The role of nodose ganglia in the regulation of cardiovascular function following pulmonary exposure to ultrafine titanium dioxide.

The inhalation of nanosized air pollutant particles is a recognised risk factor for cardiovascular disease; however, the link between occupational exposure to engineered nanoparticles and adverse cardiovascular events remains unclear. In the present study, the authors demonstrated that pulmonary exposure of rats to ultrafine titanium dioxide (UFTiO2) significantly increased heart rate and depressed diastolic function of the heart in response to isoproterenol. Moreover, pulmonary inhalation of UFTiO2 elevated mean and diastolic blood pressure in response to norepinephrine. Pretreatment of the rats ip with the transient receptor potential (TRP) channel blocker ruthenium red inhibited substance P synthesis in nodose ganglia and associated functional and biological changes in the cardiovascular system. In conclusion, the effects of pulmonary inhalation of UFTiO2 on cardiovascular function are most likely triggered by a lung-nodose ganglia-regulated pathway via the activation of TRP channels in the lung.

Immunotoxicity and allergic potential induced by topical application of dimethyl carbonate (DMC) in a murine model.

Dimethyl carbonate (DMC) is an industrial chemical, used as a paint and adhesive solvent, with the potential for significant increases in production. Using select immune function assays, the purpose of these studies was to evaluate the immunotoxicity of DMC following dermal exposure using a murine model. Following a 28-day exposure, DMC produced a significant decrease in thymus weight at concentrations of 75% and greater. No effects on body weight, hematological parameters (erythrocytes, leukocytes, and their differentials), or immune cell phenotyping (B-cells, T-cells, and T-cell sub-sets) were identified. The IgM antibody response to sheep red blood cell (SRBC) was significantly reduced in the spleen but not the serum. DMC was not identified to be an irritant and evaluation of the sensitization potential, conducted using the local lymph node assay (LLNA) at concentrations ranging from 50-100%, did not identify increases in lymphocyte proliferation. These results demonstrate that dermal exposure to DMC induces immune suppression in a murine model and raise concern about potential human exposure and the need for occupational exposure regulations.

Mitochondrial dysfunction and loss of Parkinson's disease-linked proteins contribute to neurotoxicity of manganese-containing welding fumes.

Welding generates complex metal aerosols, inhalation of which is linked to adverse health effects among welders. An important health concern of welding fume (WF) exposure is neurological dysfunction akin to Parkinson's disease (PD), thought to be mediated by manganese (Mn) in the fumes. Also, there is a proposition that welding might accelerate the onset of PD. Our recent findings link the presence of Mn in the WF with dopaminergic neurotoxicity seen in rats exposed to manual metal arc-hard surfacing (MMA-HS) or gas metal arc-mild steel (GMA-MS) fumes. To elucidate the molecular mechanisms further, we investigated the association of PD-linked (Park) genes and mitochondrial function in causing dopaminergic abnormality. Repeated instillations of the two fumes at doses that mimic ∼1 to 5 yr of worker exposure resulted in selective brain accumulation of Mn. This accumulation caused impairment of mitochondrial function and loss of tyrosine hydroxylase (TH) protein, indicative of dopaminergic injury. A fascinating finding was the altered expression of Parkin (Park2), Uchl1 (Park5), and Dj1 (Park7) proteins in dopaminergic brain areas. A similar regimen of manganese chloride (MnCl(2)) also caused extensive loss of striatal TH, mitochondrial electron transport components, and Park proteins. As mutations in PARK genes have been linked to early-onset PD in humans, and because welding is implicated as a risk factor for parkinsonism, PARK genes might play a critical role in WF-mediated dopaminergic dysfunction. Whether these molecular alterations culminate in neurobehavioral and neuropathological deficits reminiscent of PD remains to be ascertained.

Whole-body inhalation exposure to 1-bromopropane suppresses the IgM response to sheep red blood cells in female B6C3F1 mice and Fisher 344/N rats.

1-Bromopropane (1-BP) is categorized as a high-production-volume chemical and is currently used in the manufacture of pharmaceuticals, pesticides, and other chemicals. Its usage is estimated to be around 5 million pounds per year, resulting in the potential for widespread exposure in the workplace. Case reports and animal studies have suggested exposure to this compound may cause adverse reproductive and neurological effects. Using a battery of immunological assays, the immunotoxicity of 1-BP after whole body inhalation exposure in both mice and rats was evaluated. Significant decreases in the spleen immunoglobulin (Ig) M response to sheep red blood cells (SRBC) were observed in both mice (125-500 ppm) and rats (1000 ppm) after exposure to 1-BP for 10 wk. In addition, total spleen cells and T cells were significantly decreased after approximately 4 wk of 1-BP exposure in both mice (125-500 ppm) and rats (1000 ppm). No change in natural killer (NK) cell activity was observed. The observed alterations in spleen cellularity, phenotypic subsets, and impairment of humoral immune function across species raise further concern about human exposure to 1-BP and demonstrate the need for additional investigations into potential adverse health effects.

Evaluation of irritancy and sensitization potential of metalworking fluid mixtures and components.

There are approximately 1.2 million workers exposed to metalworking fluids (MWF), which are used to reduce the heat and friction associated with industrial machining and grinding operations. Irritancy and sensitization potential of 9 National Toxicology Program (NTP) nominated MWFs (TRIM 229, TRIM VX, TRIM SC210, CIMTECH 310, CIMPERIAL 1070, CIMSTAR 3800, SYNTILO 1023, SUPEREDGE 6768, and CLEAREDGE 6584) were examined in a combined local lymph node assay (LLNA). BALB/c mice were dermally exposed to each MWF at concentrations up to 50%. Significant irritation was observed after dermal exposure to all MWFs except CIMTECH 310 and SYNTILO 1023. Of the 9 MWFs, 6 induced greater than a 3-fold increase in lymphocyte proliferation and 7 tested positive in the irritancy assay. TRIM VX yielded the lowest EC3 value (6.9%) with respect to lymphocyte proliferation. Chemical components of TRIM VX identified using HPLC were screened for sensitization potential using structural activity relationship (SAR) modeling and the LLNA. TOPKAT predicted triethanolamine (TEA) as a sensitizer while Derek for Windows predicted only 4-chloro-3-methylphenol (CMP) to be positive for sensitization. When tested in the LLNA only CMP (EC3 = 11.6%) and oleic acid (OA) (EC3 = 29.7%) were identified as sensitizers. Exposure to all tested TRIM VX components resulted in statistically significant irritation. An additive proliferative response was observed when mixtures of the two identified sensitizing TRIM VX components, OA and CMP, were tested in the LLNA. This is one explanation of why the EC3 value of TRIM VX, with respect to lymphocyte proliferation, is lower than those assigned to its sensitizing components.

The humoral immune response of mice exposed to simulated road paving-like asphalt fumes.

Asphalt is a complex mixture of organic molecules, including polycyclic aromatic hydrocarbons (PAH), which have been reported to cause serious adverse health effects in humans. Workers in manufacturing and construction trades exposed to asphalt are potentially at risk for being exposed to asphalt fumes and PAHs. Epidemiological investigations have collected mounting evidence that chemicals found in asphalt fumes present carcinogenic and possibly immunotoxic hazards. Studies evaluating the immunotoxic effects of asphalt fume are limited due to the large number of variables associated with asphalt fume exposures. This work investigates the immuno-toxic effects of road paving-like asphalt fume by analyzing the in vivo IgM response to a T-dependent antigen after exposure to whole, vapor, and particulate phase road paving-like asphalt fumes and asphalt fume condensate. Systemic exposures via intraperitoneal injection of asphalt fume condensate (at 0.625 mg/kg) and the particulate phase (at 5 mg/kg) resulted in significant reductions in the specific spleen IgM response to SRBC. Pharyngeal aspiration of the asphalt fume condensate (at 5 mg/kg) also resulted in significant suppression of the IgM response to SRBC. A significant reduction in the specific spleen IgM activity was observed after inhalation exposure to whole asphalt fumes (35 mg/m(3)) and the vapor components (11 mg/m(3)). Dermal exposures to the asphalt fume condensate resulted in significant reductions in the total (at 50 mg/kg) and specific (at 250 mg/kg) spleen IgM response to SRBC. These results demonstrate that exposure to road paving-like asphalt fumes is immunosuppressive through systemic, respiratory, and dermal routes of exposure in a murine model and raise concerns regarding the potential for adverse immunological effects.

Irritancy and sensitization potential of glyoxylic acid.

Glyoxylic acid, a small dicarboxylic acid, has been detected at measurable levels in the atmosphere and is suspected to be present in indoor air environments. It is generated through the ozonolysis of several high volume production compounds that are commonly found indoors. Glyoxylic acid was tested in a combined irritancy and local lymph node assay (LLNA). It tested positive in the LLNA with an EC3 value of 5.05%. Significant increases were observed in the B220+cell population in the draining lymph nodes. No changes were identified in the IgE+B220+ cell population in the draining lymph nodes or total serum IgE levels; this suggests that glyoxylic acid functions as a T-cell-mediated contact sensitizer. Exposure to volatile organic compounds (VOC), similar to glyoxylic acid, emitted from building materials, cleaning formulations or other consumer products, and /or indoor chemistry have been linked to adverse health effects. These results may provide an explanation for some of adverse health effects associated with indoor air exposure.

Evaluation of the contact and respiratory sensitization potential of volatile organic compounds generated by simulated indoor air chemistry.

Up to 60 million people working indoors experience symptoms such as eye, nose and throat irritation, headache, and fatigue. Investigations into these complaints have ascribed the effects to volatile organic compounds (VOCs) emitted from building materials, cleaning formulations, or other consumer products. New compounds can result when the VOCs react with hydroxyl or nitrate radicals or ozone present in indoor environments. Several oxygenated organic compounds, such as glyoxal, methylglyoxal, glycolaldehyde, and diacetyl, have been identified as possible reaction products of indoor environment chemistry. Although research has previously identified diacetyl and glyoxal as sensitizers, additional experiments were conducted in these studies to further classify their sensitization potential. Sensitization potential of these four compounds was assessed using quantitative structure-activity relationship (QSAR) programs. Derek for Windows and National Institute for Occupational Safety and Health logistic regression predicted all compounds to be sensitizers, while TOPKAT 6.2 predicted all compounds except for methylglyoxal. All compounds were tested in a combined irritancy and local lymph node assay (LLNA). All compounds except for glyoxal were found to be irritants and all tested positive in the LLNA with EC3 values ranging from 0.42 to 1.9%. Methylglyoxal significantly increased both the B220(+) and IgE(+)B220(+) cell populations in the draining lymph nodes and total serum IgE levels. The four compounds generated by indoor air chemistry were predicted by QSAR and animal modeling to be sensitizers, with the potential for methylglyoxal to induce IgE. The identification of these compounds as sensitizers may help to explain some of the health effects associated with indoor air complaints.

Work, obesity, and occupational safety and health.

There is increasing evidence that obesity and overweight may be related, in part, to adverse work conditions. In particular, the risk of obesity may increase in high-demand, low-control work environments, and for those who work long hours. In addition, obesity may modify the risk for vibration-induced injury and certain occupational musculoskeletal disorders. We hypothesized that obesity may also be a co-risk factor for the development of occupational asthma and cardiovascular disease that and it may modify the worker's response to occupational stress, immune response to chemical exposures, and risk of disease from occupational neurotoxins. We developed 5 conceptual models of the interrelationship of work, obesity, and occupational safety and health and highlighted the ethical, legal, and social issues related to fuller consideration of obesity's role in occupational health and safety.

The humoral immune response of mice exposed to manual metal arc stainless steel-welding fumes.

Arc welding is one of the most common forms of welding and includes the use of stainless steel electrodes that emit fumes containing chromium and nickel. Epidemological studies suggest a correlation between arc welding and adverse respiratory health effects. Studies evaluating the immunotoxic effects of welding fumes are limited due to the large number of variables associated with welding. This work investigates the immunotoxic effects of welding fumes by analyzing the in vivo and in vitro IgM response to a T-dependent antigen after welding fume exposure. Significant decreases in the total IgM activity/10(6) viable cells and total IgM activity/well were observed in splenocytes exposed to 5 mu g/ml of either total or soluble welding fumes. A significant reduction in the specific IgM activity in lung associated lymph node cells was also observed following four pharyngeal aspirations of 10 mg/kg total or soluble welding fumes to mice. Significant elevations in the absolute lymph node cell numbers for both B- and T-cells including the CD4(+) and CD8(+) subsets were observed. These results demonstrate that exposure to manual metal-stainless steel welding fumes is immunosuppressive in the presence of increased lymphoctye numbers in mice and raises concerns regarding the potential for adverse immunological effects to impact respiratory health in humans.

Analysis of immunotoxicity by enumeration of antibody-producing B cells.

The plaque-forming cell (PFC) assay measures the humoral immune response mediated by the concerted actions of antigen-presenting cells, T lymphocytes, and B lymphocytes. The most common form of the plaque method is used for the detection of murine primary IgM antibodies directed against the T cell-dependent sheep red blood cell (sRBC) surface antigens. Research has shown that the PFC response to sRBC is not only an excellent monitor of the primary effector function of the B cell, but that it may be the most sensitive immune parameter currently available to identify chemical perturbation. Several modifications and variations of the PFC assay are described in detail in this unit.

Octamethylcyclotetrasiloxane exhibits estrogenic activity in mice via ERalpha.

Octamethylcyclotetrasiloxane (D4) is a low molecular weight cyclic silicone used in the synthesis of larger silicone polymers and in the formulation of a variety of personal care products. The effects of oral D4 exposure in mice on serum estradiol levels, uterine wet weight, and uterine peroxidase activity were investigated. Additionally, in vitro estrogen receptor binding activity was evaluated. Serum estradiol levels decreased in a dose-dependent manner after exposure to 100 mg/kg to 1000 mg/kg D4. Studies with adrenalectomized animals demonstrated that the decreased serum estradiol levels were not due to elevated serum corticosterone levels. Uterine wet weights in ovariectomized mice were significantly increased in a dose-dependent manner by exposure to 250-1000 mg of D4/kg, but not by exposure to other silicone compounds tested (hexamethylcyclotrisiloxane, decamethylcyclopentasiloxane, decamethyltetrasiloxane, and octaphenylcyclotetrasiloxane). Uterine peroxidase activity, a marker for estrogenic activity, was also significantly increased in D4-exposed mice, but not in mice exposed to the other siloxanes. Pretreating mice with the estrogen receptor antagonist ICI 182,780 completely blocked the D4-induced increase in uterine weight, and ovariectomized estrogen receptor-alpha knockout mice showed no increases in uterine weights when orally exposed to D4 or estradiol. In an in vitro estrogen receptor binding assay, D4 showed significant competition with (3)H-estradiol for binding to estrogen receptor-alpha, but not estrogen receptor-beta. The data presented here indicate that D4 has weak estrogenic activity, and that these effects are mediated through estrogen receptor-alpha.