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BEIR VII develops the most up-to-date and comprehensive risk estimates for cancer and other health effects from exposure to low-level ionizing radiation. It is among the first reports of its kind to include detailed estimates for cancer incidence in addition to cancer mortality. In general, BEIR VII supports previously reported risk estimates for cancer and leukemia, but the availability of new and more extensive data have strengthened confidence in these estimates. A comprehensive review of available biological and biophysical data supports a \"linear-no-threshold\" (LNT) risk model-that the risk of cancer proceeds in a linear fashion at lower doses without a threshold and that the smallest dose has the potential to cause a small increase in risk to humans. The report is from the Board on Radiation Research Effects that is now part of the newly formed Nuclear and Radiation Studies Board.

Immune checkpoint inhibitors (ICIs) have demonstrated significant clinical impact in improving overall survival of several malignancies associated with poor outcomes; however, only 20–40% of patients will show long-lasting survival. Further clarification of factors related to treatment response can support improvements in clinical outcome and guide the development of novel immune checkpoint therapies. In this article, we have provided an overview of the pharmacokinetic (PK) aspects related to current ICIs, which include target-mediated drug disposition and time-varying drug clearance. In response to the variation in treatment exposure of ICIs and the significant healthcare costs associated with these agents, arguments for both dose individualization and generalization are provided. We address important issues related to the efficacy and safety, the pharmacodynamics (PD), of ICIs, including exposure–response relationships related to clinical outcome. The unique PK and PD aspects of ICIs give rise to issues of confounding and suboptimal surrogate endpoints that complicate interpretation of exposure–response analysis. Biomarkers to identify patients benefiting from treatment with ICIs have been brought forward. However, validated biomarkers to monitor treatment response are currently lacking.

Abstract The Global Initiative for Asthma guidelines use the traditional terminology of “low,” “medium,” and “high” doses of inhaled corticosteroids (ICS) to define daily maintenance doses of 100 to 250 μg, >250 to 500 μg, and >500 μg, respectively, of fluticasone propionate or equivalent for adults with asthma. This concise clinical review proposes that this terminology is not evidence based and that prescribing practice based on this terminology may lead to the use of inappropriately excessive doses of ICS. Specifically, the ICS dose that achieves 80–90% of the maximum obtainable benefit is currently classified as a low dose, with the description of two higher dose levels of medium and high, which are associated with significant risk of systemic adverse effects. Asthma guidelines and clinician prescribing practice need to be modified in accordance with the currently available evidence of the dose–response relationship of ICS in adult asthma. We propose a reclassification of ICS doses based on a “standard daily dose,” which is defined as 200–250 μg of fluticasone propionate or equivalent, representing the dose at which approximately 80–90% of the maximum achievable therapeutic benefit of ICS is obtained in adult asthma across the spectrum of severity. It is recommended that ICS treatment be started at these standard doses, which then represent the doses at which maintenance ICS are prescribed at step 2 and within ICS/long-acting β-agonist combination therapy at step 3. The opportunity is available to prescribe higher doses within ICS/long-acting β-agonist maintenance therapy in accordance with the stepwise approach to asthma treatment at step 4.

The anti–interleukin-1 antibody canakinumab was effective at controlling and preventing recurrence of flares in autoimmune inflammatory diseases: familial Mediterranean fever, mevalonate kinase deficiency, and the TNF receptor–associated periodic syndrome.

Despite advances in therapy for rheumatic diseases, hydroxychloroquine remains almost universally recommended for the treatment of systemic lupus erythematosus (SLE), and is often used in the management of other rheumatic diseases such as rheumatoid arthritis (RA). However, the major dose-limiting toxicity of hydroxychloroquine is retinopathy that can lead to loss of vision. New highly sensitive screening methods can identify early stages of retinopathy, and studies that include these modalities have indicated a substantially higher prevalence of hydroxychloroquine retinopathy than was previously recognized, resulting in revisions to ophthalmology guidelines and the recommendation of a low dose of hydroxychloroquine for many patients. However, the efficacy of low-dose hydroxychloroquine for treating SLE and other rheumatic diseases is unknown. Further studies are required to establish the effectiveness and retinal safety of the latest hydroxychloroquine treatment recommendations.

Risk assessment has become a dominant public policy tool for making choices, based on limited resources, to protect public health and the environment. It has been instrumental to the mission of the U.S. Environmental Protection Agency (EPA) as well as other federal agencies in evaluating public health concerns, informing regulatory and technological decisions, prioritizing research needs and funding, and in developing approaches for cost-benefit analysis. However, risk assessment is at a crossroads. Despite advances in the field, risk assessment faces a number of significant challenges including lengthy delays in making complex decisions; lack of data leading to significant uncertainty in risk assessments; and many chemicals in the marketplace that have not been evaluated and emerging agents requiring assessment. Science and Decisions makes practical scientific and technical recommendations to address these challenges. This book is a complement to the widely used 1983 National Academies book, Risk Assessment in the Federal Government (also known as the Red Book). The earlier book established a framework for the concepts and conduct of risk assessment that has been adopted by numerous expert committees, regulatory agencies, and public health institutions. The new book embeds these concepts within a broader framework for risk-based decision-making. Together, these are essential references for those working in the regulatory and public health fields.

The majority of people with hypertension require more than one medication to achieve blood pressure control. Many patients are prescribed multipill antihypertensive regimens rather than single-pill fixed-dose combination (FDC) treatment. Although FDC use may improve medication adherence, the impact on patient outcomes is unclear. We compared clinical outcomes and medication adherence with FDC therapy versus multipill combination therapy in a real-world setting using linked clinical and administrative databases. We conducted a population-based retrospective cohort study of 13,350 individuals 66 years and older in Ontario, Canada with up to 5 years of follow-up. We included individuals who were newly initiated on one angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II-receptor blocker (ARB) plus one thiazide diuretic. High-dimensional propensity score matching was used to compare individuals receiving FDC versus multipill therapy. The primary outcome was a composite of death or hospitalization for acute myocardial infarction (AMI), heart failure, or stroke. We conducted 2 analyses to examine the association between adherence and patient outcomes. First, we performed an on-treatment analysis to determine whether outcomes differed between groups while patients were on treatment, censoring patients when they first discontinued treatment, defined as not receiving medications within 150% of the previous days' supply. Second, we conducted an intention-to-treat analysis that followed individuals allowing for breaks in treatment to quantify the difference in drug adherence between groups and assess its impact on clinical outcomes. As expected, there was no significant difference in the primary outcome between groups in the on-treatment analysis (HR 1.06, 95% CI 0.86-1.31, P = 0.60). In the intention-to-treat analysis, the proportion of total follow-up days covered with medications was significantly greater in the FDC group (70%; IQR 19-98) than in the multipill group (42%, IQR 11-91, P < 0.01), and the primary outcome was less frequent in FDC recipients (3.4 versus 3.9 events per 100 person-years; HR 0.89, 95% CI 0.81-0.97, P < 0.01). The main limitations of this study were the lack of data regarding cause of death and blood pressure measurements and the possibility of residual confounding. Among older adults initiating combination antihypertensive treatment, FDC therapy was associated with a significantly lower risk of composite clinical outcomes, which may be related to better medication adherence.

Background: Current knowledge about Chornobyl-related thyroid cancer risks comes from ecological studies based on grouped doses, case-control studies, and studies of prevalent cancers. Objective: To address this limitation, we evaluated the dose-response relationship for incident thyroid cancers using measurement-based individual iodine-131 (1-131) thyroid dose estimates in a prospective analytic cohort study. Methods: The cohort consists of individuals < 18 years of age on 26 April 1986 who resided in three contaminated oblasts (states) of Ukraine and underwent up to four thyroid screening examinations between 1998 and 2007 (n = 12,514). Thyroid doses of 1-131 were estimated based on individual radioactivity measurements taken within 2 months after the accident, environmental transport models, and interview data. Excess radiation risks were estimated using Poisson regression models. Results: Sixty-five incident thyroid cancers were diagnosed during the second through fourth screenings and 73,004 person-years (PY) of observation. The dose-response relationship was consistent with linearity on relative and absolute scales, although the excess relative risk (ERR) model described data better than did the excess absolute risk (EAR) model. The ERR per gray was 1.91 [95% confidence interval (CI), 0.43-6.34], and the EAR per 10⁴ PY/Gy was 2.21 (95% CI, 0.04-5.78). The ERR per gray varied significantly by oblast of residence but not by time since exposure, use of iodine prophylaxis, iodine status, sex, age, or tumor size. Conclusions: I-131-related thyroid cancer risks persisted for two decades after exposure, with no evidence of decrease during the observation period. The radiation risks, although smaller, are compatible with those of retrospective and ecological post-Chornobyl studies.

Background Understanding dose-response relationships is crucial in optimizing clinical outcomes, particularly in complex interventions such as psychotherapy. While dose-response research is common in pharmaceutical contexts, its application in complex interventions remains underexplored. This review examines existing statistical methods for modelling dose-response relationships in complex interventions, focusing on psychotherapy. Methods A systematic literature search following PRISMA guidelines identified studies proposing novel statistical methods or innovative applications of methods for analysing dose-response relationships. The search encompassed various databases, yielding 224 articles. After screening and exclusion, seven studies were eligible for analysis. Data synthesis categorized methods into three groups: multilevel and longitudinal modelling, non-parametric regression, and causal inference with instrumental variables. Additionally, a survey was conducted among clinical researchers to understand their perspectives on dosing decisions in psychotherapy trials. Results Multilevel and longitudinal modelling techniques, although informative, were only applicable to participants with sessional data, limiting causal interpretations. Non-parametric regression methods provided avenues for causal inference but were constrained by assumptions. Causal inference with instrumental variables showed promise in addressing these limitations, particularly in randomised controlled trials, yet still require a priori assumption of the dose-response function. The results of our survey suggested that there is not sufficient information available to clinical researchers to make empirical dosing decisions in psychotherapeutic complex interventions. Conclusions This review highlights the scarcity of robust statistical methods for evaluating dose-response relationships in psychotherapy trials. The dose-response methodology applied to RCTs remains underdeveloped, hindering causal interpretations or requiring strong assumptions. Traditional approaches oversimplify outcomes, highlighting the need for more sophisticated methodologies. Clinical researchers emphasized the necessity for clearer guidelines and enhanced patient involvement in dosing decisions, echoing the broader findings of the review. Future research requires methodological advancements to inform effective decision-making in psychotherapy trials, ultimately optimizing patient care and outcomes.

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- -dioxin (TCDD) was used as an example to demonstrate the new dose-response modeling framework. There were three major steps included: ) identifying and extracting key quantifiable events (KQEs), ) calculating essential doses that sequentially activate KQEs using the benchmark dose (BMD) methodology, and ) 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.