Journal of Immunotoxicology

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Pulmonary Immunotoxicology of Select Metals: Aluminum, Arsenic, Cadmium, Chromium, Copper, Manganese, Nickel, Vanadium, and Zinc

Mitchell D. Cohen

To cite this article: Mitchell D. Cohen (2004) Pulmonary Immunotoxicology of Select Metals: Aluminum, Arsenic, Cadmium, Chromium, Copper, Manganese, Nickel, Vanadium, and Zinc, Journal of Immunotoxicology, 1:1, 39-69, DOI: 10.1080/15476910490438360 To link to this article: https://doi.org/10.1080/15476910490438360

Published online: 29 Sep 2008.

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Pulmonary Immunotoxicology of Select Metals: Aluminum, Arsenic, Cadmium, Chromium, Copper, Manganese, Nickel, Vanadium, and Zinc

Mitchell D. Cohen Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York, 10987, USA

INTRODUCTION during host resistance against challenge with a viable bacterial The field of immunotoxicology had its inception in the early or viral pathogen) is provided. For some of the metals, poten- 1970s; the science of pulmonary toxicology has been recognized tial mechanisms of action are presented when the literature had for more than forty years. With increasing research efforts in provided same. both fields, a convergence of the two in the quest to understand While this is a large review, it is impossible to cover all metals, how inhalation of toxic agents can alter the health of a host including some that Readers may think merit more of a place here was inevitable. In general, the majority of the advances in our than those presented. It certainly would be worthwhile to have understanding of pulmonary immunotoxicology have come as had provided information about pulmonary immunotoxicologic the result of studies in humans or animal models that inhaled or effects of lead, beryllium, platinum, mercury, and/or iron. It is were instilled with toxicants. Still, it needs to be emphasized that hoped that in the subsequent issues of this new journal, one or immunomodulation in the lungs can also be caused by agents more authors will take up this challenge to survey the literature that enter the body by non-respiratory routes and that all agents covering these metals, and provide a review of either each alone are not necessarily immunomodulatory. or several in compilation. Pulmonary immunotoxicologic research over the past decade has been increasingly important in elucidating how exactly work- ALUMINUM place/environmental agents can cause those changes in immuno- Aluminum (Al) is one of the most abundant elements in the logic function in the lungs that allow for indirect alterations in environment, and daily exposure is unavoidable. Inhalation of respiratory health and, subsequently, the overall health of ex- Al by the general population is generally considered negligible posed individuals. The purpose of this review is to provide infor- (i.e., 0.14 mg Al dust/d [Jones and Bennett, 1986]). Average air mation about how our understanding of the pulmonary immuno- levels of Al for rural and urban areas are provided in Table 1. toxicology of select inorganic agents, i.e., metals, has evolved In contrast, exposures of workers in several industries often oc- over the past ≈30+ years. Specifically, the review covers the cur at significantly higher levels. Smelters, miners, and others literature to date dealing with aluminum, arsenic, cadmium, involved in various metal industries are often acutely exposed, chromium, copper, manganese, nickel, vanadium, and zinc, in accidentally or intentionally, to these much higher ambient levels each of their various inorganic forms with differing chemistries, (i.e., mgs Al/m3). The most recent National Occupational Expo- sizes, and solubilities. For each metal, information regarding sure Study conducted in the 1980s estimated that the total num- occupational and environmental levels that are readily encoun- bers of workers potentially exposed to Al compounds exceeded tered, as well as permissible levels of exposure (when infor- 3,000,000 (ATSDR, 1999a). To help minimize the risk to work- mation was available), is presented at the outset. Thereafter, ers potentially exposed to Al agents, regulatory standards for specific effects on humoral, cell-mediated, and innate immune permissible levels of ambient Al have been established (Table 1). functions, and potential overall effects within the lungs (i.e., as Al-bearing compounds, the majority of which are the var- ious forms of alumina (Al oxide; Al2O3), are widely used in chemical, abrasive, ceramic, and refractory industries as well Address correspondence to Mitchell D. Cohen, Department of Environmental Medicine, New York University School of Medicine, as in primary Al production. In the latter, the metal is refined 57 Old Forge Road, Tuxedo, New York 10987, USA; e-mail: from bauxite and then recovered by electrolytic reduction of [email protected] an Al2O3/cryolite (3NaF·AlF3)-containing melt; to minimize 39 40 COHEN

TABLE 1 lung fibrosis in occupationally exposed subjects (Chen et al., Ambient levels and acceptable workplace levels for Al 1978; Gibbs, 1985; Abramson et al., 1989; Chan-Yeung et al., 1989; Larsson et al., 1989; Schwarz et al., 1994; Sorgdrager a a a Background Rural Urban et al., 1995, 1998; Soyseth et al., 1995; Dufresne et al., 1996; Average air levels 0.005–0.018b 0.27–0.38c 0.4–10.0b Kilburn, 1998; Romundstad et al., 2000; Hull and Abraham, (ng Al/m3) 0.005–0.032d 150–1000e, f 2002; Maier, 2002). Among studies examining effects of Al compounds on devel- a,g Regulations and guidelines opment of pulmonary fibrosis and/or asthma (“potroom Accepted levels OSHA NIOSH ACGIH asthma”), only a few assessed histological changes or inflam- 3 h (mg Al/m ) matory responses after agent deposition. An examination of Total dust 15.0 10.0 10.0 lungs of rats instilled with 1 or 5 mg Al2O3/kg BW noted dose- Respirable 5.0 5.0 N/A dependent increased inflammatory responses (characterized by fraction increased neutrophil [PMN] influx and total numbers of lavage- Al metal dust N/A 10.0 10.0 able cells) and minimal interstitial inflammation/type II cell hy- Al in welding N/A 5.0 5.0 perplasia over a 2-month postexposure period (Lindenschmidt fume et al., 1990). Unlike the increased inflammatory responses as Al soluble salts N/A 2.0 2.0 a function of time postinstillation with fibrogenic dust contain- Al alkyls N/A 2.0 2.0 ing silica, effects from Al2O3 were maximal within the first 7– Aluminum oxide N/A N/A 10.0 14 days postexposure and slowly decreased to normal thereafter. A comparison of the inflammatory effects of virginal Al2O3 a ATSDR (1999a). against those of potroom dust (alumina + AlF3 mixture) indi- b United States. cated that while a single instillate of rats with the Al2O3 induced c Central Canada. lung inflammation and an associated PMN influx, effects from d Rural Hawaii. potroom dust were often greater (albeit not dose-dependent; eselect American and Japanese cities. White et al., 1987). The Authors noted that the dust-induced f Sweet and Vermette, 1993; Tsuchiyama et al., 1997; Yokel and McNamara, 2001. increases in PMN were often accompanied by concurrent de- gMany states set values for each agent (in 8- or 24-hour periods) at creases in lavageable alveolar macrophages (AM). This is impor- from <1–several hundred µg/m3. tant in that in a study of effects of virginal Al2O3 vs fluoride(F)- h Eight (8) hour time-weighted averages (TWA). adhered Al2O3, an instillate of an approximetly 8-fold higher amount (i.e., 40 mg/rat) of virginal Al2O3 failed to induce a change in total cell numbers/PMN at 1 month post-exposure fluoride release, virginal (primary) Al2O3 is used as an adsor- (Tornlinget al., 1993). Conversely, instillation of an equal amount bent. While this clearly suggests that workers might potentially of the secondary F-Al2O3 caused (in same timeframe) a dou- be at risk for exposure to Al2O3 and AlF3, other agents may also bling in recoverable total cells and AM, and a 10-fold increase be present at levels that could pose a health risk (e.g., Al: iso- in PMN. The apparent incongruous results among all of these propylate; sulfate; hydroxide; chloride; nitrate; and phosphide, studies are not surprising given that generation-related varia- and triethyl aluminum and Al metal itself [NIOSH, 1984]). tions in purity/cocontaminant composition of various alumina As reflected by these varying standards, compound solubility samples are sufficient to induce disparate immunotoxicologic is critical to the extent of pulmonary (immuno)toxicity that could effects in the lungs (Ess et al., 1993). evolve after deposition of Al agents in that it ultimately impacts A few studies have examined effects from host inhalation/ on both the extent of agent clearance and Al bioavailability. A exposure to Al agents on bronchoalveolar fluid (BAL) compo- few studies have described the distribution/excretion of Al2O3 sition. Lindenschmidt et al. (1990) reported that a single Al2O3 (Rollin et al., 1991; Priest et al., 1998; Schlesinger et al., 2000), instillate induced short-lived significant increases in the amounts Al flakes (Ljunggren et al., 1991), welding fume-associated Al of lactate dehydrogenase (LDH; index of lung cell membrane (Sjogren et al., 1985, 1988), or aluminum chlorhydrate (Stone damage), total protein (index of potential fibrotic activity et al., 1979) after their inhalation or intratracheal (IT) instillation. and/or vascular damage), β-glucuronidase and N-acetylgluco- Other Investigators have concluded that lung Al burdens tend to saminidase (markers of macrophage/PMN membrane damage) increase with host longevity, irrespective of Al source or agent in rat BAL. In determining which particular protein(s) in the (reviewed in Ganrot, 1986; DeVoto and Yokel, 1994). BAL might comprise the increase in total protein, Tornling Though data describing acute effects on human pulmonary et al. (1993) concluded that Al2O3 instillation induced time- health from environmental exposure to airborne Al is lacking, dependent increases in levels of BAL fibronectin, while albumin there are numerous reports of an increased incidence of pneumo- and hyaluronan levels remained unaffected. nia, bronchitis, asthma, hard metal pneumoconiosis, lung can- There have also been studies to examine effects from host cers, pulmonary eosinophilia, granulomatous lung disease, or inhalation/exposure to Al agents on the ability of the lungs to PULMONARY IMMUNOTOXICOLOGY OF METALS 41 resist/clear bacterial challenge. In mice exposed 3 hr to 0.2–0.5 solubility-dependent differences in effects observed with other 3 mg Al/m (as Al ammonium sulfate [Al2(SO4)3(NH4)2SO4]) or elements (reviewed in Cohen et al., 1997b, 1998). One likely 3 0.3–0.5 mg Al/m (as Al sulfate [Al2(SO4)3]) and then (within explanation for this similarity in effects has been provided by a 1 hour) infected by 15 minutes of exposure to airborne Strepto- study that noted that upon AlCl3 deposition in the lungs, there coccus zooepidemicus, those exposed to either compound had is rapid sequestration of free Al ions by resident AM and type I increased mortality rates compared to air-exposed infected con- pneumocytes such that little Al can cross the alveolar-capillary trols (Drummond et al., 1986). Unfortunately, the results contra- barrier (Berry et al., 1988). Once entrapped in cell lysosomes, dict and support earlier studies that examined whether inhalation complexing with free phosphate results in formation of insoluble of/instillation with Al agents modulated pulmonary responses aluminum (ortho)phosphate (AlPO4). As a result, Al (irrespec- to infection. In one study, while 3 hour exposure to increasing tive of parent form) remains trapped in AM and pneumocytes Al2(SO4)3 levels resulted in significantly increased host mortal- and is only slowly removed during alveolar clearance. In light ity from subsequently inhaled S. pyogenes, inhaling equivalent of this somewhat unusual mechanism, it is then not so surprising (or greater) amounts of Al2(SO4)3(NH4)2SO4 never modified that the relative toxicities of Al2O3 and AlCl3 on the AM from survival against the pathogen (Ehrlich, 1980). Conversely, if the varying host species did not differ much. agents were first instilled and the hosts then infected, mice that received Al2(SO4)3(NH4)2SO4 had greater mortality rates than those that got an equivalent amount of Al2(SO4)3 (Hatch et al., ARSENIC 1981). Of even greater interest in this latter study is that when Arsenic (As) is released into the atmosphere from both natural mice were permitted to inhale either compound rather than be de- and anthropogenic sources. Because As naturally occurs in soil, posited by instillation, no significant differences in host mortal- it will be present as a result of airborne dusts. Similarly, because ity (between the 2 agents or as compared with sham/air-exposed As is a normal constituent of seawater, its presence in the air is infected controls) were documented. also increased as a result of sea spray. The primary anthropogenic Little is known about effects of Al on lung immune cell- (nonoccupational) sources for much of the As in the air are the related functions. While one study demonstrated that potroom burning of coals, oils, and wood for heat or energy generation, workers display abnormal systemic levels of helper (CD4) and as well as municipal waste incineration. Regardless of source, suppressor (CD8) T-lymphocyte levels (and abnormal CD4/CD8 the As found in air is usually in the form of a trivalent (As[III]) ratios) as compared to control populations, subtyping of lung trioxide (As2O3), though smaller but significant contributions lymphocyte populations was not done (Davis and Milham, 1990). from volatile organic forms (primarily arsine) are also present In a study that examined lung lymphocytes in potroom work- (ATSDR, 2000a). Airborne trivalent As and arsines can undergo ers exposed up to 12 years to Al-bearing dusts, total lymphocyte oxidation to pentavalent (As[V]) forms. As such, the As found levels were not different from those in control workers. Unfortu- in air is usually as an As(III)/As(V) mixture. nately, because population subtyping was again not performed, For the general population, the other major primary environ- it remains unclear if variations in the relative percentages of mental source of inhaled As is tobacco smoke. In the days when CD4 and CD8 lymphocytes were present (Eklund et al., 1989). arsenical pesticides were used to treat tobacco plants, levels of Analyses of other immune cells recovered during lavage also >50 mg As/kg tobacco were not uncommon and smokers then indicated that both the relative percentages in total population could possibly have been inhaling ≈100 µg As/d (Dickerson, and viabilities of AM and PMN in exposed workers’ lungs were 1994). More recently, after these pesticides were banned, it was unaffected. Though it appeared that the AM from these work- calculated that an average cigarette contained as much as ≈1.5– ers had reduced abilities to bind/ingest yeast particles, it was 3 µg As (Kraus et al., 2000). Even with these lower burdens, lev- later shown that neither surface opsonin receptor expression nor els of As in mainstream (inhaled) and sidestream (secondhand) phagocytic activity was modified. A similar lack of effect on AM smokes have still been reported to be 0–1.4 and 0.015–0.023 µg viability or phagocytic activity was seen using hamster cells in- As/cigarette, respectively (Smith et al., 1997). It was then not cubated with Al2O3 (Warshawsky et al., 1994). In rabbit AM surprising to see that As levels in several indoor sites that permit- 3 co-cultured with Al2O3, oxidative metabolism (measured by ni- ted smoking were found to range from <0.1–1 ng As/m while, troblue tetrazolium [NBT] reduction in resting and stimulated in comparison, smoke-free venues had levels <0.13 ng As/m3 cells) was only nominally affected (Gusev et al., 1993). (Landsberger and Wu, 1995). With the majority of cigarettes In in vitro studies of effects from soluble Al chloride (AlCl3) containing the lower As-bearing tobaccos, it has been estimated upon rat AM, while exposure did not induce alterations in cell that the amount of As absorbed daily from 2 packs of cigarettes membrane integrity or viability, it did cause reduced O2 con- is ≈12 µg. For the nonsmoking population, based on some of sumption by resting and zymosan-stimulated cells and subse- the average urban values presented in Table 2, intake of As by · − µ quent reductions in superoxide anion [ O2 ] generation in the inhalation is only about 0.4–0.6 g/d. latter (Castranova et al., 1980). That soluble AlCl3 did not dis- Though the use of As can be traced back to the time of Hip- play an increased cytotoxic effect as compared to more insol- pocrates, arsenicals have more recently been used as in pesti- uble Al2O3 is somewhat contrary to previously documented cides, herbicides, fungicides, in metal smelters and mining, in 42 COHEN

TABLE 2 tial exposure to As, regulatory standards have been established Ambient levels and acceptable workplace levels for As (Table 2). As with many of the other metals discussed in this review, permissible levels in many states have been set substan- a a a Background Rural Urban tively lower, i.e., at fractions of a µg/m3. Average air levels <1–3b 1.0–2.8d 20–100b Although there is considerable information available on the (ng As/m3) <0.007–1.9d 20–30b immunotoxicity of As, the primary focus has been on systemic 4.2–9.6b,c immunity (reviewed in Burns, 1998). Still, pulmonary exposure 2–2300d to As-bearing agents has been shown to produce significant (im- muno)toxicologic events in the lung. Instillation of As trioxide Regulations and guidelinesa,e (As2O3; 13 mg/kg) or GaAs (1.5–52 mg/kg) led to marked lung Accepted levels OSHA NIOSH ACGIH irritation and hyperplasia in rats and hamsters (Webb et al., 1986; 3 f (mg As/m ) Ohyama et al., 1988; Garcia-Vargas and Cebrian, 1996). Huaux As, elemental N/A 0.002 0.01 et al. (1995) noted pulmonary inflammation (AM and PMN in- As, inorganic forms 0.01 0.002 0.01 flux) after instillation of rats with 5 mg As2O3/kg. Hamsters As, organic forms 0.5 0.002 0.01 IT-exposed to 7.5 mg As (as InAs) once a week for 15 weeks As, arsine N/A 0.05 ppm 0.05 ppm evidenced several histopathological events in the lung, includ- GaAs N/A 0.002 N/A ing increased rates of proteinosis-like lesions, alveolar or bron- chiolar hyperplasia, pneumonia, and metaplasia (Tanaka et al., a ATSDR (2000a). 1996). In a follow-up study, using hamsters instilled twice a bUnited States. week for 8 weeks with GaAs (7.7 mg/kg), InAs (7.7 mg/kg), or cGreat Lakes urban centers. As2O3 (1.3 mg/kg), these Authors were able to conclude that d Schroeder et al., 1987. the relative toxicity potentials (estimation based on the degree eMany states set values for each agent (in 8- or 24-hour periods) at of pulmonary (immuno)toxicologic effect in relation to dosage  µ 3 1 to several g/m . used) for these agents were InAs>GaAs>As2O3 (Tanaka et al., f Eight-(8) hour time-weighted averages (TWA). 2000). There are only limited studies on effects on humoral immu- nity after pulmonary As exposure, and all are systemic. Pul- glass production, in the pharmaceutical and microelectronics in- monary exposure to GaAs (50–200 mg/kg) or sodium arsenite dustries, and in chemical warfare (Mabuchi et al., 1979; La Dou, (NaAsO2; 5.7 mg/kg) suppressed the ability of mice to mount 1986; Farmer and Johnson, 1990; Dickerson, 1994; Steenland systemic 1◦ or 2◦ immune responses to the T-dependent antigen et al., 1996). Together, these industries represent the majority of sheep erythrocytes (SRBC) (Sikorski et al., 1989). In workers the current use of inorganic and organic arsenicals and, thus, the in a plant burning coal containing 0.9–1.5 kg As/dry ton, there primary means of occupational exposures. was no effect on basal IgG, IgA, or IgM levels in their sera as While there are several potential routes of occupational ex- compared to levels in control workers in a plant using coal with a posure to As-bearing agents, the primary means is by inhalation 10-fold lower As content. Apparent discrepancies between these of As compounds or As-contaminated dusts (Landrigan, 1992). studies may be related to exposure level and duration, basal vs Overall, the greatest occupational risk seems to be from inor- antigen-specific responses, or other factors. In a detailed study of ganic, rather than organic, As. The main settings for worker potential effects from As exposure on lymphocytes, Vega et al. exposure to significant levels of inorganic As are in metal smelt- (1999) noted that peripheral blood mononuclear cells of each of ing and pesticide manufacture, but exposure also occurs during their donors displayed inhibited proliferative responses to PHA blasting and mining of ores (as As is naturally associated with (phytohemagglutinin). Analyses of the cells indicated no change several minerals) (Maloney, 1996). Workers producing gallium in expression of CD25 (interleukin [IL]-2 receptor) but a diminu- (GaAs) or indium (InAs) arsenide for use in semiconductors tion in ability to secrete IL-2 itself. Analyses of IL-2 mRNA lev- are also at risk. Even though GaAs manufacture requires the els and intracellular IL-2 indicated that the inhibition was not at use of arsine gas (AsH3), the primary route of exposure to As the transcriptional level, while electron microscopy revealed that in this setting is via inhalation of particles generated from the ultrastructure in Golgi bodies, mitochondria, cytoskeleton, and sawing or polishing of GaAs wafers (Briggs and Owens, 1980) perinuclear membrane in these cells were altered. The Authors and subsequent dissociation of the entrained GaAs into its free concluded that exposure to As caused impared intracellular se- ions (Webb et al., 1984; Burns et al., 1991). The most recent cretion of proteins (including IL-2) and that this led to impaired National Occupational Exposure Study in the 1980s estimated T-lymphocyte proliferation. that the total number of workers (excluding miners) exposed With respect to cell-mediated responses, there are no studies daily to As was ≈58,000; taking miners into account, the poten- specifically examining pulmonary cellular immunity after As tial pool neared 1.5 million workers (NIOSH, 1990; Steenland exposure in the literature. However, because data in the literature et al., 1996; ATSDR,2000a). To help minimize the risk of poten- suggests that pulmonary exposure to As can lead to subsequent PULMONARY IMMUNOTOXICOLOGY OF METALS 43 interference with general cellular immunity in animals/humans, assessments (0.1–300 µg/ml) with As2S3 and Ca3(AsO4)2 indi- it is likely that As is immunomodulatory in the lung as well cated that both oxidation forms of As produced significant dose- · − α (Garcia-Vargas and Cebrian, 1996; Burns, 1998). related suppression of O2 production and LPS-induced TNF Most studies of As-induced pulmonary immunomodulation release by rat AM, yet had no effect on production of PGE2.In have focused on innate immunity. Systemically, pulmonary ex- contrast, in vitro exposure to soluble NaAsO2 or Na2HAsO4 posure to arsenicals produced decreased levels of several com- showed that As(III) was 10-fold more potent than As(V) in · − α plement proteins in mice (5.7 mg NaAsO2/kg; Sikorski et al., inhibiting O2 production and induced TNF release. Curiously, 1989) and altered those of several serum acute phase proteins As(V) suppressed LPS-induced PGE2 release while As(III) had (i.e., transferrin, orosomucoid, and ceruloplasmin) in humans no effect. Other Investigators had previously been unable to · − (Becko et al., 1988). Phenylarsine oxide has been shown to pos- demonstrate an effect of As(V) on O2 production (Castranova sess anti-inflammatory activity by inhibiting NADPH oxidase- et al., 1984). In contrast to the in vivo studies cited above, in · − dependent production of O2 in alveolar PMN (Roussin et al., vitro treatment of rat lung phagocytes with As2O3 (50 ng/ml) 1997). Lantz et al. (1994) compared the in vivo toxicities of a was shown to have no effect on basal or stimulated TNFα single instillate (1 mg/kg) of trivalent (NaAsO2) and pentavalent or IL-1 release, or on fibronectin or cystatin-c production (Huaux · − (sodium arsenate; Na2HAsO4) forms of soluble As on rat AM, et al., 1995), though suppression of stimulus-induced O2 · − using production of O2 , prostaglandin E2 (PGE2) and tumor production by As2O3 has been reported (Geertz et al., necrosis factor-α (TNFα) as endpoints. It was noted that only 1994). AM from As(V)-exposed rats showed significant increases in There are several possible mechanisms of toxicity for As in · − O2 production. Exposure to each form led to decreased AM the lung. These include: As(III) may interact with critical en- baseline and LPS-induced TNFα production and caused inflam- zyme thiol (−SH) or persulfide residues and inhibit function; matory responses (PMN influx) in the lung. In similar studies As(V) may inhibit endogenous substrate binding via compet- ◦ using trivalent As trisulfide (As2S3) and pentavalent calcium ar- itive interactions; As may interact with 2 molecules/enzyme senate (Ca3[AsO4]2) slightly soluble forms of As, Lantz et al. substrates to inhibit metabolic reactions; and, As may disrupt (1995) showed that rat AM exposed to Ca3(AsO4)2had increased energy systems or ion balances within cells (Squibb and Fowler, · − α O2 production and basal TNF release, whereas responses by 1983; Aposhian, 1989; Dickerson, 1994; Goyer, 1996). AM exposed to As2S3 were no different from controls. The In a broad sense, the mechanism of pulmonary immunotoxic- Authors concluded that alterations in AM may compromise host ity is likely related to functional deficits in phagocytic/cytotoxic defense, conclusions supported by the earlier observations of populations residing in (or recruited to) the lung. Decreased Aranyi et al. (1985) that inhalation by mice of 0.27–0.94 mg resistance to B16F10 melanoma has been noted following pul- 3 As/m (as As2O3) for 3 hours (even greater with 5 or 20 3-hour monary exposure to GaAs (Sikorski et al., 1989). In that study, exposures to 0.50 mg As/m3) increased their susceptibility to while lung natural killer (NK) activity was not assessed, systemic infection with S. pneumonia and decreased their pulmonary bac- NK activity was seen to be enhanced. As-Related decreases in tericidal activity against Klebsiella pneumoniae. host resistance to bacteria with concomitant decreased in situ A study by Broeckaert et al. (1997) of effects of instilled coal bactericidal activity (Aranyi et al., 1985) support a hypothe- fly ash (≈200 ng As/mg ash) or copper smelter dust (≈1447 ng sis that AM phagocytic capacity is suppressed. In addition, As As/mg dust) instilled into mice using total doses of particles that exposure alters the release of several inflammatory mediators · − α varied for each material such that each instillate delivered a total including O2 , TNF , and IL-1. These changes, particularly in µ · − of 20 g As/kg (600 ng As/mouse) reported a 90% reduction in O2 production, are likely related to inflammatory responses ex vivo LPS-induced TNFα release up to 30 days postexposure. induced after pulmonary exposure to As. The effects observed This persistent suppression of TNFα production was suggested on these inflammatory mediators (enhancement or suppression) to be related to the ability of lung phagocytes to clear the parti- are typical of what is seen with systemic As immunomodulation, cles from the lung. In contrast to studies by Lantz et al. (1994, i.e., effects appear dependent on the form (III or V) of As, solu- 1995) and Broeckaert et al. (1997), Huaux et al. (1995) found bility, concentration, and whether exposure occurred in vivo or that instillation of rats with 5 mg As2O3/kg stimulated ex vivo in vitro. Though this confuses the mechanistic picture somewhat, TNFα and IL-1 production by AM. Though the culture wells in it can be stated that exposure to As or As-bearing agents alters these studies held similar numbers of AM, they also contained pulmonary phagocytic function, probably resulting in lower cy- PMN; this presence of PMN may account for the differences in totoxicity/pathogen clearance from the lung. Though systemic observations between this study and the others cited. alterations in macrophage phagocytic ability, MHC Class II ex- In vitro exposure of AM by As(III) results in suppressed pression on splenic macrophages and B-lymphocytes, and adhe- · − phagocytic ability as well as diminished O2 production (Fisher sion molecules (suggesting macrophage capacity to recognize et al., 1986; Labedzka et al., 1989). In vitro phenylarsine oxide and bind to/phagocytize nonself-matter) have been shown fol- · − exposure was also shown to inhibit inducible O2 generation lowing pulmonary GaAs exposure (Sikorski et al., 1989), a bio- in rat AM and PMN (Roussin et al., 1997), and these results chemical or molecular immunologically related mechanism is supported the observations of Lantz et al. (1994, 1995). In vitro still uncertain. 44 COHEN

TABLE 3 agents, regulatory standards have been established (Table 3). Ambient levels and acceptable workplace levels for Cd Once again, permissible levels in many states have been set sub- stantially lower, i.e., at fractions of a µg/m3 (ATSDR, 1999b). a a a Background Rural Urban Though these guidelines are generic to cover all Cd agents, as Average air levels <1b <4–4.5c <4–10d with most metals, absorption of inhaled Cd depends on chemical > (ng Cd/m3) <4–115e form and solubility (e.g., cadmium chloride (CdCl2) cadmium > > 3–40b sulfate (CdSO4) CdO cadmium sulfide (CdS)). The effects of Cd on the humoral immune system have been a, f Regulations and guidelines well-reviewed (Koller, 1998). The majority of studies that have Accepted levels OSHA NIOSH ACGIH examined systemic effects from Cd were based on nonpulmonary 3 g (mg Cd/m ) exposure routes; however, a few did utilize inhalation/instillation. µ 3 < Acute (2-hour) exposure of mice to 190 g CdCl2/m resulted Total dust 0.005 0.01 0.01 ◦ Respirable fraction <0.005 0.01 0.002 in suppression of the 1 (IgM) antibody-forming cell response (AFC; Graham et al., 1978). Similarly, mice exposed 1 hour to a 3 ATSDR (1999b). 880 µg CdCl2/m had decreased: IgM AFC responses; spleno- bUnited States. cyte viability; and, lymphoproliferative responses to LPS 1 week c Rural Illinois. postexposure (Krzystyniak et al., 1987). In vitro studies with d Chicago. CdCl2 noted that effects on LPS-induced proliferation ranged eEast St. Louis. f from suppression to enhancement (Shenker et al., 1977; Gallagher Many states set values for each agent (in 8- or 24-hour periods) at 3 1 µg/m3. et al., 1979). Inhalation (15 minutes) of 9 mg CdO/m did not gEight-(8) hour time-weighted averages (TWA). affect antibody titers in mice subsequently challenged with in- fluenza virus (Chaumard et al., 1991). Mice inhaling 3–300 ppm CdCl2 for 10 weeks had suppressed RBC-antibody-complement rosette formation (Koller and Brauner, 1977). Based on these CADMIUM findings, it was suggested that Cd may impair complement com- Cadmium (Cd) is released into the atmosphere from both nat- ponent binding to B-lymphocyte receptors, thereby inhibiting ural and anthropogenic sources. For the general population, the the effectiveness of antibodies in the elimination/inactivation primary environmental source of inhaled Cd is tobacco smoke. It of bacterial antigens. In vitro exposure to CdCl2 has also been has been estimated that an average cigarette contains as much as shown to inhibit B-lymphocyte RNA and DNA synthesis, as well ≈2 µg Cd (Newman-Taylor, 1992). At these levels, the amount as IgG secretion (Daum et al., 1993). In general, B-lymphocyte of Cd absorbed daily from a pack of cigarettes approaches 1–3 µg mitogenicity appears to be enhanced - while antibody synthesis Cd. For the nonsmoking population, food is the primary source and secretion is suppressed - following exposure to Cd (princi- of potential Cd exposure. Still, due to industrialization, Cd is pally CdCl2). released into the ambient air (most in the form of relatively In general, in vivo and in vitro studies suggest that Cd sup- insoluble cadmium oxide (CdO, Koller, 1998), and so even presses cell-mediated immunity, in particular delayed hyper- nonsmokers are potentially exposed. Average air levels of Cd sensitivity, and may enhance allograft rejection. A single 1-hour 3 for rural and urban areas are provided in Table 3. exposure of mice to 880 µg CdCl2/m significantly reduced As with most other metals, the majority of Cd exposures are T-lymphocyte proliferation in response to allogeneic antigens occupational and occur via inhalation of Cd-bearing fumes and and mitogens (Krzystyniak et al., 1987). Changes in lympho- dusts. The last National Occupational Exposure Study in the proliferation (mitogen and MLR) in human lymphocytes ex- 1980s estimated that the number of workers potentially exposed posed in vitro have also been reported (Kastelan et al., 1981). to Cd was >500,000 (ATSDR, 1999b). Of these, it was esti- Shifts in lymphocyte populations, as well as splenomegaly, ane- mated that >200,000 were exposed to >1 µg Cd/m3, with 65, mia, neutropenia, and lymphopenia, were seen in mice and rats 20, and 15% routinely exposed at 1–39, 40–99, and >100 µg exposed for 4 weeks to 100 µg CdO/m3 (Ohsawa and Kawai, Cd/m3, respectively. Cadmium is principally used in Ni-Cd bat- 1981). Gallagher and Gray (1982) noted inhibited RNA forma- teries, electroplating, alloy production, brazing solders, stabi- tion in lymphocytes exposed to Cd in vitro; however, if this was lizers for plastics, and as pigments (Shaller and Angerer, 1992; primarily in B-lymphocytes or both T- and B-lymphocytes was Steenland et al., 1996). Because of the relatively high volatility not clear. This finding did suggest, however, that in addition of Cd, inhalation hazards are particularly important to work- to decreased antibody synthesis and secretion, similar changes ers welding Cd-plated material or using silver solder that may might occur with respect to cytokine formation or release by contain up to 25% Cd (Lauwerys, 1994). Airborne Cd also read- T-lymphocytes. ily arises as a by-product of zinc ore mining and refining, but While there is no definitive effect of Cd on innate immunity, is also found complexed with lead (Newman-Taylor, 1992). To the tendency is toward suppression. Though there is no published help minimize the risk to workers potentially exposed to Cd information on effects of inhaled Cd on NK activity, exposure by PULMONARY IMMUNOTOXICOLOGY OF METALS 45 other routes and subsequent examination of splenic NK function The majority of studies examining the potential effects of Cd suggests that Cd suppresses NK cytotoxicity (Koller, 1998). This on pulmonary innate immunity have been conducted in vitro. · − conclusion is supported by in vitro studies in which CdCl2 ex- Geertz et al. (1994) demonstrated that stimulus-induced O2 posure inhibited NK activity and antibody-dependent cell cyto- production by rabbit AM was suppressed by CdCl2, findings toxicity (ADCC) in human peripheral blood lymphocytes (PBL; similar to those by Catranova et al. (1980) using rat AM cul- Cifone et al., 1990). tured with CdCl2 or cadmium acetate. In contrast, Kramer et al. · − As noted above, of the many studies that have examined ef- (1990) could detect no effect by CdCl2 on guinea pig AM O2 fects from inhaled Cd on immunologic endpoints, very few have production. This study also noted that AM phagocytosis was · − focused on the lungs per se. What is clear from the latter is that unaffected. As with O2 , the Kramer studies again seem to con- Cd agents, like most of the metals in this review, induce inflam- flict with others wherein, using in vivo and in vitro approaches, matory responses in the lungs and induce variable effects upon Cd treatment inhibited AM phagocytosis as well as microbicidal the functionality of AM. activity (Graham et al., 1975; Loose et al., 1977, 1978a, 1978b). In studies examining inflammatory responses induced by These effects on microbicidal functions, while maybe not at the Cd agents, Morgan et al. (1997) noted that rats instilled with level of phagocytosis itself, might be due to Cd-induced damage 17 mg/kg (≈3.4 mg total) cadmium telluride (CdTe, used in to postphagocytic processes instead. A recent study using Syrian semiconductor industry) had an extensive influx of lymphocytes, hamster AM treated with CdO has indicated that exposures led AM, and PMN into their lungs over a period of 1–28 days postex- to alterations in cytoskeleton-driven motion of phagosomes, a posure, as well as significant interstitial fibrosis and hyperplasia process critical to the formation of the phagolysosomes wherein of Type II cells. The observations at 1 day postexposure in this intracellular killing of ingested organisms can occur (Niitsuya study differ from those by Bell et al. (2000) in that in guinea et al., 2003). Additionally, macrophage motility, lymphokine pigs instilled with 300 µg CdCl2, while there was an increase responsivity, and cytotoxic activity have been shown to be in- in PMN in the lungs, there were neither increases in the other hibited following in vitro Cd exposure at levels not overtly toxic cell types nor in the numbers of cells recoverable by lavage. (see Koller, 1998). This is important in that in several studies re- In a comparison of relative percentages of immune cell types porting reduced phagocytic activty by AM, the effect was often present at the 1 day postexposure time point, the rat study found concomitant with increased cytotoxicity from the Cd. that AM and PMN values changed from >80 and <15%, re- Effects from Cd on cytokine production by mononuclear cells spectively, to ≈18 and ≈82%; in guinea pigs, these went from have been variable. CdCl2 has been shown to inhibit the mRNA ≈77 and ≈18%, to ≈59 and 36%, respectively. Whether the ear- levels and production of IL-1 and TNFα in/by human peripheral lier study results were affected by the copresence of Te ions is blood mononuclear cells (Theocharis et al., 1994). IL-6 mRNA unclear. Similarly, whether these differences could be attributed and production levels were also reduced in the THP-1 human to Cd dose are also uncertain. The ability of isolated rabbit AM monocytes exposed to CdCl2 (Funkhouser et al., 1994). Unlike to produce PGE2 and LTB4 that can modulate inflammation the effects on IL-1, TNFα, and IL-6, CdCl2 treatment of human was differentially modified by varying the levels of Cd2+ ions peripheral blood mononuclear cells appeared to enhance IL-8 in the treatment (i.e., high-dose inhibitory, low-dose stimula- production (Horiguchi et al., 1993). tory for LTB4, Kudo et al., 1996). Alternatively, the differences Koller (1998) observed that, in general, mice treated with Cd in observed responses might also be due to the animal model. (any form) and then challenged with bacteria had decreased re- Species- and strain-related differential responses to Cd were sistance to the pathogen. In contrast, all Cd-exposed mice had elegantly demonstrated by McKenna et al. (1997). In these stud- increased resistance to viral pathogens. These conclusions were ies, C57Bl6 and DBA mice, as well as WF rats, were exposed based on the findings that: animals exposed to aerosolized CdCl2 to 1 mg Cd/m3 (as CdO) for 3 hours and examined 1, 3, and and then challenged with aerosolized streptococci spp. had in- 5 days postexposure. The Authors found that C57Bl6 mice had creased mortality rates (Gardner et al., 1977); mice exposed a faster and greater influx of PMN into their lungs than DBA to CdO and then infected with Pasturella multocida displayed counterparts. In comparison to mice, rats responded with more similar decreases in resistance; and, mice that inhaled CdO dis- transient inflammatory responses but with a higher degree of played decreased susceptibility to orthomyxovirus influenza A acute inflammation in their lungs. (Chaumard et al., 1983). Macrophage-mediated immune function is extremely sensi- Several possibilities exist as possible mechanisms for the im- tive to the effects of Cd (Koller, 1998). Reduced AM phagocytic munomodulatory effects of Cd. It appears that Cd exposure can activity has been seen in rabbits that inhaled CdCl2 (Graham alter: phagocytic and cytotoxic functions of AM; surface re- et al., 1975). Because impaired AM rosette formation has been ceptors (Fc or complement) on AM and other cells responsible noted following oral exposure to Cd, this suggests that deficits for effective binding of, and cytotoxicity against, lung (bacte- · − α (physical or functional) in the Fc receptor may evolve (Hadley rial) pathogens; and, AM production of O2 , IL-1, and TNF . et al., 1977). These findings are in agreement with other stud- The fact that viral pathogens do not seem to present a signif- ies that indicated that Cd can alter Fc/complement receptors on icant threat to Cd-exposed animals may be reflective of the Kupffer cells. fact that although Cd does have effects on both humoral and 46 COHEN cell-mediated immunity, generally high concentrations are re- most often dermal, inhalation of particulates or fumes containing quired for suppression, while lower concentrations tend to en- Cr occurs among welders, chromite miners, and ore processing hance these effects. and purification workers presents the primary risk to their health. Values reported as typical airborne Cr(VI) concentrations in a variety of industries have been estimated to be 5–25 µg Cr/m3 CHROMIUM (chromium plating) to as high as 400–600 µg Cr/m3 (in SS weld- Like most metals, chromium (Cr) is released into the atmo- ing, chromate production, and/or chrome pigment production) sphere from both natural and anthropogenic sources. Inhalation (ATSDR, 2000b). Airborne Cr(III) levels have been estimated to of Cr by the general population has been estimated to range from be 10–50 µg Cr/m3 in tanning industries (Arfsten et al., 1998). < µ 0.2–0.6 g/d, but this is based on an assumed abmient air level The most recent National Occupational Exposure Study from the < µ 3 of 0.01–0.03 g Cr/m (Fishbein, 1984; ATSDR, 2000b). As late 1980s estimated that the number of workers exposed daily seen in Table 4, these values tend to fall more in the range for to Cr ranged from 300,000–550,000 (ATSDR, 2000b). To help the average urban center in the United States. minimize the risk of potential exposure to Cr, regulatory stan- Chromium is found most often in nature complexed with dards have been established (Table 4). Once again, permissible other minerals such as crocoite and iron. Most natural Cr is found levels in many states have been set substantively lower, i.e., at in oxides in chromite ore (Sawyer, 1994). Chromium has found fractions of a µg/m3. As seen from the guidelines, there are very significant use in many industries and applications, including: differing values for the differing classes of Cr. While there are metallurgy (for manufacture of stainless steel [SS], alloy cast six possible valence states for Cr, only two have toxicological irons, and other alloys); paint, dye, and pigment manufacture; importance, Cr(III) and Cr(VI). There is no significant evidence leather tanning; wood product preservation; corrosion control; that inhaled Cr(III) at the current exposure limits poses any oc- and manufacture of textiles, magnetic tape, cement, joint pros- cupational health risk (Sawyer, 1994). However, inhalation of theses, and toners for copying machines (reviewed by Arfsten Cr(VI) may be carcinogenic in sufficient concentrations (IARC, et al., 1998). 1990). Though there are these clear delineations between poten- While occupational exposure to Cr in the production of SS, tial health-related outcomes from exposure to the various forms chrome alloys, pigments, chrome plating, and welding (of SS) is of Cr, it still ultimately is speciation and solubility that will govern the ability of any given inhaled Cr agent to be absorbed TABLE 4 and exert its toxicities. Ambient levels and acceptable workplace levels for Cr Effects of Cr on the humoral immune system have been well- reviewed (Arfsten et al., 1998). Again, most studies used expo- Backgrounda Rurala Urbana sure routes other than inhalation or instillation. In one inhalation Average air levels 0.005–2.6b <10b 10–30b study, humoral immunity to SRBC was increased in rats exposed 3 c (ng Cr/m ) >500 25 or 90 days to levels of sodium dichromate (Na2Cr2O7)upto >225d 100 µg Cr/m3, but suppressed at higher levels (Glaser et al., e 100–400 1985). In rats exposed to Na2Cr2O7 or a Cr(VI)/Cr(III) (3:2) oxide mix, over a 1-year recovery period, decreases (possible Regulations and guidelinesa, f related to lung Cr retention) in serum Igs (as well as elevated Accepted levels OSHA NIOSH ACGIH WBC and RBC) were noted in the oxide rats (Glaser et al., 1986). (mg Cr/m3)g Both B-lymphocyte proliferation and Ig production were inhib- Cr metal (dust) 1.0 0.5 0.5 ited in vivo in animals (Snyder, 1991) and in vitro with human Cr(III) agents 0.5 0.5 0.5 cells (Borella and Bargellini, 1993). In contrast, Boscolo et al. Cr(VI)–soluble 0.1 N/A 0.05 (1995) could find no difference in circulating serum IgM, IgG, Cr(VI)–insoluble 1.0 0.001 0.01 or IgA in dye workers despite reduced total circulating lympho- Chromic acid 0.1 N/A 0.05 cyte levels. With respect to Cr effects on cell-mediated immune Chromates 0.1 N/A 0.05 responses, most studies have examined the ability of Cr to pro- Chromum(II) 0.5 0.5 0.05 duce delayed hypersensitivity responses in humans and animal models. In vitro studies in human and animal lymphocytes in- a ATSDR (2000a). b dicated that Cr inhibited T-lymphocyte proliferative responses United States. (Borella et al., 1990; Snyder, 1994). In the human studies, Cr(VI) cSteubenville, OH. agents enhanced proliferation at low concentrations and sup- d Baltimore, MD. eCorpus Christi, TX. pressed it at the higher levels; Cr(III) was uniformly inactive. f Many states set values for each agent (in 8 or 24 hour periods) It may be that many of these observations are related to the at from 1–several µg/m3; however, these values are very class- clastogenic/cytogenetic effects of (inhaled) Cr in lymphocytes. and/or compound-specific. Recent studies have reported that in vivo or in vitro exposure to gEight-(8) hour time-weighted averages (TWA). Cr(VI) caused increases in the incidence of lymphocytes with PULMONARY IMMUNOTOXICOLOGY OF METALS 47

DNA strandbreaks (Hodges et al., 2001) or micronuclei (Benova and ≈5% of lavageable cells being PMN and monocytes, re- et al., 2002). To be fair, it must be noted that the latter study with spectively, after only a 2-week exposure; after the additional Cr platers did not report an increase in other types of clastogenic 2 weeks of exposure, levels of both cell types were still elevated endpoints, such as sister chromatid exchanges. Overall, each of but trending downward. The insoluble Cr(VI) had no effect on these studies suggest that prolonged exposure to Cr agents or PMN or monocyte levels over either exposure period. exposure to high Cr levels has the potential to produced im- The Cohen et al. (1998) study, while evaluating inflammatory munosuppression. Furthermore, as with many of the other toxi- effects as they relate to agent solubility, also evaluated effects cologic aspects of Cr agents, these studies reflect the importance on several functional parameters (i.e., formation of: inflamma- of oxidative state/speciation in the postexposure outcomes. tory cytokines, reactive oxygen specties, and basal and inducible Few studies have specifically examined immunotoxicologic nitric oxide [NO]) in AM isolated from Cr-exposed rats. As ex- effects of Cr in the lung. Glaser et al. (1985) noted that rats pected, inducible IL-1 and IL-6 production by BaCrO4-exposed 3 exposed 4 weeks to 50 µg Cr(VI)/m (as Na2Cr2O7) displayed rat AM was unaffected (but that of TNFα reduced). However, enhanced numbers of AM, with increased phagocytic activity, in and surprisingly, inducible IL-1 and TNFα but not IL-6) produc- their lungs. However, if exposure was extended by 8 weeks, the tion by AM from K2CrO4 rats with pulmonary inflammation was number of AM was decreased. As with many metals, Cr(VI) en- reduced after 4 weeks of exposure. This contrasts with in vitro hanced AM activity at a “low” level (50 µg/m3) and suppressed findings wherein Cr exposure of U937 human monocytes or iso- it at a “high” value (200 µg/m3). A study of rabbits exposed 4– lated monocytes/macrophages was shown to enhance IL-1 and 3 6 weeks to 900 µg Cr(VI)/m (as sodium chromate [Na2CrO4]) TNFα release (as well as suppress that of transforming growth reported an influx of AM into the lung, but no altered function- factor-β and induce blood monocyte proliferation) (Wang et al., ality (Johansson et al., 1986a). These exposures were also seen 1996). Solubility-related differences were also apparent with · − to have caused morphological changes in the AM that consisted respect to the degree of O2 and H2O2 formation as only the primarily of enlarged lysosomes. In contrast, rabbits exposed AM from BaCrO4 rats showed reduced abilities to form either 3 to 600 µg Cr(III)/m (as chromic nitrate [Cr(NO3)3]) had no metabolite as compared to that by AM from air control rats. In- increase in AM numbers but AM with decreased functional- terestingly, the effect on this parameter appeared to be worsened ities (metabolic, phagocytic) that correlated with an increased when the AM were pretreated with IFNγ in an attempt to boost presence of enlarged lysosomes and intercellular inclusions con- cell activities. This BaCrO4-specific effect on IFNγ responsivity taining high levels of Cr. These morphological changes in AM was also apparent when NO production was assessed; however, following Cr(VI) or Cr(III) exposure were due to direct effects these AM already had significantly higher spontaneous NO for- of Cr on these cells, and the effect in Cr(III)-exposed AM was re- mation levels compared to that of control AM. lated to impaired catabolism of surfactant in the lung (Johansson A role for oxidative stress in Cr immunotoxicity has been et al., 1986b). Again, these studies reflect the differences in po- proposed by several laboratories. Pulmonary exposure of rats tential pulmonary immunotoxicities as they relate to the oxida- to lower concentrations (2 mg) of Cr(III) (as chromic oxide tive state/speciation of Cr agents. [Cr2O3]) or Cr(VI) (as calcium chromate [CaCrO4]) had no ef- Like most metals, lung exposure to Cr agents can result in fect on AM chemiluminescence or O2 consumption (Galvin and induction of inflammatory responses. A 13-week inhalation ex- Oberg, 1984). In contrast, in vitro exposures to the same lev- 3 posure of rats to 3, 10, or 30 mg Cr(III)/m (as Cr2O3 or ba- els significantly reduced each parameter. Exposure of J774A.1 sic Cr-sulfate [Cr2(SO4)3]) caused changes in both bronchial macrophages to either Cr(III) or Cr(VI) resulted in increases in · − and mediastinal lymphatic tissues consisting of an increased NO and O2 production (Hassoun and Stohs, 1995). Tian and presence of Cr-laden AM, lymphoid hyperplasia, and intersti- Lawrence (1996) were unable to show an in vitro effect of Cr on tial (with Cr2O3) or granulomatous (with Cr2(SO4)3)inflamma- NO production using splenic macrophages. Bagchi et al. (1997), tion (Derelanko et al., 1999). Inflammatory effects were also using J774A.1 cells, demonstrated that both Cr(III)-picolinate noted by Toya et al. (1999) wherein a single instillation of rats and -nicotinate induced oxidative stress as measured by their with 10 or ≈20 mg Cr/kg (as Cr fume distillate containing effects on formation of reactive oxygen species, lipid peroxi- ≈3:1 Cr(III):Cr(VI) oxides) resulted in granuloma formation dation, and DNA fragmentation. Interestingly, while Lee et al. in the entire airways and increased presence of alveoli with pro- (2000) found a similar increased effect from Cr-picolinate on · − gressive fibrotic changes; repeated instillations aggravated the O2 formation in pig AM, other endpoints indicative of cell ac- histopathological outcomes. In a study to compare the role of tivation (such as increased glucose uptake and phagoctyosis of solubility in inflammatory effects of Cr(VI) agents, Cohen et al. bacteria) appeared to be dependent on the copresence of insulin. (1998) showed that exposure of rats for 2 or 4 weeks to 360 µg However, this insulin-dependent effect might be limited to the 3 Cr(VI)/m as soluble potassium chromate (K2CrO4) or insoluble picolinate complex since this study also showed that increases in barium chromate (BaCrO4) induced differing levels of PMN and all of these specific parameters were increased in the absence of monocyte infiltration into the lungs. While both agents caused the hormone when chromic chloride (CrCl3) was used instead. significant increases in total cell numbers recoverable in the What is interesting in Cr toxicity is the prevalence of oc- BAL from the exposed rats, the soluble form resulted in >30% cupational asthma, subtypes of which (early and late) may 48 COHEN have immunologic origins (see Arfsten et al., 1998). Early asthma TABLE 5 is mediated by antigen binding to IgE-bound mast cells Ambient levels and acceptable workplace levels for Cu and rapid mast cell degranulation and releae of mediators of a a a bronchoconstriction. Late asthma is dependent on proliferating Background Rural Urban T-lymphocytes secreting lymphokines that promote chemotaxis, Average air levels 0.029–12b, f 5–50b,e 20–200b,e bronchoconstriction, and mucous secretion, generally hours af- (ng Cu/m3)3–280b, f 3–5100b, f ter exposure. Both types of asthma have been reported in work- 17–500c ers exposed to dichromates, ammonium bichromate, chromic 13–2750d acid, chromite ore, chromate pigments, and welding fumes. In a some cases hypersensitivity to Cr was confirmed by diagnostic Regulations and guidelines patch testing, but not all (suggesting immunologic and nonim- Accepted levels OSHA NIOSH ACGIH 3 h munologic origins). Though likely related to dermal hypersensi- (mg Cu/m ) tivity associated with Cr exposure, the underlying mechanisms Cu metal (in dust) 0.1 0.1 0.2 of these pulmonary reactions remain unexplored. Similarly, the Cu metal (in mist) 1.0 1.0 1.0 mechanisms of Cr immunotoxicity, pulmonary or systemic, re- Cu metal (in fumes) 1.0 1.0 1.0 main unclear. While AM play a role in the reduction of Cr(VI) to the “less toxic” Cr(III) form, it remains to be seen whether the a ATSDR (2002). reductive events that occur in these cells may lead to cell death bUnited States. c and how/if this may contribute to immunotoxic outcomes like Canada. d decreased host resistance. Europe. eDavies and Bennet, 1985. f Schroeder et al., 1987. COPPER gEight-(8) hour time-weighted averages (TWA). Unlike some other metals discussed here, studies of the im- munotoxicity of copper (Cu) are complicated by the fact that Cu is essential to maintenance of immunocompetency. Deficiencies been established (Table 5). However, unlike with many of the of Cu, due to hereditary factors as occur in Menke’s (trichopo- other metals discussed in this review, permissible levels in many liodystrophy) and Wilson’s disease, or due to poor nutrition, are states have not been set substantively lower than the national known to give rise to compromised host resistance (Beach et al., recommendations. 1982; Lukasewycz and Prohaska, 1990). The major immune-based conditions reported to arise from Though Cu is released into the atmosphere from both natural inhaled inorganic Cu agents are metal-fume fever (“copper and anthropogenic sources, the concentrations of ambient Cu are fever”) (McCord, 1960; Cohen, 1974; Piscator, 1976; Nemery, most dependent upon proximity to major point sources. Based 1990; Borak et al., 2000) and pneumofibrosis (vineyard sprayers’ on the values shown in Table 5, the average daily intake by lung) (Pimentel and Marques, 1969; Villar, 1974). A few epi- inhalation for the general urban population has been estimated demiological studies have indicated that workers in copper to be from 0.1–4 µg/d, In the more extreme cases shown in the smelters have an increased incidence of lung cancer (Kuratsune Table (with levels in terms of µg/m3), this value increases to et al., 1974; Tokudome and Kuratsune, 1976; Ostiguy et al., >20 µg/d (ATSDR, 2002). 1995; Sorahan et al., 1995); although Cu binds with and affects A paucity of epidemiological studies reporting ill effects from the structure and integrity of DNA and RNA (Sagripanti et al., exposure to inorganic Cu agents might suggest that Cu is not 1991), a definitive linkage to cancer causation is still not at hand. particularly hazardous. However, Cu, in several environmental Deficiencies of Cu can give rise to altered immune cell num- media, is inhaled by animals and humans and instances of Cu bers and functions. These include reduced: T-lymphocyte (pri- + − intoxication that give rise to altered pulmonary immune cells marily CD4 ,CD8 -helper-T [TH] cell) numbers; B- and and functions do occur. As noted previously, the highest air T-lymphocyte responsiveness to mitogens; antibody formation; levels of Cu are generally in the vicinity of metallurgical pro- host resistance to infection; and, phagocyte microbicidal activity, cessing plants, iron and steel mills, and around coal-burning as well as increased acute and delayed inflammatory responses power plants. In these workplaces, Cu is most often found as (Newberne et al., 1968; Prohaska and Lukasewycz, 1981; Jones cuprous oxide (Cu2O) and cupric hydroxide (Cu(OH)2) (Peo- and Suttle, 1983; Lukasewycz and Prohaska, 1983; Vyas and ples et al., 1988). In the presence of ambient moisture either Chandra, 1983; Jones, 1984; Flynn, 1985; Lukasewycz et al., within the worksite or after release into the atmosphere, the 1985). Although the above ex vivo studies, for the most part, Cu2O is readily converted to cupric oxide (CuO) (Purves, 1977). utilized systemic immune cells, it is likely that lung immune The most recent National Occupational Exposure Study in the cells also display these alterations as a result of the deficiency. 1980s estimated that the number of workers exposed daily to While much attention has focused on the essential role of Cu in the 1980s was >500,000 (ATSDR, 2002). To help mini- Cu in proper immune function, immunomodulation from Cu mize risk of potential exposure to Cu, regulatory standards have toxicosis has also been examined. In studies of the clearance of PULMONARY IMMUNOTOXICOLOGY OF METALS 49 soluble cupric sulfate (CuSO4) and insoluble CuO from the lungs were increased 54–100% (compared to that in air-exposed con- of rats, it was shown that the half-time of CuO was >5 times that trols) and changes in mean survival time decreased from 4– of the sulfate (37 hours vs. 7.5 hours postinstillation) (Hirano 11 days (over a 14 day postinfection period). In mice repeatedly et al., 1990, 1993). Both CuSO4 and CuO induced strong lung exposed before infection, both endpoints were still significantly inflammatory responses (assessed using cytological, biochem- altered, but not to the same extent as that in mice that simul- ical, and elemental indices) that became predominant within taneously inhaled Cu and bacteria. Similar effects were also 12 hours of instillation and remained elevated for 3 days there- observed in mice instilled with CuSO4 and then challenged with after. As each agent induced similar effects in situ, even though S. pyogenes (Hatch et al., 1981). In this study, the Investiga- their clearance times strikingly differed, it was concluded that tors determined that the bactericidal activity of AM was im- CuO particles undergo rapid dissolution following deposition in pacted by the Cu ion, with in situ killing of bacteria decreasing the deep lung. in a dose-dependent manner. This latter effect was in keeping Proinflammatory effects of Cu may help explain the increased with previous observations that inhalation of CuSO4 reduced pulmonary fibrosis following host exposure to copper sulfide AM phagocytic/endocytic activity in situ in the absence of any (CuS)-bearing dusts or CuSO4-bearing Bordeaux mixtures used concurrent change in total cell numbers (Skornik and Brain, to treat crops (Lutsenko et al., 1997; Eckert and Jerochin, 1982). 1983). However, it must be noted that although somewhat similar ef- Several studies provide evidence that AM are a target of im- fects (i.e., strong proinflammatory responses, type II cell hyper- munotoxicity by inhaled Cu. After a single instillate of CuO, plasia, and increases in biochemical indices of fibrosis) were rat AM underwent hypertrophy and developed increased lev- also seen in the lungs of hosts exposed to Cu-gallium- or Cu- els of polymorphic nuclei with margination of the chromatin, indium-diselenide (routinely used in photovoltaic and semicon- crystalloid-like inclusions, concentric and parallel lamellar struc- ductor industries) (Morgan et al., 1995, 1997), neither of these tures, lattice formations, and degenerative membranous struc- novel agents induced histologic changes indicative of increased tures (Murthy et al., 1982). Exposure of AM was also seen to pulmonary interstitial fibrosis. cause decreased lysosomal permeability and levels of lysosomal Recent studies (that didn’t deal with fibrosis) have reported enzymes (without changes in enzyme activities), but increased several acute pulmonary and related immunologic effects (i.e., secretion of lysosomal enzymes from vesicles and lysosome la- acute alveolitis, interstitial inflammation, and AM hyperplasia) bilization (Ludwig and Chvapil, 1981). The AM recovered from 3 in mice instilled with 12.5–100 µg beryllium-copper (BeCu) al- rabbits exposed to 0.6 mg/m cupric chloride (CuCl2) 5 days/wk loy (Benson et al., 2000). Using comparative studies of Be alone, for 1 month had increases in cytoplasmic lamellated inclusions, these Authors were able to conclude that the observed effects lysosyme content, and surface blebs (Johansson et al., 1983; were attributable to the presence of the Cu. Proinflammatory Lundborg and Camner, 1984; Camner et al., 1985; Johansson effects were also noted in mice instilled with copper smelter and Camner, 1986). However, unlike the AM from mice exposed dust (delivering 2.5 or 8 µg Cu/mouse). In this study, exposed to CuSO4, the rabbit cells did not have changed phagocytic ac- hosts evidenced increased total protein, LDH, AM, and PMN in tivity, oxidative metabolism, or bactericidal function. It should their BAL during the first 1–7 days postexposure (Broeckaert be noted that the basis for these disparate results may not simply et al., 1999). Similarly, Prieditis and Adamson (2002) showed have been due to differences in host species or Cu compound that instillation of 4.8 µg CuSO4 into mice resulted in short-lived used but, rather, because the functional tests with the rabbit AM increased lung levels of AM, PMN, and total protein. A study were all performed ex vivo as opposed to in situ. Functionally, by Kennedy et al. (1998) may have provided a basis for many of AM recovered from mice 1 or 30 days postexposure with copper these observations as these Investigators noted that when particu- smelter dust (delivering 2.5 or 8 µg Cu/mouse) were severely late matter (PM) from Provo, Utah was instilled in rats, cytokine- inhibited in their ability to produce TNFα (Broeckaert et al., induced neutrophil chemoattractant (CINC)-dependent inflam- 1999). However, if AM were collected at 7 days postexposure, mation was induced. Parallel studies with human epithelial cell the dust seemed to have had a stimulatory effect. cultures indicated that the particles, and primarily their Cu com- Many of the in vitro studies performed to try to delineate ponents (assessed using CuSO4), induced IL-6 and -8 production the mechanisms by which Cu induces immunomodulation have and increased ICAM-1 adhesion molecule expression. Further- used Cu ions in complexes with serum proteins. This is logical more, these studies also showed that ceruloplasmin (CP) alone since ≈90% of all extrapulmonary Cu is bound to CP, associ- was capable of inducing an increase in formation/release of the ated with Cu-dependent enzymes (e.g., superoxide dismutase cytokines. [SOD], ferroxidase, cytochrome oxidase, and amine oxidase), Other effects of Cu on pulmonary immunocompetence have or complexed with free amino acids (i.e., histidine). Unlike sys- been documented. In mice that underwent single or multiple temic leukocytes, however, pulmonary immune cells are more 3-hour exposures to CuSO4 aerosols (over a broad range of likely to encounter “free” noncomplexed Cu (either as solubi- concentrations), resistance to challenge with S. zooepidemicus lized ions or particulates). Nevertheless, these in vitro studies was drastically reduced (Ehrlich et al., 1978; Ehrlich, 1980; do provide information useful for determining how inhaled Cu Drummond et al., 1986). In Cu-exposed mice, mortality rates induces pulmonary immunomodulation. 50 COHEN

In several in vitro studies, it has been demonstrated that TABLE 6 Cu, both as “free” (loosely associated) ions and in CP-bound Ambient levels and acceptable workplace levels for Mn forms, inhibited T-lymphocyte function more than that of a a a B-lymphocytes or monocytes. The depressed lymphocyte activ- Background Rural Urban ities (mitogen-induced T-lymphocyte responsiveness, and TH- Average air levels 1–3b 5–60b,c 33–110b,c directed B-lymphocyte stimulation and antibody synthesis) were (ng Mn/m3) 130–150b,d apparently related to a Cu-dependent enhanced formation of a,e hydrogen peroxide. An increase in peroxide formation, cou- Regulations and guidelines pled with a deficiency of peroxide-metabolizing enzymes in Accepted levels OSHA NIOSH ACGIH 3 f T-lymphocytes, caused extensive oxidative damage to these cells (mg Mn/m ) that could then lead to reduced functional capacities during cell- Mn metal (in fume) 5.0 N/A 1.0 mediated or humoral immune responses (Lipsky and Ziff, 1980; Mn metal (in dust) 0.2 N/A 5.0 Lipsky, 1981, 1984; Anderson and Tomasi, 1984). However, be- Mn–inorganic form 0.2 N/A 5.0 cause B-lymphocytes do contain necessary enzymes that could Mn tetroxide 1.0 N/A 1.0 minimize the impact of any Cu-initiated excess extracellular CMT/MMT 0.1/NA N/A 0.1/0.2 peroxide, alternative mechanisms were needed to explain the re- duced mitogenic responses of these cells. It was determined that a ATSDR (2000b). Cu complexes directly oxidized essential surface thiol groups on bUnited States. c lymphocytes, and that B-lymphocytes were far more sensitive Low-end values shown are those from most recent studies, in- to the effect than were T-lymphocytes (Duncan and Lawrence, dicative of a downward trend over the past 50 years. d Source-dominated site values. 1988). eMany states set values for each agent (in 8- or 24-hour periods) In vitro studies have also been performed to determine the at from several µg–tens of µg/m3. mechanisms by which Cu-induced modulation of AM functions f Eight-(8) hour time-weighted averages (TWA). arise. Some studies have shown that Cu treatment influenced directional migration by AM (as well as by PMN), and altered ATSDR, 2000c). However, controversy over the environmental prostaglandin (i.e., PGE ) and thromboxane (TBX ) production 2 2 and health effects from use of these agents (see Davis, 1999; (Lewis, 1982; Elliott et al., 1987). It was shown that Cu could Davis et al., 1998, 1999; Gerber et al., 2002) has caused level of affect the ability of AM to act as antigen-presenting cells (Smith their usage to vary of late. Based on the values in Table 6, av- and Lawrence, 1988). However, it is still not clear as to which erage daily intake by inhalation for urban populations has been phase of the antigen presentation process (e.g., antigen capture, estimated to be 4–6 µg Mn/d (compared to <2 µg/d in areas processing, or presentation in the context of MHC proteins) was without Mn-sources). primarily altered by Cu treatment. Agents that contain Mn are widely employed in alloy steel manufacture, dry cell production, fertilizer manufacture, pro- MANGANESE duction of glass and glazes, and as: oxidants in the chemical While manganese (Mn) is widely distributed in nature, it nor- industry, catalysts, and wood-impregnating agents (Stokinger, mally occurs only in trace amounts in most biologic materials. 1981). Although guidelines for workplace airborne Mn exist, It is known that Mn is an essential element for all organisms; in occupational levels often are on the order of 1–≥100 µg Mn/m3. general, it is believed that Mn most often acts as a dissociable Recent studies in Mn alloy plants reported average ambient in- co-factor for several enzymes, including one of great importance halable Mn levels of 250–300 µg Mn/m3; of this, only ≈10–11% in the lungs, SOD. Still, numerous reports describe toxicologic (i.e., 28–35 µg Mn/m3) was respirable (Thomassen et al., 2001; effects from acute or chronic exposure to Mn agents, with the Ellingsen et al., 2003). In some facilities, levels of ambient Mn most common clinical presentations being manganic pneumoni- in the range of several mg Mn/m3 have routinely been mea- tis and croupous pneumonia (Flinn et al., 1940; Davies, 1946; sured (ATSDR, 2000c). With respect to the controversy regard- NAS, 1973; Smyth et al., 1973; Saric et al., 1977; Benko and ing MMT, it was shown that garage workers and taxi drivers were Crikt, 1984; Saric, 1992). routinely exposed to levels 10 times that of blue-collar workers Though Mn is released into the atmosphere from both natural (i.e., ≈400 vs. ≈40 ng Mn/m3; Loranger and Zayed, 1995; Zayed and anthropogenic sources, ambient Mn levels are again mostly et al., 1996). The most recent National Occupational Exposure dependent upon proximity to major point sources (such as min- Study conducted in the 1980s estimated that the number of work- ing industries and alloy/steel production facilities). Increased ers exposed daily to Mn was >625,000 (ATSDR,2000c). To help use in the recent past of methylcyclopentadienyl Mn tricarbonyl minimize the risk of potential exposure to Mn, regulatory stan- (MMT) and its demethylated form (CMT) as antiknock addi- dards have been established (Table 6). Once again, permissible tives and combustion improvers for fuels has meant that levels levels in many states have been set substantively lower. of Mn in the air even in nonurban settings have become in- As with the other metals discussed in this review, the effect of creasingly related to traffic volume (Loranger and Zayed, 1997; solubility on clearance of inhaled Mn-bearing particles is critical PULMONARY IMMUNOTOXICOLOGY OF METALS 51 to the extent of pulmonary immunomodulation that occurs. In et al., 1996). In all 3 species, Clara cell necrosis was evident studies to compare soluble manganous chloride (MnCl2) and in- within 1 day of IP MMT exposure. In the mouse and hamster, soluble manganomanganic oxide (Mn3O4), the rate of clearance Clara cell loss was nearly total in the teminal bronchioles and of the instilled soluble form from lungs of rats was 4 times that murine basement membranes became greatly denuded and par- of the instilled insoluble agent over the first 7 days postexpo- tially covered with flattened abnormal-looking ciliated epithe- sure (Drown et al., 1986). However, both agents were cleared in lium. Clara cell changes in rats were the least severe and usu- a biphasic manner and posttranslocation dispositions of Mn to ally consisted of some flattening and cytoplasmic vacuolation. distal organs were similar. In a study by Vitarella et al. (2000), Except for the parenchymal damage in rats, each prior-noted a comparison of Mn agent clearance in rats instilled once with pathology was resolved by the end of a 3-week postexposure 40, 80, or 160 µg Mn/kg as Mn sulfate (MnSO4), Mn phosphate period. CMT exposure resulted primarily in localized damage (Mn3[PO4]2), or Mn3O4 (3 major MMT combustion byprod- to alveolar regions of the lung and only minor bronchiolar dam- ucts) indicated that rates were equivalent (all had half-times of age. While the potential for damage to lung cells should be of <0.5 days) at each dosage. These Authors suggest that one rea- concern, it must be noted that atmospheric MMT/CMT have son their results differed from those by Drown et al. might be very short half-lives due to photochemical decomposition (Ter due to the differences in diameters of the instilled particles in Haar et al., 1975). As such, it is their combustion byproducts each study. Initially rapid clearance rates were also noted in mice (primarily Mn3O4, MnO2, and manganosite (MnO) [Ter Haar exposed to Mn3O4 (Adkins et al., 1980), and mice (Maigetter et al., 1975; Loranger and Zayed, 1997]) that potentially present et al., 1976) or guinea pigs (Bergstrom, 1977) inhaling high the major risks to pulmonary (immuno)compentence. (i.e., >20 mg Mn/m3) levels of insoluble manganese dioxide Several studies have examined effects from host inhalation (MnO2). Interexperimental variations in length of exposure, test and/or exposure to Mn on the ability of the lungs to resist and levels, and particle diameter have made direct comparison (with clear bacterial/viral challenges. In guinea pigs exposed to 22 mg 3 regards to biologic half-times) between Mn agents difficult to MnO2/m for 24 hours and then immediately infected by 10 min- achieve. However, among studies that examined only the clear- utes exposure to aerosols of Enterobacter cloacae, hosts exposed ance of MnO2, half-time values ranged from <1 day in the to Mn initially had significantly lower burdens of the organism mouse, to ≈2 days in the guinea pig, to 38 days in dogs, to than air-exposed counterparts. However, after 2 hours and over 65 days in humans (Morrow et al., 1964, 1967; Maigetter et al., the next 22 hours, burdens of E. cloacae remained significantly 1976; Bergstrom, 1977). greater in the lungs of the Mn-treated guinea pigs (Bergstrom, While several studies have directly examined effects of in- 1977). In mice that inhaled one of several levels of Mn3O4 haled Mn agents on immune parameters in the lungs, most have for 2 hours prior to a 20-minute exposure to a S. pyogenes- focused on histological changes or inflammatory responses. The containing aerosol, rates of mortaility increased in direct rela- 3 lungs of monkeys that inhaled 0.7 or 3.0 mg Mn/m (as MnO2) tion to the amounts of Mn deposited in their lungs (Adkins et al., daily for 10 months evidenced hyperplasia of interstitial lym- 1980c). In the mice, there was delayed clearance and continuous phoidal tissues, overdeposition of dusts in the interstitium, bron- enhanced growth of the orgnaism over a 4-day period postinfec- chiolar retention of exudate, pulmonary emphysema, and aterec- tion. In comparison, burdens of S. pyogenes in the air-exposed tasis (Suzuki et al., 1978). Similarly, rats exposed to 0.3 mg infected hosts peaked within 2 days of infection and decreased 3 MnO2/m for 6 months displayed perivascular and peribronchial thereafter. Similarly, in mice exposed 3 hours to MnO2 and then sclerosis of the lung (reviewed in Ulrich et al., 1979). Using challenged 1–5 hours postexposure with airborne K. pneumo- mice, it was shown that the inflammatory effects of MnO2 in niae, host mortality was increased (and survival time decreased) this species (and likely, as well, in all other mammals) were a compared to that in air counterparts (Maigetter et al., 1976). function of both the total surface area and gravimetric amount It is of note that while increasing the number of daily expo- of MnO2 particles in the atmosphere (Lison et al., 1997). sures to MnO2 did not significantly enhance the observed ef- Studies that used soluble MnCl2 or volatile MMT helped fects on host resistance to K. pneumoniae, increasing the period demonstrate the role of solubility upon intrapulmonary effects between MnO2 exposure and initiation of infection did. When from exposure to Mn-bearing agents. Inhalation by rabbits of hosts were already bearing a lung infection (i.e., mice infected 3 1–4 mg Mn/m (as MnCl2) for 5 days/week for 4–6 weeks with influenze A/PR/8/34 virus) for 24 or 48 hours prior to ex- failed to induce any gross histopathologic changes in the lungs or posure to MnO2, a single 3-hour exposure after either period any inflammatory response as had been seen with insoluble Mn was sufficient to reduce host survival against the virus. It was agents (Camner et al., 1985). With MMT, a single intraperitoneal also seen that the effect of MnO2 was greater in animals that (IP) treatment of rats, mice, or hamsters (at respective LC50s) re- already bore greater viral titres. Oddly, if already infected mice sulted in substantial interstitial pneumonitis characterized by in- underwent further daily MnO2 exposures, host mortality levels terstitial thickening, PMN infiltration, and increased numbers of decreased to levels almost equivalent to those in air-exposed AM (Hakkinen and Haschek, 1982). Similar acute pneumotoxic control mice. effects have been seen in rats when MMT or CMT was adminis- At the level of lung immune cell function, effects of Mn on tered subcutaneously (Hakkinen and Haschek, 1982; Blanchard AM have been the best studied. In rabbits exposed 6 hours/day 52 COHEN

3 for 4–6 months to 1–4 mg Mn (as MnCl2)/m , although AM TABLE 7 numbers and viabilities remained unaffected (Camner et al., Ambient levels and acceptable workplace levels for Ni 1985), they had Mn level-related increases in diameter. Ox- idative metabolism (NBT reduction in resting and stimulated Rural/ cells) and phagocytic activity of the AM were similarly unim- Background suburban Urban 3 paired. In mice acutely exposed (2 hours; 532 or 897 µg Mn/m ) Average air levels 0.14–0.45a,d 0.6–78a,b 1–328a,b , , to Mn3O4, AM numbers, viabilities, and phagocytic activities (ng Ni/m3)6–17b c 120—170b c were again unaffected; however, levels of ATP and cellular acid ≈1.0a,d 1–20a,d phosphatase activity were significantly increased (Adkins et al., a,e 1980b). These in vivo results contrast with those obtained in Regulations and guidelines in vitro studies wherein treatment of cultured rabbit AM with Accepted levels OSHA NIOSH ACGIH (mg Ni/m3) f MnCl2 resulted in decreased AM viablity and number, increased cell lysis (Waters et al., 1975), and reduced phagocytic activities Ni metal 1.0 0.015 1.0 (0.05)g (Graham et al., 1975). Ni in insoluble form 1.0 0.015 0.1 Far less is known about effects from insoluble Mn agents on Ni in soluble salts 1.0 0.015 0.1 AM or other immune cells of the lungs. Lundborg et al. (1984) (0.005–0.01)g demonstrated that freshly harvested rabbit AM were readily able Ni subsulfide N/A 0.015 0.05 to phagocytose 0.1–0.5 µm MnO2 particles and that ingested particles were subsequently dissolved in a pH-dependent process a ATSDR (1997). b within phagosomes. The study also showed that the processes United States. c were time-dependent and that the overall percentage of Mn dis- Costa, 2000. d Canada. solved was highly dependent on the amount of MnO added to 2 eMany states set values for each agent (in 8- or -24 hour periods) at each culture and saturable. Interestingly, when rabbit AM were from 1–several µg/m3. cultured for 48–72 hours prior to exposure to MnO2, the capacity f Eight-(8) hour time-weighted averages (TWA). to dissolve the particles was near-completely ablated. It has also gValues in parentheses represent intended change in standard. been reported that incubation of freshly harvested guinea pig AM with MnO2 resulted in increased release to the surround- ings of a short-lived chemotactic/PMN-recruiting factor within a few hours of particle uptake initiation (Snella, 1985). These Ni-Cd batteries, and as a catalyst and pigment (Steenland et al., results are important in that they provide a partial mechanistic 1996). In these types of occupational settings, both inhalation basis for the repeatedly observed time-limited increased influx and dermal contact present the major routes for human expo- of imflammatory cells to the lungs after inhalation of this agent sure. The most recent National Occupational Exposure Study (Bergstrom, 1977; Lison et al., 1997). in the 1980s estimated that the numbers of workers potentially exposed to Ni compounds exceeded 725,000 (ATSDR, 1997). To help minimize the risk to workers potentially exposed to Ni NICKEL agents, regulatory standards have been established (Table 7). Nickel is a commonly-used metal that is readily found in Nonetheless, while the carcinogenic effects of Ni (primarily of two major ores: nickel-iron sulfides and the oxide or silicate lung and nasal cavity) are of predominant concern, other ef- laterites (Smialowicz, 1998). Nickel can occur in a variety of fects on the lung have been reported. Of these, occupational valence states, but Ni2+ is the most common and toxicologi- asthma as a result of irritation or allergic response is an im- cally important. The presence of ambient Ni is normal as it is portant adverse event related to Ni exposure (Snow and Costa, released in natural processes (i.e., volcanic eruptions and wind- 1992; Mastromatteo, 1994; Smialowicz, 1998). blown dust). However, Ni is also placed in the atmosphere as The effects of Ni on the humoral immune system have been a result of fossil fuel combustion, Ni mining and refining, al- recently reviewed (Smialowicz, 1998). Unfortunately, again loy production, and waste incineration (Mastromatteo, 1994; most studies examined effects following exposures via routes ATSDR, 1997; Smialowicz, 1998). Based on the values reported other than inhalation or instillation. In general, exposure to Ni in Table 7, it has been estimated that the general population in- appears to suppress 1◦ humoral immune responses in animal hales an average of 0.1–1.0 mg Ni/d. In individuals who smoke, models. Acute inhalation exposure of mice to nickel chloride 3 daily exposures to Ni is often higher, as tobacco has been shown (NiCl2; 250 µg/m ) suppressed the splenic humoral response to to contain levels as high as 1–3 mg Ni/cigarette (ATSDR, 1987; T-dependentSRBC (Graham et al., 1978). Similarly, rats exposed Mastromatteo, 1994). to nickel oxide (NiO) particles suppressed the serum anti-SRBC The principal current uses of Ni and Ni salts are in the response, although exposure was for 4 months (Spiegelberg production of stainless steel, nonferrous alloys, electroplating, et al., 1984). In rats provided 0.02, 0.05, or 0.10% NiSO4 in high temperature and electrical resistance alloys, cast irons, and their water for 13 weeks, an analyses of spleen cells 1 day PULMONARY IMMUNOTOXICOLOGY OF METALS 53 postexposure indicated dose-dependent increases in the total Many studies have examined inflammatory responses induced numbers of B-lymphocytes and CD4+ T-lymphocytes at the low by Ni. Dunnick et al. (1989) noted a general inflammatory re- and middle levels, but overt toxicity (and concurrent decrements sponse along with AM hyperplasia in the lungs of mice and rats in cell levels) at the high dose (Obone et al., 1999). However, exposed 6 hours/day, 5 days/week for 13 weeks to nickel subsul- + in these rats, levels of CD8 T-lymphocytes were uniformly in- fide (Ni3S2), NiO, or Ni(CO)4. Exposure of rats for 4 months to creased (albeit maximal effect was at 0.05% level) and CD4/CD8 25 µg NiO/m3 resulted in fewer AM in BAL fluid (Spiegelberg 3 ratios lowered. Benko et al. (1983) examined the concentration et al., 1984). Rats exposed to 0.6 or 2.5 mg Ni3S2/m for 6 hours of serum IgM, IgG, and IgA in workers exposed to Ni and found per day for up to 22 days displayed significant increases in to- that all 3 Igs were significantly decreased compared to those lev- tal lavageable cells, β-glucuronidase, LDH, and total protein in els in unexposed controls. Despite the ability to demonstrate Ni- their BAL after only 2 days of exposure. Interestingly, rats re- induced humoral immunosuppression in animal models, human ceiving the higher dose had increased numbers of PMN in their data is still somewhat lacking. Though not common, cases of lungs after just 1 exposure (and thereafter) while those at the occupational asthma have been reported in Ni-sensitive workers lower level required 4 days of exposures (Benson et al., 1995b). and it appears that at least some of these are Type I (immedi- Furthermore, only the lower level of Ni3S2 caused continual el- ate) hypersensitivity reactions (Malo et al., 1982; Nieboer et al., evations in the numbers of AM in the lungs while the higher 1984). Ni-specific IgE antibodies have been detected in work- dose caused “spikings” after 2 or 12 days of exposures. In rats ers exposed to Ni along with positive results in other tests for inhaling 2% NiCl2 atmospheres for 5 hours/day for 5 days, the Ni allergy. In one case report, antibodies to Ni-albumin were numbers of lavageable cells increased over the ongoing exposure found in the serum, and subsequent studies indicated that the Ni period with values returning to controls during the subsequent was bound to the Cu binding site on albumin (Malo et al., 1985). 3 days postexposure (Ishihara et al., 2002). During the entire With respect to cell-mediated immunity (see Smialowicz, 1998), exposure and recovery phases, AM levels were continuosly de- in general, occupational and nonoccupational exposure to Ni re- pressed and PMN levels increased (and peaked) by the fourth day sulted in development of a Type IV delayed hypersensitivity of the regimen. Similar inflammatory effects from NiSO4 were responses (T-lymphocyte-mediated). Nickel has been described observed in mice exposed 24 hour to 108 µg Ni/m3(McDowell as a strong sensitizer in humans (contact sensitivity), although et al., 2003). However, in this case, while levels of PMN lev- significant animal data has been difficult to generate. els remained elevated for up to 3 days postexposure, AM levels Animals exposed by inhalation or instillation to Ni exhibit seemed unaffected. changes in their ability to defend against pathogenic infection. With regard to the potential of various Ni agents to affect Generally, Ni exposure appears to suppress AM activity, and data release of inflammatory cytokines/chemokines, the studies of from Sunderman et al. (1989) suggest that AM are a cellular tar- Ishihara et al. (2002) also reported significant increases in the get for Ni-induced toxicity. In their studies, parenteral exposure BAL levels of CINC in exposed hosts, Unfortunately, the in- to NiCl2 caused activation of AM followed within 48 hours by duction of these types of mediators might be agent specific, as suppressed phagocytosis and enhanced lipid peroxidation. Sim- rats instilled with 125 µg ultrafine Ni powder were unable to ilar events occur following pulmonary exposures, with rabbits manifest any change in BAL levels of macrophage inflamma- exposed to aerosols of Ni dust for 1–6 months demonstrating tory protein-2 (MIP-2) (Dick et al., 2003). Oddly, in vitro, the gross and histopathological changes in the lung, including an ultrafine Ni did cause significant release of TNFα by AM iso- activated appearance of AM with reduced phagocytic capacities lated from control rats. The possibility of compound-specific (Johansson and Camner, 1980; Johansson et al., 1983; Camner effects are further borne out by the studies of McDowell et al. et al., 1984). In rabbits exposed 6 hours/day, 5 days/wk for 4 that indicated that a 24-hour exposure of mice to NiSO4 caused 3 months to 600 µg Ni/m (as NiCl2), the percentage of AM with significant increases in lung mRNA levels of MIP-2, interferon surfactant-like inclusion bodies increased 40-fold and AM with (IFN)γ , monocyte chemotactic protein (MCP)-1, IL-6, IL-1β, surface smoothing 8-fold (Johansson et al., 1989, 1992). These and TNFα that persisted for >96 hours postexposure (for some, results appear to have been mimicked in rats exposed once to up to 2 weeks). Of note in this study, release of the proinflamma- 0.15–2.5 mg ultrafine Ni/m3. In these rats, there were increases in tory agents/chemotaxins appeared dependent on the enhanced the levels of “foamy” AM as well as degenerated AM within the presence of NO in the lungs even though inducible nitric oxide host alveoli over a 7–28-day postexposure period (Serita et al., synthase (iNOS) activity and mRNA levels were not affected by 1999). Decreased AM phagocytosis was observed when mice Ni exposure (though that of endothelial [e]NOS was enhanced). were exposed 6 hours/day, 5 days/week for ≈9 weeks to aerosols The finding regarding TNFα mRNA is puzzling in a single in- 3 3 of 0.47–7.9 mg Ni/m (as NiO) or 0.45–1.8 mg Ni/m (as Ni3S2) stillate of 1–8 µmol NiSO4 into rats was shown to cause de- (Haley et al., 1990). However, in the same study, effects from creases in BAL levels of TNFα for up to 7 days postexposure 3 0.027–0.45 mg Ni/m (as NiSO4) were questionable and incon- (Goutet et al., 2000). It may be the repetitive exposure to Ni sistent. Last, AM from rabbits exposed 1 month to NiCl2 had ions over the 24-hour period (as opposed to a “one-shot” reg- suppressed phagocytic abilities and decreased lysozyme levels imen) underlies the differing observations among these cited (Wiernik et al., 1983; Lundborg and Camner, 1984). studies. 54 COHEN

Benson et al. (1989) reported similar results regarding in- 65 days (Haley et al., 1990). In contrast, mice exposed for ≈9 3 flammatory effects of Ni. However, by comparing equivalent weeks to up to 1.8 mg Ni/m (as Ni3S2) displayed dose-trend levels of effect in the context of minimal dose required, these decreases in these activities. Unfortunately, data dealing specif- Investigators were able to provide a ranking of toxic potentials of ically with lung NK function were not presented in any of these the three most commonly-tested agents, i.e., NiSO4 > Ni3S2∼ studies. An evaluation of lung NK activity in monkeys instilled NiO. Interestingly, when the Authors exposed mice and rats for with Ni3S2 indicated that the exposure resulted in enhanced ac- 2–6 months to NiSO4 or NiO (at levels comparable to those tivity of these cell types (Haley et al., 1987). In contrast, inhala- in their 1989 study), it was noted that persistent states of AM tion of Ni by mice prior to challenge with cytomegalovirus did hyperplasia became evident (along with chronic alveolitis) in not alter either NK activity or host resistance to the virus (Daniels rats exposed to either agent; however, only NiO induced similar et al., 1987). Goutet et al. (2000) recently demonstrated that a changes in mice (Benson et al., 1995a). single instillate of 2–8 µmol NiSO4 into rats caused siginificant That species-dependent differences in pulmonary inflamma- decrements in lung NK activities, and that the effect lasted for tory responses to Ni existed was not unexpected. What is of up to 7 days postexposure. In this study, it was noted that the greater importance have been recent elegant studies using sev- point of maximal NK suppression (on day 2 postexposure) was eral strains of mice that have shown that there are also signifi- concurrent with that of the maximal percentage of PMN and cant strain-dependent variations in lung responsivity to Ni agents eosinophils (and minima of lymphocytes) being present in the (i.e., to NiSO4; Prows et al., 2000). At this time, the basis for exposed rats’ lungs. these variations is still unknown. In vitro Ni exposure studies have confirmed many obser- VANADIUM vations made in vivo. Rabbit and rat AM exposed to Ni ex- Vanadium (V) is a ubiquitous trace metal in the environ- hibited both reduced phagocytic ability and metabolic capacity ment (reviewed in Cohen, 1998). Since clays/shales can contain (Graham et al., 1975; Adkins et al., 1979; Castranova et al., >300 ppm V,coals upwards of 1% V (by weight), and petroleum 1980b). In addition, Lundborg et al. (1987) showed that in vitro oils 100–1,400 ppm V, combustion of fossil fuels is the most exposure of rabbit AM to NiCl2 produced a similar dose-related identifiable nonoccupational sources for deliving V-bearing par- decrease in lysozyme activity, confirming a direct effect of Ni ticles into the air. Representative air levels of V for several rural ions on macrophages. In vitro suppression by NiCl2 of rabbit AM and urban sites are presented in Table 8 (ATSDR, 1992). Values · − stimulus-induced O2 production has also been noted (Geertz for ambient V levels in some highly polluted cities, i.e., Mex- et al., 1994) Finally, 1 in vitro study compared the effect of 6 NiO ico City, though not listed here, can be found in publications by compounds on AM from beagle dogs, mice, and rats (Benson Barcelaux (1999), Fortoul et al. (2002), and the World Health et al., 1988b). The study concluded that there was species sensi- Organization (2001). tivity of AM to the effects of Ni with the dog being most sensitive It is important to note that in all cases, there is a seasonal- and the rat and mouse being nearly equal. This species sensitiv- ity to the values for ambient V - winter urban V levels can be ity appeared to correlate with alterations in phagocytic function, with the dog showing greatest inhibition of activity. TABLE 8 This apparent inhibition of AM activity in the lung appears Ambient levels and acceptable workplace levels for V to be at least partially responsible for changes in host resis- Backgrounda Rurala Urbana tance in animals exposed to Ni. For example, mice exposed b b 2 hours to NiCl2 or NiSO4 and then subsequently challenged Average air levels 0.001–0 002 1–40 3–22 with an aerosol of S. pyogenes displayed decreased resistance. (ng V/m3) 0.21–1.9c 150–1400e This increase in susceptibility to infection in these hosts was 0.02–0.80d correlated with both decreased pathogen clearance and AM , Regulations and guidelinesa f phagocytic ability. Similarly, hamsters instilled with NiO had an Accepted levels OSHA NIOSH ACGIH increased mortality to subsequent challenge with influenza virus (mg V/m3)g (Port et al., 1975). NK cells are also part of the immunosurveillance team, scout- V pentoxide (dust) 0.05 N/A 0.05 ing the body primarily for transformed or virally-infected cells. V pentoxide (fume) 0.05 N/A 0.05

Parenteral exposure to NiCl2 was shown to inhibit the abil- a ity of mice to clear syngeneic melanoma cells from the lung ATSDR (1992). bUnited States. (Smialowicz et al., 1984, 1985, 1987). Interestingly, while con- cNorthwest Canada. sistent suppression of NK function was seen following parenteral d Eastern Pacific. Ni exposure, pulmonary exposure has yielded variable results. eNortheastern United States. No effects on splenic NK function or host resistance have been f Many states set values for V (in 8- or -24 hour periods) at 1 shown in mice exposed to either Ni3S2 or NiSO4 for 12 days µg/m3. g (Benson et al., 1987, 1988a) or mice exposed to NiSO4 for Eight-(8) hour time-weighted averages (TWA). PULMONARY IMMUNOTOXICOLOGY OF METALS 55

6-fold higher than in summer due to the increased combustion gitis, (‘Boilermakers’) bronchitis, and pneumonia (Lees, 1980; of V-bearing oils, shales, and coals for heat and electricity. The Musk and Tees, 1982; Levy et al., 1984; Pistelli et al., 1991; majority of V in air is in its pentavalent form (V[V]), and of Kielkowski and Rees, 1997; Irsigler et al., 1999; Woodin et al., these species the most common form is its pentoxide (V2O5), 2000), metal fume fever-like syndrome (Vandenplaset al., 2002), with ferrovanadium, vanadium carbide, and various vanadates as well as increased localized fibrotic foci (Kivuoloto et al., − 3− (VO3 and VO4 ) in lesser amounts. Based on the values shown 1979; Kivuoloto, 1980) and lung cancers (arising from non-V in Table 8 (the level actually used was 50 ng V/m3), the average sources; Stocks, 1960; Hickey et al., 1967). Cytologic studies daily intake by inhalation for the general urban population has with cells obtained from exposed workers noted disturbances been estimated to ≈1 µg V/day. in the number and cellularityof PMN and in plasma cell num- In occupational settings, while there are several potential ber/immunoglobulin production (Kivuoloto et al., 1979, 1980, routes of exposure to V, inhalation of dusts of V compounds 1981). Due to this cumulative evidence for V exposure-related or V-contaminated dusts is the most important Jobs with a high increases in the risk to worker health, acceptable limits (0.14– risk for exposure to V include mining and milling of V-bearing 50 µg V/m3 per 8–24-hour period) for workplace V-bearing ores, oil-fired boiler cleaning, and the production of vanadium dusts or fumes were established (Table 8). metal, oxides, and catalysts. In some of these environments, Changes in pulmonary immune function induced by V are ambient V levels have been noted to sometimes exceed 30 mg reproducible in a variety of animal models. Subchronic and/or V/m3, a value that approximates the established value for im- acute exposure of various rodent hosts to V[V] induced: de- mediate danger to life or health (i.e., 70 mg V/m3) (NIOSH, creased AM phagocytosis and lysosomal enzyme activity and 1985; WHO, 2001). The most recent National Occupational release (Waters et al., 1974; Fisher et al., 1978; Labedzka et al., Exposure Study (NOES) in the 1980s estimated that the total 1989; Cohen et al., 1997a); altered lung immune cell population numbers of workers potentially exposed to V compounds was numbers and profiles (Knecht et al., 1985, 1992; Cohen et al., only ≈5,000 (ATSDR, 1992). In comparison to the other metals 1996b; Toya et al., 2001); modified mast cell histamine release discussed in this review, this seems to most likely be an un- (Al Laith and Pearce, 1989); reduced cytokine (e.g., IL-6, TNFα, derestimation. Regardless of the NOES value, regulatory stan- and IFNγ ) and both bactericidal and tumoricidal factor produc- dards have been established (Table 8) to help minimize the risk tion in situ and ex vivo (Cohen et al., 1996b, 1997a); disturbed of potential worker exposure to V. As with most of the met- macrophage calcium (Ca2+) ion balance (Cohen et al., 1996b; als covered here, permissible levels in many states have been Ishiguro et al., 2000) and MHC Class II antigen expression in- set substantively lower, i.e., at fractions of a µg/m3 (ATSDR, duced by IFNγ (Cohen et al., 1996b); increased in situ (but not in 1992). vitro) AM expression and/or production of MIP-2 and KC CXC Once inhaled, V is rapidly transported into the systemic circu- chemokine mRNA with subsequent PMN recruitment during the lation. Initial clearance, as either insoluble V2O5 or soluble vana- inflammatory response (Pierce et al., 1996); and airway fibrosis dates/vanadyl (VO2+) ions, is fairly rapid, with ≈40% cleared (Bonner et al., 2000, 2002). This latter study also reported a sim- in 1 hour (Conklin et al., 1982; Sharma et al., 1987). However, ilar effect when tetravalent vanadyl sulfate (VOSO4) was used, after 24 hours, the 2 forms diverge in ability to be cleared, with suggesting that some aspects of the pulmonary immunotoxicity V2O5 persisting (Edel and Sabbioni, 1988). Thus, absorption of of V may not be valence-dependent. V compounds (50–85% of an inhaled dose) vary as a function Several studies implicate the presence of V as a significant of solubility; total V clearance is never achieved and commonly factor in the pulmonary immunomodulation induced after in- 1–3% of an original dose can persist for extended periods (i.e., halation or instillation of urban PM or residual oil fly ash (ROFA) months →years; Oberg et al., 1978; Rhoads and Sanders, 1985; (Schiff and Graham, 1984; Pritchard et al., 1996; Dreher et al., Paschoa et al., 1987). Though inhalation is the primary means of 1997; Gavett et al., 1997; Kodavanti et al., 1998; Saldiva et al., delivery of V into the lungs, exposure by other routes also gives 2002). Many effects, including: intense inflammation, rise to increased lung V burden and subsequent toxic manifes- eosinophilia, neutrophilic alveolitis; changes in lung compliance tations (Hopkins and Tilton, 1966; Kacew et al., 1982). and/or resistance to acetylcholine; and, modified host resistance Pentavalent vanadates and oxides have long been known to al- to lung infection were found to correlate with the V levels in the ter pulmonary immunity in exposed hosts (reviewed in Zelikoff particles and were reproduced by exposures of parallel sets of and Cohen, 1995; Cohen, 1998, 2000). Workers exposed to air- animals to soluble or insoluble V at amounts equivalent to that borne V display an increased occurrence of prolonged cough- of the V in the parent particles. Through in vitro studies, it has ing spells, tuberculosis, and general respiratory tract irritation; been shown that the V in the ROFA/PM likely undermines pul- postmortems indicated extensive lung damage with the primary monary immunocompetency, in part, by inducing dysregulation cause of death being bacterial infection-induced respiratory fail- of cytokine and/or chemokine production by local immune and ure. Epidemiological studies of workers have shown that acute epithelial cells (Schiff and Graham, 1984; Carter et al., 1997; exposure to high (or chronic exposure to moderate) levels of Dye et al., 1999). V-bearing dusts or fumes resulted in a higher incidence of a va- Studies using nonpulmonary exposure regimens have pro- riety of pulmonary diseases, including: asthma, rhinitis, pharyn- vided information for determining mechanisms that underly 56 COHEN increased host susceptibility to lung infection following V in- and subsequent activation of cytokine DNA response elements halation. A decreased resistance to, and increased mortaility (Igarishi et al., 1993) that, in turn, lead to down-regulation of from, a Listeria monocytogenes infection in mice that under- cytokine receptor expression and function. This is exemplified went acute/subchronic IP ammonium metavanadate (NH4VO3) in a study in which activation of protein kinases A and C, an exposure suggested that cell-mediated immuity was primarily event that can result in down-regulated IFNγ R expression, was affected (Cohen et al., 1989). Peritoneal macrophages (PEM) in seen in PEM harvested from V-treated mice and in naive cells the mice had decreased capacities to phagocytize opsonized Lis- exposed in vitro (Vaddi and Wei, 1996). teria and to kill even the few organisms ingested; these defects It is possible that the effects of V on receptor expression · − were attributed to V-induced disturbances in O2 formation, glu- and/or functionality might be a result of effects on various pro- tathione redox cycle activity, and hexose-monophosphate shunt cesses involved in cytokine-receptor complex handling. Agents activation (Cohen and Wei, 1988). While effects on pathways (like V) able to disrupt: endocytic delivery of surface receptor- critical to maintaining PEM energy levels alone might underly ligand complexes to lysosomes; subsequent complex dissocia- these changes in cell function and host resistance, other studies tion; receptor recycling, and de novo receptor synthesis, can di- suggested that the decreased phagocytic activity and intracellu- minish cytokine-induced responses by macrophages. In macro- lar killing were related to reduced surface opsonin receptor ex- phages and other cell types, V has been shown to: disrupt micro- pression/binding activity and lysosomal enzyme release and ac- tubule or microfilament structural integrity (Wang and Choppin, tivity (Cohen et al., 1986; Vaddiand Wei, 1991a, 1991b). Studies 1981; Bennett et al., 1993; Ramirez et al., 1997); induce altered with V-treatedmurine WEHI-3 macrophages also noted that pro- local pH due to V polyanion formation (Rehder, 1995); modify duction/release of monokines essential to anti-listeric responses lysosomal enzyme release and activity (Vaddi and Wei, 1991b); were diminished in conjunction with increases in the sponta- alter secretory vesicle fusion to lysosomes (Goren et al., 1984), neous formation and release of potentially immunoinhibitory and disrupt cell protein metabolism at the levels of both synthe- PGE2 (Cohen et al., 1993). sis and catabolism (Montero et al., 1981; Seglen and Gordon, Recent research has shown that an important aspect of im- 1981). mune responses that is very sensitive to V, and may even con- The effect on intracellular phosphorylation may also un- tribute to the previously described defects in macrophage func- derlie some observations regarding general activation states of tion, is the capacity of V-exposed cells to bind with, and respond macrophages overall as well as induction of local inflammation to, IFNγ (Cohen et al., 1996a, 1996b, 1997a). Results of in vitro after V exposure. In studies with AM and lung myofibroblasts, exposures of macrophage cell lines with V indicated that surface V-induced inhibition of tyrosine phosphatases (in conjunction levels and binding affinities of 2 classes of surface IFNγ R were with subsequently induced increase in formation of intracellular greatly modified by V. As a result, IFNγ -inducible responses reactive oxygen species via NADPH oxidase) (Grinstein et al., (such as enhanced: Ca2+ influx, Class II antigen expression, and 1990; Trudel et al., 1991; Grabowski et al., 1999 - using AM and zymosan-induced reactive oxygen intermediate [ROI] forma- other types of granulocytes) led to activation of 3 MAP kinase tion) in all V-treated cells were diminished; similar decrements families (JNK, p38, and ERK; Zhao et al., 1996; Samet et al., in macrophage responsiveness to IFNγ were observed with AM 1998; Wang and Bonner, 2000; Torres and Forman, 2002). The recovered from rats subchronically exposed to NH4VO3. Ef- precise implication from prolonged activation of JNK and p38 fects on surface receptor are apparently a common feature of kinases (mediators of signals in response to cytokines) or ERKs the overall toxicology of V; lymphocytes (and other nonimmune (transducers in cell signaling cascades in response to growth cell types) treated in vitro with vanadate also displayed altered factors and/or hormone signals) on cell cytokine receptors or affinity for hormones (i.e., epidermal growth factor and insulin) responsivity to cytokines remain undefined. However, it is clear or cytokines (Kadota et al., 1987; Torossian et al., 1988; Evans that the activation of ERKs is associated with increases in the et al., 1994). inducibility of macrophage NO (that can then act as a suppressor Though the underlying causation for the effects on IFNγ R of cell activation) and both MIP-1α and MIP-2 chemoattractant are unknown, it may be that V directly modifies proteins that formation (Chan and Riches, 2001; Jaramillo and Oliver, 2002; constitute this and other surface cytokine/opsonin receptors on Kurosaka et al., 2003). Activation of ERKs provides one of the macrophages (Cohen et al., 1996a). Modified receptor responses best plausible mechanisms to explain the in vivo and in vitro might also be related to induced changes in cellular protein ki- findings of Chong et al. (2000a, 2000b) wherein levels of both nase and/or phosphatase activities (Swarup et al., 1982; Nechay chemokines were increased by instillation of rats, or treatment et al., 1986; Klarlund et al., 1988; Grinstein et al., 1990; Trudel of mouse RAW264.7 cells, with soluble sodium orthovanadate et al., 1991). By this, V-induced prolonged phosphorylation (NaVO3). of receptor proteins and cytokine-induced 2◦ messenger pro- teins might induce prolonged states of cell activation (Pumiglia et al., 1992; Imbert et al., 1994) that modulate cytokine recep- ZINC tor expression. This prolonged phosphorylation of cell proteins Zinc (Zn) is one of the more abundant trace metals found could also lead to bypass of normal signal transduction pathways in all organisms. While exposure to airborne Zn is somewhat PULMONARY IMMUNOTOXICOLOGY OF METALS 57

TABLE 9 >130,000 (ATSDR, 1994). Zinc metal is commonly used as Ambient levels and acceptable workplace levels for Zn a protective coating for other metals, in alloys (i.e., bronze and brass), and in chemical reduction processes. Salts of Zn are used a a a Background Rural Urban in photographic paper preparation, wood preservatives, fertiliz- Average air levels <3–27b 10–50b 293–380c ers, pesticides, textiles, ceramics, and in vulcanization of rubber; (ng Zn/m3)20–160e 27–500d some also have practical applications in medicine as solubilizing 20–60 f 20–160b agents for pharmaceuticals or remediation of Zn deficiency. The 170–670e industrial processes that result in greatest emission of Zn into 70–590 f the environment include the production of iron or steel as well as the smelting/refining of Zn, with mean annual high concentra- a,g Regulations and guidelines tions approaching 5 µg Zn/m3 (24-hour values of 0.27–15.7 µg Accepted levels OSHA NIOSH ACGIH Zn/m3) or higher (ATSDR, 1994; WHO, 2001; Newhook et al., 3 h (mg Zn/m ) 2003). Galvanized welding represents another process where Zn metal (dust) N/A N/A N/A significant amounts of Zn are released to the atmosphere at a Zn metal (fume) N/A N/A N/A more localized level (Mali and Carter, 1987; Weir et al., 1989; Zn oxide (dust) 10.0 5.0 10.0 Mali et al., 1993; Contreras and Chan-Yeung, 1997). However, Zn oxide (fume) 5.0 5.0 5.0 unlike in steel/iron production or smelting operations, this re- Zn chloride 1.0 1.0 1.0 lease is most problematic to the exposed worker rather than Zn chromate 0.1 N/A N/A nonworkers or the surroundings. To help minimize risk of po- tential worker exposure to Zn, regulatory standards have been a ATSDR (1994). established (Table 9). Permissible levels in many states are once bUnited States. again set substantively lower; however, while some have autho- c New York City. rized levels at fractions of a µg/m3, others are on the order of d San Francisco Bay area. “tens” of µg/m3. In all cases, regulations tend to vary depending eSeven U.S. cities/2 rural sites. on agent solubility or generation source. f New Jersey. gMany states set values for each agent (in 8- or 24-hour periods) While solubility is a critical factor that impacts upon the at from 1–several µg/m3. some states (MD, ME, MO, NY, VT) clearance of Zn-bearing particles from the lungs (and, thus, also set values for Zn metal alone. their ultimate immunotoxicologic potential in same), informa- h Eight-(8) hour time-weighted averages (TWA). tion regarding both solubility and clearance of Zn agents is lim- ited primarily to zinc oxide (ZnO) (i.e., Dinslage-Schlunz and unavoidable, the majority of human Zn exposure is via the diet. Rosmanith, 1976). Furthermore, though the immunotoxic ef- As with many of the other metals discussed in this review, the fects of ZnO in the lung have been extensively studied due to its major means by which individuals are exposed to greater than long-recognized role in “metal fume fever” (Lehman et al., 1910; normal levels of Zn is via tobacco smoke or in occupational Drinker et al., 1927), far less is known about the immunotoxic settings. Representative air levels of Zn for several rural and properties of the wide variety of other Zn-bearing agents en- urban sites are presented in Table 9 (ATSDR, 1994). More re- countered in industrial and environmental settings. With regard cent values from several European nations are available from the to the latter, the majority of information available was derived World Health Organization (WHO, 2001). Apart from in highly from clinical and autopsy reports that described occupational or industrialized regions, ambient Zn levels are relatively low and personal overexposure to Zn agents (Evans, 1945; Matarese and constant overall, with the majority of Zn being derived from Matthews, 1986; Hjortso et al., 1988; van Netten et al., 1990; automobile exhaust, soil erosion, and local commercial, indus- Homma et al., 1992). trial, or construction activity. Oddly, unlike what is observed Exposure of humans or animal models to ZnO/hexachloro- with V, additional coal burning required for heating during the ethane smoke is known to induce strong proinflammatory re- winter does not correlate with increased concentrations of at- sponses, type II cell hyperplasia, and increases in fibrosis (pri- mospheric Zn relative to those in the summer (Barrie and Hoff, marily interstitial) (Marrs et al., 1983; Karlsson et al., 1986; 1985; Daisey, 1987). Based on the ambient Zn values listed in Hjortso et al., 1988; Brown et al., 1990). It is interesting to note Table 9, it has been estimated that average inhaled intake of Zn that mice exposed 3 hours/day for 1, 3, or 5 days to ZnO alone is ≈0.7 and 20 µg/day in rural and urban environs, respectively (at 1 mg ZnO/m3) developed tolerance to the agent, with PMN (Cleven et al., 1993; WHO, 2001). infiltration into their lungs decreasing as the number of expo- As noted previously, the majority of Zn inhalation events are sures increased; however, similar tolerance with respect to BAL occupational and occur among individuals exposed to worksite total protein was not evident nor was the PMN-related resistance Zn-bearing fumes and dusts. The most recent National Occu- apparent in mice reexposed to ZnO after a 5-day reprieve (Chen pational Exposure Study in the 1980s estimated that the total and Gordon, 2001). Somewhat contradictory results were also numbers of workers potentially exposed to Zn compounds was reported by Fine et al. (2000) in clinical studies of naive subjects 58 COHEN and sheet metal workers; the former tended to have reduced PMN exposed infected controls) were evident when the mice were per- and IL-6 in their BAL upon repeat exposure to 5 mg ZnO/m3 mitted to inhale either compound rather than have them instilled. while the latter had very mild PMN recruitment but elevated IL-6 The effects of Zn agents on AM have been the most studied after a single exposure. Instillation with the zinc chloride/hexite among all lung immune cell types. For example, AM recovered (ZnCl2) combustion product of a ZnO/hexachloroethane mix- from rats instilled with 5 mg ZnO displayed distinct changes ture induced similar effects; however, ZnCl2 also caused an in- in both size and ultrastructure (Migally et al., 1982). Within crease in the amount of lymphocytic infiltration into areas of 7 days of exposure, both AM and interstitial macrophages were alveolar damage and numbers of foamy AM-containing aggre- found to possess electron-dense structures containing Zn; the gates in the alveolar lumena. Except for the presence of foamy Authors suggested that this indicated a likely transfer of Zn par- AM, the immunohistological changes in the lungs observed af- ticles among macrophage types. At the functional level, a single ter host exposure to ZnCl2 were very similar to those seen in 4-hour exposure of hamsters to increasing amounts of ZnSO4 lungs of rats instilled with zinc hydroxide (Zn(OH)2) colloid or Zn2(NH4)2(SO4)2 resulted in decreases in the phagocytic ac- (Ishiyama et al., 1997). In this study, instillation with soluble tivity of AM recovered in the period 1–48 hours postexposure zinc sulfate (ZnSO4) solution did not induce altered lung im- (Skornik and Brain, 1983). When effects on phagocytosis are munologic profiles. analyzed in the context of exposure levels used, the results in These latter results could lead to the suggestion that soluble this study parallel those in the mouse antibacterial resistance forms of Zn may not be inflammatory. Gavett et al. (1997), using studies of Ehrlich (1980) in that the effect from ZnSO4 was far rats instilled with ROFA having high Zn levels or its leachate greater than that by Zn2(NH4)2(SO4)2. A similar, but apparently (≈63 µg Zn/leachate instillate), showed that these “soluble” species-dependent, effect on phagocytic activity was noted in forms were in fact extremely inflammatory. While both this AM recovered 24 hours after guinea pigs were exposed 3 hours ROFA and another with l/30 the level of Zn induced equiva- to 5 mg ZnO/m3 (Gordon et al., 1992); no effects were demon- lent increases in lung AM, lymphocyte, and eosinophil levels, strable in cells from rabbits exposed to the atmosphere. This only “high” Zn ROFA induced significant increases in PMN. latter study showed that while phagocytic activity was impaired Whether these effects were attributable to soluble Zn species by ZnO exposure, the effect was at the level of capacity rather as opposed to resuspension of very small particles of insoluble than index. Zn, or a combination of the two, was not discernible as both the Inhibition of macrophage phagocytic activity has also been leachate and intact ROFA were equipotent in this regard. It was demonstrated ex vivo using ZnO (Fisher et al., 1986). However, studies by Prieditis and Adamson (2002) and Adamson et al. in this study, while Zn was a weaker inhibitor of phagocytic (2000), using a single instillation of mice with ≈4.8 µgZn(as function than some of the other metals discussed in this review ZnCl2), that seemed to have conclusively shown that the soluble (i.e., V and Mn), it was more directly cytotoxic than the Mn Zn ion was able to induce increases in PMN and total protein agent tested and had less of an effect on cell adherence than the over a period of 7 days postexposure and that the effects were V compound employed. In a study of AM recovered from hosts dose-dependent. Unfortunately, the issue has since been thrown instilled with Zn(OH)2, it was found that the cells displayed into confusion again. Kodavanti et al. (2002) reported that while increased levels of proliferating cell nuclear antigen (Ishiyama instillation of rats with 33 or 66 µg Zn/kg (as ZnSO4)or0.8– et al., 1997). In addition, if lung slices from naive rats were 8.3 mg PM/kg (14.5 µg soluble Zn/mg PM) induced PMN influx incubated with Zn(OH)2, the oxidative metabolism (measured and increased BAL total protein levels, inhalation of the intact via NBT reduction) in each was significantly stimulated. Con- 3 3 PM (2, 5, or 10 mg PM/m , 6 hours/day, 4 days or 10 mg PM/m , versely, treatment of the hosts or naive rat lung slices with ZnSO4 6 hours/day, 1 day/week for 1, 4, or 16 weeks) did not induce failed to induce any effect on either the nuclear antigen levels or any influx—rather, there were both dose- and time-dependent ROI formation. increases in particle-loaded AM levels instead. As noted earlier, the majority of information about pulmonary There have been a few studies that examined effects from immunotoxicologic effects of Zn was obtained from studies of inhalation of/exposure to Zn agents on the ability of the lungs ZnO and its relation to development of metal fume fever. In one to resist/clear viable bacterial challenges. One 3-hour exposure study that examined effects from 1, 2, or 3 days (3 hours/day) ex- 3 of mice to increasing amounts of ZnSO4 resulted in increased posures of guinea pigs to 2.3, 5.9, or 12.1 mg ZnO/m , there were mortality due to subsequently inhaled S. pyogenes compared to consistent dose- and number of exposure-dependent increases in that in air-exposed controls or mice exposed to equivalent or total protein (indicative of in situ fibrotic activity and/or vascu- greater amounts of zinc ammonium sulfate (Zn2(NH4)2(SO4)2) lar damage) and in activities of angiotensin-converting enzyme, (Ehrlich, 1980). Unlike what was noted with similar sulfates LDH, β-glucuronidase, and AP (Conner et al., 1988). Due to the or ammonium sulfates of Al, if the Zn agents were first instilled design of this study by Conner et al., it was not clear whether the and the hosts then infected with the S. pyogenes, mice that re- appearance of effects on these endpoints in guinea pigs sacrificed ceived Zn2(NH4)2(SO4)2 did not now display the greater mor- after their second exposure was an acute-onset response or some tality rates (Hatch et al., 1981). Again, no significant differences latent effect from the first exposure. The studies by Gordon et al. in mortality (between the 2 agents or compared with sham/air- (1992) clarified it was the latter by showing that both guinea pigs PULMONARY IMMUNOTOXICOLOGY OF METALS 59 and rats that underwent a single 3-hour exposure to 2.5 or 5 mg reflecting the initial attempts of several Investigators to describe ZnO/m3, did not display changes in several of these parameters potential mechanisms of action underlying some effects was also (i.e., total protein, LDH, and β-glucuronidase activities) until 4– presented. 24 hours postexposure. Interestingly, this same study indicated Still, after all that, the question remains, where to from here? that interspecies variations in response to ZnO could occur in The most obvious need is for many of the cited studies to be that rabbits exposed once for 2 hours to 5 mg ZnO/m3 only had repeated using environmentally relevant levels of each metal. a change in β-glucuronidase activity, and that this was actually Furthermore, as it is highly unlikely that an individual is ex- a decrement rather than an increase. posed to only a single metal agent at any given time (except Since metal fume fever is a febrile inhalational syndrome, it under extraordinary occupational settings), studies using vary- is plausible to expect that levels of pyrogenic cytokines in the ing combinations of metals (as occur in mixtures like particulate lungs would increase after inhalation of ZnO. Studies of human matter) would also be highly relevant. Along these lines, studies volunteers exposed to either galvanized steel welding fumes for to analyze how entrainment of one metal might impact upon 15–30 minutes (Blanc et al., 1993) have noted that significant the immunotoxicity of another co-inhaled metal are needed. Of amounts of several cytokines that are pyrogenic, chemotactic, great use would also be studies to clarify the role, if any, of physi- or anti-inflammatory are released in a time-associated manner cochemical properties in governing how different metals (or over the postexposure period. In was observed that there was a compounds of a given metal)—when inhaled at equal doses— very rapid (in 3 hours) increase in IL-1, TNFα, and IL-8 lev- can yield completely varying effects on immune responses in the els in the BAL of exposed hosts. With increasing time (i.e., 8– lungs. Regarding mechanisms, the pool of information about ef- 22 hours) postexposure, levels of these biomediators decreased fects of inhaled metals on the expression and/or activities of while those of IL-6 increased; analyses of IL-4 or IL-10 anti- critical surface antigens and receptors (as well as their related inflammatory cytokines were inconclusive or not performed. In signal pathways) on various lung immune cell types is scant studies with volunteers exposed to furnace-generated ZnO par- and needs to be expanded. With increasing utilization of pro- ticles for 2 hours (2.5 or 5.0 mg ZnO/m3), plasma levels of teomic and genomic analyses, the generation of “broadbrush” IL-6 were shown to undergo continual increases over the period descriptions of what genes might be up- or down-regulated, or 3–6 hours postexposure (Fine et al., 1997). Similar studies of what mono-/lymphokines may have their production altered, by volunteers exposed 10, 15, or 30 minutes to 33 mg Zn/m3 at- inhaled/instilled metals could expedite the mechanism-defining mospheres (to yield ≈540 mg Zn [as ZnO]·min/m3 cumulative process by helping Investigators to sharpen their focus on par- dose) again displayed significant elevations in IL-8 and TNFα ticular pathways that would be impacted on by these induced in their BAL even 24 hours after termination of individual ex- changes. Last, expanding the numbers of investigations of ge- posures (Kuschner et al., 1995). In a follow-up study (1997), netic susceptibility to individual metals (or various forms of a analysis of BAL from volunteers 3 hours after ≈770 mg Zn given metal) would not only clarify why the pulmonary immune (as ZnO)·min/m3 cumulative dose exposure showed that lev- system is more affected by a particular metal agent in certain els of these cytokines were again elevated. However, while the individuals but would also assist in the defining of mechanism levels of IL-1, IL-8, and TNFα did undergo a decrease over of effect(s) for that metal by pinpointing likely target proteins the 3–24-hour postexposure period similar to that observed in or molecules within lung immune cells. the above-described study of humans exposed to galvanized Clearly, these items represent only a few potential challenges steel welding fumes, the levels of IL-6 did not significantly that might be made to current and future investigators. 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