Dose-response Assessment Research Articles

Systemic immune inflammation index with all-cause and cause-specific mortality: a meta-analysis.

Studies have reported an association among systemic immune inflammation index (SII), all-cause and cause-specific mortality, but the results are inconsistent. To comprehensively explore the association between Systemic Immune Inflammation (SII) and the risk of all-cause mortality, cardiovascular disease (CVD), and cancer mortality. A meta-analysis was conducted by reviewing existing literature. The search encompassed prominent databases including PubMed, Embase, Cochrane, and the Web of Science, with the cutoff date set at March 1, 2024. Furthermore, subgroup analyses and dose-response assessments were undertaken to provide a nuanced exploration of mortality risk factors. A total of 33 articles were included (427,819 participants). In the study, SII was associated with an increased risk of all-cause mortality (HR = 1.45, 95%CI [1.36,1.54], P < 0.05). SII increased the risk of CVD mortality (HR = 1.44, 95%CI [1.29,1.60], P < 0.05). The Linear independence shows that for every 100 units increase in SII, the risk of all-cause and CVD death increases by 5% and 6%. SII was not associated with a statistically significant risk of cancer death (HR = 1.09, 95%CI [0.96,1.23], P < 0.05). Meta-analysis showed that SII was associated with all-cause mortality and CVD mortality. More data and basic research are needed to confirm the association.

Industry Perspective on First-in-Human and Clinical Pharmacology Strategies to Support Clinical Development of T-Cell Engaging Bispecific Antibodies for Cancer Therapy.

T-cell-engaging bispecific antibodies (TCEs) that target tumor antigens and T cells have shown great promise in treating cancer, particularly in hematological indications. The clinical development of TCEs often involves a lengthy first-in-human (FIH) trial with many dose-escalation cohorts leading up to an early proof of concept (POC), enabling either a no-go decision or dose selection for further clinical development. Multiple factors related to the target, product, disease, and patient population influence the efficacy and safety of TCEs. The intricate mechanism of action limits the translatability of preclinical models to the clinic, thereby posing challenges to streamline clinical development. In addition, unlike traditional chemotherapy, the top dose and recommended phase II doses (RP2Ds) for TCEs in the clinic are often not guided by the maximum tolerated dose (MTD), but rather based on the integrated dose-response assessment of the benefit/risk profile. These uncertainties pose complex challenges for translational and clinical pharmacologists (PK/PD scientists), as well as clinicians, to design an efficient clinical study that guides development. To that end, experts in the field, under the umbrella of the American Association of Pharmaceutical Scientists, have reviewed learnings from published literature and currently marketed products to share perspectives on the FIH and clinical pharmacology strategies to support early clinical development of TCEs.

LP-45 Application of a unified probabilistic framework to the dose-response assessment of selected nitrosamines and derivation of health-based exposure limits (HBELs)

LP-45 Application of a unified probabilistic framework to the dose-response assessment of selected nitrosamines and derivation of health-based exposure limits (HBELs)

432. POSTOPERATIVE SAFETY AND TOLERABILITY OF INTRAMUSCULAR OCTREOTIDE IN PATIENTS WITH GASTROESOPHAGEAL CANCER: AN OPEN-LABEL PHASE 2 PILOT STUDY

Abstract Background Dietary peptides are believed to contribute to persistent weight loss following gastrectomy or esophagectomy due to cancer. Previous studies have suggested that this effect might be partially mitigated by octreotide. This study aims to investigate the safety and tolerability of intramuscular Sandostatin® LAR depot 10mg, including the frequency and nature of adverse events. It serves as a pilot study for future research aiming to comprehensively assess its effects. Methods A prospective open-label phase-2 study was conducted from November 2021 to June 2023. Twenty patients (10 undergoing gastrectomy, 10 undergoing esophagectomy) were enrolled. Patients received three doses of intramuscular Sandostatin® LAR depot 10mg at 7 days, 1 month, and 2 months post-surgery. All patients were evaluated at 7 days, 1, 2, 3, and 6 months post-surgery. The primary endpoint was safety, determined by the incidence and nature of adverse events, with no occurrence of serious or severe events defined as successful. Tolerability was defined as at the completion of the treatment protocol by at least 90% of patients. Secondary endpoints included weight loss (percent from baseline), Health-Related Quality of Life (assessed via EORTC-QLQ-C30 and OG25 at baseline, 1, 2, 3, and 6 months post-surgery), and the proportion of subjects requiring enteral nutrition via jejunostomy. Results The study protocol was completed by 95% of participants. No serious or severe adverse events were reported. Median weight loss at 6 months was 11% (3 months: 7%, 2 months: 4%, 1 month: 5%). Mean and median Global Quality of Life (part of EORTC-QLQ-C30) remained unchanged at 6 months compared to baseline (mean: 67.6 vs. 67.2; median 66.7 [25-100] vs 70.8 [16.7-100]). The percentage of subjects requiring enteral nutrition was 40%, 30%, and 15% at 1, 2, and 3 months respectively. Conclusion This pilot study suggests that Sandostatin® LAR depot was well tolerated and safe, with no serious or severe adverse events observed. Weight loss, Health Related Quality of Life, and the proportion of subjects requiring enteral nutrition were consistent with expectations. Future studies should consider a double-blinded randomized controlled design preferably with dose-response assessment for more robust investigation.

Schizosaccharomyces pombe as a predictor toxicity tool

The fission yeast Schizosaccharomyces pombe is frequently used as a genetically manipulable model system, offering valuable understandings into cellular mechanisms. In the present study, a comprehensive step-by-step methodology for the research of the action mechanisms and detoxification by efflux pumps is showed. The protocol involves the thawing and culture of yeast cells in liquid medium under controlled conditions to ensure exponential growth. After that, a dose-response assessment is carried out by culturing wild-type cells in liquid medium, followed by exposure to increasing concentrations of the toxic substances. Optical density measurements are taken spectrophotometrically after exposure, and the process is repeated at least three times for quantitative analysis. Subsequently, defective mutants are selected to explore specific mechanisms of action or detoxification by efflux pumps, with cultures prepared and treated similarly to the wild type. Optical density measurements are again taken after exposure for quantitative analysis. This methodology ensures robust and reproducible results for the research toxic substances effects on S. pombe.-Schizosaccharomyces pombe is an adequate tool to evaluate contaminants toxicity.-Dose-responses curves are obtained on wild type to evaluate toxicity mechanisms.-This methodology ensures robust and reproducible results for the research toxic substances effects on S. pombe.

A novel method for rapid estimation of active bone marrow dose for radiotherapy patients in epidemiological studies.

In a dedicated effort to improve the assessment of clonal hematopoiesis (CH) and study leukemia risk following radiotherapy, we are developing a large-scale cohort study among cancer patients who received radiation. To that end, it will be critical to analyze dosimetric parameters of red bone marrow (ABM) exposure in relation to CH and its progression to myeloid neoplasms, requiring reconstruction method for ABM doses of a large-scale patients rapidly and accurately. To support a large-scale cohort study on the assessment of clonal hematopoiesis and leukemia risk following radiotherapy, we present a new method for the rapid reconstruction of ABM doses of radiotherapy among cancer patients. The key idea of the presented method is to segment patient bones rapidly and automatically by matching a whole-body computational human phantom, in which the skeletal system is divided into 34 bone sites, to patient CT images via 3D skeletal registration. The automatic approach was used to segment site-specific bones for 40 radiotherapy patients. Also, we segmented the bones manually. The bones segmented both manually and automatically were then combined with the patient dose matrix calculated by the treatment planning system (TPS) to derive patient ABM dose. We evaluated the performance of the automatic method in geometric and dosimetric accuracy by comparison with the manual approach. The pelvis showed the best geometric performance [volume overlap fraction (VOF): 52% (mean) with 23% (σ) and average distance (AD): 0.8cm (mean) with 0.5cm (σ)]. The pelvis also showed the best dosimetry performance [absorbed dose difference (ADD): 0.7Gy (mean) with 1.0Gy (σ)]. Some bones showed unsatisfactory performances such as the cervical vertebrae [ADD: 5.2Gy (mean) with 10.8Gy (σ)]. This impact on the total ABM dose, however, was not significant. An excellent agreement for the total ABM dose was indeed observed [ADD: 0.4Gy (mean) with 0.4Gy (σ)]. The computation time required for dose calculation using our method was robust (about one minute per patient). We confirmed that our method estimates ABM doses across treatment sites accurately, while providing high computational efficiency. The method will be used to reconstruct patient-specific ABM doses for dose-response assessment in a large cohort study. The method can also be applied to prospective dose calculation within a clinical TPS to support clinical decision making at the point of care.

Probabilistic Reference and 10% Effect Concentrations for Characterizing Inhalation Non-cancer and Developmental/Reproductive Effects for 2,160 Substances.

Chemicals assessment and management frameworks rely on regulatory toxicity values, which are based on points of departure (POD) identified following rigorous dose-response assessments. Yet, regulatory PODs and toxicity values for inhalation exposure (i.e., reference concentrations [RfCs]) are available for only ∼200 chemicals. To address this gap, we applied a workflow to determine surrogate inhalation route PODs and corresponding toxicity values, where regulatory assessments are lacking. We curated and selected inhalation in vivo data from the U.S. EPA's ToxValDB and adjusted reported effect values to chronic human equivalent benchmark concentrations (BMCh) following the WHO/IPCS framework. Using ToxValDB chemicals with existing PODs associated with regulatory toxicity values, we found that the 25th %-ile of a chemical's BMCh distribution () could serve as a suitable surrogate for regulatory PODs (Q2 ≥ 0.76, RSE ≤ 0.82 log10 units). We applied this approach to derive for 2,095 substances with general non-cancer toxicity effects and 638 substances with reproductive/developmental toxicity effects, yielding a total coverage of 2,160 substances. From these , we derived probabilistic RfCs and human population effect concentrations. With this work, we have expanded the number of chemicals with toxicity values available, thereby enabling a much broader coverage for inhalation risk and impact assessment.

Probing the anti-Aβ42 aggregation and protective effects of prenylated xanthone against Aβ42-induced toxicity in transgenic Caenorhabditis elegans model

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β (Aβ) protein aggregates, leading to synaptic dysfunction and neuronal cell death. In this study, we used a comprehensive approach encompassing in vitro assays, computational analyses, and an in vivo Caenorhabditis elegans model to evaluate the inhibitory effects of various xanthones, focusing on Garcinone D (GD), on Aβ42 oligomer formation. Dot blot analysis revealed concentration-dependent responses among xanthones, with GD consistently inhibiting Aβ42 oligomer formation at low concentrations (0.1 and 0.5 μM, inhibitions of 84.66 ± 2.25% and 85.06 ± 6.57%, respectively). Molecular docking and dynamics simulations provided insights into the molecular interactions between xanthones and Aβ42, highlighting the disruption of key residues involved in Aβ42 aggregation. The neuroprotective potential of GD was established using transgenic C. elegans GMC101, with substantial delays in paralysis reported at higher concentrations. Our findings show that GD is a potent suppressor of Aβ42 oligomer formation, suggesting its potential as a therapeutic candidate for AD. The concentration-dependent effects observed in both in vitro and in vivo models underscore the need for nuanced dose-response assessments. These findings contribute novel insights into the therapeutic landscape of xanthones against AD, emphasizing the multifaceted potential of GD for further translational endeavors in neurodegenerative disorder research.

A strategy for the investigation of toxic mechanisms and protection by efflux pumps using Schizosaccharomyces pombe strains: Application to rotenone

Effects not related with the inhibition of complex I of the mitochondrial electron transport chain are studied in S. pombe, which lacks it. This study aims: First, the use of a strategy with S. pombe strains to investigate the toxicity, mechanisms of action, interactions and detoxication by efflux pumps. Second, to investigate the mechanisms of toxic action of rotenone. In the dose-response assessment, the yeast presented a good correlation with the toxicity in Daphnia magna for 15 chemicals. In the mechanistic study, the mph1Δ strain presented marked specificity to the interaction with microtubules by carbendazim. DNA damage caused by hydroxyurea, an inhibitor of deoxynucleotide synthesis, was identified with marked specificity with the rad3Δ strain. The sty1Δ strain was very sensitive to the oxidative and osmotic stress induced by hydrogen peroxide and potassium chloride, respectively, being more sensitive to oxidative stress than the pap1Δ strain. The protection by exclusion pumps was also evaluated. Rotenone presented low toxicity in S. pombe due to the lack of its main target, and the marked protection by the exclusion transporters Bfr1, Pmd1, Caf5 and Mfs1. Marked cellular stress was detected. Finally, the toxicity of rotenone could be potentiated by the fungicide carbendazim and the antimetabolite hydroxyurea. In conclusion, the use of S. pombe strains is a valid strategy to: a) assess global toxicity; b) investigate the main mechanisms of toxic action, particularly spindle and DNA interferences, and osmotic and oxidative stress not related to complex I inhibition; c) explore the detoxication by efflux pumps; and d) evaluate possible chemical interactions. Therefore, it should be useful for the investigation of adverse outcome pathways.

A data-centric perspective on exposomics data analysis

Abstract Exposomics represents a systematic approach to investigate the etiology of diseases by formally integrating individuals’ entire environmental exposures and associated biological responses into the traditional genotype-phenotype framework. The field is largely enabled by various omics technologies which offer practical means to comprehensively measure key components in exposomics. The bottleneck in exposomics has gradually shifted from data collection to data analysis. Effective and easy-to-use bioinformatics tools and computational workflows are urgently needed to help obtain robust associations and to derive actionable insights from the observational, heterogenous, and multi-omics datasets collected in exposomics studies. This data-centric perspective starts with an overview of the main components and common analysis workflows in exposomics. We then introduce six computational approaches that have proven effective in addressing some key analytical challenges, including linear modeling with covariate adjustment, dimensionality reduction for covariance detection, neural networks for identification of complex interactions, network visual analytics for organizing and interpreting multi-omics results, Mendelian randomization for causal inference, and cause-effect validation by coupling effect-directed analysis with dose-response assessment. Finally, we present a series of well-designed web-based tools, and briefly discuss how they can be used for exposomics data analysis.

Derivation of no significant risk levels for three lower acrylates: Conclusions and recommendations from an expert panel

A panel of toxicology, mode of action (MOA), and cancer risk assessment experts was engaged to derive no-significant-risk-levels (NSRLs) for three lower acrylates: methyl acrylate (MA), ethyl acrylate (EA), and 2-ethylhexyl acrylate (2EHA) using the best available science, data, and methods. The review was structured as a five-round, modified Delphi format, a systematic process for collecting independent and deliberative input from panel members, and it included several procedural elements to reduce potential sources of bias and groupthink. Input from the panel for key decisions in the dose-response assessments resulted in NSRL values of 530 μg/day (330–800 μg/day), 640 μg/day (280–670 μg/day), and 1700 μg/day (1300–2700 μg/day) for MA, EA, and 2EHA, respectively. Novel to this approach were the use of nonneoplastic lesions reported at point of contact where tumors have been reported in laboratory rodents, along with nonlinear extrapolation to low doses (uncertainty factor approach) based upon panel recommendations. Confidence in these values is considered medium to high for exposures applied to the routes of exposure tested (inhalation for MA and EA, dermal for 2EHA), but confidence is considered lower when applied to other routes of exposure.

Dose-response modeling and treatment plan assessment with a python software toolkit

This software assistant aims at calculating the dose-response relations of tumors and normal tissues, or clinically assessing already determined values by other researchers. It can also indicate the optimal dose prescription by optimizing the expected treatment outcome. The software is developed solely in python programming language, and it employs PSFL license for its Graphical User Interface (GUI), NUMPY, MATPLOTLIB, and SCIPY libraries. It comprises of two components. The first is the Dose-response relations derivation component, which takes as input the dose volume histograms (DVHs) of patients and their recorded responses regarding a given clinical endpoint to determine the parameters of different tumor control probability (TCP) or normal tissue complication probability (NTCP) models. The second is the Treatment Plan Assessment component, which uses the DVHs of a plan and the dose-response parameters values of the involved tumors and organs at risk (OARs) to calculate their expected responses. Additionally, the overall probabilities of benefit (PB), injury (PI) and complication-free tumor control (P+) are calculated. The software calculates rapidly the corresponding generalized equivalent uniform doses (gEUD) and biologically effective uniform doses (D‾‾) for the Lyman-Kutcher-Burman (LKB), parallel volume (PV) and relative seriality (RS) models respectively, determining the model parameters. In the Dose-Response Relations Derivation component, the software plots the dose-response curves of the irradiated organ with the relevant confidence internals along with the data of the patients with and without toxicity. It also calculates the odds ratio (OR) and the area under the curve (AUC) of different dose metrics or model parameter values against the individual patient outcomes to determine their discrimination capacity. It also performs a goodness-of-fit evaluation of any model parameter set. The user has the option of viewing plots like Scatter, 3D surfaces, and Bootstrap plots. In the Treatment Plan Assessment part, the software calculates the TCP and NTCP values of the involved tumors and OARs, respectively. Furthermore, it plots the dose-response curves of the TCPs, NTCPs, PB, PI, and P+ for a range of prescription doses for different treatment plans. The presented software is ideal for efficiently conducting studies of radiobiological modeling. Furthermore, it is ideal for performing treatment plan assessment, comparison, and optimization studies.

Abuse-like toluene exposure during early adolescence alters subsequent ethanol and cocaine behavioral effects and brain monoamines in male mice

Currently, there is a gap in understanding the neurobiological impact early adolescent toluene exposure has on subsequent actions of other drugs. Adolescent (PND 28–32) male Swiss-Webster mice (N = 210) were exposed to 0, 2000, or 4000 ppm of toluene vapor for 30 min/day for 5 days. Immediately following the last toluene exposure (PND 32; n = 15) or after a short delay (PND 35; n = 15), a subset of subjects' brains was collected for monoamine analysis. Remaining mice were assigned to one of two abstinence periods: a short 4-day (PND 36) or long 12-day (PND 44) delay after toluene exposure. Mice were then subjected to a cumulative dose response assessment of either cocaine (0, 2.5, 5, 10, 20 mg/kg; n = 60), ethanol (0, 0.5, 1, 2, 4 g/kg; n = 60), or saline (5 control injections; n = 60). Toluene concentration-dependently increased locomotor activity during exposure. When later challenged, mice exposed previously to toluene were significantly less active after cocaine (10 and 20 mg/kg) compared to air-exposed controls. Animals were also less active at the highest dose of alcohol (4 g/kg) following prior exposure to 4000 ppm when compared to air-exposed controls. Analysis of monoamines and their metabolites using High Pressure Liquid Chromatography (HPLC) within the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and ventral tegmental area (VTA) revealed subtle effects on monoamine or metabolite levels following cumulative dosing that varied by drug (cocaine and ethanol) and abstinence duration. Our results suggest that early adolescent toluene exposure produces behavioral desensitization to subsequent cocaine-induced locomotor activity with subtle enhancement of ethanol's depressive effects and less clear impacts on levels of monoamines.

Confirming resistance to PPO-inhibiting herbicides applied preemergence and postemergence in a Georgia Palmer amaranth population

Abstract Herbicides that inhibit protoporphyrinogen oxidase (PPO) are used in more than 40 agronomic and specialty crops across Georgia to manage weeds through residual and postemergence (POST) control. In 2017, a population of Palmer amaranth exhibiting reduced sensitivity to POST applications of PPO-inhibiting herbicides was identified by the University of Georgia. Seed were collected from the site along with a known sensitive population; distance between the samples was 200 m, increasing the likelihood of similar environmental and genetic characteristics. To quantify sensitivity for both preemergence (PRE) and POST uses, 21 greenhouse dose-response assessments were conducted from 2017 to 2022. After conducting initial rate-response studies, 13 doses per herbicide were chosen for the POST experiment; field use rates of fomesafen (420 g ai ha−1), lactofen (219 g ai ha−1), acifluorfen (420 g ai ha−1), and trifludimoxazin (25 g ai ha−1) ranging from 0× to 4× the field use rate for the susceptible population, and 0× to 40× for the suspect population were applied. Herbicide treatments included adjuvants and were applied to plants 8 to 10 cm in height. Relative resistance factors (RRFs) were calculated for control ratings, mortality, and biomass, and ranged from 105 to 318, 36 to 1,477, 215 to 316, and 9 to 49 for fomesafen, lactofen, acifluorfen, and trifludimoxazin, respectively. In the PRE experiment, herbicide applications included five to nine doses of fomesafen (1× = 210 g ai ha−1), flumioxazin (1× = 57 g ai ha−1), oxyfluorfen (1× = 561 g ai ha−1), and trifludimoxazin (1× = 38 g ai ha−1); doses ranged from 0× to 6× for the suspect population and 0× to 2× for the susceptible population. Visual control, mortality, and biomass RRFs ranged from 3 to 5 for fomesafen, 21 to 31 for flumioxazin, 6 to 22 for oxyfluorfen, and 8 to 38 for trifludimoxazin. Results confirm that a Georgia Palmer amaranth population is resistant to PPO-inhibiting herbicides applied both PRE and POST.

New insight into PAH4 induced hepatotoxicity and the dose-response assessment in rats model

PAH4 (sum of benzo[a]pyrene, chrysene, benz[a]anthracene and benzo[b]fluoranthene) has been proposed as better marker than benzo[a]pyrene to assess total PAHs exposure in foodstuffs. However, the toxicological behaviors of PAH4 combined exposure remain unclear. This study aimed to investigate PAH4 toxicity effects with non-targeted metabolomics approach and evaluate the external and internal dose-response relationships based on benchmark dose (BMD) analysis. Male Sprague-Dawley rats were treated by gavage with vehicle (corn oil) or four doses of PAH4 (10, 50, 250, 1000 μg/kg·bw) for consecutive 30 days. After the final dose, the liver, blood and urine samples of rats were subsequently collected for testing. The concentrations of urinary mono-hydroxylated PAHs metabolites (OH-PAHs) including 3-hydroxybenzo[a]pyrene (3-OHB[a]P), 3-hydroxychrysene (3-OHCHR) and 3-hydroxybenz[a]anthracene (3-OHB[a]A) were determined to reflect internal PAH4 exposure. Our results showed PAH4 exposure increased relative liver weight and serum aspartate aminotransferase (AST) activity and caused hepatocyte swelling and degeneration, implying hepatotoxicity induced by PAH4. Serum metabolomics suggested PAH4 exposure perturbed lipid metabolism through upregulating the expression of glycerolipids metabolites, which was evidenced by markedly increased serum triglyceride (TG) level and hepatic TG content. Additionally, urinary OH-PAHs concentrations presented strong positive correlations with the external dose, indicating they were able to reflect PAH4 exposure. Furthermore, PAH4 exposure led to a dose-response increase of hepatic TG content, based on which the 95% lower confidence value of BMDs for external and internal doses were estimated as 5.45 μg/kg·bw and 0.11 μmol/mol·Cr, respectively. In conclusion, this study suggested PAH4 exposure could induce hepatotoxicity and lipid metabolism disorder, evaluating the involved dose-response relationships and providing a basis for the risk assessment of PAHs.

Health Risk Assessment of Occupational Exposure to Chemical Materials in a Combined-Cycle Power Plant

Background: This study aimed to evaluate the occupational exposure of workers at a combined-cycle power plant located in the southwestern region of Iran. The assessment focuses on the inhalation exposure route to workplace emissions. Methods: The primary locations for potential pollutant emissions were identified in close proximity to the areas where chemicals were introduced and utilized within the production process. Sulfuric acid, sodium hydroxide, ammonia, oil mist, toluene, hydrogen sulfide, hydrazine, and tetrachloromethane were measured and analyzed using the NIOSH standard. Dose-response assessment was estimated using inhalation unit risk (IUR) for cancer risks and reference concentration (RFC) and reference exposure levels (REL) for non-cancer risks. Risk assessment was performed based on the Environmental Health Hazard Assessment guideline. Results: The results showed that ammonia and toluene had the highest and lowest concentration of pollutants emitted in workplace, respectively. The inhalation of ammonia and sulfuric acid and their daily absorption were at high risk level (HQ&gt;1). Other noncancerous compounds had HQ&lt;1. While the hazard index (HI) for total non-cancer risks was 5.34E+01 (HI&gt;1), it was likely to have non-cancerous risks. For carcinogenic risks, they were calculated to be 9.58E-03 and 5.47E-04 for hydrazine and tetrachloromethane, respectively. The total carcinogenic risk of the emissions was calculated at 1.01E-02, which was in the significant range (more than 10-4) (i.e. in the range of hazardous cancer effects). Conclusion: This study confirmed the presence of non-carcinogenic risks, while the quantity of cancer risks fell within the Significant range, indicating a potential for carcinogenic risks.

Quantitative Integration of Mode of Action Information in Dose-Response Modeling and POD Estimation for Nonmutagenic Carcinogens: A Case Study of TCDD.

Traditional dose-response assessment applies different low-dose extrapolation methods for cancer and noncancer effects and assumes that all carcinogens are mutagenic unless strong evidence suggests otherwise. Additionally, primarily focusing on one critical effect, dose-response modeling utilizes limited mode of action (MOA) data to inform low-dose risk. We aimed to build a dose-response modeling framework that continuously extends the curve into the low-dose region via a quantitative integration of MOA information and to estimate MOA-based points of departure (PODs) for nonmutagenic carcinogens. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was used as an example to demonstrate the new dose-response modeling framework. There were three major steps included: a) identifying and extracting key quantifiable events (KQEs), b) calculating essential doses that sequentially activate KQEs using the benchmark dose (BMD) methodology, and c) characterizing pathway dose-response relationship for MOA-based POD estimation. We identified and extracted six KQEs and corresponding essential events composing the MOA of TCDD-induced liver tumors. With the essential doses estimated from the BMD method using various settings, three link functions were applied to model the pathway dose-response relationship. Given a toxicologically plausible definition of adversity, an MOA-based POD was derived from the pathway dose-response curve. The estimated MOA-based PODs were generally comparable with traditional PODs and can be further used to calculate reference doses (RfDs). The proposed framework quantitatively integrated mechanistic information in the modeling process and provided a promising strategy to harmonize cancer and noncancer dose-response assessment through pathway dose-response modeling. However, the framework can also be limited by data availability and the understanding of the underlying mechanism. https://doi.org/10.1289/EHP12677.

Comparison of Multiple Segmentation Methods for Volumetric Delineation of Primary Prostate Cancer with Prostate-Specific Membrane Antigen-Targeted 18F-DCFPyL PET/CT.

This study aimed to assess the accuracy of intraprostatic tumor volume measurements on prostate-specific membrane antigen-targeted 18F-DCFPyL PET/CT made with various segmentation methods. An accurate understanding of tumor volumes versus segmentation techniques is critical for therapy planning, such as radiation dose volume determination and response assessment. Methods: Twenty-five men with clinically localized, high-risk prostate cancer were imaged with 18F-DCFPyL PET/CT before radical prostatectomy. The tumor volumes and tumor-to-prostate ratios (TPRs) of dominant intraprostatic foci of uptake were determined using semiautomatic segmentation (applying SUVmax percentage [SUV%] thresholds of SUV30%-SUV70%), adaptive segmentation (using adaptive segmentation percentage [A%] thresholds of A30%-A70%), and manual contouring. The histopathologic tumor volume (TV-Histo) served as the reference standard. The significance of differences between TV-Histo and PET-based tumor volume were assessed using the paired-sample Wilcoxon signed-rank test. The Spearman correlation coefficient was used to establish the strength of the association between TV-Histo and PET-derived tumor volume. Results: Median TV-Histo was 2.03 cm3 (interquartile ratio [IQR], 1.16-3.36 cm3), and median TPR was 10.16%. The adaptive method with an A40% threshold most closely determined the tumor volume, with a median difference of +0.19 (IQR, -0.71 to +2.01) and a median relative difference of +7.6%. The paired-sample Wilcoxon test showed no significant difference in PET-derived tumor volume and TV-Histo using A40%, A50%, SUV40%, and SUV50% threshold segmentation algorithms (P > 0.05). For both threshold-based segmentation methods, use of higher thresholds (e.g., SUV60% or SUV70% and A50%-A70%) resulted in underestimation of tumor volumes, and use of lower thresholds (e.g., SUV30% or SUV40% and A30%) resulted in overestimation of tumor volumes relative to TV-Histo and TPR. Manual segmentation overestimated the tumor volume, with a median difference of +2.49 (IQR, 0.42-4.11) and a median relative difference of +130%. Conclusion: Segmentation of intraprostatic tumor volume and TPR with an adaptive segmentation approach most closely approximates TV-Histo. This information might be used to guide the primary treatment of men with clinically localized, high-risk prostate cancer.

Use of Pesticides and Health Risks to Chinese Water Chestnut Farmers in Suphanburi Province, Thailand.

We aimed to study the relationship between the use of pesticides and the health risks faced by Chinese water chestnut farmers in this country. This cross-sectional survey was conducted among 425 farmers in Sriprachan district, Suphanburi Province, Thailand in 2021. Samples were recruited using the cluster sampling method, and data collection took place through questionnaires. The questionnaire consisted of 3 parts, 76 items, namely personal information of farmers (12 items checklist), the use of pesticides by chemical risk assessment was a 5-point rating scale (40 items), and health risk assessment exposure to pesticides was a 5-point rating scale (24 items). The content validity index for scale (S-CVI) was 0.963 and the reliability with Cronbach's alpha coefficient was 0.904. Data were analyzed using descriptive statistics, chi-square, relative risk, and 95% CI. The overall pesticide use among farmers was at a moderate level (Mean=3.26, SD=0.60). Farmers' signs and symptoms of exposure were compared to their use of pesticides. The pesticide use increased health risks by 15.57 (95% CI: 12.33 to 18.14). Hazard identification was 10.79 higher (95% CI: 8.19 to 13.40). Dose-response assessment was -16.23 higher (95% CI: -17.63 to -14.82). Exposure assessment was 11.49 higher (95% CI: 9.87 to 13.10) and the risk characteristic was -7.46 (95% CI: -8.49 to -6.44). It was statistically significant at <.001. Careless and incorrect use of pesticides by Chinese water chestnut farmers can lead to health risks from exposure to toxic substances.

In vitro inhalation bioaccessibility and health risk assessment of difenoconazole in the atmosphere.

Assessment of the risk of pesticide inhalation in populations around farmland is necessary because inhalation is one of the ways in which pesticides can risk human health. This study aimed to identify the inhalation risk of difenoconazole on humans by using dose-response and exposure assessments. In the field simulation application, respiratory exposure in populations around farmland ranged from 71 to 430 ng/m3 . Using response surface methodology, the maximum bioaccessibility of difenoconazole in three simulated lung fluids was 35.33% in Gamble's solution (GS), 34.12% in artificial lysosomal fluid (ALF), and 42.06% in simulated interstitial lung fluid (SLF). Taking the proliferation activity of the A549 cell model as the endpoint, the benchmark dose limit and benchmark dose of difenoconazole on A549 cells were 16.36 and 5.60 mg/kg, respectively. The margin of exposure to difenoconazole in GS, ALF and SLF were, respectively, 8.66 × 105 to 5.28 × 106 , 8.97 × 105 to 5.47 × 106 and 7.28 × 105 to 4.44 × 106 . The risk assessment results indicate that under all circumstances, applying difenoconazole is safe for populations around farmland. However, a fan-shaped nozzle, suspension concentrate and greater inhalation height increase the risk of inhalation. © 2023 Society of Chemical Industry.