The Conflict between Regulatory Agencies over the 20,000-Fold Lowering of the Tolerable Daily Intake (TDI) for Bisphenol A (BPA) by the European Food Safety Authority (EFSA).

BACKGROUND: The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to 0.2 ng/kg body weight (BW)/day. BPA is an extensively studied high production volume endocrine disrupting chemical (EDC) associated with a vast array of diseases. Prior risk assessments of BPA by EFSA as well as the US Food and Drug Administration (FDA) have relied on industry-funded studies conducted under good laboratory practice protocols (GLP) requiring guideline end points and detailed record keeping, while also claiming to examine (but rejecting) thousands of published findings by academic scientists. Guideline protocols initially formalized in the mid-twentieth century are still used by many regulatory agencies. EFSA used a 21st century approach in its reassessment of BPA and conducted a transparent, but time-limited, systematic review that included both guideline and academic research. The German Federal Institute for Risk Assessment (BfR) opposed EFSA's revision of the TDI for BPA. OBJECTIVES: We identify the flaws in the assumptions that the German BfR, as well as the FDA, have used to justify maintaining the TDI for BPA at levels above what a vast amount of academic research shows to cause harm. We argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications using the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) nonguideline academic studies in a collaborative government-academic program model. DISCUSSION: We strongly endorse EFSA's revised TDI for BPA and support the European Commission's (EC) apparent acceptance of this updated BPA risk assessment. We discuss challenges to current chemical risk assessment assumptions about EDCs that need to be addressed by regulatory agencies to, in our opinion, become truly protective of public health. Addressing these challenges will hopefully result in BPA, and eventually other structurally similar bisphenols (called regrettable substitutions) for which there are known adverse effects, being eliminated from all food-related and many other uses in the EU and elsewhere. https://doi.org/10.1289/EHP13812.

Is Aging a Disease? A Critical Review Within the Framework of Ageism.

Ageism is a type of discrimination characterized by negative social representations of old age and aging, with prejudices and stereotypes that cause rejection and marginalization of older adults, generally considering them as fragile and unproductive. For this reason, it is recognized as one of the main enemies of healthy aging, especially when it arises from the scientific and professional fields. In this sense, the proposals promoted by some researchers regarding the World Health Organization (WHO) classifying aging as a disease goes against the healthy aging approach. In this sense, we consider that there is no theoretical or scientific support to classify aging as a disease, so we must advocate before the WHO so that aging is eliminated within its disease classification codes. In this framework, this review proposes the concept of "hallmarks of ageism" defined as the characteristics, representations and attitudes of rejection and discrimination towards aging, old age and older people, at the political and institutional, scientific or professional, technological and digital, social, family and personal levels, which are presented in an articulated and structured manner. For this reason, it is essential to comprehensively identify and analyze the "hallmarks of ageism", in order to propose programs that include strategies and public policies that promote "anti-ageism" as a counterproposal to the "hallmarks of aging", whose biological changes related to aging are intended to be comparable to chronic non-communicable diseases.

Effect of Phase Encoding Direction on Image Quality in Single-Shot EPI Diffusion-Weighted Imaging of the Breast.

BACKGROUND: In breast diffusion-weighted imaging (DWI), distortion and physiologic artifacts affect clinical interpretation. Image quality can be optimized by addressing the effect of phase encoding (PE) direction on these artifacts. PURPOSE: To compare distortion artifacts in breast DWI acquired with different PE directions and polarities, and to discuss their clinical implications. STUDY TYPE: Prospective. POPULATION: Eleven healthy volunteers (median age: 47 years old; range: 22-74 years old) and a breast phantom. FIELD STRENGTH/SEQUENCE: Single-shot echo planar DWI and three-dimensional fast gradient echo sequences at 3 T. ASSESSMENT: All DWI data were acquired with left-right, right-left, posterior-anterior, and anterior-posterior PE directions. In phantom data, displacement magnitude was evaluated by comparing the location of landmarks in anatomical and DWI images. Three breast radiologists (5, 17, and 23 years of experience) assessed the presence or absence of physiologic artifacts in volunteers' DWI datasets and indicated their PE-direction preference. STATISTICAL TESTS: Analysis of variance with post-hoc tests were used to assess differences in displacement magnitude across DWI datasets and observers. A binomial test and a chi-squared test were used to evaluate if each in vivo DWI dataset had an equal probability (25%) of being preferred by radiologists. Inter-reader agreement was evaluated using Gwet's AC1 agreement coefficient. A P-value <0.05 was considered statistically significant. RESULTS: In the phantom study, median displacement was the significantly largest in posterior-anterior data. While the displacement in the anterior-posterior and left-right data were equivalent (P = 0.545). In the in vivo data, there were no physiological artifacts observed in any dataset, regardless of PE direction. In the reader study, there was a significant preference for the posterior-anterior datasets which were selected 94% of the time. There was good agreement between readers (0.936). DATA CONCLUSION: This study showed the impact of PE direction on distortion artifacts in breast DWI. In healthy volunteers, the posterior-to-anterior PE direction was preferred by readers. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Modeling Mammary Organogenesis from Biological First Principles: A Systems Biology Approach.

Stromal-epithelial interactions mediate mammary gland development and the formation and progression of breast cancer. To study these interactions in vitro, 3D models are essential. We have successfully developed novel 3D in vitro models that allow the formation of mammary gland structures closely resembling those found in vivo and that respond to the hormonal cues that regulate mammary gland morphogenesis and function. Due to their simplicity when compared to in vivo studies, and to their accessibility to visualization in real time, these models are well suited to conceptual and mathematical modeling.

European Medicines Agency Conflicts With the European Food Safety Authority (EFSA) on Bisphenol A Regulation.

The European Food Safety Authority (EFSA) has revised their estimate of the toxicity of bisphenol A (BPA) and, as a result, have recommended reducing the tolerable daily intake (TDI) by 20 000-fold. This would essentially ban the use of BPA in food packaging such as can liners, plastic food containers, and in consumer products. To come to this conclusion, EFSA used a systematic approach according to a pre-established protocol and included all guideline and nonguideline studies in their analysis. They found that Th-17 immune cells increased with very low exposure to BPA and used this endpoint to revise the TDI to be human health protective. A number of regulatory agencies including the European Medicines Agency (EMA) have written formal disagreements with several elements of EFSA's proposal. The European Commission will now decide whether to accept EFSA's recommendation over the objections of EMA. If the Commission accepts EFSA's recommendation, it will be a landmark action using knowledge acquired through independent scientific studies focused on biomarkers of chronic disease to protect human health. The goal of this Perspective is to clearly articulate the monumental nature of this debate and decision and to explain what is at stake. Our perspective is that the weight of evidence clearly supports EFSA's proposal to reduce the TDI by 20 000-fold.

Restriction spectrum imaging with elastic image registration for automated evaluation of response to neoadjuvant therapy in breast cancer.

Purpose: Dynamic contrast-enhanced MRI (DCE) and apparent diffusion coefficient (ADC) are currently used to evaluate treatment response of breast cancer. The purpose of the current study was to evaluate the three-component Restriction Spectrum Imaging model (RSI3C), a recent diffusion-weighted MRI (DWI)-based tumor classification method, combined with elastic image registration, to automatically monitor breast tumor size throughout neoadjuvant therapy. Experimental design: Breast cancer patients (n=27) underwent multi-parametric 3T MRI at four time points during treatment. Elastically-registered DWI images were used to generate an automatic RSI3C response classifier, assessed against manual DCE tumor size measurements and mean ADC values. Predictions of therapy response during treatment and residual tumor post-treatment were assessed using non-pathological complete response (non-pCR) as an endpoint. Results: Ten patients experienced pCR. Prediction of non-pCR using ROC AUC (95% CI) for change in measured tumor size from pre-treatment time point to early-treatment time point was 0.65 (0.38-0.92) for the RSI3C classifier, 0.64 (0.36-0.91) for DCE, and 0.45 (0.16-0.75) for change in mean ADC. Sensitivity for detection of residual disease post-treatment was 0.71 (0.44-0.90) for the RSI3C classifier, compared to 0.88 (0.64-0.99) for DCE and 0.76 (0.50-0.93) for ADC. Specificity was 0.90 (0.56-1.00) for the RSI3C classifier, 0.70 (0.35-0.93) for DCE, and 0.50 (0.19-0.81) for ADC. Conclusion: The automatic RSI3C classifier with elastic image registration suggested prediction of response to treatment after only three weeks, and showed performance comparable to DCE for assessment of residual tumor post-therapy. RSI3C may guide clinical decision-making and enable tailored treatment regimens and cost-efficient evaluation of neoadjuvant therapy of breast cancer.

A vision for safer food contact materials: Public health concerns as drivers for improved testing.

Food contact materials (FCMs) and food contact articles are ubiquitous in today's globalized food system. Chemicals migrate from FCMs into foodstuffs, so called food contact chemicals (FCCs), but current regulatory requirements do not sufficiently protect public health from hazardous FCCs because only individual substances used to make FCMs are tested and mostly only for genotoxicity while endocrine disruption and other hazard properties are disregarded. Indeed, FCMs are a known source of a wide range of hazardous chemicals, and they likely contribute to highly prevalent non-communicable diseases. FCMs can also include non-intentionally added substances (NIAS), which often are unknown and therefore not subject to risk assessment. To address these important shortcomings, we outline how the safety of FCMs may be improved by (1) testing the overall migrate, including (unknown) NIAS, of finished food contact articles, and (2) expanding toxicological testing beyond genotoxicity to multiple endpoints associated with non-communicable diseases relevant to human health. To identify mechanistic endpoints for testing, we group chronic health outcomes associated with chemical exposure into Six Clusters of Disease (SCOD) and we propose that finished food contact articles should be tested for their impacts on these SCOD. Research should focus on developing robust, relevant, and sensitive in-vitro assays based on mechanistic information linked to the SCOD, e.g., through Adverse Outcome Pathways (AOPs) or Key Characteristics of Toxicants. Implementing this vision will improve prevention of chronic diseases that are associated with hazardous chemical exposures, including from FCMs.

The impact of the Covid-19 pandemic and previous natural disasters on the mental health of healthcare workers in Puerto Rico.

The objective of this study was to assess the impact of COVID-19 pandemic worries (e.g., fear of contagion) and previous exposure to natural disasters (e.g., hurricanes) on Healthcare Workers (HCWs) mental health in Puerto Rico. Participants completed a self-administered online survey including items on sociodemographic information, working conditions, fears, and worries about the COVID-19 pandemic, past natural disaster experiences, depressive symptoms, and resilience. Logistic regressions models were performed to explain the relationship between depressive symptomatology and COVID-19 experiences and worries. 40.9% (n = 107) of the sample were classified as having some level (mild to severe) of depressive symptomatology (PHQ-8 ≥5). Results reflect normal to high levels of psychological resilience (BRS; M = 3.7, SD = 0.7). A significant association was found between depressive symptomatology and psychological resilience (OR = 0.44, 95% CI: 0.25-0.77). The odds of having depressive symptomatology were almost five times higher (OR = 4.79, 95% CI: 1.71-13.44) among those who reported emotional coping difficulties during the pandemic after experiencing a natural disaster compared to those that did not, when adjusting for psychological resilience and residence region. Despite normal to high psychological resilience levels, HCWs who reported emotional coping difficulties due to previous disasters were at risk of developing depressive symptomatology. Results suggest interventions to address the mental health of HCWs could benefit from considering other individual and environmental factors beyond resilience. Findings could inform future interventions to promote HCWs' well-being before, during, and after a natural disaster or pandemic outbreak.

The role of resilience in the potential benefits of cognitive-behavioural stress management therapy during pregnancy.

PURPOSE: Stress during pregnancy has many negative repercussions on maternal and foetal health. It is therefore important to understand which therapies are effective in reducing stress levels and which variables influence the outcomes of these therapies. In this line, psychological resilience could play a key role. Thus, the aim of the study was to check whether pregnant women with different levels of resilience have different benefits in reducing cortisol levels, perceived stress, pregnancy worries, stress vulnerability, anxiety or depression through Cognitive Behavioural Stress Management Therapy. METHOD: The total sample consisted of 56 pregnant women: one group of pregnant women with high levels of resilience (n = 35); and another group with low levels of resilience (n = 21). Participants' cortisol concentration levels, perceived stress, pregnancy concerns, stress vulnerability, anxiety and depressive symptoms were assessed before and after therapy. Linear mixed models were performed to compare the two groups, which showed a group x time interaction for perceived stress. RESULTS: The low resilience group showed a reduction in their perceived stress levels with a medium effect after the intervention compared to the high resilience group, but no reduction was found in this group. No differences were found between the two groups on the other variables. CONCLUSION: Knowing which variables have a differential effect on the results of psychological therapy would allow delimiting the groups that obtain greater benefits from the therapy. This may lead to more efficient implementation of effective intervention programmes.

High taxonomic diversity and miniaturization in benthic communities under persistent natural CO2 disturbances.

Metabarcoding techniques have revolutionized ecological research in recent years, facilitating the differentiation of cryptic species and revealing previously hidden diversity. In the current scenario of climate change and ocean acidification, biodiversity loss is one of the main threats to marine ecosystems. Here, we explored the effects of ocean acidification on marine benthic communities using DNA metabarcoding to assess the diversity of algae and metazoans. Specifically, we examined the natural pH gradient generated by the Fuencaliente CO2 vent system, located near La Palma Island (Canary Islands). High-resolution COI metabarcoding analyses revealed high levels of taxonomic diversity in an acidified natural area for the first time. This high number of species arises from the detection of small and cryptic species that were previously undetectable by other techniques. Such species are apparently tolerant to the acidification levels expected in future oceans. Hence and following our results, future subtropical communities are expected to keep high biodiversity values under an acidification scenario, although they will tend toward overall miniaturization due to the dominance of small algal and invertebrate species, leading to changes in ecosystem functions.

Solubility of Amino Acids in the Eutectic Solvent Constituted by Sodium Acetate Trihydrate and Urea and in Its Mixture with Water.

Industrial fish and aquaculture processing leads to the generation of a huge quantity of by-products, whose accumulation and mismanagement involve serious environmental consequences as well as high economic losses. Taking advantage of these residues as a source of added-value compounds must be a priority in a circular economy. This work is a preliminary study to analyze the possibility of using the eutectic mixture of urea and sodium acetate trihydrate as a solvent for collagen extraction. To that end, the solid-liquid equilibrium of the system was determined in order to define the exact composition and temperature of the eutectic. The solubility in this solvent of the main amino acids that constitute fish collagen was studied at several temperatures and atmospheric pressure. At 308.15 K, solubilities of the major constituents of the target protein, namely L-proline, trans-4-hydroxy-L-proline, and glycine, were 0.19, 0.16, and 0.12 (mass fraction), respectively. These values increased with temperature. Dilution with water (50 wt%) allowed operation at lower temperature and led to an increase in the solubilities. The van 't Hoff model was satisfactorily used to correlate the experimental data and to calculate apparent properties of dissolution. All the dissolution processes studied herein are endothermic, non-spontaneous, and enthalpy-driven. Both the eutectic and its mixture with water are promising solvents for the design of an environmentally benign process for collagen extraction.

Automated Patient-level Prostate Cancer Detection with Quantitative Diffusion Magnetic Resonance Imaging.

Background: Multiparametric magnetic resonance imaging (mpMRI) improves detection of clinically significant prostate cancer (csPCa), but the subjective Prostate Imaging Reporting and Data System (PI-RADS) system and quantitative apparent diffusion coefficient (ADC) are inconsistent. Restriction spectrum imaging (RSI) is an advanced diffusion-weighted MRI technique that yields a quantitative imaging biomarker for csPCa called the RSI restriction score (RSIrs). Objective: To evaluate RSIrs for automated patient-level detection of csPCa. Design setting and participants: We retrospectively studied all patients (n = 151) who underwent 3 T mpMRI and RSI (a 2-min sequence on a clinical scanner) for suspected prostate cancer at University of California San Diego during 2017-2019 and had prostate biopsy within 180 d of MRI. Intervention: We calculated the maximum RSIrs and minimum ADC within the prostate, and obtained PI-RADS v2.1 from medical records. Outcome measurements and statistical analysis: We compared the performance of RSIrs, ADC, and PI-RADS for the detection of csPCa (grade group ≥2) on the best available histopathology (biopsy or prostatectomy) using the area under the curve (AUC) with two-tailed α = 0.05. We also explored whether the combination of PI-RADS and RSIrs might be superior to PI-RADS alone and performed subset analyses within the peripheral and transition zones. Results and limitations: AUC values for ADC, RSIrs, and PI-RADS were 0.48 (95% confidence interval: 0.39, 0.58), 0.78 (0.70, 0.85), and 0.77 (0.70, 0.84), respectively. RSIrs and PI-RADS were each superior to ADC for patient-level detection of csPCa (p < 0.0001). RSIrs alone was comparable with PI-RADS (p = 0.8). The combination of PI-RADS and RSIrs had an AUC of 0.85 (0.78, 0.91) and was superior to either PI-RADS or RSIrs alone (p < 0.05). Similar patterns were seen in the peripheral and transition zones. Conclusions: RSIrs is a promising quantitative marker for patient-level csPCa detection, warranting a prospective study. Patient summary: We evaluated a rapid, advanced prostate magnetic resonance imaging technique called restriction spectrum imaging to see whether it could give an automated score that predicted the presence of clinically significant prostate cancer. The automated score worked about as well as expert radiologists' interpretation. The combination of the radiologists' scores and automated score might be better than either alone.

A Multicompartmental Diffusion Model for Improved Assessment of Whole-Body Diffusion-weighted Imaging Data and Evaluation of Prostate Cancer Bone Metastases.

Purpose To develop a multicompartmental signal model for whole-body diffusion-weighted imaging (DWI) and apply it to study the diffusion properties of normal tissue and metastatic prostate cancer bone lesions in vivo. Materials and Methods This prospective study (ClinicalTrials.gov: NCT03440554) included 139 men with prostate cancer (mean age, 70 years ± 9 [SD]). Multicompartmental models with two to four tissue compartments were fit to DWI data from whole-body scans to determine optimal compartmental diffusion coefficients. Bayesian information criterion (BIC) and model-fitting residuals were calculated to quantify model complexity and goodness of fit. Diffusion coefficients for the optimal model (having lowest BIC) were used to compute compartmental signal-contribution maps. The signal intensity ratio (SIR) of bone lesions to normal-appearing bone was measured on these signal-contribution maps and on conventional DWI scans and compared using paired t tests (α = .05). Two-sample t tests (α = .05) were used to compare compartmental signal fractions between lesions and normal-appearing bone. Results Lowest BIC was observed from the four-compartment model, with optimal compartmental diffusion coefficients of 0, 1.1 × 10-3, 2.8 × 10-3, and >3.0 ×10-2 mm2/sec. Fitting residuals from this model were significantly lower than from conventional apparent diffusion coefficient mapping (P < .001). Bone lesion SIR was significantly higher on signal-contribution maps of model compartments 1 and 2 than on conventional DWI scans (P < .008). The fraction of signal from compartments 2, 3, and 4 was also significantly different between metastatic bone lesions and normal-appearing bone tissue (P ≤ .02). Conclusion The four-compartment model best described whole-body diffusion properties. Compartmental signal contributions from this model can be used to examine prostate cancer bone involvement. Keywords: Whole-Body MRI, Diffusion-weighted Imaging, Restriction Spectrum Imaging, Diffusion Signal Model, Bone Metastases, Prostate Cancer Clinical trial registration no. NCT03440554 Supplemental material is available for this article. © RSNA, 2023 See also commentary by Margolis in this issue.

Apparent Diffusion Coefficient Reproducibility Across 3 T Scanners in a Breast Diffusion Phantom.

BACKGROUND: To date, the accuracy and variability of diffusion-weighted MRI (DW-MRI) metrics have been reported in a limited number of scanner/protocol/coil combinations. PURPOSE: To evaluate the reproducibility of DW-MRI estimates across multiple scanners and DW-MRI protocols and to assess the effects of using an 8-channel vs. 16-channel breast coil in a breast phantom. STUDY TYPE: Prospective. PHANTOM: Breast phantom containing tubes of water and differing polyvinylpyrrolidone (PVP) concentrations with apparent diffusion coefficients (ADCs) matching breast tissue. FIELD STRENGTH/SEQUENCE: 3 T (three standard and one wide bore), three DW-MRI single-shot echo planar imaging protocols of varying acquired spatial resolution. ASSESSMENT: Accuracy of estimated ADCs was assessed using percent differences (PD) relative to nuclear magnetic resonance spectroscopy-derived reference values. Coefficients of variation (CV) were calculated to determine variation across scanners. CVs based on the median standard deviation (CVM ) were used to evaluate tube-specific dispersion using 8- or 16-channel coils at a single scanner. ADCs of PVP-containing tubes were additionally normalized by the median water tube ADC to account for temperature effects. STATISTICAL TESTS: Two-way repeated measures analysis of variance and post hoc tests were used to evaluate differences in ADC, CV, and CVM across scanners and protocols (α = 0.05). RESULTS: ADCs were within 11% (interquartile range [IQR] 7%) of reference values and significantly improved to 2% (IQR 7%) after normalization to an internal water reference. Normalization significantly reduced interscanner variability of ADC estimates from 7% to 4%. DW-MRI protocol did not affect ADC accuracy; however, the clinical and higher-resolution clinical protocols resulted in the greatest (9%) and least (6%) interscanner variability, respectively. The 8- and 16-channel receive coils yielded similar accuracy (PD: 12% vs. 16%) and precision (CVM : 2.7% vs. 2.9%). DATA CONCLUSION: Normalization by an internal reference improved interscanner ADC reproducibility. High-resolution protocols yielded comparably accurate and significantly less variable ADCs compared to a clinical standard protocol. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Effects of perinatal exposure to bisphenol A on induction of prostate cancer in Sprague Dawley rats by MNU and testosterone.

Perinatal and neonatal exposure to bisphenol A (BPA) has been linked to enhancement of prostate carcinogenesis in rats induced by combined treatment with estradiol and testosterone, but human data are lacking. This study aimed to determine the effects of perinatal BPA exposure on induction of prostate cancer in rats by sequential treatment with N-methyl-N-nitrosamine (MNU) and continuous low dose administration of testosterone. Pregnant Sprague Dawley rats were exposed to BPA administered by subcutaneous Alzet minipumps at doses of 2.5 or 25 µg/kg body weight/day from gestational day 9 until postnatal day 28 when pups were weaned providing exposure of offspring in utero and via the mother's milk. At 10-12 weeks of age, one male offspring per litter was treated with an intraperitoneal injection of MNU after hormonal stimulation of prostatic cell proliferation followed two weeks later by subcutaneous insertion of Silastic implants containing testosterone until the termination of the study 57-58 weeks after MNU injection. The perinatal BPA exposure did not significantly affect the incidence of prostate carcinomas which was slightly lower in exposed rats (33-23 %) than in control animals (40 %). Carcinomas in all accessory sex glands combined were also insignificantly less frequent in exposed (46-48 %) than in control rats (60 %). The incidence of malignant tumors at any site in the body was significantly lower in exposed rats (81-65 %) than in controls (93 %). In conclusion, perinatal BPA exposure did not significantly modify prostate cancer induction by MNU plus testosterone in rats, unlike the enhancement of prostate carcinogenesis induced by treatments involving estradiol administration. Which of the two models of prostate carcinogenesis is more relevant for the human situation is unclear at present.

Infection with SARS-CoV-2 as a potential achalasia trigger.

Idiopathic achalasia is a chronic oesophageal motility disorder caused by loss of inhibitory neurons at the esophageal myenteric plexus resulting in incomplete relaxation of the lower oesophageal sphincter and abnormal peristaltism.  Among the possible causes of this, an immune response secondary to infection by some viruses has been implicated. SARS-CoV-2 could be considered among them. The therapy option should be aimed at achieving the greatest clinical effectiveness according to each patient's health status.