Translational toxicology in setting occupational exposure limits for dusts and hazard classification – a critical evaluation of a recent approach to translate dust overload findings from rats to humans

Background We analyze the scientific basis and methodology used by the German MAK Commission in their recommendations for exposure limits and carcinogen classification of “granular biopersistent particles without known specific toxicity” (GBS). These recommendations are under review at the European Union level. We examine the scientific assumptions in an attempt to reproduce the results. MAK’s human equivalent concentrations (HECs) are based on a particle mass and on a volumetric model in which results from rat inhalation studies are translated to derive occupational exposure limits (OELs) and a carcinogen classification. Methods We followed the methods as proposed by the MAK Commission and Pauluhn 2011. We also examined key assumptions in the metrics, such as surface area of the human lung, deposition fractions of inhaled dusts, human clearance rates; and risk of lung cancer among workers, presumed to have some potential for lung overload, the physiological condition in rats associated with an increase in lung cancer risk. Results The MAK recommendations on exposure limits for GBS have numerous incorrect assumptions that adversely affect the final results. The procedures to derive the respirable occupational exposure limit (OEL) could not be reproduced, a finding raising considerable scientific uncertainty about the reliability of the recommendations. Moreover, the scientific basis of using the rat model is confounded by the fact that rats and humans show different cellular responses to inhaled particles as demonstrated by bronchoalveolar lavage (BAL) studies in both species. Conclusion Classifying all GBS as carcinogenic to humans based on rat inhalation studies in which lung overload leads to chronic inflammation and cancer is inappropriate. Studies of workers, who have been exposed to relevant levels of dust, have not indicated an increase in lung cancer risk. Using the methods proposed by the MAK, we were unable to reproduce the OEL for GBS recommended by the Commission, but identified substantial errors in the models. Considerable shortcomings in the use of lung surface area, clearance rates, deposition fractions; as well as using the mass and volumetric metrics as opposed to the particle surface area metric limit the scientific reliability of the proposed GBS OEL and carcinogen classification.International Carbon Black Associatio

Fatigue, reduced sleep quality and restless legs syndrome in Charcot-Marie-Tooth disease: a web-based survey

To investigate the prevalence of fatigue, daytime sleepiness, reduced sleep quality, and restless legs syndrome (RLS) in a large cohort of patients with Charcot-Marie-Tooth disease (CMT) and their impact on health-related quality of life (HRQoL). Participants of a web-based survey answered the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, the Multidimensional Fatigue Inventory, and, if the diagnostic criteria of RLS were met, the International RLS Severity Scale. Diagnosis of RLS was affirmed in screen-positive patients by means of a standardized telephone interview. HRQoL was assessed by using the SF-36 questionnaire. Age- and sex-matched control subjects were recruited from waiting relatives of surgical outpatients. 227 adult self-reported CMT patients answered the above questionnaires, 42.9% were male, and 57.1% were female. Age ranged from 18 to 78 years. Compared to controls (n = 234), CMT patients reported significantly higher fatigue, a higher extent and prevalence of daytime sleepiness and worse sleep quality. Prevalence of RLS was 18.1% in CMT patients and 5.6% in controls (p = 0.001). RLS severity was correlated with worse sleep quality and reduced HRQoL. Women with CMT were affected more often and more severely by RLS than male patients. With regard to fatigue, sleep quality, daytime sleepiness, RLS prevalence, RLS severity, and HRQoL, we did not find significant differences between genetically distinct subtypes of CMT. HRQoL is reduced in CMT patients which may be due to fatigue, sleep-related symptoms, and RLS in particular. Since causative treatment for CMT is not available, sleep-related symptoms should be recognized and treated in order to improve quality of life

Effects of early, combined endurance and resistance training in mechanically ventilated, critically ill patients: a study protocol for a randomised controlled trial

BACKGROUND Prolonged need for intensive care is associated with neuromuscular weakness, termed Intensive Care Unit Acquired Weakness. Those affected suffer from severe functional impairment that can persist for years. First studies suggest a positive effect of physiotherapy and early mobilisation. However, the ideal intervention for a preferential functional outcome is not known. So far no randomised controlled trial has been conducted to specifically evaluate an early endurance and resistance training in the mechanically ventilated, critically ill patient. METHODS/DESIGN A randomised controlled trial with blinded assessors and 6-month follow-up will be conducted in a tertiary, interdisciplinary intensive care unit in Switzerland. Participants (n = 115; expected dropouts: n = 15) will be randomised to a control group receiving standard physiotherapy and to an experimental group that undergoes early mobilisation combined with endurance and resistance training. The inclusion criteria are being aged 18 years or older, expected mechanical ventilation for more than 72 h and qualitative independence before the illness. Primary endpoints are functional capacity (6-Minute Walk Test) and the ability to perform activities of daily living (Functional Independence Measure) measured at hospital discharge. Secondary endpoints include muscle strength (Medical Research Council sum score, handgrip strength and handheld dynamometry for quadriceps muscle), joint contractures (range of motion), exercise capacity (Timed 'Up & Go' Test) and health-related quality of life (Short Form 36). Safety will be monitored during interventions by indirect calorimetry and continuous intensive care standard monitoring. All previously defined adverse events will be noted. The statistical analysis will be by intention-to-treat with the level of significance set at p < 0.05. DISCUSSION This prospective, single-centre, allocation-concealed and assessor-blinded randomised controlled trial will evaluate participant's function after an early endurance and resistance training compared to standard care. Limitations of this study are the heterogeneity of the critically ill and the discontinuity of the protocol after relocation to the ward. The strengths lie in the pragmatic design and the clinical significance of the chosen outcome measures. TRIAL REGISTRATION German Clinical Trials Register (DRKS): DRKS00004347 , registered on 10 September 2012