Applying the adverse outcome pathway concept for assessing non-monotonic dose responses: biphasic effect of bis(2-ethylhexyl) phthalate (DEHP) on testosterone levels.

Male reproduction is one of the primary health endpoints identified in rodent studies for some phthalates, such as DEHP (Bis(2-ethylhexyl) phthalate), DBP (Dibutyl phthalate), and BBP (Benzyl butyl phthalate). The reduction in testosterone level was used as an intermediate key event for grouping some phthalates and to establish a reference point for risk assessment. Phthalates, and specifically DEHP, are one of the chemicals for which the greatest number of non-monotonic dose responses (NMDRs) are observed. These NMDRs cover different endpoints and situations, often including testosterone levels. The presence of NMDR has been the subject of some debate within the area of chemical risk assessment, which is traditionally anchored around driving health-based guidance values for apical endpoints that typically follow a clear monotonic dose-response. The consequence of NMDR for chemical risk assessment has recently received considerable attention amongst regulatory agencies, which confirmed its relevance particularly for receptor-mediated effects. The present review explores the relationship between DEHP exposure and testosterone levels, investigating the biological plausibility of the observed NMDRs. The Adverse Outcome Pathway (AOP) concept is applied to integrate NMDRs into Key Event Relationships (KERs) for exploring a mechanistic understanding of initial key events and possibly associated reproductive and non-reproductive adverse outcomes.

Indoor PM2.5, VOCs and asthma outcomes: A systematic review in adults and their home environments.

INTRODUCTION: As the amount of time people spend indoors increases globally, exposure to indoor air pollutants has become an important public health concern. Asthma is a complex disease caused and/or exacerbated by increased exposure to diverse chemical, physical and biological exposures from multiple indoor and outdoor sources. This review aims to investigate the relationship between increased indoor PM and VOC concentrations (i.e. objectively measured) and the risk of adult asthma in higher-income countries. METHODS: Eleven databases were systematically searched on the February 1, 2019 and again on the February 2, 2020. Articles were limited to those published since 1990. Reference lists were independently screened by three reviewers and authors were contacted to identify relevant articles. Backwards and forward citation chasing was used to identify further studies. Data were extracted from included studies meeting our eligibility criteria by three reviewers and assessed for quality using the Newcastle-Ottawa scale designed for case-control and cohort studies. RESULTS: Twelve studies were included in a narrative synthesis. We found insufficient evidence to determine the effect of PM2.5 on asthma in the indoor home environment. However, there was strong evidence to suggest that VOCs, especially aromatic compounds, and aliphatic compounds, were associated with increased asthma symptoms. DISCUSSION & CONCLUSION: Although no single exposure appears to be responsible for the development of asthma or its associated symptoms, the use of everyday products may be associated with increased asthma symptoms. To prevent poor health outcomes among the general population, health professionals and industry must make a concerted effort to better inform the general population of the importance of appropriate use of and storage of chemicals within the home as well as better health messaging on product labelling.

Lessons from a publicly funded tier 2 healthy weight programme in Cornwall, UK.

BACKGROUND: The UK has one of the highest prevalence rates of obesity worldwide. Public health departments have a duty to provide some obesity treatment and prevention services. With evidence of effective programmes lacking, we investigate lessons learned from a healthy weight programme in Cornwall, UK. METHODS: Data from the 12-week multi-component adult healthy weight management programme were obtained for 2012-2016. Descriptive statistics and statistical tests were used to describe participants' demographics, health status and anthropometric measures to explore the enrolment and retention of the programme as well as the impact. RESULTS: A total of 1872 adults were referred into the programme. Overall, 646 completed the programme and, 48.8% achieved the programme's aim of a >3% reduction in weight. Those who completed and met the programme aim tended to have had healthier outcomes at baseline. CONCLUSIONS: For those who engage with the programme the impact can be meaningful. However, <1% of the population of Cornwall with overweight or obesity enroled in the programme, and those who benefitted most might have been in least need. Providing services that meet the needs of the population is challenging when a variety of services is needed, and the evidence base is poor.

Household energy efficiency and health: Area-level analysis of hospital admissions in England.

INTRODUCTION: Fuel poverty affects up to 35% of European homes, which represents a significant burden on society and healthcare systems. Draught proofing homes to prevent heat loss, improved glazing, insulation and heating (energy efficiency measures) can make more homes more affordable to heat. This has prompted significant investment in energy efficiency upgrades for around 40% of UK households to reduce the impact of fuel poverty. Despite some inconsistent evidence, household energy efficiency interventions can improve cardiovascular and respiratory health outcomes. However, the health benefits of these interventions have not been fully explored; this is the focus of this study. METHODS: In this cross sectional ecological study, we conducted two sets of analyses at different spatial resolution to explore population data on housing energy efficiency measures and hospital admissions at the area-level (counts grouped over a 3-year period). Housing data were obtained from three data sets covering housing across England (Household Energy Efficiency Database), Energy Performance Certificate (EPC) and, in the South West of England, the Devon Home Analytics Portal. These databases provided data aggregated to Lower Area Super Output Area and postcode level (Home Analytics Portal only). These datasets provided measures of both state (e.g. EPC ratings) and intervention (e.g. number of boiler replacements), aggregated spatially and temporally to enable cross-sectional analyses with health outcome data. Hospital admissions for adult (over 18 years) asthma, chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) were obtained from the Hospital Episode Statistics database for the national (1st April 2011 to 31st March 2014) and Devon, South West of England (1st April 2014 to 31st March 2017) analyses. Descriptive statistics and regression models were used to describe the associations between small area household energy efficiency measures and hospital admissions. Three main analyses were undertaken to investigate the relationships between; 1) household energy efficiency improvements (i.e. improved glazing, insulation and boiler upgrades); 2) higher levels of energy efficiency ratings (measured by Energy Performance Certificate ratings); 3) energy efficiency improvements and ratings (i.e. physical improvements and rating assessed by the Standard Assessment Procedure) and hospital admissions. RESULTS: In the national analyses, household energy performance certificate ratings ranged from 37 to 83 (mean 61.98; Standard Deviation 5.24). There were a total of 312,837 emergency admissions for asthma, 587,770 for COPD and 839,416 for CVD. While analyses for individual energy efficiency metrics (i.e. boiler upgrades, draught proofing, glazing, loft and wall insulation) were mixed; a unit increase in mean energy performance rating was associated with increases of around 0.5% in asthma and CVD admissions, and 1% higher COPD admission rates. Admission rates were also influenced by the type of dwelling, tenure status (e.g. home owner versus renting), living in a rural area, and minimum winter temperature. DISCUSSION: Despite a range of limitations and some mixed and contrasting findings across the national and local analyses, there was some evidence that areas with more energy efficiency improvements resulted in higher admission rates for respiratory and cardiovascular diseases. This builds on existing evidence highlighting the complex relationships between health and housing. While energy efficiency measures can improve health outcomes (especially when targeting those with chronic respiratory illness), reduced household ventilation rates can impact indoor air quality for example and increase the risk of diseases such as asthma. Alternatively, these findings could be due to the ecological study design, reverse causality, or the non-detection of more vulnerable subpopulations, as well as the targeting of areas with poor housing stock, low income households, and the lack of "whole house approaches" when retrofitting the existing housing stock. CONCLUSION: To be sustainable, household energy efficiency policies and resulting interventions must account for whole house approaches (i.e. consideration of the whole house and occupant lifestyles). These must consider more alternative 'greener' and more sustainable measures, which are capable of accounting for variable lifestyles, as well as the need for adequate heating and ventilation. Larger natural experiments and more complex modelling are needed to further investigate the impact of ongoing dramatic changes in the housing stock and health. STUDY IMPLICATIONS: This study supports the need for more holistic approaches to delivering healthier indoor environments, which must consider a dynamic and complex system with multiple interactions between a range of interrelated factors. These need to consider the drivers and pressures (e.g. quality of the built environment and resident behaviours) resulting in environmental exposures and adverse health outcomes.

Animal models of maternal high fat diet exposure and effects on metabolism in offspring: a meta-regression analysis.

Animal models of maternal high fat diet (HFD) demonstrate perturbed offspring metabolism although the effects differ markedly between models. We assessed studies investigating metabolic parameters in the offspring of HFD fed mothers to identify factors explaining these inter-study differences. A total of 171 papers were identified, which provided data from 6047 offspring. Data were extracted regarding body weight, adiposity, glucose homeostasis and lipidaemia. Information regarding the macronutrient content of diet, species, time point of exposure and gestational weight gain were collected and utilized in meta-regression models to explore predictive factors. Publication bias was assessed using Egger's regression test. Maternal HFD exposure did not affect offspring birthweight but increased weaning weight, final bodyweight, adiposity, triglyceridaemia, cholesterolaemia and insulinaemia in both female and male offspring. Hyperglycaemia was found in female offspring only. Meta-regression analysis identified lactational HFD exposure as a key moderator. The fat content of the diet did not correlate with any outcomes. There was evidence of significant publication bias for all outcomes except birthweight. Maternal HFD exposure was associated with perturbed metabolism in offspring but between studies was not accounted for by dietary constituents, species, strain or maternal gestational weight gain. Specific weaknesses in experimental design predispose many of the results to bias.

Timing of Maternal Exposure and Foetal Sex Determine the Effects of Low-level Chemical Mixture Exposure on the Foetal Neuroendocrine System in Sheep.

We have shown that continuous maternal exposure to the complex mixture of environmental chemicals (ECs) found in human biosolids (sewage sludge), disrupts mRNA expression of genes crucial for development and long-term regulation of hypothalamic-pituitary gonadal (HPG) function in sheep. The present study investigated whether exposure to ECs only during preconceptional period or only during pregnancy perturbed key regulatory genes within the hypothalamus and pituitary gland and whether these effects were different from chronic (life-long) exposure to biosolid ECs. The findings demonstrate that the timing and duration of maternal EC exposure influences the subsequent effects on the foetal neuroendocrine system in a sex-specific manner. Maternal exposure prior to conception, or during pregnancy only, altered the expression of key foetal neuroendocrine regulatory systems such as gonadotrophin-releasing hormone and kisspeptin to a greater extent than when maternal exposure was 'life-long'. Furthermore, hypothalamic gene expression was affected to a greater extent in males than in females and, following EC exposure, male foetuses expressed more 'female-like' mRNA levels for some key neuroendocrine genes. This is the first study to show that 'real-life' maternal exposure to low levels of a complex cocktail of chemicals prior to conception can subsequently affect the developing foetal neuroendocrine system. These findings demonstrate that the developing neuroendocrine system is sensitive to EC mixtures in a sex-dimorphic manner likely to predispose to reproductive dysfunction in later life.

High-fat diet disrupts metabolism in two generations of rats in a parent-of-origin specific manner.

Experimental and epidemiological evidence demonstrate that ancestral diet might contribute towards offspring health. This suggests that nutrition may be able to modify genetic or epigenetic information carried by germ cells (GCs). To examine if a parental high fat diet (HFD) influences metabolic health in two generations of offspring, GC-eGFP Sprague Dawley rats were weaned onto HFD (45% fat) or Control Diet (CD; 10% fat). At 19 weeks, founders (F0) were bred with controls, establishing the F1 generation. HFD resulted in 9.7% and 14.7% increased weight gain in male and female F0 respectively. F1 offspring of HFD mothers and F1 daughters of HFD-fed fathers had increased weight gain compared to controls. F1 rats were bred with controls at 19 weeks to generate F2 offspring. F2 male offspring derived from HFD-fed maternal grandfathers exhibited increased adiposity, plasma leptin and luteinising hormone to testosterone ratio. Despite transmission via the founding male germline, we did not find significant changes in the F0 intra-testicular GC transcriptome. Thus, HFD consumption by maternal grandfathers results in a disrupted metabolic and reproductive hormone phenotype in grandsons in the absence of detectable changes in the intra-testicular GC transcriptome.

From FAST to E-FAST: an overview of the evolution of ultrasound-based traumatic injury assessment.

Ultrasound is a ubiquitous and versatile diagnostic tool. In the setting of acute injury, ultrasound enhances the basic trauma evaluation, influences bedside decision-making, and helps determine whether or not an unstable patient requires emergent procedural intervention. Consequently, continued education of surgeons and other acute care practitioners in performing focused emergency ultrasound is of great importance. This article provides a synopsis of focused assessment with sonography for trauma (FAST) and the extended FAST (E-FAST) that incorporates basic thoracic injury assessment. The authors also review key pitfalls, limitations, controversies, and advances related to FAST, E-FAST, and ultrasound education.

Clinician-performed ultrasound in hemodynamic and cardiac assessment: a synopsis of current indications and limitations.

Accurate hemodynamic and intravascular volume status assessment is essential in the diagnostic and therapeutic management of critically ill patients. Over the last two decades, a number of technological advances were translated into a variety of minimally invasive or non-invasive hemodynamic monitoring modalities. Despite the promise of less invasive technologies, the quality, reliability, reproducibility, and generalizability of resultant hemodynamic and intravascular volume status data have been lacking. Since its formal introduction, ultrasound technology has provided the medical community with a more standardized, higher quality, broadly applicable, and reproducible method of accomplishing the above-mentioned objectives. With the advent of portable, hand-carried devices, the importance of sonography in hemodynamic and volume status assessment became clear. From basic venous collapsibility and global cardiac assessment to more complex tasks such as the assessment of cardiac flow and tissue Doppler signals, the number of real-life indications for sonology continues to increase. This review will provide an outline of the essential ultrasound applications in hemodynamic and volume status assessment, focusing on evidence-based uses and indications.

Description of Ophthalmic Pharmaceutical and Device Start-Up Companies.

AIMS: To describe the number, type and location of ophthalmic companies and their associated product areas and indications. METHODS: A retrospective, non-patient-based, observational review of ophthalmic pharmaceutical and device companies with a new product in development. Data was compiled by Internet searches. RESULTS: We identified 190 companies currently developing ophthalmic products: 134 (71%) were privately held and 56 (29%) publicly held, while 136 (72%) were in the United States and 53 (28%) were outside the United States. There were 436 total products of which 338 (78%) were pharmaceuticals and 98 (22%) devices. With pharmaceuticals we identified 46 separate indications with age-related macular degeneration (n = 75), glaucoma (n = 52) and dry eye (n = 46) as most common; anti-vascular endothelial growth factor, hormone therapy and anti-inflammatory products were also common classes. With devices there were 30 indications with glaucoma (n = 26), age-related macular degeneration (n = 19) and dry eye (n = 6) as most common; drug delivery, ocular implants and prostheses were less common classes. CONCLUSIONS: Ophthalmology as a specialty is benefited by a wide effort in new medicine and device development. However, a concentration of effort into relatively few indications suggests a potential lack of market analysis and possible difficulty for many companies in commercializing their product.

Techniques to Reduce the Placebo Effect in Glaucoma Clinical Trials.

AIM: To evaluate techniques used to reduce the placebo effect in prior well-controlled, single or double-masked placebo-controlled glaucoma trials. METHODS: This study was a retrospective, non-patient-based, observational review of phase I-III trials with a placebo arm for glaucoma medicines available after 1977. RESULTS: This study included 20 articles with 20 placebo control arms consisting of 458 patients evaluating 10 different glaucoma medications with 58 treatment arms. There was no statistical difference across the evaluated types of study designs to limit the placebo effect either for the morning trough or diurnal curve. The average reduction of the intraocular pressure in the placebo groups was 1.6 ± 1.5 mm Hg for the morning trough and 1.3 ± 1.3 mm Hg for the diurnal curve across all studies. CONCLUSION: The results of this study suggest that current design techniques described in the literature to limit the placebo effect appear ineffective compared to no additional techniques.

Variable risk of atopic disease due to indoor fungal exposure in NHANES 2005-2006.

BACKGROUND: Exposure to damp indoor environments is associated with increased risk of eczema, allergy and asthma. The role of dampness-related exposures and risk of allergic diseases are yet to be fully explored in the US population. OBJECTIVE: We assess whether exposure to fungi, house dust mites and endotoxin increases the risk of eczema, allergy and asthma in children and adults participating in NHANES 2005-2006. METHODS: A total of 8412 participants (2849 were children aged between 6 and 17 years) were recruited in the 2005-2006 survey. We used multiple logistic regression to investigate whether mildew/musty odour and increased concentrations of Alternaria alternata allergen, Aspergillus fumigatus antigens, house dust mite and endotoxin antigens increase the risk of eczema, allergy and asthma. We stratified models by total IgE < 170 and ≥ 170 KU/L to assess allergic and non-allergic asthma outcomes. Exposure to multiple biological agents and risk of reporting eczema, allergy and asthma were also investigated. RESULTS: Reporting of a mildew/musty odour was associated with increased risk of childhood asthma (OR 1.60; 95% CI 1.17-2.19), and adult eczema, allergy and asthma (OR 1.92; 95% CI 1.39-2.63, OR 1.59 95% CI 1.26-2.02 and OR 1.61 95% CI 1.00-2.57, respectively). Risk of asthma was associated with total IgE ≥ 170 KU/L in children (OR 1.81; 95% CI 1.01-3.25) and total IgE < 170 KU/L in adults (OR 1.91; 95% CI 1.07-3.42). Children and adults exposed to more than eight biological agents present in the home were at reduced risk of eczema (OR 0.17; 95% CI 0.04-0.77) and asthma (OR 0.49; 95% CI 0.25-0.97), respectively. CONCLUSION: Exposure to a mildew/musty odour, as a proxy for exposure to fungus, was implicated in an increased risk of atopic diseases. Sensitisation may play a different role in children and adults, and exposure to multiple allergens may reduce the risk of atopic disease.

The placebo effect in early-phase glaucoma clinical trials.

PURPOSE: To analyze the extent and prevalence of the placebo effect in prior early-phase glaucoma clinical studies. METHODS: Articles were evaluated on phase I and II trials of glaucoma medicines that became commercially available after 1977 with a placebo arm that involved glaucoma patients. RESULTS: We included 23 studies with 23 treatment arms with a total of 1703 patients in articles evaluating 10 different glaucoma medications. This study showed that at 8 AM (n = 18), the average decrease in placebo from untreated baseline was 2.3 ± 1.6 mm Hg (9%), while for the diurnal curve (n = 17), the mean decrease was 1.4 ± 1.1 mm Hg (6%). At 8 AM, 8/18 treatment arms had greater than 2 mm Hg intraocular pressure (IOP) decrease, and all had at least some reduction in IOP. For the diurnal curve, 4 of 17 studies had reduced IOP greater than 2 mm Hg. One treatment arm had no placebo effect. CONCLUSIONS: This study suggests that a placebo effect is common in glaucoma clinical trials and potentially could limit the ability to evaluate the efficacy of a new medicine.

Reproduction Symposium: does grazing on biosolids-treated pasture pose a pathophysiological risk associated with increased exposure to endocrine disrupting compounds?

Biosolids (processed human sewage sludge), which contain low individual concentrations of an array of contaminants including heavy metals and organic pollutants such as polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls (PCB), and polychlorinated dibenzodioxins/polychlorinated dibenzofurans known to cause physiological disturbances, are increasingly being used as an agricultural fertilizer. This could pose a health threat to both humans and domestic and wild animal species. This review summarizes results of a unique model, used to determine the effects of exposure to mixtures of environmentally relevant concentrations of pollutants, in sheep grazed on biosolids-treated pastures. Pasture treatment results in nonsignificant increases in environmental chemical (EC) concentrations in soil. Whereas EC concentrations were increased in some tissues of both ewes and their fetuses, concentrations were low and variable and deemed to pose little risk to consumer health. Investigation of the effects of gestational EC exposure on fetal development has highlighted a number of issues. The results indicate that gestational EC exposure can adversely affect gonadal development (males and females) and that these effects can impact testicular morphology, ovarian follicle numbers and health, and the transcriptome and proteome in adult animals. In addition, EC exposure can be associated with altered expression of GnRH, GnRH receptors, galanin receptors, and kisspeptin mRNA within the hypothalamus and pituitary gland, gonadotroph populations within the pituitary gland, and regional aberrations in thyroid morphology. In most cases, these anatomical and functional differences do not result in altered peripheral hormone concentrations or reproductive function (e.g., lambing rate), indicating physiological compensation under the conditions tested. Physiological compensation is also suggested from studies that indicate that EC effects may be greater when exposure occurs either before or during gestation compared with EC exposure throughout life. With regard to human and animal health, this body of work questions the concept of safe individual concentration of EC when EC exposure typically occurs as complex mixtures. It suggests that developmental EC exposure may affect many different physiological systems, with some sex-specific differences in EC sensitivity, and that EC effects may be masked under favorable physiological conditions.

Bacterial community dynamics during the early stages of biofilm formation in a chlorinated experimental drinking water distribution system: implications for drinking water discolouration.

AIMS: To characterize bacterial communities during the early stages of biofilm formation and their role in water discolouration in a fully representative, chlorinated, experimental drinking water distribution systems (DWDS). METHODS AND RESULTS: Biofilm development was monitored in an experimental DWDS over 28 days; subsequently the system was disturbed by raising hydraulic conditions to simulate pipe burst, cleaning or other system conditions. Biofilm cell cover was monitored by fluorescent microscopy and a fingerprinting technique used to assess changes in bacterial community. Selected samples were analysed by cloning and sequencing of the 16S rRNA gene. Fingerprinting analysis revealed significant changes in the bacterial community structure over time (P < 0·05). Cell coverage increased over time accompanied by an increase in bacterial richness and diversity. CONCLUSIONS: Shifts in the bacterial community structure were observed along with an increase in cell coverage, bacterial richness and diversity. Species related to Pseudomonas spp. and Janthinobacterium spp. dominated the process of initial attachment. Based on fingerprinting results, the hydraulic regimes did not affect the bacteriological composition of biofilms, but they did influence their mechanical stability. SIGNIFICANCE AND IMPORTANCE OF THE STUDY: This study gives a better insight into the early stages of biofilm formation in DWDS and will contribute to the improvement of management strategies to control the formation of biofilms and the risk of discolouration.

Modifiable factors governing indoor fungal diversity and risk of asthma.

Exposure to dampness and fungi in the home is a known risk factor for individuals with allergic asthma. Inadequate heating and ventilation may lead to dampness and concomitant increased exposure to spores of allergenic fungi such as Aspergillus and Penicillium. These fungi have been cultured from sputum of asthmatic and non-asthmatic individuals, and implicated in the initiation or exacerbation of asthma. Indoor environmental factors influence the presence and concentrations of fungal propagules and, in turn, risk of asthma outcomes. This review aims to identify modifiable risk factors in the built environment that have been shown to influence fungal composition indoors, and to examine this association with the risk of asthma development and/or exacerbation. A complex interaction between residential characteristics, the built environment and the behaviour of people regulate the diversity and concentrations of indoor fungi. Modifiable factors include build age, architectural design, level of maintenance, variations in construction materials, presence of pets, heating and ventilation patterns. Risk of fungal contamination and asthma outcomes are also influenced by low occupant awareness concerning potential health effects and socio-economic factors. Addressing these factors provides an opportunity to improve future housing interventions, though it is not clear how the built environment and occupant behaviours interact to modify the diversity of indoor fungi and resultant risk of asthma. A combination of housing improvements combined with awareness programmes and the alleviation of fuel poverty can be used to lower the allergen burden associated with damp homes. Further research is needed to identify factors that regulate the concentration and diversity of indoor fungi and how this may act as a modifier for asthma outcomes.