The toxicology of air pollution predicts its epidemiology.

The epidemiologic investigation has successively delineated associations of air pollution exposure with non-malignant and malignant lung disease, cardiovascular disease, cerebrovascular disease, pregnancy outcomes, perinatal effects and other extra-pulmonary disease including diabetes. Defining these relationships between air pollution exposure and human health closely parallels results of an earlier epidemiologic investigation into cigarette smoking and environmental tobacco smoke (ETS), two other particle-related exposures. Humic-like substances (HULIS) have been identified as a chemical component common to cigarette smoke and air pollution particles. Toxicology studies provide evidence that a disruption of iron homeostasis with sequestration of host metal by HULIS is a fundamental mechanistic pathway through which biological effects are initiated by cigarette smoke and air pollution particles. As a result of a common chemical component and a shared mechanistic pathway, it should be possible to extrapolate from the epidemiology of cigarette smoking and ETS to predict associations of air pollution exposure with human disease, which are currently unrecognized. Accordingly, it is anticipated that the forthcoming epidemiologic investigation will demonstrate relationships of air pollution with COPD causation, peripheral vascular disease, hypertension, renal disease, digestive disease, loss of bone mass/risk of fractures, dental disease, eye disease, fertility problems, and extrapulmonary malignancies.

Dopaminergic neurotoxicity following pulmonary exposure to manganese-containing welding fumes.

The potential for development of Parkinson's disease (PD)-like neurological dysfunction following occupational exposure to aerosolized welding fumes (WF) is an area of emerging concern. Welding consumables contain a complex mixture of metals, including iron (Fe) and manganese (Mn), which are known to be neurotoxic. To determine whether WF exposure poses a neurological risk particularly to the dopaminergic system, we treated Sprague-Dawley rats with WF particulates generated from two different welding processes, gas metal arc-mild steel (GMA-MS; low Mn, less water-soluble) and manual metal arc-hard surfacing (MMA-HS; high Mn, more water-soluble) welding. Following repeated intratracheal instillations (0.5 mg/rat, 1/week x 7 weeks) of GMA-MS or MMA-HS, elemental analysis and various molecular indices of neurotoxicity were measured at 1, 4, 35 or 105 days after last exposure. MMA-HS exposure, in particular, led to increased deposition of Mn in striatum and midbrain. Both fumes also caused loss of tyrosine hydroxylase (TH) protein in the striatum (~20%) and midbrain (~30%) by 1 day post-exposure. While the loss of TH following GMA-MS was transient, a sustained loss (34%) was observed in the midbrain 105 days after cessation of MMA-HS exposure. In addition, both fumes caused persistent down-regulation of dopamine D2 receptor (Drd2; 30-40%) and vesicular monoamine transporter 2 (Vmat2; 30-55%) mRNAs in the midbrain. WF exposure also modulated factors associated with synaptic transmission, oxidative stress, neuroinflammation and gliosis. Collectively, our findings demonstrate that repeated exposure to Mn-containing WF can cause persistent molecular alterations in dopaminergic targets. Whether such perturbations will lead to PD-like neuropathological manifestations remains to be elucidated.

Pulmonary toxicity and extrapulmonary tissue distribution of metals after repeated exposure to different welding fumes.

Welders are exposed to fumes with different metal profiles. The goals of this study were to compare lung responses in rats after treatment with chemically different welding fumes and to examine the extrapulmonary fate of metals after deposition in the lungs. Rats were treated by intratracheal instillation (0.5 mg/rat, once a week for 7 weeks) with gas metal arc-mild steel (GMAW-MS) or manual metal arc-hardsurfacing (MMAW-HS) welding fumes. Controls were treated with saline. At 1, 4, 35, and 105 days after the last treatment, lung injury and inflammation were measured, and elemental analysis of different organs was determined to assess metal clearance. The MMAW-HS fume was highly water-soluble and chemically more complex with higher levels of soluble Mn and Cr compared to the GMAW-MS fume. Treatments with the GMAW-MS fume had no effect on toxicity when compared with controls. The MMAW-HS fume induced significant lung damage early after treatment that remained elevated until 35 days. Metals associated with each fume sample was cleared at different rates from the lungs. Mn was cleared from the lungs at a faster rate and to a greater extent compared to the other metals over the 105-day recovery period. Mn and Cr in the MMAW-HS fume translocated from the respiratory tract and deposited in other organs. Importantly, increased deposition of Mn, but not other metals, was observed in discrete brain regions, including dopamine-rich areas (e.g., striatum and midbrain).