On the Utility of ToxCast-Based Predictive Models to Evaluate Potential Metabolic Disruption by Environmental Chemicals

Background: Research suggests environmental contaminants can impact metabolic health; however, high costs prohibit in vivo screening of putative metabolic disruptors. High-throughput screening programs, such as ToxCast, hold promise to reduce testing gaps and prioritize higher-order (in vivo) testing.Objectives: We sought to a) examine the concordance of in vitro testing in 3T3-L1 cells to a targeted literature review for 38 semivolatile environmental chemicals, and b) assess the predictive utility of various expert models using ToxCast data against the set of 38 reference chemicals.Methods: Using a set of 38 chemicals with previously published results in 3T3-L1 cells, we performed a metabolism-targeted literature review to determine consensus activity determinations. To assess ToxCast predictive utility, we used two published ToxPi models: a) the 8-Slice model published by Janesick et al. (2016) and b) the 5-Slice model published by Auerbach et al. (2016). We examined the performance of the two models against the Janesick in vitro results and our own 38-chemical reference set. We further evaluated the predictive performance of various modifications to these models using cytotoxicity filtering approaches and validated our best-performing model with new chemical testing in 3T3-L1 cells.Results: The literature review revealed relevant publications for 30 out of the 38 chemicals (the remaining 8 chemicals were only examined in our previous 3T3-L1 testing). We observed a balanced accuracy (average of sensitivity and specificity) of 0.86 comparing our previous in vitro results to the literature-derived calls. ToxPi models provided balanced accuracies ranging from 0.55 to 0.88, depending on the model specifications and reference set. Validation chemical testing correctly predicted 29 of 30 chemicals as per 3T3-L1 testing, suggesting good adipogenic prediction performance for our best adapted model.Discussion: Using the most recent ToxCast data and an updated ToxPi model, we found ToxCast performed similarly to that of our own 3T3-L1 testing in predicting consensus calls. Furthermore, we provide the full ranked list of largely untested chemicals with ToxPi scores that predict adipogenic activity and that require further investigation. https://doi.org/10.1289/EHP6779     

Analyzing selected risk factors for the development of kidney cancer

The aim of this study was to determine influence of selected lifestyle factors on kidney cancer. The study brings data from two centres of international multicentric hospital-based analytical observational case-control studies. Data were obtained from a group of 300 patients newly diagnosed with kidney cancer (ICD-O-2 code C64) and 335 controls from two centres in the Czech Republic. Results showed that smoking increased OR to 1.09 (95% CI 0.77–1.55) and 1.06 (95% CI 0.73–1.52), but the results were not statistically significant. Obesity (BMI⩾30) created adjusted OR 1.71 (95% CI 1.11–2.66) and 1.44 (95% CI 0.91–2.28), showing a minor, statistically insignificant, effect of obesity on the development of kidney cancer. For hypertension, adjusted OR was 1.73 (95% CI 1.25–2.40), suggesting a minor to moderate effect of hypertension on kidney cancer. The analysis results showed a positive association between hereditary predisposition and the development of kidney cancer with an OR of 1.97 (95% CI 1.41–2.76) and 1.97 (95% CI 1.40–2.77) depending on the model of adjustment. The reasons for the high incidence of kidney cancer are not fully understood. Genetic polymorphisms, together with other lifestyle and environmental factors, are likely to contribute to various rates of kidney cancer incidence throughout the world.     

A cross-sectional study of quality of life in an elderly population (75 years and over) with atrial fibrillation: secondary analysis of data from the Birmingham Atrial Fibrillation Treatment of the Aged study

AIMS: To compare the quality of life (QoL) of those in atrial fibrillation (AF) aged 75 years and over with that of the general population, to explore what factors affect the QoL of those with AF, and to assess the sensitivity of the EuroQol (EQ-5D) and Short-Form 12 (SF-12) generic health questionnaires in detecting differences in health status in those with AF in this age group. METHODS AND RESULTS: The study population was 1762 men and women aged 75 years and over with confirmed AF who attended a randomization clinic for the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) study, a primary care based trial of stroke prevention. Patients self-completed the EQ-5D and SF-12 questionnaires, and a simple measure of disability (Rankin). Cardiovascular co-morbidities were collected and number of drugs used as an additional proxy for co-morbidity. Quality-of-life outcomes were compared with general population samples of the same age. On multiple regression, female gender, greater medication use, and disability were independently associated with lower QoL scores in AF. Those in AF with a Rankin score ≥2 had lower QoL scores, while those with a Rankin score <2 had higher scores than the general population. Increasing co-morbidity was associated with reduced QoL scores, with the EQ-5D and SF-12 Physical Component Score showing similar sensitivity to these associations, and the SF-12 Mental Component Score showing less sensitivity. CONCLUSION: In the absence of co-morbidity, chronic AF has little impact on generic QoL in an elderly non-acutely ill population.     

Socioeconomic,psychological and demographic determinants of Australian baby boomers' financial planning for retirement

Aim: Research from around the Western World has shown that psychological, socioeconomic and demographic factors can influence levels of financial planning. This study aims to determine how these factors interrelate to predict planning outcomes. Method: Data from the Ageing Baby Boomers in Australia Study were used to examine the effects of multiple factors on financial planning for 709 employed Australians nearing retirement. Results: The results showed that higher income, future time perspective (FTP) and financial knowledge independently predicted levels of retirement planning. The effects of FTP and financial knowledge on financial planning were consistent across levels of socioeconomic status. Conclusions: While similar issues in financial planning appeared across socioeconomic status, a ‘one size fits all’ approach to retirement policy may not be effective. Instead, policy should be targeted towards the diverse needs of different groups. Raising public awareness of FTP and financial knowledge may provide a useful starting point.     

Differences between hospitals in attainment of parathyroid hormone treatment targets in chronic kidney disease do not reflect differences in quality of care

ABSTRACT: BACKGROUND: Transparency in quality of care (QoC) is stimulated and hospitals are compared and judged on the basis of indicators of performance on specific treatment targets. In patients with chronic kidney disease, QoC differed significantly between hospitals. In this analysis we explored additional parameters to explain differences between centers in attainment of parathyroid hormone (PTH) treatment targets. METHODS: Using MASTERPLAN baseline data, we selected one of the worst (center A) and one of the best (center B) performing hospitals. Differences between the two centers were analyzed from the year prior to start of the MASTERPLAN study until the baseline evaluation. Determinants of PTH were assessed. RESULTS: 101 patients from center A (median PTH 9.9 pmol/l, in 63 patients exceeding recommended levels) and 100 patients from center B (median PTH 6.5 pmol/l, in 32 patients exceeding recommended levels), were included. Analysis of clinical practice did not reveal differences in PTH management between the centers. Notably, hyperparathyroidism resulted in a change in therapy in less than 25% of patients. In multivariate analysis kidney transplant status, MDRD-4, and treatment center were independent predictors of PTH. However, when MDRD-6 (which accounts for serum urea and albumin) was used instead of MDRD-4, the center effect was reduced. Moreover, after calibration of the serum creatinine assays treatment center no longer influenced PTH. CONCLUSIONS: We show that differences in PTH control between centers are not explained by differences in treatment, but depend on incomparable patient populations and laboratory techniques. Therefore, results of hospital performance comparisons should be interpreted with great caution.     

Spatial Variability of Metal Bioaccumulation in Estuarine Killifish (Fundulus heteroclitus) at the Callahan Mine Superfund Site, Brooksville, ME

The former Callahan Mine Site in Brooksville, ME, is an open-pit, hardrock mine site in an intertidal system, thus providing a unique opportunity to evaluate how metal-enriched sediments and overlying water impact estuarine food webs. Copper, zinc, cadmium, and lead concentrations in sediment, whole water, and Atlantic killifish (Fundulus heteroclitus) were evaluated at sites in Goose Pond (GP; Callahan Mine Site) and at reference sites. The metal concentrations of sediment, water, and fish were spatially distinct and significantly greater at the mine site than in the reference estuary. Sediment concentrations were particularly elevated and were above probable effects levels for all four metals adjacent to the tailings pile. Even in this well-mixed system, water metal concentrations were significantly elevated adjacent to the tailings pile, and concentrations of Cu and Zn were above ambient water-quality criteria for chronic marine exposure. Neither organic matter in the sediment nor salinity or pH of the water explained the metal concentrations. Adjacent to the tailings pile, killifish metal body burdens were elevated and were significantly related to both sediment and aqueous concentrations. In conclusion, (1) the contaminated sediment and seepage from the tailings impoundment and waste rock pile no. 3 create a continual flux of metals into the water column, (2) the metals are bioavailable and bioconcentrating as evident in the killifish tissue concentrations, and (3) Callahan Mine is directly affecting metal bioaccumulation in fauna residing in the GP estuary and, potentially, in Penobscot Bay by the way of “trophic nekton relay.”