Faculty Bibliography

Soluble and insoluble hexavalent chromium (Cr6+) agents are concomitantly released with ozone (O3) during welding. Although pulmonary/immunologic implications from exposure to each agent individually have been investigated, the effects from simultaneous exposure, as occurs under actual working conditions, are unclear. To investigate immunomodulatory effects of inhaled Cr6+, F-344 rats were exposed for 5 h/day, 5 days/week for 2 or 4 weeks to atmospheres containing soluble potassium chromate (K2CrO4) or insoluble barium chromate (BaCrO4), each alone at 360 micrograms Cr/m3 or in combination with 0.3 ppm O3. One day after the final exposure, rats were euthanized, their lungs were lavaged, and pulmonary macrophages (PAM) were recovered for assessment of basal and inducible functions. Rats inhaling K2CrO4-containing atmospheres had greater levels of total recoverable cells, neutrophils, and monocytes in bronchopulmonary lavage compared to rats exposed to insoluble Cr6+ atmospheres, O3 alone, or air; these rats also had a reduced percentage of PAM, although total PAM levels remained unaffected. Although Cr exposure-related changes in PAM functionality were evident, any dependence upon Cr solubility was variable. K2CrO4-containing atmospheres modulated PAM-inducible interleukins-1 and -6, and tumor necrosis factor-alpha production to a greater degree than those containing BaCrO4. Conversely, BaCrO4-containing atmospheres affected PAM basal nitric oxide production and interferon-gamma-primed/zymosan-stimulated reactive oxygen intermediate production to a greater extent than did those containing K2CrO4. In none of the PAM assays did co-inhalation of O3 result in a modulation of the effects obtained with either Cr6+ compound itself. The results indicate that, while immunomodulatory effects of inhaled Cr6+ upon PAM are related to particle solubility, the co-inhalation of O3 apparently does not cause further modifications of the metal-induced effects.

Through the efforts of different laboratories, a battery of immunological assays is available to predict the immunotoxicity of xenobiotics. These assays, originally developed in rodents, have been adapted for use in a variety of animal species and are now used routinely in these models to assess the immunotoxicity of different chemical classes. For example, our laboratory has employed assays that measure antibody-forming cell response to T-dependent antigens, T- and B-cell lymphoproliferation, macrophage function, and host resistance against infectious bacteria to assess metal-induced immunotoxicity in laboratory-reared Japanese medaka (Oryzias latipes); immunologically-related assays measuring antioxidant activity have also been used in this capacity. Results of the aforementioned investigations have shown the usefulness of these endpoints to reliably demonstrate chemical-mediated immunotoxicity in teleost systems. Many of these same endpoints have also proved successful for predicting the immunotoxic effects of contaminated aquatic environments in feral fish populations. For example, smallmouth bass collected from a chlorinated hydrocarbon-contaminated site demonstrated significant changes in blood cell profiles and kidney phagocyte function compared to fish collected from a 'clean water' reference site. Some of these same immune parameters have also been used successfully to predict the immunotoxicity of polluted aquatic environments in feral populations of fish-eating birds and harbor seals. While interspecies extrapolation is difficult and should be approached with caution due to variables such as metabolism and pharmacokinetics, results from these studies demonstrate the usefulness of these immune assays to predict the immunomodulating effects of xenobiotics in fish and other wildlife species, as well as the applicability of fish to serve as additional/alternate animal models for mammalian species in immunotoxicological studies

Determination of the ability of a medical device to interact with the immune system currently involves assessment of the immunogenic potential and biocompatibility of the device or an extract of the device. However, implants are often in the body for extended periods of time and/or are placed by a surgical procedure that in and of itself will generate an acute inflammatory response. This symposium discussed studies that have been performed to evaluate the immunogenicity of various devices consisting of several different compositions (i.e., silicone, metals, and latex) in contact with different anatomical sites, the ability of a device to modulate an inflammatory response generated by a surgical procedure or trauma, and the response of the body to a material left in place for extended periods of time. This symposium brought together scientists from many different disciplines to begin to identify and fill in the gaps in this area.

Monitoring fishery resources affected by contaminant discharges can include two distinct components: (1) monitoring contaminant exposure (e.g., residues in fish tissues), and (2) monitoring biological effects. Although exposure monitoring may be appropriate for evaluating the efficacy of ecological restoration programs, effects monitoring is an equally important and often overlooked aspect of monitoring programs. Advantages of monitoring effects indices include (1) biotic integration of diverse exposure pathways and temporal variability; (2) ability to integrate responses across multiple stressors; and (3) cost effectiveness relative to extensive chemical analyses. The objective of our work was to develop and review biomarker selection criteria including: (1) sensitivity (response time, permanence of response, degree of responsiveness); (2) specificity (specific to contaminant exposure); (3) applicability (cost-effectiveness, scientific acceptance); and (4) reproducibility (biological, methodological). Emphasis is placed on selection criteria for biomarkers associated with organochlorine, petroleum hydrocarbon, or metal exposure and effects.

The potential for chemicals to adversely affect human immunologic health has traditionally been evaluated in rodents, under laboratory conditions. These laboratory studies have generated valuable hazard identification and immunotoxicologic mechanism data; however, genetically diverse populations exposed in the wild may better reflect both human exposure conditions and may provide insight into potential immunotoxic effects in humans. In addition, comparative studies of species occupying reference and impacted sites provide important information on the effects of environmental pollution on the immunologic health of wildlife populations. In this symposium overview, Peter Hodson describes physiological changes in fish collected above or below the outflows of paper mills discharging effluent from the bleaching process (BKME). Effects attributable to BKME were identified, as were physiological changes attributable to other environmental factors. In this context, he discussed the problems of identifying true cause and effect relationships in field studies. Mohamed Faisal described changes in immune function of fish collected from areas with high levels of polyaromatic hydrocarbon contamination. His studies identified a contaminant-related decreases in the ability of anterior kidney leukocytes to bind to and kill tumor cell line targets, as well as changes in lymphocyte proliferation in response to mitogens. Altered proliferative responses of fish from the contaminated site were partially reversed by maintaining fish in water from the reference site. Peter Ross described studies in which harbor seals were fed herring obtained from relatively clean (Atlantic Ocean) and contaminated (Baltic Sea) waters. Decreased natural killer cell activity and lymphoproliferative responses to T and B cell mitogens, as well as depressed antibody and delayed hypersensitivity responses to injected antigens, were identified in seals fed contaminated herring. In laboratory studies, it was determined that rats fed freeze-dried Baltic Sea herring had higher virus titers after challenge with rat cytomegalovirus (RCMV) than rats fed Atlantic Ocean herring; perinatal exposure of rats to oil extracted from Baltic herring also reduced the response to challenge with RCMV. Keith Grassman reported an association between exposure to polyhalogenated aryl hydrocarbons and decreased T cell immunity in the offspring of fish-eating birds (herring gulls and Capsian terns) at highly contaminated sites in the Great Lakes. The greatest suppression of skin test responses to phytohemagglutinin injection (an indicator of T cell immunity) was consistently found at sites with the highest contaminant concentrations. Judith Zelikoff addressed the applicability of immunotoxicity studies developed in laboratory-reared fish for detecting altered immune function in wild populations. She presented data from studies done in her laboratory with environmentally relevant concentrations of metals as examples. Although the necessity of proceeding with caution when extrapolating across species was emphasized, she concluded that published data, and results presented by the other Symposium participants, demonstrate that assays similar to those developed for use in laboratory rodents may be useful for detecting immune system defects in wildlife species directly exposed to toxicants present in the environment.