RMSE ranged from 0.41 - 0.68 log10-mg/kg/day. Differences between organ-level effects from chronic (CHR) and subchronic (SUB) dosing regimens were also quantified. Odds ratios indicated CHR organ effects were unlikely if the SUB study was negative. Mean differences of CHR - SUB organ-level LELs ranged from -0.38 to -0.19 log10 mg/kg/day; the magnitudes of these mean differences were less than RMSE for replicate studies. Finally, in vitro to in vivo extrapolation (IVIVE) was employed to compare bioactive concentrations from in vitro NAMs for kidney and liver to LELs. The observed mean difference between LELs and mean IVIVE dose predictions approached 0.5 log10-mg/kg/day, but differences by chemical ranged widely. Overall, variability in repeat dose organ-level effects suggests expectations for quantitative accuracy of NAM prediction of LELs should be at least ± 1 log10-mg/kg/day, with qualitative accuracy not exceeding 70%.

Characterisation of former manufactured gas plant soils using parent and alkylated polycyclic aromatic hydrocarbons and Rock-Eval(6) pyrolysis.

Soils sampled from 10 former manufactured gas plants (MGP) in the UK were investigated using gas chromatography mass spectrometry (GC-MS/MS) and Rock-Eval (6) Pyrolysis (RE). RE is a screening tool used to characterise bulk organic matter in soils via the release of carbon compounds during pyrolysis and oxidation. Both the distributions and concentrations of 30 parent and 21 alkylated polycyclic aromatic hydrocarbons (PAHs) and the parameters of RE were analysed to establish relationships between soils and the MGP processes history. Principal component analysis (PCA) using the PAHs distributions and RE parameters can assist with differentiating between MGP processes. MGP processes utilizing oil provided the clearest results, attributed to petrogenic signatures with high proportions of low molecular weight PAHs. Processes using lower temperature processes were distinguished by higher proportions of high molecular weight PAHs. RE parameters alone were unable to distinguish MGP processes but showed potential in estimating the lability and thus the amount of PAH that could be released from soils. This research provides new insights that may be useful in understanding and characterising the risks posed to human health from PAHs in soils.

From data to decisions: Empowering brownfield redevelopment with a novel decision support system.

This research evaluates a novel decision support system (DSS) for planning brownfield redevelopment. The DSS is implemented within a web-based geographical information system that contains the spatial data informing three modules comprising land use suitability, economic viability, and ground risk. Using multi-criteria decision analysis, an evaluation was conducted on 31,942 ha of post-industrial land and around Liverpool, UK. The representativeness and credibility of the DSS outputs were evaluated through user trials with fifteen land-use planning and development stakeholders from the Liverpool City Region Comined Authority. The DSS was used to explore land use planning scenarios and it could be used to support decision making. Our research reveals that the DSS has the potential to positively inform the identification of brownfield redevelopment opportunities by offering a reliable, carefully curated, and user-driven digital evidence base. This expedites the traditionally manual process of conducting assessments of land suitability and viability. This research has important implications for assessing the impact of current and future planning policy and the potential for the use of digital tools for land use planning and sustainability in the UK and globally.

Evaluation of a high-throughput H295R homogenous time resolved fluorescence assay for androgen and estrogen steroidogenesis screening.

The H295R test guideline assay evaluates the effect of test substances on synthesis of 17ß-estradiol (E2) and testosterone (T). The objective of this study was to leverage commercial immunoassay technology to develop a more efficient H295R assay to measure E2 and T levels in 384-well format. The resulting Homogenous Time Resolved Fluorescence assay platform (H295R-HTRF) was evaluated against a training set of 36 chemicals derived from the OECD inter-laboratory validation study, EPA guideline 890.1200 aromatase assay, and azole fungicides active in the HT-H295R assay. Quality control performance criteria were met for all conditions except E2 synthesis inhibition where low basal hormone synthesis was observed. Five proficiency chemicals were active for both the E2 and T endpoints, consistent with guideline classifications. Of the nine OECD core reference chemicals, 9/9 were concordant with outcomes for E2 and 7/9 for T. Likewise, 9/13 and 11/13 OECD supplemental chemicals were concordant with anticipated effects for E2 and T, respectively. Of the 10 azole fungicides screened, 7/10 for E2 and 8/10 for T exhibited concordant outcomes for inhibition. Generally, all active chemicals in the training set demonstrated equivalent or greater potency in the H295R-HTRF assay, supporting the sensitivity of the platform. The adaptation of HTRF technology to the H295R model provides an efficient way to evaluate E2 and T modulators in accordance with guideline specifications.

Evidence of leaky protection following COVID-19 vaccination and SARS-CoV-2 infection in an incarcerated population.

Whether SARS-CoV-2 infection and COVID-19 vaccines confer exposure-dependent ("leaky") protection against infection remains unknown. We examined the effect of prior infection, vaccination, and hybrid immunity on infection risk among residents of Connecticut correctional facilities during periods of predominant Omicron and Delta transmission. Residents with cell, cellblock, and no documented exposure to SARS-CoV-2 infected residents were matched by facility and date. During the Omicron period, prior infection, vaccination, and hybrid immunity reduced the infection risk of residents without a documented exposure (HR: 0.36 [0.25-0.54]; 0.57 [0.42-0.78]; 0.24 [0.15-0.39]; respectively) and with cellblock exposures (0.61 [0.49-0.75]; 0.69 [0.58-0.83]; 0.41 [0.31-0.55]; respectively) but not with cell exposures (0.89 [0.58-1.35]; 0.96 [0.64-1.46]; 0.80 [0.46-1.39]; respectively). Associations were similar during the Delta period and when analyses were restricted to tested residents. Although associations may not have been thoroughly adjusted due to dataset limitations, the findings suggest that prior infection and vaccination may be leaky, highlighting the potential benefits of pairing vaccination with non-pharmaceutical interventions in crowded settings.

Incidence of surgical rib fixation at chest wall injury society collaborative centers and a guide for expected number of cases (CWIS-CC1).

PURPOSE: Surgical stabilization of rib fractures (SSRF) improves outcomes in certain patient populations. The Chest Wall Injury Society (CWIS) began a new initiative to recognize centers who epitomize their mission as CWIS Collaborative Centers (CWIS-CC). We sought to describe incidence and epidemiology of SSRF at our institutions. METHODS: A retrospective registry evaluation of all patients (age > 15 years) treated at international trauma centers from 1/1/20 to 7/30/2021 was performed. Variables included: age, gender, mechanism of injury, injury severity score, abbreviated injury severity score (AIS), emergency department disposition, length of stay, presence of rib/sternal fractures, and surgical stabilization of rib/sternal fractures. Classification and regression tree analysis (CART) was used for analysis. RESULTS: Data were collected from 9 centers, 26,084 patient encounters. Rib fractures were present in 24% (n = 6294). Overall, 2% of all patients underwent SSRF and 8% of patients with rib fractures underwent SSRF. CART analysis of SSRF by AIS-Chest demonstrated a difference in management by age group. AIS-Chest 3 had an SSRF rate of 3.7, 7.3, and 12.9% based on the age ranges (16-19; 80-110), (20-49; 70-79), and (50-69), respectively (p = 0.003). AIS-Chest > 3 demonstrated an SSRF rate of 9.6, 23.3, and 39.3% for age ranges (16-39; 90-99), (40-49; 80-89), and (50-79), respectively (p = 0.001). CONCLUSION: Anticipated rate of SSRF can be calculated based on number of rib fractures, AIS-Chest, and age. The disproportionate rate of SSRF in patients age 50-69 with AIS-Chest 3 and age 50-79 with AIS-Chest > 3 should be further investigated, as lower frequency of SSRF in the other age ranges may lead to care inequalities.

Cutting-edge computational chemical exposure research at the U.S. Environmental Protection Agency.

Exposure science is evolving from its traditional "after the fact" and "one chemical at a time" approach to forecasting chemical exposures rapidly enough to keep pace with the constantly expanding landscape of chemicals and exposures. In this article, we provide an overview of the approaches, accomplishments, and plans for advancing computational exposure science within the U.S. Environmental Protection Agency's Office of Research and Development (EPA/ORD). First, to characterize the universe of chemicals in commerce and the environment, a carefully curated, web-accessible chemical resource has been created. This DSSTox database unambiguously identifies >1.2 million unique substances reflecting potential environmental and human exposures and includes computationally accessible links to each compound's corresponding data resources. Next, EPA is developing, applying, and evaluating predictive exposure models. These models increasingly rely on data, computational tools like quantitative structure activity relationship (QSAR) models, and machine learning/artificial intelligence to provide timely and efficient prediction of chemical exposure (and associated uncertainty) for thousands of chemicals at a time. Integral to this modeling effort, EPA is developing data resources across the exposure continuum that includes application of high-resolution mass spectrometry (HRMS) non-targeted analysis (NTA) methods providing measurement capability at scale with the number of chemicals in commerce. These research efforts are integrated and well-tailored to support population exposure assessment to prioritize chemicals for exposure as a critical input to risk management. In addition, the exposure forecasts will allow a wide variety of stakeholders to explore sustainable initiatives like green chemistry to achieve economic, social, and environmental prosperity and protection of future generations.

New approach methodologies in human regulatory toxicology - Not if, but how and when!

The predominantly animal-centric approach of chemical safety assessment has increasingly come under pressure. Society is questioning overall performance, sustainability, continued relevance for human health risk assessment and ethics of this system, demanding a change of paradigm. At the same time, the scientific toolbox used for risk assessment is continuously enriched by the development of "New Approach Methodologies" (NAMs). While this term does not define the age or the state of readiness of the innovation, it covers a wide range of methods, including quantitative structure-activity relationship (QSAR) predictions, high-throughput screening (HTS) bioassays, omics applications, cell cultures, organoids, microphysiological systems (MPS), machine learning models and artificial intelligence (AI). In addition to promising faster and more efficient toxicity testing, NAMs have the potential to fundamentally transform today's regulatory work by allowing more human-relevant decision-making in terms of both hazard and exposure assessment. Yet, several obstacles hamper a broader application of NAMs in current regulatory risk assessment. Constraints in addressing repeated-dose toxicity, with particular reference to the chronic toxicity, and hesitance from relevant stakeholders, are major challenges for the implementation of NAMs in a broader context. Moreover, issues regarding predictivity, reproducibility and quantification need to be addressed and regulatory and legislative frameworks need to be adapted to NAMs. The conceptual perspective presented here has its focus on hazard assessment and is grounded on the main findings and conclusions from a symposium and workshop held in Berlin in November 2021. It intends to provide further insights into how NAMs can be gradually integrated into chemical risk assessment aimed at protection of human health, until eventually the current paradigm is replaced by an animal-free "Next Generation Risk Assessment" (NGRA).

Identifying xenobiotic metabolites with in silico prediction tools and LCMS suspect screening analysis.

Understanding the metabolic fate of a xenobiotic substance can help inform its potential health risks and allow for the identification of signature metabolites associated with exposure. The need to characterize metabolites of poorly studied or novel substances has shifted exposure studies towards non-targeted analysis (NTA), which often aims to profile many compounds within a sample using high-resolution liquid-chromatography mass-spectrometry (LCMS). Here we evaluate the suitability of suspect screening analysis (SSA) liquid-chromatography mass-spectrometry to inform xenobiotic chemical metabolism. Given a lack of knowledge of true metabolites for most chemicals, predictive tools were used to generate potential metabolites as suspect screening lists to guide the identification of selected xenobiotic substances and their associated metabolites. Thirty-three substances were selected to represent a diverse array of pharmaceutical, agrochemical, and industrial chemicals from Environmental Protection Agency's ToxCast chemical library. The compounds were incubated in a metabolically-active in vitro assay using primary hepatocytes and the resulting supernatant and lysate fractions were analyzed with high-resolution LCMS. Metabolites were simulated for each compound structure using software and then combined to serve as the suspect screening list. The exact masses of the predicted metabolites were then used to select LCMS features for fragmentation via tandem mass spectrometry (MS/MS). Of the starting chemicals, 12 were measured in at least one sample in either positive or negative ion mode and a subset of these were used to develop the analysis workflow. We implemented a screening level workflow for background subtraction and the incorporation of time-varying kinetics into the identification of likely metabolites. We used haloperidol as a case study to perform an in-depth analysis, which resulted in identifying five known metabolites and five molecular features that represent potential novel metabolites, two of which were assigned discrete structures based on in silico predictions. This workflow was applied to five additional test chemicals, and 15 molecular features were selected as either reported metabolites, predicted metabolites, or potential metabolites without a structural assignment. This study demonstrates that in some-but not all-cases, suspect screening analysis methods provide a means to rapidly identify and characterize metabolites of xenobiotic chemicals.

Absolute dosimetry for FLASH proton pencil beam scanning radiotherapy.

A paradigm shift is occurring in clinical oncology exploiting the recent discovery that short pulses of ultra-high dose rate (UHDR) radiation-FLASH radiotherapy-can significantly spare healthy tissues whilst still being at least as effective in curing cancer as radiotherapy at conventional dose rates. These properties promise reduced post-treatment complications, whilst improving patient access to proton beam radiotherapy and reducing costs. However, accurate dosimetry at UHDR is extremely complicated. This work presents measurements performed with a primary-standard proton calorimeter and derivation of the required correction factors needed to determine absolute dose for FLASH proton beam radiotherapy with an uncertainty of 0.9% (1[Formula: see text]), in line with that of conventional treatments. The establishment of a primary standard for FLASH proton radiotherapy improves accuracy and consistency of the dose delivered and is crucial for the safe implementation of clinical trials, and beyond, for this new treatment modality.

A value of information framework for assessing the trade-offs associated with uncertainty, duration, and cost of chemical toxicity testing.

A number of investigators have explored the use of value of information (VOI) analysis to evaluate alternative information collection procedures in diverse decision-making contexts. This paper presents an analytic framework for determining the value of toxicity information used in risk-based decision making. The framework is specifically designed to explore the trade-offs between cost, timeliness, and uncertainty reduction associated with different toxicity-testing methodologies. The use of the proposed framework is demonstrated by two illustrative applications which, although based on simplified assumptions, show the insights that can be obtained through the use of VOI analysis. Specifically, these results suggest that timeliness of information collection has a significant impact on estimates of the VOI of chemical toxicity tests, even in the presence of smaller reductions in uncertainty. The framework introduces the concept of the expected value of delayed sample information, as an extension to the usual expected value of sample information, to accommodate the reductions in value resulting from delayed decision making. Our analysis also suggests that lower cost and higher throughput testing also may be beneficial in terms of public health benefits by increasing the number of substances that can be evaluated within a given budget. When the relative value is expressed in terms of return-on-investment per testing strategy, the differences can be substantial.