Applying Definitions of “Asbestos” to Environmental and “Low-Dose” Exposure Levels and Health Effects, Particularly Malignant Mesothelioma

Although asbestos research has been ongoing for decades, this increased knowledge has not led to consensus in many areas of the field. Two such areas of controversy include the specific definitions of asbestos, and limitations in understanding exposure-response relationships for various asbestos types and exposure levels and disease. This document reviews the current regulatory and mineralogical definitions and how variability in these definitions has led to difficulties in the discussion and comparison of both experimental laboratory and human epidemiological studies for asbestos. This review also examines the issues of exposure measurement in both animal and human studies, and discusses the impact of these issues on determination of cause for asbestos-related diseases. Limitations include the lack of detailed characterization and limited quantification of the fibers in most studies. Associated data gaps and research needs are also enumerated in this review

MPPDep version 1.11: een model voor humane en rattenluchtweg deeltjes depositie

Rapport is vervallen. Zie rapport 650010030 voor nieuwe versie / Report has expired. See report 650010030 for new versionHet programma is grotendeels gebaseerd op in de literatuur beschreven 'multiple path' modellen voor aerosolen, wat als belangrijk voordeel ten opzichte van bestaande modellen heeft dat het gebruik maakt van de morfologische gegevens van een individu. Het omvat zowel modules voor het bepalen van de gedeponeerde dosis in zowel de mens als in proefdieren (rat). De modellen zijn in staat om op basis van bestaande morfologische en functionele gegevens de dosis en flux in een bepaald segment of regio van de luchtwegen vast te berekenen. Daarnaast kunnen binnen een zekere range de functionele parameters als ademhalingsfrequentie worden aangepast om hiermee bepaalde luchtwegaandoeningen te kunnen simuleren. Een andere belangrijke modificatie is het toevoegen van functies voor de inhaleerbaarheid van aerosolen, het invoeren van gegevens over poydisperse aerosolen. Het softwarepakket is gebruikersvriendelijk door toepassing van een grafische interface en geschreven voor een MS-Windows 9x/NT.The programme is largely based on multiple-path models for particle deposition and existing models described in the literature. It encompasses both modules for human and experimental animal (rat) calculations. The software can calculate the dose ratio and flux of particulates in certain segments or regions within the airways. By adjusting the functional parameters like breathing frequency or tidal volume, the influence of certain respiratory diseases on particle deposition can be simulated. Another important modification is the addition of functions for the inhalability of particulate matter and the option to calculate the deposition of both mono- and poly-disperse aerosols. The software package has been made user-friendly through the application of a graphical interface for a MS Windows 9x/NT computer operating system.DGM-DL

Novel multi-functional europium-doped gadolinium oxide nanoparticle aerosols facilitate the study of deposition in the developing rat lung

Ambient ultrafine particulate matter (UPM), less than 100 nm in size, has been linked to the development and exacerbation of pulmonary diseases. Age differences in susceptibility to UPM may be due to a difference in delivered dose as well as age-dependent differences in lung biology and clearance. In this study, we developed and characterized aerosol exposures to novel metal oxide nanoparticles containing lanthanides to study particle deposition in the developing postnatal rat lung. Neonatal, juvenile and adult rats (1, 3 and 12 weeks old) were nose only exposed to 380 μg/m(3) of ~30 nm europium doped gadolinium oxide nanoparticles (Gd(2)O(3):Eu(3+)) for 1 h. The deposited dose in the nose, extrapulmonary airways and lungs was determined using inductively-coupled plasma mass spectroscopy. The dose of deposited particles was significantly greater in the juvenile rats at 2.22 ng/g body weight compared to 1.47 ng/g and 0.097 ng/g for the adult and neonate rats, respectively. Toxicity was investigated in bronchoalveolar lavage fluid (BALF) by quantifying recovered cell types, and measuring lactate dehydrogenase activity and total protein. The toxicity data suggests that the lanthanide particles were not acutely toxic or inflammatory with no increase in neutrophils or lactate dehydrogenase activity at any age. Juvenile and adult rats had the same mass of deposited NPs per gram of lung tissue, while neonatal rats had significantly less NPs deposited per gram of lung tissue. The current study demonstrates the utility of novel lanthanide-based nanoparticles to study inhaled particle deposition in vivo and has important implications for nanoparticles delivery to the developing lung either as therapies or as a portion of particulate matter air pollution

A geometrical approach to the PKPD modelling of inhaled bronchodilators

The present work introduces a new method to model the pharmacokinetics and pharmacodynamics (PKPD) of an inhaled dose of bronchodilator. This method provides an alternative approach to classic compartmental representations or computational fluid dynamics. A five compartment lung model comprising the upper airways, bronchial tree mucosa, bronchial muscles, alveoli and plasma has been modified to take into account anatomical, geometrical features such as bronchial branching and smooth muscle distribution. Many anatomical and physiological features of the bronchial tree depend, as a first approximation, on bronchial generation or on mean distance from the larynx. Among these are diameters, resistances, and receptor density, which work together in determining the local response to the inhaled dose; integrating these local responses over the whole bronchial tree allows an approximation of total broncodilator response, particularly with respect to airflow resistance. While the PK part of the model reflects classical compartmental assumptions, the PD part substitutes a simplified geometrical and functional description of the bronchial tree for the typical PD models of effect, leading to the direct computation of the approximate FEV1. In the present work the construction of the model is detailed, and literature data are used to derive the anatomical approximations used. Simulation of two asthmatic subjects is employed to illustrate the behaviour of the model in representing the evolution over time of the distribution and effect of an inhaled dose of bronchodilator. The relevance of formulation diffusivity on therapeutic efficacy is discussed and conclusions regarding the applicability of the model in interpreting single-subject and population experiments are drawn