Exposure-response Relationship Research Articles

Exposure-Response Analyses of Sacituzumab Govitecan Efficacy and Safety in Patients With Metastatic Triple-Negative Breast Cancer.

Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is approved for patients with metastatic triple-negative breast cancer (mTNBC) who received ≥2 prior systemic therapies (≥1 in metastatic setting). Exposure-response (E-R) relationships between SG exposure and efficacy and safety outcomes were characterized in 277 patients with mTNBC using data from the phase I/II IMMU-132-01 and phase III ASCENT (IMMU-132-05) studies. Evaluated endpoints included complete response (CR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety endpoints (individual first worst grade of select adverse events (AEs)). E-R analyses were also conducted for time to first dose reduction or delay. Patients received SG at 8 or 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle. Average SG-related serum exposure over the treatment duration (until the event) was consistently the most significant exposure metric correlated with efficacy and safety endpoints. Higher average concentration over the treatment duration for SG (CAVGSG) was the best predictor of CR and ORR. The model-predicted proportions of patients with CR and ORR at 10 mg/kg were 4.26% and 32.6%, respectively. Higher CAVG for total antibody was the best predictor of OS and PFS. The model-predicted probability of OS at 12 months at median lactate dehydrogenase (227 IU/L) was 53%. The probability of grade ≥1 evaluated AEs and the risk of dose reductions and delays significantly increased with increasing CAVGSG. The model-predicted proportions of patients with any-grade AEs were 35.9%, 67.4%, 64.7%, and 67.1% for vomiting, diarrhea, nausea, and neutropenia, respectively (10 mg/kg dose group). Neutropenia was the only evaluated AE for which CAVGSG was significantly associated with grade ≥3 events. The clinically meaningful efficacy and manageable safety achieved with SG 10 mg/kg on days 1 and 8 of every 21-day cycle dosing regimen supports the appropriateness of this clinical dosage in patients with mTNBC.

Population pharmacokinetics and exposure-response relationships of dostarlimab in primary advanced or recurrent endometrial cancer in part 1 of RUBY.

Dostarlimab-gxly is a humanized monoclonal antibody of the IgG4 isotype that binds to the programmed cell death protein-1 (PD-1) receptor and blocks its ligands. RUBY (NCT03981796) is a two-part multicentre study in patients with recurrent or primary advanced endometrial cancer. The overall aims were to characterise the population pharmacokinetics (PopPK) from Part 1 of this study, identify relevant covariates of interest, and assess exposure-efficacy/safety (ER) relationships. A PopPK model developed using GARNET (NCT02715284) study data for dostarlimab monotherapy was externally validated with RUBY Part 1 study data. Subsequently, the model was updated with data across the two studies. Exposure-safety analyses for adverse events related to dostarlimab alone or in combination with standard of care (SOC) were modelled using logistic regression. Exposure-efficacy analysis included Cox proportional hazards analysis of the primary efficacy endpoint of progression-free survival (PFS). For the model update, 7957 pharmacokinetics observations from 868 patients pooled from both RUBY and GARNET studies were available. The model was consistent with the previous model. Dostarlimab clearance was estimated to be 7.79% lower when dostarlimab was given as SOC combination therapy. However, no significant covariates were clinically relevant. Hepatic or renal impairment did not affect pharmacokinetics. Among the safety endpoints, only rash showed a small yet statistically significant effect (P < .05) in all subjects; however, this was not not deemed clinically relevant. There were no other clinically significant exposure-safety or exposure-PFS relationships. The addition of chemotherapy to dostarlimab had limited effect on dostarlimab PopPK, with no clinically significant covariates or clinically relevant exposure-safety or exposure-PFS relationships.

Untangling the Exposure-Response Relationship of Allopurinol in the Setting of Chronic Kidney Disease and Diuretic Use: Implications for Dosing.

Allopurinol dose reduction proportional to creatinine clearance (CLcr) results in suboptimal urate lowering in patients with gout. Similarly, diuretic therapy reduces oxypurinol clearance but is unexpectedly associated with the need for higher allopurinol doses to achieve the serum urate target (<0.36 mmol/L). The authors aimed to clarify the relationship between oxypurinol exposure and urate-lowering response in patients with gout at different stages of chronic kidney disease and those taking diuretics to determine the implications for maintenance dose selection. Oxypurinol and urate data from 5 clinical studies were available. Model-derived steady-state oxypurinol areas under the concentration-time curves (AUCss0-tau) were estimated using a Bayesian methodology. The observed response metrics included the percentage reduction in urate from baseline and achievement of the target urate level. Exposure-response was explored graphically and using logistic regression. In addition, the influence of chronic kidney disease and diuretic use on the allopurinol dose and oxypurinol AUCss0-tau requirements to achieve the serum urate target were explored. Data from 258 patients with gout taking allopurinol representing 1288 paired steady-state oxypurinol and serum urate measurements were available. Higher oxypurinol exposure seems to be required for urate-lowering response normalization and achieve the serum urate target in individuals with reduced kidney function and those taking diuretics. However, allopurinol dose requirements were reduced by 2-fold at the extremes of kidney function and unchanged in those taking or not taking diuretics. A lower allopurinol maintenance dose was required in patients with reduced kidney function (CLcr <30 mL/min), but this was not proportional to CLcr. Diuretic therapy did not influence allopurinol dose requirements.

Impact of fine particulate matter (PM2.5) on ocular health among people living in Chiang Mai, Thailand

Considering the limited information on the impact of PM2.5 content on ocular health, a follow-up study was conducted on 50 healthy adults. Samples were collected twice, once before the PM2.5 exposure season and again after exposure. Daily PM2.5 concentration data was gathered from Thung Satok monitoring station. All subjects completed the self-structured ocular symptom questionnaire. The concentrations of 1-OHP were determined using HPLC-FLD. Logistic regression analysis investigated the relationship between PM2.5 toxicity and ocular symptoms. The findings revealed that daily PM2.5 concentrations surpassed the WHO-recommended range by around threefold. Exposure to PM2.5 significantly raised the likelihood of ocular redness (adjusted OR: 12.39, 95% CI), watering (adjusted OR: 2.56, 95% CI), and dryness (adjusted OR: 5.06, 95% CI). Additionally, these symptoms had an exposure-response relationship with increasing 1-OHP levels. Ocular symptoms worsened in frequency and severity during the high PM2.5 season, showing a strong link to elevated PM2.5 levels. Lymphocyte counts were also positively correlated with redness, watering, and dryness during high PM2.5 exposure. In conclusion, our study shows that subjects exposed to higher PM2.5 levels presented more significant ocular surface alterations.

Review article: Optimisation of biologic (monoclonal antibody) therapeutic response in inflammatory bowel disease.

There are a plethora of therapeutic options for the management of inflammatory bowel disease (IBD). Despite this, clinical outcomes with standard dosing often fall short of established targets. While efforts centre on developing novel therapies, there is an ongoing need to optimise the use of existing agents. To focus on strategies to optimise response to biologic (monoclonal antibody) therapies in IBD, including use of therapeutic drug monitoring (TDM). An extensive review of the published literature. TDM is a strategy aimed at enhancing the effectiveness of drugs with variable exposure-response relationships by measuring serum concentrations of biologic therapies and detecting neutralising antibodies. Reactive TDM is performed when therapeutic goals have not been achieved. Tumour necrosis factor alpha (TNF) inhibitors are the treatment class most frequently associated with immunogenicity and loss of response. Immunogenicity can be reduced through avoidance of low serum drug concentrations by dose optimisation or use of concomitant immunomodulator therapy. Subtherapeutic dosing in the absence of antidrug antibodies is best managed by dose escalation or dose interval reduction. Persistent neutralising drug antibodies necessitate switching to an alternative therapy. Proactively ensuring adequate serum trough levels might help sustain treatment durability and prevent loss of response. Newer non-TNF inhibitors demonstrate less robust exposure-response relationships, and TDM may not prove as beneficial. In the treat-to-target paradigm of IBD treatment, optimising treatment effect with dose optimisation, which may involve strategies including TDM, increases the likelihood of achieving clinical remission and may accomplish deeper levels of remission beyond symptom control.

Analysis of Nirmatrelvir Entry into Pulmonary Lining Fluid in Patients with COVID-19: A Unique Perspective to Explore and Understand the Target Plasma Concentration of 292 ng/mL in Antiviral Activity.

Currently, the applicant has chosen a target plasma trough concentration for nirmatrelvir, which is adjusted to 292 ng/mL based on the drug's molecular weight (499.54 Daltons), its binding to human plasma proteins (69%), and the in vitro antiviral EC90 value (181 nM). However, the current exposure-effect relationships (ER) analysis of viral load in patients enrolled in the EPIC-HR study has not revealed clinically significant trends in the ER. Given that the lungs are the primary site of COVID-19 infection, we aim to further understand this exposure relationship by exploring and analyzing the penetration characteristics of nirmatrelvir in the lungs. To explore and understand the target plasma concentration of 292 ng/mL in antiviral activity. We identified all critically ill patients with coronavirus disease 2019 who received nirmatrelvir/ritonavir treatment in the respiratory intensive care unit of Changhai hospital between January 2023 and October 2023. Samples of plasma and bronchoalveolar lavage fluid were obtained at pre-dose trough concentrations after administration of nirmatrelvir (NMV). The relationship between NMV levels in plasma and the epithelial lining fluid (ELF) was assessed by determining concentrations of NMV. There was a significant relationship between NMV levels in plasma and ELF (ELF = 0.4976*PLASMA- 204; R = 0.96), with a correlation whose slope (0.4976) suggested that the blood-to-ELF ratio of drug penetration was 2:1. A negative value from the equation indicates that NMV requires to reach baseline concentration to penetrate the ELF. The relationship between NMV levels in plasma and ELF with low permeability and a negative baseline value suggests that the target plasma concentration of 292 ng/mL is insufficient for antiviral activity. This study provides a unique perspective to explore and understand no clinically meaningful trend of exposure-response relationships in patients enrolled in EPIC-HR.

Effect of Preoperative Oral Cannabidiol-Rich Cannabis Extract on Anxiety and Postoperative Pain after Endodontic Treatment: A Double-Blind Randomized Clinical Trial

IntroductionThe aim of the present study was to evaluate the effectiveness of cannabidiol (CBD)-rich Cannabis extract in reducing anxiety and postoperative pain in patients submitted to endodontic treatment. MethodsThe study was carried out after approval by the Research Ethics Committee (Registration No. 5.075.961). The following groups were tested: CBD and placebo. Pain was measured using a visual analog scale before the start of treatment and 24, 48, and 72 hours and 7 days after the session. Anxiety was assessed using the Modified Dental Anxiety Scale and a visual analog scale, before and immediately after treatment. In addition, salivary cortisol was measured before drug administration and after anesthesia. Data were analyzed descriptively using absolute frequencies and percentages, with a 5% margin of error. ResultsThe mean anxiety scores were higher in the CBD group than in the placebo group in each assessment (pre: 5.06 vs 3.07, respectively; post: 4.61 vs 2.60). However, there was no significant difference in the reduction of dental anxiety at the beginning of the consultation and throughout the procedure. We did not find statistically significant differences in postoperative pain between the CBD and placebo groups at any of the time points. ConclusionsThere was no evidence of an exposure-response relationship between the intervention and control groups. However, more studies are needed to determine clinical outcomes.

Characterisation of the pharmacokinetic and pharmacodynamic relationship of milvexian in total knee replacement patients

Abstract Background Milvexian, an oral factor XIa inhibitor, is currently being evaluated in patients at risk for thrombotic events due to atrial fibrillation, ischaemic stroke, or acute coronary syndrome. The exposure-response relationship between clinical efficacy and safety endpoints and milvexian pharmacokinetic (PK) metrics was recently submitted as a separate publication. Characterisation of the relationship between the coagulation pharmacodynamic (PD) markers versus milvexian PK metrics at the patient level has yet to be reported. Purpose This analysis characterised the relationship between the coagulation biomarkers, activated partial thromboplastin time (aPTT) and prothrombin time (PT), and milvexian systemic exposure in patients undergoing total knee replacement (TKR) evaluated in the AXIOMATIC-TKR study. Methods A population pharmacokinetic (PopPK) model was previously developed and characterised the PK of milvexian in TKR patients well. The PK/PD relationships between observed aPTT and PT versus PopPK model estimated time-matched milvexian plasma concentrations via nonlinear mixed effects modeling. The relationship between key clinical safety endpoints (e.g., any bleeding or clinically relevant non-major bleeding) and individual PD marker change (e.g., aPTT ratio to baseline) was also explored. Results The aPTT increased with increasing plasma concentration of milvexian over the range of doses evaluated in the study (25mg QD to 200mg BID). An Emax type of model reasonably characterised the PK/PD relationship between the aPTT and model predicted time-matched milvexian plasma concentration, which is consistent with previously observed relationships in healthy volunteers. No change was observed in PT with increased milvexian exposure. No obvious relationship was identified between any (including clinically relevant non-major) bleeding and aPTT ratio to baseline. Conclusions Increased milvexian exposure is directly correlated with aPTT prolongation over the range of doses evaluated in the TKR study. There was no obvious relationship between any (including clinically relevant non-major) bleeding and aPTT ratio. The PK/PD relationship of aPTT without a parallel relationship in PT distinguishes milvexian, a FXIa inhibitor, from previously studied FXa inhibitors. These analyses were a complementary component in dose selection for the milvexian Phase 3 program. Figure 1. PK/PD relationship between aPTT (left) and PT (right) and estimated time-matched plasma concentration (AXIOMATIC-TKR study)

Occupational exposure to nickel or hexavalent chromium and the risk of lung cancer (SYNERGY)

Abstract Background Hexavalent chromium (Cr(VI)) and nickel (Ni) are known occupational carcinogens, with frequent exposures, for example, in welding-related activities. However, limited evidence exists on the exposure-response relationship of Cr(VI) or Ni with lung-cancer risk. We estimated lung-cancer risks based on quantitative indices of occupational exposure to each metal, and their interaction with smoking habits. Methods Fourteen case-control studies from Europe and Canada (16,901 cases, 20,965 control subjects) were pooled. A measurement-based job-exposure matrix was used to estimate year- and region-specific exposure levels for Cr(VI) and Ni, which were linked to the study subjects’ occupational histories. Odds ratios (OR) and 95% confidence intervals (CI) were calculated, adjusting for study, age group, smoking, and exposure to other occupational lung carcinogens. Results The OR for the highest quartile (&amp;gt;99.5 μg/m3-years) of cumulative exposure to Cr(VI) in men was 1.32 (95% CI 1.19-1.47) and for nickel (highest quartile &amp;gt;78.1 μg/m3-years) OR = 1.29 (95% CI 1.15-1.45). Corresponding effect estimates in women were slightly lower. The joint effects of Cr(VI) and nickel with smoking were generally greater than additive. Conclusions We observed positive exposure-response relationships in the low-dose range of Cr(VI) and Ni exposures, based on a large study population including detailed information on smoking habits and a measurement-based job-exposure matrix. Although, we cannot rule out a combined classical measurement and Berkson error structure that may have caused bias in our risk estimates, our results provide empirical evidence to further specify preventive measures at the workplace in order to protect workers from hazardous substances. Key messages • Relatively low cumulative levels of occupational exposure to Cr(VI) and Ni were associated with increased ORs for lung cancer, particularly in men. • Important empirical insights for the prevention of cancer at the workplace can be drawn from the results.

Low ambient temperature and incident myocardial infarction with or without obstructive coronary arteries: a Chinese nationwide study.

Although non-optimum ambient temperature is a major non-traditional risk factor for acute myocardial infarction, there is no prior knowledge on whether non-optimum ambient temperature could differentially affect myocardial infarction with obstructive coronary artery disease (MI-CAD) and myocardial infarction with non-obstructive coronary arteries (MINOCA). Using the Chinese Cardiovascular Association database-Chest Pain Center Registry, a nationwide, time-stratified, case-crossover investigation was conducted from 2015 to 2021. Meteorological data were obtained from an established satellite-based model, and daily exposures were assigned according to the onset of myocardial infarction in each patient. A conditional logistic regression model combined with distributed lag non-linear models (10 days) was used to estimate the exposure-response relationships. A total of 83 784 MINOCA patients and 918 730 MI-CAD patients were included. The risk of MINOCA and MI-CAD associated with low temperature occurred at lag 2 day and lasted to 1 week. Extremely low temperature was associated with a substantially greater odds ratio (OR) of MINOCA [OR 1.58, 95% confidence interval (CI) 1.31-1.90] than MI-CAD (unmatched: OR 1.32, 95% CI 1.23-1.43; equally matched by age and sex: OR 1.25, 95% CI 1.04-1.50), compared with the corresponding reference temperatures (30°C, 35°C, and 30°C). Stronger associations were observed for patients who were aged ≥65 years, female, or resided in the south. There was no significant difference for the impacts of high temperature on MINOCA and MI-CAD. This nationwide study highlights the particular susceptibility of MINOCA patients to ambient low temperature compared with that of MI-CAD patients.

The burden of lung cancer attributable to ambient PM2.5 exposure: a systematic literature review

Abstract Background Lung cancer is recognized as one of the most common causes of cancer morbidity and mortality worldwide and is the second cause of death with highest years of life lost in highly developed regions. Ambient exposure to particulate matter (PM2.5) is the leading global environmental risk factor. Long-term exposure to PM2.5 is associated with several health outcomes, including lung cancer, ischemic heart disease, and chronic obstructive pulmonary disease. Aim To review and estimate the impact attributable to PM2.5 exposure due to lung cancer. Methods A systematic review and a meta-analysis were conducted to determine whether long-term exposure to PM2.5 increases the risk of lung cancer and to derive exposure-response relationships between PM2.5 and lung cancer. The literature search was performed in databases (i.e., Pubmed/Scopus) and studies published from January 1, 2010 onwards were considered. Studies describing the association between long-term exposure to the pollutant under research and the incidence, prevalence, and mortality of lung cancer, considering a relative measure of association were included, with no restriction in geographical area. Results In the literature review, 2215 articles were considered for the first step of data synthesis, all articles were screened, considering the screening of titles (first step), abstracts (second step) and full-text (third step) considering the inclusion criteria. In a second step the data was extracted from the included articles (n = 129) and considering the variables related to the characteristics of the study and the study population, exposure, and outcome measurement, and details of risk of bias assessment. Conclusions These findings provide data to synthesize effect size estimates using a Meta-Regression - Bayesian, Ensemble, Regularized, Trimmed (MR-BRT) model, important to provide evidence data on the impact of air pollution on human health, which is crucial for decision-making. Key messages • Long-term exposure to PM2.5 increases lung cancer risk so the estimating of the impact of the exposure is an urgent need to provide evidence-based data for air quality improvement. • Meta-analysis aims to establish a relation between PM2.5 exposure and the burden of lung cancer.

Long-term ozone exposure and asthma: a systematic review and meta-analysis

Abstract Background Ambient air pollution, particularly surface ozone, is a significant global health concern, with 9 out of 10 people exposed to levels exceeding WHO guidelines. This exposure is linked to approximately 7 million premature deaths annually, a number expected to double by 2050. While the effects of short-term exposure to ozone on exacerbation of asthma symptoms and mortality are well-documented, the impact of long-term exposure remains unclear. Aim This systematic literature review aims to quantify the association between long-term exposure to ozone and asthma incidence and prevalence and derive an exposure-response relationship. Methods International electronic databases, including PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science, were searched, supplemented by grey literature sources such as Google Scholar and WHO - Global Index Medicus from conception to July 31, 2023. Observational epidemiological cohort, case-control, or cross-sectional studies reporting quantitative associations between exposure and outcome were included. Meta-analysis will synthesize effect size estimates using a Meta-Regression - Bayesian, Ensemble, Regularized, Trimmed (MR-BRT) model. Results A total of 5,947 titles were initially identified from databases, and following the removal of duplicates, 3,235 titles and abstracts were screened, resulting in 84 articles deemed eligible for full-text review. The full-text screening identified 29 studies comprising 38 articles. A comprehensive overview of the included studies will be provided. We will describe the study settings, design, and measurement methods used by the identified studies. Furthermore, results of the MR-BRT model will be summarized, and exposure-response functions will be discussed. Funding: This work is part of the BEST-COST project which is funded by the European Union’s Horizon Europe programme under Grant Agreement No.101095408. Key messages • This research fills the gap in understanding the association between long-term exposure to ambient ozone and asthma incidence and prevalence. • Developing exposure-response functions would enable estimation of the disease burden associated with long-term ozone exposure.

Coordinating public and government responses to air pollution exposure: A multi-source data fusion approach

Aligning public demand with government supply of clean air aids in efficient air pollution control and enhancement of public happiness. However, comparative empirical analyses of public and government attention to air quality changes are still sparse due to data and methodological constraints. Here, we adopt multi-source data fusion approaches to assess the impacts of air pollution exposure on public and government attention. Specifically, remote and social sensing data, alongside keywords extracted from textual data, are utilized to quantify air pollution exposure and corresponding public and government attention levels in 273 Chinese cities from 2011 to 2019, and a two-stage least squares regression model is employed to tackle reverse causality issues underlying the exposure-response relationship. Our findings reveal that, on average, a unit increase in PM2.5 levels would result in a 17.7% growth in public attention and a 12.7% rise in government attention, respectively, suggesting that demand-driven public attention tends to be more sensitive to air quality changes than policy-driven government attention. Results for the spatial-temporal heterogeneity further demonstrate that public attention varies across time and space, whereas government attention remains relatively consistent. Additionally, we have identified 116 cities exhibiting disparities between the public and government responses to air quality changes, calling for environmental policy refinements to better serve the needs of residents. This study emphasizes the necessity of public engagement in environmental governance and offers rich policy implications for air pollution control in China.

Exposure-Efficacy Analysis and Dopamine D2 Receptor Occupancy in Adults with Schizophrenia after Treatment with the Monthly Intramuscular Injectable Risperidone ISM.

Dopamine D2 receptor occupancy (D2RO) significantly influences the clinical effectiveness and safety of many antipsychotic drugs. Maintaining a D2RO range of 65%-80% provides the best antipsychotic effects while minimizing adverse reactions. Data from a Phase III trial were used to establish an exposure-response relationship for monthly intramuscular Risperidone ISM (75 and 100 mg) or placebo administered to adults with schizophrenia. Pharmacodynamic analysis was based on an Emax model for Positive and Negative Syndrome Scale (PANSS) developed in NONMEM. Plasma concentrations of the active moiety were derived using a previously developed population pharmacokinetic model, which was used for D2RO simulations in conjunction with a published Emax model. The optimal D2RO range (65%-80%) was reached for the median within hours following the first injection of both Risperidone ISM doses. At steady state, median D2RO for both doses remained above 65% throughout the 28-day dosing period and demonstrated lower variability than oral risperidone. PANSS response did not differ significantly between dose groups, most likely because active moiety concentrations had already reached the plateau of the concentration-response relationship. The pharmacokinetic/pharmacodynamic analysis showed a profound placebo effect (-11.7%), and an additional maximal drug effect (-6.6%) resulting in a total PANSS improvement over time of -18.3%. Pharmacokinetic/pharmacodynamic modeling quantified a PANSS improvement over time after Risperidone ISM administration. The response was not significantly different in either dose group, likely because D2RO was already above the proposed efficacy threshold (65%) within 1 h after the first Risperidone ISM injection and remained above this level following repeated administrations.

The impact of exposure assessment on associations between air pollution and cardiovascular mortality risks in the city of Rio de Janeiro, Brazil

Despite a growing literature for complex air quality models, scientific evidence lacks of the influences of varying exposure assessments and air quality data sources on the estimated mortality risks. This case-crossover study estimated cardiovascular mortality risks from fine particulate matter (PM2.5) and ozone (O3) exposures, using varying exposure methods, to aid understanding of the impact of exposure methods in the health risk estimation. We used individual-level cardiovascular mortality data in the city of Rio de Janeiro, 2012–2016. PM2.5 and O3 exposure levels (from the date of death to seven prior days [lag0–7]) were estimated at the individual level or district level using either the WRF-Chem modeling data or monitoring data, resulting in a total of 10 exposure methods. The exposure-response relationships were estimated using multiple logistic regressions. The changes in cardiovascular mortality were represented as an odds ratio (OR) and 95% confidence intervals (CIs) for an interquartile range (IQR) increase in the exposures. Results showed that socioeconomically more advantaged populations had lower access to the stationary monitoring networks. Higher variance in the estimated exposure levels across the 10 exposure methods was found for PM2.5 than O3. PM2.5 exposure was not associated with mortality risk in any exposure methods. WRF-Chem-based O3 exposure estimated for each individual of the entire population found a significant mortality risk (OR = 1.06, 95% CI: 1.01, 1.11), but not the other exposure methods. Higher risks for females and older populations were suggested for O3 estimates estimated for each individual using the WRF-Chem data. Findings indicate that decisions on exposure methods and data sources can lead to substantially varying implications for air pollution risks and highlight the need for comprehensive exposure and health impact assessments to aid local decision-making for air pollution and public health.

What Explains Hop Growers' Fungicide Use Intensity and Management Costs in Response to Powdery Mildew?

Methods for causal inference from observational data are common in human disease epidemiology and social sciences but are used relatively little in plant pathology. We draw upon an extensive data set of the incidence of hop plants with powdery mildew (caused by Podosphaera macularis) collected from yards in Oregon from 2014 to 2017 and associated metadata on grower cultural practices, cultivar susceptibility to powdery mildew, and pesticide application records to understand variation in and causes of growers' fungicide use and associated costs. An instrumental causal forest model identified growers' spring pruning thoroughness, cultivar susceptibility to two of the dominant pathogenic races of P. macularis, network centrality of yards during May-June and June-July time transitions, and the initial strain of the fungus detected as important variables determining the number of pesticide active constituents applied by growers and the associated costs they incurred in response to powdery mildew. Exposure-response function models fit after covariate weighting indicated that both the number of pesticide active constituents applied and their associated costs scaled linearly with the seasonal mean incidence of plants with powdery mildew. Although the causes of pesticide use intensity are multifaceted, biological and production factors collectively influence the incidence of powdery mildew, which has a direct exposure-response relationship with the number of pesticide active constituents that growers apply and their costs. Our analyses point to several potential strategies for reducing pesticide use and costs for management of powdery mildew on hop. We also highlight the utility of these methods for causal inference in observational studies.

Urine is better for rare earth elements bimonitoring in long-term exposed population: An exposure-response relationship study

With the soaring use of rare earth elements (REEs) worldwidely in high-technology and clean energy industries, there were growing concerns for adverse health effect from the REEs exposure. However, there is a lack of biomonitoring research concerning both urine and blood in population with definite exposure. We performed a biomonitoring study that involved 103 REEs exposed males and 110 males as non-REEs exposed controls. We measured the levels of REEs in environment and urine and blood samples from participants, and explored the exposure-response relationship between REEs in environment and body fluids. The effects of exposure duration and smoking status on the internal exposure level of REEs were also investigated. The results showed environmental REEs level of exposure group was significantly higher than that of control group (range of geometric mean of exposure vs. control: 1.08-4.07 × 104 ng/m3 vs. <LOD-2.16 × 102 ng/m3). Six elements with detection rates higher than 60% in blood or urine samples were lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), samarium (Sm), gadolinium (Gd). We found the REEs concentrations both in urine and blood of exposure population were significantly higher than controls, median range of the above 6 elements of urine and blood was 0.02–1.06 μmol/mol vs. <LOD-0.01 μmol/mol creatinine and 0.01–0.79 μg/L vs. <LOD-0.38 μg/L. The correlations between both blood and urine level of REEs and environment level showed significant. The correlation coefficients with urine levels are higher than with blood. Biomonitoring results showed good exposure-response relationship in urine REEs, while no positive response in blood samples. Smoking status, drinking status and years of exposure showed little effect on the level of REEs. Our results suggested that both blood and urine can be used to monitor REEs exposure, while urinary REEs is promising for risk assessment in population.

Per- and poly-fluoroalkyl substances (PFAS) accelerate biological aging mediated by increased C-reactive protein

Unhealthy biological aging is related to higher incidence of varied age-related diseases, even higher all-cause mortality. Previous small sample size study suggested that Per- and poly-fluoroalkyl substances (PFAS) was associated with biological aging, but the evidence of exposure-response relationships, potential effect modifiers, and potential mediators were not investigated. Therefore, we conducted a cross-sectional analysis of national study including 14, 865 adults in the US from 8 survey cycles of NHANES from 2003 to 2018, to investigate the associations of PFAS compounds in body serum, including perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), with biological aging. Generalized linear models showed that higher human exposure to PFAS was associated with accelerated biological aging. Importantly, human exposure to PFOA, PFOS, PFNA, and PFHxS with detected level (above 0.10 ng/mL) was associated with an average of 3.3 year (95 %CI: 2.7, 3.9, P < 0.001), 14.9 year (95 %CI: 7.2, 22.7, P < 0.001), 10.9 years (95 %CI: 3.9, 17.7, P < 0.001), and 8.8 years (95 %CI: 4.8, 12.9, P < 0.001) of biological aging acceleration. Cubic spline models indicated exposure-response relationships where there was no safe threshold of PFAS level regarding harms to human healthy aging. The weighted sum regression model found the significant associations of PFAS compound mixture with biological aging acceleration, and PFOA was the dominant contributor among 4 PFAS compounds. Mediation analysis suggested that C-reactive protein, one of the inflammation biomarkers, might play as mediator in PFAS-induced accelerated biological aging, but not Triglyceride-glucose index. In summary, our study suggests that the effects of PFAS on biological aging acceleration should be of concern and more action plans to address their negative impact on human health should be launched.

Respiratory Symptoms and Paper Dust Exposure among Workers in the Paper Industry in Ethiopia: A Comparative Cross-Sectional Study

Chronic respiratory symptoms are a health concern in the paper industry. This study evaluates the association between personal inhalable paper dust exposure and chronic respiratory symptoms among workers in this industry. In total, 270 workers from the paper industry and 267 from a water bottling factory participated. Chronic respiratory symptoms were assessed using a standardized questionnaire, modified from the American Thoracic Society. A job exposure matrix, based on cross-sectional personal measurements of inhalable paper dust, was used to estimate the exposure–response relationship between cumulative dust exposure and chronic respiratory symptoms. There was a higher prevalence of chronic coughs (27.4% vs. 7.5%), breathlessness (25.6% vs. 11%), coughs with sputum (21.1% vs. 1.1%), and wheezing (25.6% vs. 5%) among paper workers compared to those in the water bottling industry. A Poisson regression analysis revealed that the prevalence ratios for chronic coughs (APR = 3.3 and 95% CI: 2.0–5.4), breathlessness (APR = 2.2 and 95% CI: 1.4–3.4), and wheezing (APR = 4.3 and 95% CI: 2.3–7.7) were significantly higher in paper workers than in water bottling workers. Among paper workers, a significant exposure–response relationship was observed between cumulative dust exposure and chronic coughs after adjusting for age, sex, history of respiratory illnesses, work in other dusty industries, and use of biofuels. As there were only four ever-smokers, smoking was not included in the regression analysis. The results show a significant association between dust exposure and coughing, highlighting the need for control measures to prevent the development of respiratory symptoms among workers.

A case study on the exposure-response relationship of sleep disturbance due to road traffic noise - As a case in Japan in the 2020s

A socio-acoustic survey was conducted among residents living along major arterial roads in Kanagawa Prefecture, Japan, to examine the occurrence of sleep disturbances due to road traffic noise. Lnight noise maps was introduced for estimating ranges from 30 dB to 80 dB. We asked the frequency of "difficulty falling asleep," "nocturnal awakenings," "early morning awakenings", "feeling unrefreshed in the morning",and "daytime sleepiness" due to road traffic noise. Cases experiencing any of these items more than three times a week were defined as "highly sleep disturbed (HSD)", and that one or twice a week were defined as "sleep disturbed (SD)", respectively. The exposure response relationships between those and Lnight were examined with the independent variables of noise sensitivity, gender, and age. The results of multiple logistic regression analysis revealed that Lnight, and noise sensitivity had a significant effect on SD, while noise sensitivity significantly affected HSD. We show the results of this study in comparison with previous surveys on sleep disturbances conducted in Japan and other regions.