Linking a dermal permeation and an inhalation model to a simple pharmacokinetic model to study airborne exposure to di(n-butyl) phthalate

Six males clad only in shorts were exposed to high levels of airborne di(n-butyl) phthalate (DnBP) and diethyl phthalate (DEP) in chamber experiments conducted in 2014. In two 6 h sessions, the subjects were exposed only dermally while breathing clean air from a hood, and both dermally and via inhalation when exposed without a hood. Full urine samples were taken before, during, and for 48 h after leaving the chamber and measured for key DnBP and DEP metabolites. The data clearly demonstrated high levels of DnBP and DEP metabolite excretions while in the chamber and during the first 24 h once leaving the chamber under both conditions. The data for DnBP were used in a modeling exercise linking dose models for inhalation and transdermal permeation with a simple pharmacokinetic model that predicted timing and mass of metabolite excretions. These models were developed and calibrated independent of these experiments. Tests included modeling of the “hood-on” (transdermal penetration only), “hood-off” (both inhalation and transdermal) scenarios, and a derived “inhalation-only” scenario. Results showed that the linked model tended to duplicate the pattern of excretion with regard to timing of peaks, decline of concentrations over time, and the ratio of DnBP metabolites. However, the transdermal model tended to overpredict penetration of DnBP such that predictions of metabolite excretions were between 1.1 and 4.5 times higher than the cumulative excretion of DnBP metabolites over the 54 h of the simulation. A similar overprediction was not seen for the “inhalation-only” simulations. Possible explanations and model refinements for these overpredictions are discussed. In a demonstration of the linked model designed to characterize general population exposures to typical airborne indoor concentrations of DnBP in the United States, it was estimated that up to one-quarter of total exposures could be due to inhalation and dermal uptake

Collateral fattening in body composition autoregulation: its determinants and significance for obesity predisposition

Collateral fattening refers to the process whereby excess fat is deposited as a result of the body’s attempt to counter a deficit in lean mass through overeating. Its demonstration and significance to weight regulation and obesity can be traced to work on energy budget strategies in growing mammals and birds, and to men recovering from experimental starvation. The cardinal features of collateral fattening rests upon (i) the existence of a feedback system between lean tissue and appetite control, with lean tissue deficit driving hyperphagia, and (ii) upon the occurrence of a temporal desynchronization in the recovery of body composition, with complete recovery of fat mass preceeding that of lean mass. Under these conditions, persistent hyperphagia driven by the need to complete the recovery of lean tissue will result in the excess fat deposition (hence collateral fattening) and fat overshooting. After reviewing the main lines of evidence for the phenomenon of collateral fattening in body composition autoregulation, this article discusses the causes and determinants of the desynchronization in fat and lean tissue recovery leading to collateral fattening and fat overshooting, and points to their significance in the mechanisms by which dieting, developmental programming and sedentariness predispose to obesity

Nutraceutical therapies for atherosclerosis

Atherosclerosis is a chronic inflammatory disease affecting large and medium arteries and is considered to be a major underlying cause of cardiovascular disease (CVD). Although the development of pharmacotherapies to treat CVD has contributed to a decline in cardiac mortality in the past few decades, CVD is estimated to be the cause of one-third of deaths globally. Nutraceuticals are natural nutritional compounds that are beneficial for the prevention or treatment of disease and, therefore, are a possible therapeutic avenue for the treatment of atherosclerosis. The purpose of this Review is to highlight potential nutraceuticals for use as antiatherogenic therapies with evidence from in vitro and in vivo studies. Furthermore, the current evidence from observational and randomized clinical studies into the role of nutraceuticals in preventing atherosclerosis in humans will also be discussed

More rapid polar ozone depletion through the reaction of HOCI with HCI on polar stratospheric clouds

THE direct reaction of HOC1 with HC1, known to occur in liquid water1 and on glass surfaces2, has now been measured on surfaces similar to polar stratospheric clouds3,4 and is shown here to play a critical part in polar ozone loss. Two keys to understanding the chemistry of the Antarctic ozone hole5-7 are, one, the recognition that reactions on polar stratospheric clouds transform HC1 into more reactive species denoted by ClOx(refs 812) and, two, the discovery of the ClO-dimer (C12O2) mechanism that rapidly catalyses destruction of O3(refs 1315). Observations of high levels of OClO and ClO in the springtime Antarctic stratosphere1619 confirm that most of the available chlorine is in the form of ClOx (refs 20, 21). But current photochemical models22,23 have difficulty converting HC1 to ClOx rapidly enough in early spring to account fully for the observations5-7,20,21. Here I show, using a chemical model, that the direct reaction of HOC1 with HC1 provides the missing mechanism. As alternative sources of nitrogen-containing oxidants, such as N2O5 and ClONO2, have been converted in the late autumn to inactive HNO3 by known reactions on the sulphate-layer aerosols24-27, the reaction of HOC1 with HC1 on polar stratospheric clouds becomes the most important pathway for releasing that stratospheric chlorine which goes into polar night as HC1. © 1992 Nature Publishing Group

Does metabolic compensation explain the majority of less-than-expected weight loss in obese adults during a short-term severe diet and exercise intervention?

Objective: We investigated to what extent changes in metabolic rate and composition of weight loss explained the less-than-expected weight loss in obese men and women during a diet-plus-exercise intervention. Design: 16 obese men and women (41 ± 9 years; BMI 39 ± 6 kg/m2) were investigated in energy balance before, after and twice during a 12-week VLED (565–650 kcal/day) plus exercise (aerobic plus resistance training) intervention. The relative energy deficit (EDef) from baseline requirements was severe (74-87%). Body composition was measured by deuterium dilution and DXA and resting metabolic rate (RMR) by indirect calorimetry. Fat mass (FM) and fat-free mass (FFM) were converted into energy equivalents using constants: 9.45 kcal/gFM and 1.13 kcal/gFFM. Predicted weight loss was calculated from the energy deficit using the '7700 kcal/kg rule'. Results: Changes in weight (-18.6 ± 5.0 kg), FM (-15.5 ± 4.3 kg), and FFM (-3.1 ± 1.9 kg) did not differ between genders. Measured weight loss was on average 67% of the predicted value, but ranged from 39 to 94%. Relative EDef was correlated with the decrease in RMR (R=0.70, P<0.01) and the decrease in RMR correlated with the difference between actual and expected weight loss (R=0.51, P<0.01). Changes in metabolic rate explained on average 67% of the less-than-expected weight loss, and variability in the proportion of weight lost as FM accounted for a further 5%. On average, after adjustment for changes in metabolic rate and body composition of weight lost, actual weight loss reached 90% of predicted values. Conclusion: Although weight loss was 33% lower than predicted at baseline from standard energy equivalents, the majority of this differential was explained by physiological variables. While lower-than-expected weight loss is often attributed to incomplete adherence to prescribed interventions, the influence of baseline calculation errors and metabolic down-regulation should not be discounted