Immunomodulation by Metals

A symposium entitled Immunomodulation by Metals was held atthe 32nd Annual Meeting of the Society of Toxicology (SOT) inNew Orleans, Louisiana. The symposium was cosponsored by theImmunotoxicology and Metals Specialty Sections of SOT and wasdesigned to describe the types of adverse immunological reactionswhich occur in response to environmental and/or occupationalexposure to metals. Epidemiological evidence and underlyingmechanisms responsible for the observed alterations were alsodiscussed. The following is a summary of each of the individualpresentations.     

Pulmonary Immunotoxicity of Inhaled Ammonium Metavanadate in Fisher 344 Rats

Male Fisher 344 rats were exposed to 2 mg vanadium(V)/m³ (asammonium metavanadate NH⁴VO³, 0.32 µm MMD) atmospheresfor 8 hr/day for 4 days in a nose-only exposure system. In exposedrats, lung V burdens increased in a time-dependent fashion.Analysis of lung cells and lavage fluid 24 hr after the finalexposure suggested that tissue damage and a strong inflammatoryresponse was elicited; numbers of neutrophil and small macrophages(M), as well as levels of lavageable protein and lactate dehydrogenase,were significantly elevated as compared with levels observedwith air-exposed rats. Vanadium also affected pulmonary alveolarM (PAM) capacities to produce and respond to immunoregulatingcytokines. Inducible PAM production of tumor necrosis factor-awas significantly inhibited, as was the ability to increasecell surface Class II/I-A molecule expression in response tointerferon- (rFN-). PAM from V-exposed hosts were also inhibitedin their ability to be primed by EFN- to produce superorideanion and hydrogen peroxide in response to stimulation withopsonized zy-mosan. These studies indicate that short-term repeatedexposure of rats to atmospheric V, at levels encountered inan occupational setting, can alter host pulmonary immunomocompetence,with one major effect occurring at the level of cytokine-relatedfunctions. These alterations may be underlying mechanisms forthe well-documented increases in bronchopulmonary infectionsand cancers in workers chronically exposed to V-containing atmospheres.     

Health Risks Associated with Prenatal Metal Exposure

A symposium entitled Health Risks Associated with Prenatal MetalExposure was held at the 33rd Annual Meeting of the Societyof Toxicology (SOT) in Dallas, Texas. The symposium was cosponsoredby the Metals and Reproductive and Developmental Specialty Sectionsof SOT and was designed to elaborate the health risks associatedwith in utero exposure to metals commonly found in the workplaceand/or ambient environment on the mother and developing offspring.Epidemiological and toxi-cological evidence that demonstratesthe health effects and underlying mechanisms associated withexposure to arsenic (As), lead (Pb), and methyl mercury (MeHg)were discussed, as well as the legal ramifications and personalimplications associated with prenatal metal exposure. The followingis a summary of each of the individual presentations.     

Modulation of Pulmonary Eicosanoid Metabolism following Exposure to Sulfuric Acid

Modulation of Pulmonary Eicosanoid Metabolism following Exposureto Sulfuric Acid. SCHLESINGER, R. B., GUNNISON, A. F., AND ZELIKOFF,J. T. (1990). Fundam. Appl. Toxicol. 15, 151–162. Eicosanoids(arachidonic acid metabolites) are potent biological mediators.Modulation of their metabolism by air pollutants may be a possiblefactor in the pathogenesis of environmentally related lung disease.Sulfuric acid (H₂SO₄) aerosols are components of ambient airin many areas. Rabbits were exposed to H₂SO₄ (0.3 µm)at 250, 500, or 1000 µg/m³ for 1 hr/ day for 5 days. Theywere then euthanized, the lungs lavaged, and eicosanoid analysesperformed by radioimmunoassay of acellular lavage fluid. Anexposure-concentration-dependent decrease in levels of prostaglandinsE₂ and F₂ and thromboxane B₂ was found; no change in leukotrieneB₄ was observed. Tracheal explants exposed to acidic environmentsin vitro also showed reduced production of PGE₂, PGF₂, and TxB₂.Incubation with sodium sulfate (Na₂SO₄ showed no effect of thesulfate ion (SO₄^2–). This study, the first to examineeicosanoid production after in vivo exposure to pure H₂SO₄ droplets,indicates that such exposure can modulate arachidonic acid metabolism,and that this is likely due to the deposition of hydrogen ion(H⁺ on target issue.     

Development of Fish Peritoneal Macrophages as a Model for Higher Vertebrates in Immunotoxicological Studies: I. Characterization of Trout Macrophage Morphological, Functional, and Biochemical Properties

Development of Fish Peritoneal Macrophages as a Model for HigherVertebrates in Immunotoxicological Studies. I. Characterizationof Trout Macrophage Morphological, Functional, and BiochemicalProperties. ZELIKOFF, J. T., ENANE, N. A., BOWSER, D., SQUIBB,K. S., AND FRENKEL, K. (1991). Fundam. Appl. Toxicol. 16, 576–589.The immune defense mechanisms of fish are not as well characterizedas those of mammals but seem to be related and similarly competent.Because of this, there is an increased interest in the immuneresponses of fish as models for higher vertebrates in immunotoxicologicalstudies. Prior to such studies, baseline criteria for specificcomponents of the immune response needed to be established.For this study, we have examined trout macrophage morphologyusing light and scanning electron microscopy, phagocytic activity,random and stimulus-directed migration, and superoxide anionradical (^{dot}) production for resident and lipopolysacharide (LPS) or Aeromonas salmonicidae-elicited rainbowtrout (Oncorhynchus mykiss) peritoneal macrophages (M). Followingperitoneal lavage, >89% of the cells were M as determinedby differential counts and nonspecific esterase staining. Immunizationwith LPS and A. salmonicidae increased M number {small tilde}5and 13-fold, respectively, and overall size. Trout M were phagocyticallyactive engulfing serum opsonized latex particles and were mobile,migrating both randomly and in a directed fashion towards formyl-methionine-L-leucine-L-phenylalanine(FMLP) and trout serum-derived complement fragment C5a. Concentrationsof FMLP (100 nM) and C5a (0.01–1%) effective for attractingtrout M are the same as those used to attract rabbit M. Residenttrout M produced negligable quantities of-(^{dot}) following stimulation with 1 µg/ml phorbol myristate acetate;Aeromonas-elicited M produced (^{dot}) in a time-dependen manner which peaked after 60 min at 2.9 nmolper 2 ? 10₅ cells and then declined. The results of this studyprovide a data base for future toxicological studies with troutperitoneal M and indicate the usefulness of this system forimmunotoxicological studies.     

Immunotoxicity of Medical Devices

Determination of the ability of a medical device to interactwith the immune system currently involves assessment of theimmuno-genic potential and biocompatibility of the device oran extract of the device. However, implants are often in thebody for extended periods of time and/or are placed by a surgicalprocedure that in and of itself will generate an acute inflammatoryresponse. This symposium discussed studies that have been performedto evaluate the immunogenicity of various devices consistingof several different compositions (i.e., silicone, metals, andlatex) in contact with different anatomical sites, the abilityof a device to modulate an inflammatory response generated bya surgical procedure or trauma, and the response of the bodyto a material left in place for extended periods of time. Thissymposium brought together scientists from many different disciplinesto begin to identify and fill in the gaps in this area.