Toxicological Effects of Inhaled Crude Oil Vapor.

PURPOSE OF REVIEW: The purpose of this review is to assess the toxicological consequences of crude oil vapor (COV) exposure in the workplace through evaluation of the most current epidemiologic and laboratory-based studies in the literature. RECENT FINDINGS: Crude oil is a naturally occuring mixture of hydrocarbon deposits, inorganic and organic chemical compounds. Workers engaged in upstream processes of oil extraction are exposed to a number of risks and hazards, including getting crude oil on their skin or inhaling crude oil vapor. There have been several reports of workers who died as a result of inhalation of high levels of COV released upon opening thief hatches atop oil storage tanks. Although many investigations into the toxicity of specific hydrocarbons following inhalation during downstream oil processing have been conducted, there is a paucity of information on the potential toxicity of COV exposure itself. This review assesses current knowledge of the toxicological consequences of exposures to COV in the workplace.

Consensus on the Key Characteristics of Immunotoxic Agents as a Basis for Hazard Identification.

BACKGROUND: Key characteristics (KCs), properties of agents or exposures that confer potential hazard, have been developed for carcinogens and other toxicant classes. KCs have been used in the systematic assessment of hazards and to identify assay and data gaps that limit screening and risk assessment. Many of the mechanisms through which pharmaceuticals and occupational or environmental agents modulate immune function are well recognized. Thus KCs could be identified for immunoactive substances and applied to improve hazard assessment of immunodulatory agents. OBJECTIVES: The goal was to generate a consensus-based synthesis of scientific evidence describing the KCs of agents known to cause immunotoxicity and potential applications, such as assays to measure the KCs. METHODS: A committee of 18 experts with diverse specialties identified 10 KCs of immunotoxic agents, namely, 1) covalently binds to proteins to form novel antigens, 2) affects antigen processing and presentation, 3) alters immune cell signaling, 4) alters immune cell proliferation, 5) modifies cellular differentiation, 6) alters immune cell-cell communication, 7) alters effector function of specific cell types, 8) alters immune cell trafficking, 9) alters cell death processes, and 10) breaks down immune tolerance. The group considered how these KCs could influence immune processes and contribute to hypersensitivity, inappropriate enhancement, immunosuppression, or autoimmunity. DISCUSSION: KCs can be used to improve efforts to identify agents that cause immunotoxicity via one or more mechanisms, to develop better testing and biomarker approaches to evaluate immunotoxicity, and to enable a more comprehensive and mechanistic understanding of adverse effects of exposures on the immune system. https://doi.org/10.1289/EHP10800.

Biological effects of inhaled crude oil. VI. Immunotoxicity.

Crude oil is an unrefined petroleum product that is a mixture of hydrocarbons and other organic material. Studies on the individual components of crude oil and crude oil exposure itself suggest it has immunomodulatory potential. As investigations of the immunotoxicity of crude oil focus mainly on ingestion and dermal exposure, the effects of whole-body inhalation of 300 ppm crude oil vapor [COV; acute inhalation exposure: (6 h × 1 d); or a 28 d sub-chronic exposure (6 h/d × 4 d/wk. × 4 wks)] was investigated 1, 28, and 90 d post-exposure in Sprague-Dawley rats. Acute exposure increased bronchoalveolar lavage (BAL) fluid cellularity, CD4+ and CD8+ cells, and absolute and percent CDllb+ cells only at 1 d post-exposure; additionally, NK cell activity was suppressed. Sub-chronic exposure resulted in a decreased frequency of CD4+ T-cells at 1 d post-exposure and an increased number and frequency of B-cells at 28 d post-exposure in the lung-associated lymph nodes. A significant increase in the number and frequency of B-cells was observed in the spleen at 1 d post-exposure; however, NK cell activity was suppressed at this time point. No effect on cellularity was identified in the BALF. No change in the IgM response to sheep red blood cells was observed. The findings indicate that crude oil inhalation exposure resulted in alterations in cellularity of phenotypic subsets that may impair immune function in rats.

Potential classification of chemical immunologic response based on gene expression profiles.

Occupational immune diseases are a serious public health burden and are often a result of exposure to low molecular weight (LMW) chemicals. The complete immunological mechanisms driving these responses are not fully understood which has made the classification of chemical allergens difficult. Antimicrobials are a large group of immunologically-diverse LMW agents. In these studies, mice were dermally exposed to representative antimicrobial chemicals (sensitizers: didecyldimethylammonium chloride (DDAC), ortho-phthalaldehyde (OPA), irritants: benzal-konium chloride (BAC), and adjuvant: triclosan (TCS)) and the mRNA expression of cytokines and cellular mediators was evaluated using real-time qPCR in various tissues over a 7-days period. All antimicrobials caused increases in the mRNA expression of the danger signals Tslp (skin), and S100a8 (skin, blood, lung). Expression of the TH2 cytokine Il4 peaked at different timepoints for the chemicals based on exposure duration. Unique expression profiles were identified for OPA (Il10 in lymph node, Il4 and Il13 in lung) and TCS (Tlr4 in skin). Additionally, all chemicals except OPA induced decreased expression of the cellular adhesion molecule Ecad. Overall, the results from these studies suggest that unique gene expression profiles are implicated following dermal exposure to various antimicrobial agents, warranting the need for additional studies. In order to advance the development of preventative and therapeutic strategies to combat immunological disease, underlying mechanisms of antimicrobial-induced immunomodulation must be fully understood. This understanding will aid in the development of more effective methods to screen for chemical toxicity, and may potentially lead to more effective treatment strategies for those suffering from immune diseases.

Topical Application of the Antimicrobial Agent Triclosan Induces NLRP3 Inflammasome Activation and Mitochondrial Dysfunction.

5-Chloro-2-(2,4-dichlorophenoxy)phenol (triclosan) is an antimicrobial chemical widely used in consumer household and clinical healthcare products. Human and animal studies have associated triclosan exposure with allergic disease. Mechanistic studies have identified triclosan as a mitochondrial uncoupler; recent studies suggest that mitochondria play an important role in immune cell function and are involved in activation of the NLRP3 inflammasome. In this study, early immunological effects were evaluated via NLRP3 activation following dermal triclosan application in a BALB/c murine model. These investigations revealed rapid caspase-1 activation and mature IL-1ß secretion in the skin and draining lymph nodes (dLNs) after 1.5% and 3% triclosan exposure. Correspondingly, pro-Il-1b and S100a8 gene expression increased along with extracellular ATP in the skin. Peak gene expression of chemokines associated with caspase-1 activation occurred after 2 days of exposure in both skin tissue and dLNs. Phenotypic analysis showed an increase in neutrophils and macrophages in the dLN and myeloid and inflammatory monocytes in the skin tissue. Triclosan also caused mitochondrial dysfunction shown through effects on mitochondrial reactive oxygen species, mass, mitochondrial membrane potential, and mitochondrial morphology. These results indicate that following triclosan exposure, activation of the NLRP3 inflammasome occurs in both the skin tissue and dLNs, providing a possible mechanism for triclosan's effects on allergic disease and further support a connection between mitochondrial involvements in immunological responses.

Surface area- and mass-based comparison of fine and ultrafine nickel oxide lung toxicity and augmentation of allergic response in an ovalbumin asthma model.

Background: The correlation of physico-chemical properties with mechanisms of toxicity has been proposed as an approach to predict the toxic potential of the vast number of emerging nanomaterials. Although relationships have been established between properties and the acute pulmonary inflammation induced by nanomaterials, properties' effects on other responses, such as exacerbation of respiratory allergy, have been less frequently explored.Methods: In this study, the role of nickel oxide (NiO) physico-chemical properties in the modulation of ovalbumin (OVA) allergy was examined in a murine model. Results: 181 nm fine (NiO-F) and 42 nm ultrafine (NiO-UF) particles were characterized and incorporated into a time course study where measured markers of pulmonary injury and inflammation were associated with NiO particle surface area. In the OVA model, exposure to NiO, irrespective of any metric was associated with elevated circulating total IgE levels. Serum and lung cytokine levels were similar with respect to NiO surface area. The lower surface area was associated with an enhanced Th2 profile, whereas the higher surface area was associated with a Th1-dominant profile. Surface area-normalized groups also exhibited similar alterations in OVA-specific IgE levels and lung neutrophil number. However, lung eosinophil number and allergen challenge-induced alterations in lung function related more to particle size, wherein NiO-F was associated with an increased enhanced pause response and NiO-UF was associated with increased lung eosinophil burden.Conclusions: Collectively, these findings suggest that although NiO surface area correlates best with acute pulmonary injury and inflammation following respiratory exposure, other physico-chemical properties may contribute to the modulation of immune responses in the lung.

Investigative Immunotoxicology.

Immunotoxicology is the study of immune system dysfunction that can result from occupational, inadvertent, or therapeutic exposure to a variety of chemical or biologic agents that alter the immune system and affect human health. Immunotoxicology can manifest in a variety of ways, with one of the most prominent effects being immunosuppression. Immunosuppression can be defined as a reduced ability of the immune system to respond to a challenge from a level considered normal, regardless of whether clinical disease results. Although immunosuppression can lead to an increased incidence and severity of infectious and neoplastic disease, interpreting data from experimental immunotoxicology studies, or even epidemiologic studies, for quantitative risk assessment has been a persistent challenge. Decades of research has resulted in the development of specific assays and the identification of sensitive endpoints that measure effects on the immune response, from which many regulatory agencies have developed specific immunotoxicity testing guidelines. However, establishing a direct link between exposure and disease manifestations for immunosuppression in humans is an ongoing challenge due to inherent limitations of epidemiological studies to draw causal conclusions. Efforts have been made to examine the relationships between laboratory measures of immune response and disease resistance in experimental animal models and also in human studies. The identification of sensitive endpoints and the development of experimental assays to identify suspect immunotoxicants are a primary focus of the field of immunotoxicology. This chapter is organized around sections discussing the impact and scientific basis of immunotoxicity testing, predictive immunotoxicity testing strategies, examples of immunotoxicity testing, and key considerations and recent developments related to effective testing strategies for health risk reduction.

Topical application of the anti-microbial chemical triclosan induces immunomodulatory responses through the S100A8/A9-TLR4 pathway.

The anti-microbial compound triclosan is incorporated into numerous consumer products and is detectable in the urine of 75% of the general United States population. Recent epidemiological studies report positive associations with urinary triclosan levels and allergic disease. Although not sensitizing, earlier studies previously found that repeated topical application of triclosan augments the allergic response to ovalbumin (OVA) though a thymic stromal lymphopoietin (TSLP) pathway in mice. In the present study, early immunological effects following triclosan exposure were further evaluated following topical application in a murine model. These investigations revealed abundant expression of S100A8/A9, which reportedly acts as an endogenous ligand for Toll-like Receptor 4 (TLR4), in skin tissues and in infiltrating leukocytes during topical application of 0.75-3.0% triclosan. Expression of Tlr4 along with Tlr1, Tlr2 and Tlr6 increased in skin tissues over time with triclosan exposure; high levels of TLR4 were expressed on skin-infiltrating leukocytes. In vivo antibody blockade of the TLR4/MD-2 receptor complex impaired local inflammatory responses after four days, as evidenced by decreased Il6, Tnfα, S100a8, S100a9, Tlr1, Tlr2, Tlr4 and Tlr6 expression in the skin and decreased lymph node cellularity and production of IL-4 and IL-13 by lymph node T-cells. After nine days of triclosan exposure with TLR4/MD-2 blockade, impaired T-helper cell type 2 (TH2) cytokine responses were sustained, but other early effects on skin and lymph node cellularity were lost; this suggested alternative ligands/receptors compensated for the loss of TLR4 signaling. Taken together, these data suggest the S100A8/A9-TLR4 pathway plays an early role in augmenting immunomodulatory responses with triclosan exposure and support a role for the innate immune system in chemical adjuvancy.

Immune stimulation following dermal exposure to unsintered indium tin oxide.

In recent years, several types of pulmonary pathology, including alveolar proteinosis, fibrosis, and emphysema, have been reported in workers in the indium industry. To date, there remains no clear understanding of the underlying mechanism(s). Pulmonary toxicity studies in rats and mice have demonstrated the development of mediastinal lymph node hyperplasia and granulomas of mediastinal lymph nodes and bronchus-associated lymphoid tissues following exposure to indium tin oxide. Given the association between exposure to other metals and the development of immune-mediated diseases, these studies were undertaken to begin to investigate the immuno-modulatory potential of unsintered indium tin oxide (uITO) in a mouse model. Using modifications of the local lymph node assay, BALB/c mice (five animals/group) were exposed topically via intact or breached skin or injected intradermally at the base of the ear pinnae with either vehicle or increasing concentrations 2.5-10% uITO (90:10 indium oxide/tin oxide, particle size <50 nm). Dose-responsive increases in lymphocyte proliferation were observed with a calculated EC3 of 4.7% for the intact skin study. Phenotypic analysis of draining lymph node cells following intradermal injection with 5% uITO yielded a profile consistent with a T-cell-mediated response. These studies demonstrate the potential for uITO to induce sensitization and using lymphocyte proliferation as a biomarker of exposure, and demonstrate the potential for uITO to penetrate both intact and breached skin.

Potential health effects associated with dermal exposure to occupational chemicals.

There are a large number of workers in the United States, spanning a variety of occupational industries and sectors, who are potentially exposed to chemicals that can be absorbed through the skin. Occupational skin exposures can result in numerous diseases that can adversely affect an individual's health and capacity to perform at work. In general, there are three types of chemical-skin interactions of concern: direct skin effects, immune-mediated skin effects, and systemic effects. While hundreds of chemicals (metals, epoxy and acrylic resins, rubber additives, and chemical intermediates) present in virtually every industry have been identified to cause direct and immune-mediated effects such as contact dermatitis or urticaria, less is known about the number and types of chemicals contributing to systemic effects. In an attempt to raise awareness, skin notation assignments communicate the potential for dermal absorption; however, there is a need for standardization among agencies to communicate an accurate description of occupational hazards. Studies have suggested that exposure to complex mixtures, excessive hand washing, use of hand sanitizers, high frequency of wet work, and environmental or other factors may enhance penetration and stimulate other biological responses altering the outcomes of dermal chemical exposure. Understanding the hazards of dermal exposure is essential for the proper implementation of protective measures to ensure worker safety and health.

Evaluation of Pulmonary and Systemic Toxicity of Oil Dispersant (COREXIT EC9500A(®)) Following Acute Repeated Inhalation Exposure.

INTRODUCTION: Oil spill cleanup workers come into contact with numerous potentially hazardous chemicals derived from the oil spills, as well as chemicals applied for mitigation of the spill, including oil dispersants. In response to the Deepwater Horizon Macondo well oil spill in the Gulf of Mexico in 2010, a record volume of the oil dispersant, COREXIT EC9500A, was delivered via aerial applications, raising concern regarding potential health effects that may result from pulmonary exposure to the dispersant. METHODS: The current study examined the effects on pulmonary functions, cardiovascular functions, and systemic immune responses in rats to acute repeated inhalation exposure of COREXIT EC9500A at 25 mg/m(3), five hours per day, over nine work days, or filtered air (control). At one and seven days following the last exposure, a battery of parameters was measured to evaluate lung function, injury, and inflammation; cardiovascular function; peripheral vascular responses; and systemic immune responses. RESULTS: No significant alterations in airway reactivity were observed at one or seven days after exposure either in baseline values or following methacholine (MCh) inhalation challenge. Although there was a trend for an increase in lung neutrophils and phagocyte oxidant production at one-day post exposure, there were no significant differences in parameters of lung inflammation. In addition, increased blood monocytes and neutrophils, and decreased lymphocyte numbers at one-day post exposure also did not differ significantly from air controls, and no alterations in splenocyte populations, or serum or spleen immunoglobulin M (IgM) to antigen were observed. There were no significant differences in peripheral vascular responsiveness to vasoconstrictor and vasodilator agonists or in blood pressure (BP) responses to these agents; however, the baseline heart rate (HR) and HR responses to isoproterenol (ISO) were significantly elevated at one-day post exposure, with resolution by day 7. CONCLUSIONS: In summary, acute repeated exposure to COREXIT EC9500A did not alter pulmonary function, lung injury/inflammation, systemic immune responses, or vascular tone, but did cause transient chronotropic effects on cardiac function.

Toxicological analysis of limonene reaction products using an in vitro exposure system.

Epidemiological investigations suggest a link between exposure to indoor air chemicals and adverse health effects. Consumer products contain reactive chemicals which can form secondary pollutants which may contribute to these effects. The reaction of limonene and ozone is a well characterized example of this type of indoor air chemistry. The studies described here characterize an in vitro model using an epithelial cell line (A549) or differentiated epithelial tissue (MucilAir™). The model is used to investigate adverse effects following exposure to combinations of limonene and ozone. In A549 cells, exposure to both the parent compounds and reaction products resulted in alterations in inflammatory cytokine production. A one hour exposure to limonene+ozone resulted in decreased proliferation when compared to cells exposed to limonene alone. Repeated dose exposures of limonene or limonene+ozone were conducted on MucilAir™ tissue. No change in proliferation was observed but increases in cytokine production were observed for both the parent compounds and reaction products. Factors such as exposure duration, chemical concentration, and sampling time point were identified to influence result outcome. These findings suggest that exposure to reaction products may produce more severe effects compared to the parent compound.

Evaluation of furfuryl alcohol sensitization potential following dermal and pulmonary exposure: enhancement of airway responsiveness.

Furfuryl alcohol is considered by the U.S. Environmental Protection Agency to be a high volume production chemical, with over 1 million pounds produced annually. Due to its high production volume and its numerous industrial and consumer uses, there is considerable potential for work-related exposure, as well as exposure to the general population, through pulmonary, oral, and dermal routes of exposure. Human exposure data report a high incidence of asthma in foundry mold workers exposed to furan resins, suggesting potential immunologic effects. Although furfuryl alcohol was nominated and evaluated for its carcinogenic potential by the National Toxicology Program, studies evaluating its immunotoxicity are lacking. The studies presented here evaluated the immunotoxic potential of furfuryl alcohol following exposure by the dermal and pulmonary routes using a murine model. When tested in a combined irritancy local lymph node assay, furfuryl alcohol was identified to be an irritant and mild sensitizer (EC3 = 25.6%). Pulmonary exposure to 2% furfuryl alcohol resulted in enhanced airway hyperreactivity, eosinophilic infiltration into the lungs, and enhanced cytokine production (IL-4, IL-5, and interferon-γ) by ex vivo stimulated lung-associated draining lymphoid cells. Airway hyperreactivity and eosinophilic lung infiltration were augmented by prior dermal exposure to furfuryl alcohol. These results suggest that furfuryl alcohol may play a role in the development of allergic airway disease and encourage the need for additional investigation.

Potential immunotoxicological health effects following exposure to COREXIT 9500A during cleanup of the Deepwater Horizon oil spill.

Workers involved in the Deepwater Horizon oil spill cleanup efforts reported acute pulmonary and dermatological adverse health effects. These studies were undertaken to assess the immunotoxicity of COREXIT 9500A, the primary dispersant used in cleanup efforts, as a potential causative agent. COREXIT 9500A and one of its active ingredients, dioctyl sodium sulfosuccinate (DSS), were evaluated using murine models for hypersensitivity and immune suppression, including the local lymph node assay (LLNA), phenotypic analysis of draining lymph node cells (DLN), mouse ear swelling test (MEST), total serum immunoglobulin E (IgE), and the plaque-forming cell (PFC) assay. Dermal exposure to COREXIT 9500A and DSS induced dose-responsive increases in dermal irritation and lymphocyte proliferation. The EC3 values for COREXIT 9500A and DSS were 0.4% and 3.9%, respectively, resulting in a classification of COREXIT 9500A as a potent sensitizer and DSS as a moderate sensitizer. A T-cell-mediated mechanism underlying the LLNA was supported by positive responses in the MEST assay for COREXIT and DSS, indicated by a significant increase in ear swelling 48 h post challenge. There were no marked alterations in total serum IgE or B220+/IgE+ lymph-node cell populations following exposure to COREXIT 9500A. Significant elevations in interferon (IFN)-γ but not interleukin (IL)-4 protein were also observed in stimulated lymph node cells. The absence of increases in IgE and IL-4 in the presence of enhanced lymphocyte proliferation, positive MEST responses, and elevations in IFN-γ suggest a T-cell-mediated mechanism. COREXIT 9500A did not induce immunosuppression in the murine model.

Allergic Potential and Immunotoxicity Induced by Topical Application of 1-Chloro-4-(Trifluoromethyl)Benzene (PCBTF) in a Murine Model.

The purpose of the studies in this paper was to evaluate the allergic potential, immunotoxicity, and irritancy of the occupationally relevant chemical, 1-chloro-4-(trifluoromethyl)benzene, also known as parachlorobenzotrifluoride (PCBTF), following dermal exposure in a murine model. Evaluation of the sensitization potential, conducted using the local lymph node assay (LLNA) at concentrations ranging from 50% to 100%, identified a dose-dependent increase in lymphocyte proliferation with a calculated EC3 value of 53.1%. While no elevations in total or specific IgE were observed after exposure to any concentration of the chemical, significant increases in IFN-γ protein production by stimulated draining lymphoid cells were observed, indicating a T-cell-mediated response. Dermal exposure to PCBTF was not found to alter the immune response to a T-cell-dependant antigen. These results demonstrate that PCBTF has the potential to induce allergic sensitization following dermal exposure and based on LLNA results would be classified as a weak sensitizer.

Evaluation of dicarbonyls generated in a simulated indoor air environment using an in vitro exposure system.

Over the last two decades, there has been increasing awareness regarding the potential impact of indoor air pollution on health. Exposure to volatile organic compounds (VOCs) or oxygenated organic compounds formed from indoor chemistry has been suggested to contribute to adverse health effects. These studies use an in vitro monitoring system called VitroCell, to assess chemicals found in the indoor air environment. The structurally similar dicarbonyls diacetyl, 4-oxopentanal (4-OPA), glyoxal, glutaraldehyde, and methyl glyoxal were selected for use in this system. The VitroCell module was used to determine whether these dicarbonyls were capable of inducing inflammatory cytokine expression by exposed pulmonary epithelial cells (A549). Increases in the relative fold change in messenger RNA expression of the inflammatory mediators, interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNF-alpha) were identified following exposure to diacetyl, 4-OPA, glyoxal, glutaraldehyde, and methyl glyoxal when compared to a clean air control. Consistent results were observed when the protein levels of these cytokines were analyzed. Exposure to 4-OPA significantly elevated IL-8, IL-6, GM-CSF, and TNF-alpha while glutaraldehyde caused significant elevations in IL-6, IL-8, and TNF-alpha. IL-6 and IL-8 were also significantly elevated after exposure to diacetyl, glyoxal, and methyl glyoxal. These studies suggest that exposure to structurally similar oxygenated reaction products may be contributing to some of the health effects associated with indoor environments and may provide an in vitro method for identification and characterization of these potential hazards.

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.

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.