Human Challenge Studies

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Human exposure studies assess biological responses to controlled levels of specific air mixtures by a range of approaches, allowing precise control of delivered concentrations, adjustment of ventilation rates and measurement of a range of biological responses. These studies are ideal for assessing acute (i.e. immediate to 24 hours) responses to pollutants but not for assessing the effects of long-term exposure to specific substances.

The range of biological responses studied will vary from invasive procedures such as biopsy of the lung by bronchoscopy to less invasive assessment of systemic responses from blood samples. Timing of response in relation to exposure is also crucial but a key issue is determining what could be regarded as a "normal", physiological response rather than a patho-physiological (abnormal) response. Understanding these differences is crucial when considering exposures that may have subtle yet important effects after short-term exposures.

As there are no studies specifically of manufactured NPs, the available information comes from studies of particles derived from the internal combustion engine or from laboratory-generated particles, whose content is part of that seen in ambient particles. The great majority of published human exposure studies considered a source of particles for which either the exact particle size range was unknown or where the range included, but was not limited to, the nanoparticle range (e.g. exposures to diesel exhaust particles (DEPs) and Concentrated Ambient Particles (CAPs)). The only studies of particles solely in the nanoparticle range are those where the particles are specifically generated in the laboratory (usually using an electrical spark generator) and thus usually comprise a single type of particle (e.g. carbon, iron or zinc).

For a range of reasons, including availability of volunteers and ethical concerns about exposing individuals with moderate to severe disease to a potentially risky substance, most subjects used in these studies have been younger, healthy volunteers, although some studies have exposed subjects with mild asthma. Only two studies have exposed individuals with significant cardiac disease60 or chronic lung disease.61

There have been studies of DEP exposure giving adequate information on particle size distribution.62 66 Most delivered moderately high concentrations in mass terms (100-300 mg m~3). These studies broadly suggested that DEPs can cause a neutrophilic inflammatory response in both normal and asthmatic subjects, probably mediated through IL-8, with some evidence of endothelial activation especially in the asthmatic subjects. There are two reports of CAP exposures, which suggest an airway neutrophilic response perhaps with an endothelial response.67

Exposure to zinc oxide fume produces conflicting results. Spark-generated zinc oxide produces no effects on any inflammatory marker.68 Zinc oxide fume at high exposures (up to 37 mg m~3) produced systemic effects typical of metal fume fever, increased plasma IL-6 and a dose-related increase in BAL neutrophils.69,70

Exposure to sulfuric acid particles (in the nanometre range) has shown no effects on lung function or inflammatory markers.71,72 However, one study of the effects of ultrafine sulfuric acid (1000 mg m~3) on response to allergen exposure73 showed enhancement of the allergen response in the airways. Two studies of ultrafine carbon exposure showed an immediate effect on cardiac autonomic control in patients with cardiac disease60 and a suggestion that on exercise there was shortening of the Q-T interval of the ECG in older subjects.74

Most reported human challenge work relates to particles in ambient air. These particles constitute an insoluble, solid core (in the case of ambient particles, carbon) or comprise soluble substances (e.g. sulfuric acid or sulfates). The solid particles form a base for the carriage of other molecules of greater or lesser bio-activity so an approach to decide on mechanisms of such complex structures needs either to take the pragmatic view that the whole particle should be assessed or to study the individual components in isolation. In addition, the dose and the physico-chemical characteristics of the particles are fundamental drivers of biological responses. Now that particles in the ultrafine range are recognised as important, mass may be an inappropriate index of dose as NPs are very light but have a vast surface area. There is a need to be able to develop systems for delivering nanomaterials in these studies in sufficient dose but using surface area or number as the dosing metric.

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Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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