Albert F Gunnison, Ph.D.

Comparative pulmonary toxicity of inhaled nickel nanoparticles; role of deposited dose and solubility
Kang, Gi Soo; Gillespie, Patricia A; Gunnison, Albert; Rengifo, Hernan; Koberstein, Jeffrey; Chen, Lung-Chi
2011 Feb;23(2):95-103, Inhalation toxicology
In this pilot study, we investigated which physicochemical properties of nickel hydroxide nanoparticles (nano-NH) were mainly responsible in inducing pulmonary toxicity. First, we studied the role of nickel ions solubilized from nano-NH by comparing the toxic effects of nano-NH to those of readily soluble nickel sulfate nanoparticles (nano-NS). Additionally, to test whether there was a non-specific stress response due to particle morphology, we compared the toxicity of nano-NH with that of carbon nanoparticles (nano-C) and titanium dioxide nanoparticles (nano-Ti), both of which had similar physical properties such as particle size and shape, to nano-NH. We exposed mice to each type of nanoparticles for 4?h via a whole-body inhalation system and examined oxidative stress and inflammatory responses in the lung. We also determined the lung burden and clearance of Ni following nano-NH and nano-NS exposures. The results showed that lung deposition of nano-NH was significantly greater than that of nano-NS and nano-NH appeared to have stronger inflammogenic potential than nano-NS even when lung Ni burden taken into consideration. This suggests that the toxicity of nano-NH is not driven solely by released Ni ions from deposited nano-NH particles. However, it is unlikely that the greater toxic potential of nano-NH is attributable to a generic stress response from any nanoparticle exposure, since nano-C and nano-Ti did not elicit toxic responses similar to those of nano-NH. These results indicate that the observed pulmonary toxicity by inhaled nano-NH were chemical-specific and deposited dose and solubility are key factors to understand toxicity induced by nano-NH
— id: 123206, year: 2011, vol: 23, page: 95, stat: Journal Article,

Long-term inhalation exposure to nickel nanoparticles exacerbated atherosclerosis in a susceptible mouse model
Kang, Gi Soo; Gillespie, Patricia Anne; Gunnison, Albert; Moreira, Andre Luis; Tchou-Wong, Kam-Meng; Chen, Lung-Chi
2011 Feb;119(2):176-181, Environmental health perspectives
BACKGROUND: Because associations have been reported between inhaled ambient ultrafine particles and increased risk of cardiopulmonary disease, it has been suggested that inhaled engineered nanoparticles (NPs) may also induce adverse effects on the cardiovascular system. OBJECTIVE: We examined the long-term cardiovascular effects of inhaled nickel hydroxide NPs (nano-NH) using a sensitive mouse model. METHODS: Hyperlipidemic, apoprotein E-deficient (ApoE-/-) mice were exposed to nano-NH at either 0 or 79 mug Ni/m3, via a whole-body inhalation system, for 5 hr/day, 5 days/week, for either 1 week or 5 months. We measured various indicators of oxidative stress and inflammation in the lung and cardiovascular tissue, and we determined plaque formation on the ascending aorta. RESULTS: Inhaled nano-NH induced significant oxidative stress and inflammation in the pulmonary and extrapulmonary organs, indicated by up-regulated mRNA levels of certain antioxidant enzyme and inflammatory cytokine genes; increased mitochondrial DNA damage in the aorta; significant signs of inflammation in bronchoalveolar lavage fluid; changes in lung histopathology; and induction of acute-phase response. In addition, after 5-month exposures, nano-NH exacerbated the progression of atherosclerosis in ApoE-/- mice. CONCLUSIONS: This is the first study to report long-term cardiovascular toxicity of an inhaled nanomaterial. Our results clearly demonstrate that long-term exposure to inhaled nano-NH can induce oxidative stress and inflammation, not only in the lung but also in the cardiovascular system, and that this stress and inflammation can ultimately contribute to progression of atherosclerosis in ApoE-/- mice
— id: 138234, year: 2011, vol: 119, page: 176, stat: Journal Article,

Age, strain, and gender as factors for increased sensitivity of the mouse lung to inhaled ozone
Vancza, Elizabeth M; Galdanes, Karen; Gunnison, Al; Hatch, Gary; Gordon, Terry
2009 Feb;107(2):535-543, Toxicological sciences
Ozone (O(3)) is a respiratory irritant that leads to airway inflammation and pulmonary dysfunction. Animal studies show that neonates are more sensitive to O(3) inhalation than adults, and children represent a potentially susceptible population. This latter notion is not well established, and biological mechanisms underlying a predisposition to pollution-induced pulmonary effects are unknown. We examined age and strain as interactive factors affecting differential pulmonary responses to inhaled O(3). Male and female adult mice (15 weeks old) and neonates (15-16 days old) from eight genetically diverse inbred strains were exposed to 0.8 ppm O(3) for 5 h. Pulmonary injury and lung inflammation were quantified as total protein concentration and total polymorphonuclear neutrophil (PMN) number in lavage fluid recovered 24-h postexposure. Dose-response and time-course curves were generated using SJL/J pups, and (18)O lung burden dose was assessed in additional mice. Interstrain differences in response to O(3) were seen in neonatal mice: Balb/cJ and SJL/J being most sensitive and A/J and 129x1/SvJ most resistant. The PMN response to O(3) was greater in neonates than in adults, specifically for SJL/J and C3H/HeJ strains, independent of dose. Small gender differences were also observed in adult mice. Variation in protein concentrations and PMN counts between adults and pups were strain dependent, suggesting that genetic determinants do play a role in age-related sensitivity to O(3). Further research will help to determine what genetic factors contribute to these heightened responses, and to quantify the relative contribution of genes vs. environment in O(3)-induced health effects
— id: 97452, year: 2009, vol: 107, page: 535, stat: Journal Article,

Using high throughput resequencing microarrays to detect mutations in genes involved in lung cancer
Piao, LC; Gunnison, A; Nadas, A; Chen, WC; Nonaka, D; Spivack, S; Pass, H; Rom, WN; Tang, MS
2008 DEC 11 ;4(3):159-159, Cancer biomarkers : section A of Disease markers
— id: 91475, year: 2008, vol: 4, page: 159, stat: Journal Article,

Effects of subchronic exposures to concentrated ambient particles (CAPs) in mice. VI. Gene expression in heart and lung tissue
Gunnison, Albert; Chen, Lung Chi
2005 Apr;17(4-5):225-233, Inhalation toxicology
The purpose of this exploratory study within the integrated subchronic inhalation exposure study (Lippmann et al., 2005) was to identify genes in heart and lung tissue that changed in expression level as a result of subchronic exposure to concentrated ambient particles (CAPs). Identification of CAPs exposure-related changes in gene expression could serve in the formulation of mechanistic hypotheses and/or to suggest possible biomarkers of exposure. In this exploratory study undertaken here, tissues from multiple replicates of ApoE/low-density-lipoprotein double knockout (DK) mice were examined for relative exposure-related changes in gene expression. Due to limited resources, the number of replicates was three for each tissue (lung and heart) of each exposure condition (CAPs or air control). A rigorous comparison of exposure versus control data using the 'significance analysis of microarrays' (SAM) method indicated that only one gene was differentially expressed at a significant level. However, when using a less restrictive, nonstatistical analytical treatment of the data, several genes that might be involved in PM-related heart or lung pathology, and/or the circadian rhythm of physiological processes, were identified. A more comprehensive study is required to mre definitively assess differences in gene expression in heart and lung resulting from exposure to CAPs
— id: 55793, year: 2005, vol: 17, page: 225, stat: Journal Article,

Arginine metabolism in lung tissue: Implications for measurement of NOS activity
Fang, K; Gunnison, A; Nadziejko, C
2003 MAR ;72(1):295-295, Toxicological sciences
— id: 38507, year: 2003, vol: 72, page: 295, stat: Journal Article,

O3-induced inflammation in prepregnant, pregnant, and lactating rats correlates with O3 dose estimated by 18O
Gunnison AF; Hatch GE
1999 Feb;276(2 Pt 1):L332-L340, American journal of physiology. Lung cellular & molecular physiology
Previous studies have shown that rats late in pregnancy and throughout lactation are more susceptible to ozone (O3)-induced pulmonary inflammation than are prepregnant (virgin) or postlactating rats. The major aim of the present study was to determine whether these differences in response intensity could be accounted for by the O3 dose to the lower region of the lung. The relative O3 dose to the lower lung of groups of pregnant, lactating, and virgin female rats was estimated by measuring the incorporation of the 18O isotope into low-speed (cells) and high-speed (surfactant) pellets of bronchoalveolar lavage fluid immediately after acute exposure to 0.5-1.1 parts/million 18O3. The polymorphonuclear leukocyte (PMN) and protein inflammatory responses were established 20 h after acute exposure of identical physiological groups to 0.5-1.1 parts/million 16O3 (common isotope). A single regression of PMN inflammation data against surfactant 18O concentration for all physiological groups gave a linear relationship, indicating direct proportionality of PMN inflammation with this estimate of relative dose to the lower lung regardless of physiological status. This implies that the chemical species that react with surfactant molecules, i.e., O3 or its metabolites, are the same as or proportional to those chemical species responsible for initiating PMN inflammation. Additional experiments showed that lung tissue ascorbic acid concentration was significantly lower in pregnant and lactating rats than in virgin female rats. Although a causative relationship cannot be assumed, the deficit in tissue ascorbic acid concentration in pregnant and lactating rats compared with virgin female rats is consistent with their greater responsiveness and higher relative surfactant O3 dose
— id: 7984, year: 1999, vol: 276, page: L332, stat: Journal Article,

Modulation of the inflammatory effects of inhaled ozone in rats by subcutaneous prolactin-secreting, pituitary-derived tumors
Gunnison AF; Bowers A; Nadziejko C; Adler RA
1997 May;37(1):88-94, Fundamental & applied toxicology
Rats are more sensitive to ozone-induced pulmonary inflammation and damage during late pregnancy and throughout lactation than in pre- or early pregnancy or postlactation. This window of sensitivity coincides with a period of elevated levels of pituitary-derived prolactin or placental lactogen. In this study, we investigated the hypothesis that prolactin exerts an enhancing effect on ozone-induced pulmonary inflammation and damage, thus presenting a plausible explanation for the sensitivity profile observed in rats. Hyperprolactinemia was achieved by using rats with subcutaneous tumors that were derived from the MMQ tumor model previously described by Adler and co-workers (Adler, R. A., Krieg, R. J., Farrell, M. E., Deiss, W. P., and MacLeod, R. M., Metabolism 40, 286-291, 1991). A variant of the MMQ tumor, the MMQr tumor, which appeared spontaneously from a single passage of MMQ tumor tissue, produced elevated levels of corticosterone in addition to high levels of prolactin. These two subcutaneous tumors had markedly different effects on adrenal, thymus, and spleen weights because of the different hormonal milieu they generated. There was also a significant difference between MMQ- and MMQr-bearing rats in their inflammatory response to acute ozone exposure as assessed by polymorphonuclear leukocytes (PMNs) in the airways. Rats with MMQ tumors were not significantly different from non-tumor-bearing controls in their baseline level of airway PMNs and PMN inflammation following ozone exposure, whereas MMQr-bearing rats had significantly elevated baseline PMNs in their airways and a greater PMN response to inhaled ozone. The hormonal milieu and elevated PMNs in the airways of both unexposed and ozone-exposed rats with MMQr tumors were similar to levels observed in lactating rats. The role of corticosterone in pulmonary inflammation in this model was investigated further by treating MMQ tumor-bearing rats with dexamethasone. Dexamethasone was effective in producing changes in organ weights similar to those observed in MMQr rats, but did not elicit higher airway PMN concentrations in unexposed rats as observed in the MMQr rats. We conclude that in this animal model prolactin did not significantly elevate airway PMN inflammation induced by ozone, and supplementation with exogenous glucocorticoid did not duplicate the endogenous airway PMNs numbers observed in MMQr-bearing rats or lactating rats
— id: 56908, year: 1997, vol: 37, page: 88, stat: Journal Article,

Rat lung phospholipid fatty acid composition in prepregnant, pregnant, and lactating rats: relationship to ozone-induced pulmonary toxicity
Gunnison AF; Finkelstein I
1997 ;175(2):127-137, Lung
Our laboratory has demonstrated recently that pulmonary inflammation induced by acute ozone exposure is much more severe in late stage pregnant and lactating rats than in postlactating rats or age-matched virgin females. It is currently widely believed that such pulmonary damage results, at least in part, from the reaction of ozone at sites of unsaturation in phospholipid fatty acid (PLFA) molecules located in the epithelial fluid layer lining the lung surfaces and/or the plasma membranes of epithelial cells underlying this fluid layer. The objective of this study was to compare the PLFA composition of lung tissue and surfactant from ozone-sensitive late stage pregnant and lactating rats with comparable tissue from relatively ozone-insensitive age-matched prepregnant (virgin female) rats to explore the possibility that changes in lung PLFA composition during pregnancy and/or lactation contribute to the enhanced sensitivity of these physiologic states to ozone. In addition, the correlation of changes in plasma PLFA composition with those in lung was investigated. There were minor differences in the composition of lung tissue and surfactant PLFAs between prepregnant rats and pregnant rats at day 17 of gestation and only slightly greater differences between prepregnant and lactating rats. Changes from the prepregnant state in the PLFA composition of lung tissue, but not surfactant, correlated with changes in the plasma only in lactating rats and not in pregnant rats. Overall, the double bond index of PLFAs in surfactant and lung tissue was decreased in pregnant and lactating rats compared with prepregnant rats. Thus, the increased sensitivity of pregnant and lactating rats to ozone-induced lung injury cannot be attributed to an increased availability of unsaturated fatty acids. In addition, the arachidonic acid composition of phospholipids did not appear to explain differences between prepregnant rats and pregnant or lactating rats in their inflammatory response to ozone. In conclusion, there is no evidence that the relatively minor changes in lung tissue PLFA composition which occur during pregnancy and lactation predispose rats in these physiologic states to ozone-induced pulmonary toxicity
— id: 10365, year: 1997, vol: 175, page: 127, stat: Journal Article,

Comparative sensitivity of lactating and virgin female rats to ozone-induced pulmonary inflammation
Gunnison, AF; Hatch, GE; Crissman, K; Bowers, A
1996 AUG ;8(6):607-623, Inhalation toxicology
Studies from this laboratory have shown that lactating rats exhibit a greater inflammatory response to inhaled ozone than age-matched nulligravidous or postlactating rats. One factor contributing to this enhanced response by lactating rats is their greater ventilation, which results in a higher inhaled dose rate. In the study reported here, we investigate the concept that lactating rats are predisposed to ozone-induced inflammation, not only because of their higher ventilation but also because of the inherently greater sensitivity of their tissues. We found that the airways of naive, 13-day postpartum lactating Sprague-Dawley rats have significantly greater numbers of polymorphonuclear leukocytes (PMNs), a higher protein concentration, and a lower concentration of the antioxidant ascorbic acid than do the airways of virgin females. Lactating rats also have a higher PMN concentration in their circulating blood. These differences in the steady state condition of lactating rats, particularly the airways of the respiratory tract, suggest that predisposition of lactating rats to pulmonary inflammation induced by ozone may be due in part to changes in immunological status during lactation and to the greater propensity of the respiratory tract tissues of lactating rats to respond to stimulation by ozone. We compared the kinetics of airway inflammatory changes detected in bronchoalveolar lavage fluid following acute exposure of lactating and virgin female rats to 0.3 and 0.5 ppm ozone for 6 h, and observed an earlier onset and greater intensity and persistence of the inflammatory response in the lactating animals
— id: 52825, year: 1996, vol: 8, page: 607, stat: Journal Article,

Enhanced pulmonary inflammatory response to ozone during lactation in rats: Evaluation of the influence of inhaled dose
Weideman, PA; Chen, LC; Gunnison, AF
1996 JUN-JUL ;8(5):495-519, Inhalation toxicology
We previously demonstrated that rats in a late stage of pregnancy and throughout lactation were more susceptible to pulmonary inflammation induced by exposure to 1 ppm ozone than were age-matched virgin females or rats following lactation. The purpose of the study reported here was to extend the comparison of ozone-induced pulmonary inflammation in lactating and postlactating rats to lower concentrations of ozone and to investigate the hypothesis that the enhanced response demonstrated by lactating rats is attributable to a greater inhaled ozone dose. During pregnancy and lactation the metabolic demands on the female are substantially increased above prepregnancy levels, In response to this metabolic demand, it was shown in this study that the minute volume of air-breathing postpartum rats on day 13 of lactation increased to approximately 150%, of that of age-matched postlactating rats with the same lung size. Heightened ventilation in lactating rats was maintained during exposure to 0.3, 0.5, and 1.0 ppm ozone for 6 h, resulting in greater inhaled ozone doses in lactating rats compared to postlactating rats exposed identically The pulmonary inflammatory response to ozone was assessed in the same rats 18 h after exposure by comparison of protein concentration and polymorphonuclear cell (PMN) numbers in bronchoalveolar lavage fluid (BALF). Both of these parameters were significantly greater in lactating than postlactating rats at 0.3, 0.5, and 1.0 ppm ozone. Statistical analysis indicated that most or all of the greater BALF protein in lactating rats could be accounted for by their greater inhaled dose, whereas a significant portion of the enhanced PMN influx in lactating rats remained unexplained by inhaled ozone dose
— id: 52878, year: 1996, vol: 8, page: 495, stat: Journal Article,

Increased pulmonary response to inhaled endotoxin in lactating rats
Gordon T; Weideman PA; Gunnison AF
1993 May;147(5):1100-1104, American review of respiratory disease
An important aspect of risk assessment is identification of subpopulations particularly susceptible to the effects of inhaled pollutants. The present study examined whether female rats were more sensitive during lactation to the acute pulmonary injury produced by inhaled endotoxin. Lactating and age-matched virgin female rats were exposed to aerosols of saline or endotoxin for 3 h and lavaged at 24 h after exposure. No significant differences in lactate dehydrogenase, beta-glucuronidase, total protein, and total cell and PMN counts were observed between virgin and lactating rats after exposure to saline. Each marker of pulmonary injury except beta-glucuronidase was 1.5- to 3-fold greater in lactating than in virgin female rats exposed to 29.6 micrograms/m3 endotoxin. PMNs (6-fold), total cell counts, and protein were also significantly increased (p < 0.05) in lactating rats exposed to 1.3 micrograms/m3 endotoxin, a concentration reported to occur in a number of agricultural settings. These results demonstrate that the physiologic state of lactation is associated with an increased sensitivity to the acute pulmonary injury produced by inhaled endotoxin and are consistent with previous work demonstrating a similar increased sensitivity to ozone exposure. The possibility of a similar pattern of enhanced response in analogous groups of humans merits examination
— id: 6392, year: 1993, vol: 147, page: 1100, stat: Journal Article,

Enhanced inflammatory response to acute ozone exposure in rats during pregnancy and lactation
Gunnison AF; Weideman PA; Sobo M
1992 Nov;19(4):607-612, Fundamental & applied toxicology
Experimental evidence from several studies suggests that pregnant animals and women are more susceptible to oxidants than nonpregnant controls. In the study reported here, we sought to determine whether pregnant rats are more sensitive than age-matched virgin females to the inflammatory effects of ozone, a gaseous oxidant of considerable environmental significance. Rats at several stages of pregnancy and lactation, as well as age-matched virgin females, were exposed to 1 ppm ozone for 6 hr. Controls were sham-exposed to pure air for an identical period of time. Bronchoalveolar lavage was performed 24 hr after the beginning of exposure, and components of the lavage fluid considered to be indicators of inflammation were used to assess the severity of pulmonary inflammation. The results of this experiment showed that significantly enhanced sensitivity to ozone-induced pulmonary inflammation develops during pregnancy, is maintained during lactation, and disappears following lactation. Implicit in this pattern of differential sensitivity in rats is the possibility of a similar pattern of inflammatory response in analogous groups of humans as well as the potential for applicability to other oxidative pollutants
— id: 13377, year: 1992, vol: 19, page: 607, stat: Journal Article,

Age-dependence of responses to acute ozone exposure in rats
Gunnison AF; Weideman PA; Sobo M; Koenig KL; Chen LC
1992 Apr;18(3):360-369, Fundamental & applied toxicology
Previous work from this laboratory demonstrated that neonatal rats and postweanling rabbits are more sensitive to ozone-induced stimulation of pulmonary arachidonic acid (AA) metabolism than are young adults (Fundam. Appl. Toxicol. 15, 779.) In the study reported here, we have extended our initial investigation to include the influence of animal age on temporal aspects of pulmonary AA metabolism and several other responses to brief exposures to 1 ppm ozone. Rats of discrete ages ranging from 13 days to 16 weeks were exposed to 1 ppm ozone or to air for 2, 4, or 6 hr. Immediately following exposure the lungs were lavaged with six consecutive volumes of phosphate-buffered saline and the acellular fluid from the first lavage volume recovered was analyzed for its content of prostaglandin E2 (PGE2), protein, and lactate dehydrogenase. Leukocytes recovered by lavage were quantitated and characterized by viability and percentage of polymorphonuclear (PMN) cells. Several lines of evidence verified that PGE2 was produced by the lung as a consequence of ozone exposure and that its concentration in the fluid from the first lavage was a reasonably good index of pulmonary AA metabolism to prostanoids. We also demonstrated that the lavage process itself stimulates the lung, resulting in increased AA metabolism to prostanoids that were recovered in the second and following lavage volumes. The time course of PGE2 production by the ozone-exposed lung varied considerably with animal age. Neonatal rats 13 days of age were the most sensitive to ozone stimulation. At 2 hr of exposure, PGE2 concentration in the first lung lavage of these animals peaked at values approximately two orders of magnitude above controls and then decreased sharply with continued exposure. Adults and older neonates (18 days of age) were much less responsive to 2-hr exposures; however, continued exposure of these rats for up to 6 hr resulted in increasing PGE2 concentration in the first lung lavage. Other responses showed various degree of age dependence. The percentage of lavaged leukocytes that were nonviable (i.e., trypan blue-positive) showed a strong inverse correlation with animal age. In 13-day-old rats that were exposed for 6 hr, the percentage of dead leukocytes reached nearly 50%. In addition, sheets or clumps of dead cells that were judged to be epithelial cells were lavaged from these animals. Conversely, 16-week-old adult males exposed to ozone for 6 hr showed little evidence of damage to cells of the respiratory tract.(ABSTRACT TRUNCATED AT 400 WORDS)
— id: 13637, year: 1992, vol: 18, page: 360, stat: Journal Article,

Age-dependent effect of ozone on pulmonary eicosanoid metabolism in rabbits and rats
Gunnison AF; Finkelstein I; Weideman P; Su WY; Sobo M; Schlesinger RB
1990 Nov;15(4):779-790, Fundamental & applied toxicology
Acute exposures to ozone have previously been shown to cause quantitative changes in the spectrum of arachidonic acid (AA) metabolites in lung lavage fluid. Since age appears to be an important variable in the toxicity of inhaled ozone, we investigated its effect on ozone-induced changes in pulmonary eicosanoid metabolism. Rats and rabbits ranging in age from neonates to young adults were exposed either to air or to 1 ppm ozone for 2 hr. Lung lavage fluid was collected within 1 hr following exposure and analyzed for its content of selected eicosanoids. In both species, there was a pronounced effect of age on ozone-induced pulmonary eicosanoid metabolism. Ozone-exposed animals at the youngest ages examined had severalfold greater amounts of two products of the cyclooxygenase pathway, prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha), than did age-matched controls. This effect lessened and eventually disappeared as the animals grew toward adulthood. In rabbits, ozone also induced increases in 6-keto-prostaglandin F1 alpha and thromboxane B2, but these changes were of lesser magnitude and evident only in the youngest rabbits exposed. There was no observed effect of ozone on lung lavage content of leukothriene B4. Indices of nonspecific pulmonary damage, i.e., protein concentration in lung lavage fluid and total number and viability of lavaged lung cells, were affected by ozone exposure, but not in an age-dependent manner that correlated with changes in pulmonary eicosanoid metabolism. In vitro ozone exposure of lung macrophages from naive rabbits of the same age range as those exposed in vivo demonstrated that ozone is capable of stimulating the elaboration of PGF2 alpha and especially PGE2. However, the increase in lavage fluid PGE2 and PGF2 alpha caused by ozone inhalation could not be attributed to macrophage metabolism conclusively since elaboration of PGE2 and PGF2 alpha by cultured macrophages was not enhanced by prior in vivo ozone exposure. In an ancillary study it was shown that 15-hydroxyprostaglandin dehydrogenase (PGDH) activity in rabbit lung homogenates was not affected by prior exposure to ozone, indicating that the increase in lung lavage fluid eicosanoids that occurred in these animals could not be explained by inhibition of PGDH
— id: 14307, year: 1990, vol: 15, page: 779, stat: Journal Article,

Pulmonary arachidonic acid metabolism following acute exposures to ozone and nitrogen dioxide
Schlesinger RB; Driscoll KE; Gunnison AF; Zelikoff JT
1990 Dec;31(4):275-290, Journal of toxicology & environmental health
Ozone (O3) and nitrogen dioxide (NO2) are common air pollutants, and exposure to these gases has been shown to affect pulmonary physiology, biochemistry, and structure. This study examined their ability to modulate arachidonic acid metabolites (eicosanoids) in the lungs. Rabbits were exposed for 2 h to O3 at 0.1, 0.3, or 1 ppm; NO2 at 1, 3, or 10 ppm; or to a mixture of 0.3 ppm O3 and 3 ppm NO2. Groups of animals sacrificed either immediately or 24 h after each exposure underwent broncho-pulmonary lavage. Selected eicosanoids were assessed in lavage fluid by radioimmunoassay. Increases in prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha) were found immediately after exposure to 1 ppm O3. Exposure to 10 ppm NO2 resulted in a depression of 6-keto-PGF1 alpha, while thromboxane B2 (TxB2) was elevated after exposure to 1 ppm NO2 and depressed following 3 and 10 ppm. The O3/NO2 mixture resulted in synergistic increases in PGE2 and PGF2 alpha, with the response appearing to be driven by O3. This study has demonstrated that acute exposure to either O3 or NO2 can alter pulmonary arachidonic acid metabolism and that the responses to these oxidants differ, both quantitatively and qualitatively
— id: 14263, year: 1990, vol: 31, page: 275, stat: Journal Article,

Modulation of pulmonary eicosanoid metabolism following exposure to sulfuric acid
Schlesinger RB; Gunnison AF; Zelikoff JT
1990 Jul;15(1):151-162, Fundamental & applied toxicology
Eicosanoids (arachidonic acid metabolites) are potent biological mediators. Modulation of their metabolism by air pollutants may be a possible factor in the pathogenesis of environmentally related lung disease. Sulfuric acid (H2SO4) aerosols are components of ambient air in many areas. Rabbits were exposed to H2SO4 (0.3 microns) at 250, 500, or 1000 micrograms/m3 for 1 hr/day for 5 days. They were then euthanized, the lungs lavaged, and eicosanoid analyses performed by radioimmunoassay of acellular lavage fluid. An exposure-concentration-dependent decrease in levels of prostaglandins E2 and F2 alpha and thromboxane B2 was found; no change in leukotriene B4 was observed. Tracheal explants exposed to acidic environments in vitro also showed reduced production of PGE2, PGF2 alpha, and TxB2. Incubation with sodium sulfate (Na2SO4) showed no effect of the sulfate ion (SO4(2-)). This study, the first to examine eicosanoid production after in vivo exposure to pure H2SO4 droplets, indicates that such exposure can modulate arachidonic acid metabolism, and that this is likely due to the deposition of hydrogen ion (H+) on target tissue
— id: 17587, year: 1990, vol: 15, page: 151, stat: Journal Article,

The effect of inhaled sulfur dioxide and systemic sulfite on the induction of lung carcinoma in rats by benzo[a]pyrene
Gunnison AF; Sellakumar A; Snyder EA; Currie D
1988 Jun;46(1):59-73, Environmental research
In a previous study at this Institute, inhaled sulfur dioxide (SO2) was shown to enhance the induction by inhaled benzo[a]pyrene (BaP) of squamous cell carcinoma (SQCA) of the respiratory tract of rats (S. Laskin, M. Kuschner, A. Sellakumar, and G. V. Katz, 1976, In 'Air Pollution and the Lung,' pp. 190-213). We attempted to confirm and extend this finding by using an experimental protocol intended to illuminate the role of SO2. Rats were treated with BaP by 15 consecutive weekly intratracheal instillations. Some of these rats were simultaneously exposed either to SO2 by inhalation or to sulfite/bisulfite anions that accumulated systemically from endogenous generation in rats with induced sulfite oxidase deficiency. The total treatment period spanned 21 weeks, after which the rats were observed for the development of tumors. BaP-treated rats began to die with SQCA of the respiratory tract at approximately 200 days after the first BaP treatment and at 2 years after the first treatment nearly all rats in the BaP-treated groups had died, most with SQCA. Survival in the control groups was excellent and the health of all groups (aside from pulmonary SQCA in BaP-treated groups) was also excellent. The probability of dying with a pulmonary SQCA in the experimental groups treated with BaP, BaP plus inhaled SO2, and BaP plus systemic sulfite/bisulfite was calculated by the logrank analysis. The data sets of SQCA probability from these groups were not statistically different (i.e., P greater than 0.05) by the chi 2 test indicating that, in this experiment, neither inhalation exposure to SO2 nor systemic exposure to sulfite/bisulfite anions affected the induction of SQCA of the lung by intratracheally instilled BaP. We conclude that the results of this study do not support an etiological role for either SO2 or sulfite/bisulfite anions in the induction of SQCA of the respiratory tract by BaP
— id: 11075, year: 1988, vol: 46, page: 59, stat: Journal Article,

Sulfite hypersensitivity. A critical review
Gunnison AF; Jacobsen DW
1987 ;17(3):185-214, Critical reviews in toxicology
Sulfiting agents (sulfur dioxide and the sodium and potassium salts of bisulfite, sulfite, and metabisulfite) are widely used as preservatives in foods, beverages, and pharmaceuticals. Within the past 5 years, there have been numerous reports of adverse reactions to sulfiting agents. This review presents a comprehensive compilation and discussion of reports describing reactions to ingested, inhaled, and parenterally administered sulfite. Sulfite hypersensitivity is usually, but not exclusively, found within the chronic asthmatic population. Although there is some disagreement on its prevalence, a number of studies have indicated that 5 to 10% of all chronic asthmatics are sulfite hypersensitive. This review also describes respiratory sulfur dioxide sensitivity which essentially all asthmatics experience. Possible mechanisms of sulfite hypersensitivity and sulfur dioxide sensitivity are discussed in detail. Sulfite metabolism and the role of sulfite oxidase in the detoxification of exogenous sulfite are reviewed in relationship to the etiology of sulfite hypersensitivity
— id: 17589, year: 1987, vol: 17, page: 185, stat: Journal Article,

Distribution, metabolism and toxicity of inhaled sulfur dioxide and endogenously generated sulfite in the respiratory tract of normal and sulfite oxidase-deficient rats
Gunnison AF; Sellakumar A; Currie D; Snyder EA
1987 ;21(1-2):141-162, Journal of toxicology & environmental health
We report on the distribution, metabolism, and toxicity of sulfite in the respiratory tract and other tissues of rats exposed to endogenously generated sulfite or to inhaled sulfur dioxide (SO2). Graded sulfite oxidase deficiency was induced in several groups of rats by manipulating their tungsten to molybdenum intake ratio. Endogenously generated sulfite and S-sulfonate compounds (a class of sulfite metabolite) accumulated in the respiratory tract tissues and in the plasma of these rats in inverse proportion to hepatic sulfite oxidase activity. In contrast to this systemic mode of exposure, sulfite exposure of normal, sulfite oxidase-competent rats via inhaled SO2 (10 and 30 ppm) was restricted to the airways. Minor pathological changes consisting of epithelial hyperplasia, mucoid degeneration, and desquamation of epithelium were observed only in the tracheas and bronchi of the rats inhaling SO2, even though the concentration of sulfite plus S-sulfonates in the tracheas and bronchi of these rats was considerably lower than that in the endogenously exposed rats. We attribute this histological damage to hydrogen ions stemming from inhaled SO2, not to the sulfite/bisulfite ions that are also a product of inhaled SO2. In addition to the lungs and trachea, all other tissues examined, except the testes, appeared to be refractory to high concentrations of endogenously generated sulfite. The testes of grossly sulfite oxidase-deficient rats were severely atrophied and devoid of spermatogenic cells
— id: 17588, year: 1987, vol: 21, page: 141, stat: Journal Article,

A sulphite oxidase-deficient rat model: reproductive toxicology of sulphite in the female
Dulak L; Chiang G; Gunnison AF
1984 Aug;22(8):599-607, Food & chemical toxicology
The reproductive toxicology of sulphite was investigated in female rats with induced deficiencies of sulphite oxidase. Induction of sulphite oxidase deficiency was accomplished by administration of a diet with a high tungsten to molybdenum ratio. This animal model was chosen because it enables exposure of tissues to high systemic sulphite concentrations without debilitating side effects. The reproductive performance of female sulphite oxidase-deficient rats, exposed continuously to sulphite from about 3 wk before mating until the experiment was terminated on day 20 of gestation, was compared to that of unexposed rats with normal sulphite oxidase activity. There was no treatment-related trend in any of the parameters observed, including mating and pregnancy rates, gestational weight gain, pre-implantation loss, resorbed and dead foetuses, litter size, foetal weight and malformations. Of the spectrum of malformations observed in control and treated animals, only anophthalmia may have been treatment related. From these experiments, performed in an animal model that is a conservative metabolic analogue for man, we have concluded that there is no evidence to indicate that exposure of females to sulphite poses a significant reproductive hazard
— id: 17590, year: 1984, vol: 22, page: 599, stat: Journal Article,

Identification of plasma proteins containing sulfite-reactive disulfide bonds
Gregory RE; Gunnison AF
1984 Apr;49(1-2):55-69, Chemico-biological interactions
Plasma protein S-sulfonate compounds (RS-SO-3) have previously been shown to form, presumably by sulfitolysis of disulfide bonds, as a result of exposure to sulfite. In the investigations reported here, we identify two proteins in rabbit plasma, namely albumin and plasma fibronectin, which contain reactive sites for S-sulfonate formation. Separation and identification of these proteins following in vitro and in vivo exposure to sulfite was accomplished primarily by column chromatographic and electrophoretic techniques. In addition, the structure of presumed S-sulfonate groups was confirmed by the identification of cysteinyl-S-sulfonate residues in protein hydrolysates generated by enzymatic digestion. The molar ratio of RS-SO-3 in both albumin and plasma fibronectin was less than one. Data from our experiments suggest that the mixed disulfide site of non- mercaptalbumin is the reactive site for S-sulfonate formation. The site(s) of formation within the plasma fibronectin molecule was not investigated. The possible physiological significance of disulfide sulfitolysis of albumin and plasma fibronectin is discussed
— id: 17591, year: 1984, vol: 49, page: 55, stat: Journal Article,

Sulphite toxicity: a critical review of in vitro and in vivo data
Gunnison AF
1981 Oct;19(5):667-682, Food & cosmetics toxicology
— id: 17592, year: 1981, vol: 19, page: 667, stat: Journal Article,

A sulphite-oxidase-deficient rat model: subchronic toxicology
Gunnison AF; Dulak L; Chiang G; Zaccardi J; Farruggella TJ
1981 Apr;19(2):221-232, Food & cosmetics toxicology
— id: 17593, year: 1981, vol: 19, page: 221, stat: Journal Article,

A sulphite-oxidase-deficient rat model: metabolic characterization
Gunnison AF; Farruggella TJ; Chiang G; Dulak L; Zaccardi J; Birkner J
1981 Apr;19(2):209-220, Food & cosmetics toxicology
— id: 17594, year: 1981, vol: 19, page: 209, stat: Journal Article,

TISSUE DISTRIBUTION OF S-SULFONATE METABOLITES FOLLOWING EXPOSURE TO SULFUR-DIOXIDE
GUNNISON, AF; ZACCARDI, J; DULAK, L; CHIANG, G
1981 ;24(2):432-443, Environmental research
— id: 40340, year: 1981, vol: 24, page: 432, stat: Journal Article,

Preferential S-sulfonate formation in lung and aorta
Gunnison AF; Farruggella TJ
1979 May;25(2-3):271-277, Chemico-biological interactions
S-sulfonate (S-SO-3) compounds have previously been identified as metabolites of sulfite in the plasma of several species of mammals [6--8]. We now report the formation of non-diffusible and relatively stable S-sulfonates in the aorta and lung lobes of rabbits exposed intravenously to constant arterial sulfite concentrations of approx. 550 microM. Under these conditions the kinetics of S-SO-3 formation were first order with coefficients in the range of 0.3--0.4 h-1 and asymptotic concentrations of approx. 900 and 9000 nmol S-SO-3/g dry wt. of lung and aorta respectively. The kinetics of this reaction in aorta tissue were closely approximated in vitro. Clearance of S-SO-3 from both lungs and aorta appeared to be first order with a half-life of 2--3 days
— id: 17595, year: 1979, vol: 25, page: 271, stat: Journal Article,

MATURATION OF SULFITE OXIDASE ACTIVITY IN RAT AND RABBIT
Gregory, RE; Gunnison, AF
1978 ;45(1):247-247, Toxicology & applied pharmacology
— id: 29784, year: 1978, vol: 45, page: 247, stat: Journal Article,

Species variability in plasma S-sulfonate levels during and following sulfite administration
Gunnison AF; Palmes ED
1978 Jun;21(2-3):315-329, Chemico-biological interactions
It has been shown that S-sulfonate compounds (R-S-SO-3) are produced by the action of sulfite on reactive disulfide bonds [4,5]. Plasma S-sulfonate production was determined as a function of sulfite ingestion and intraperitoneal injection in rats, mice and rhesus monkeys. The tendency of these species and of the rabbit [8] to produce S-sulfonates in plasma was related to the availability of sulfite and of reactive disulfide bonds and to the stability of plasma protein S-sulfonates. The rhesus monkey and the rabbit accumulated plasma S-sulfonates much more readily than did the rat, while the mouse produced little, if any, under the same test conditions. Plasma protein S-sulfonate fractions in the rat and rhesus monkey were characterized by half-lives of approximately 4 and 8 days respectively. The sensitivity and precision of the analytical method for plasma protein S-sulfonate were improved by incorporation of 35S into the outer sulfur atom of the S-sulfonate moiety (R-S-35SO-3)
— id: 17596, year: 1978, vol: 21, page: 315, stat: Journal Article,

S-SULFONATES IN ELASTIC TISSUES FOLLOWING INVIVO EXPOSURE TO SULFITE
Gunnison, AF; Palmes, ED
1978 ;45(1):247-247, Toxicology & applied pharmacology
— id: 29785, year: 1978, vol: 45, page: 247, stat: Journal Article,

Comparative sulfite metabolism in the rat, rabbit, and rhesus monkey
Gunnison AF; Bresnahan CA; Palmes ED
1977 Oct;42(1):99-109, Toxicology & applied pharmacology
— id: 17597, year: 1977, vol: 42, page: 99, stat: Journal Article,

A model for the metabolism of sulfite in mammals
Gunnison AF; Palmes ED
1976 Oct;38(1):111-126, Toxicology & applied pharmacology
— id: 17599, year: 1976, vol: 38, page: 111, stat: Journal Article,

MODEL FOR INVIVO SULFITE OXIDATION
Gunnison, AF; Palmes, ED
1976 ;37(1):93-93, Toxicology & applied pharmacology
— id: 28748, year: 1976, vol: 37, page: 93, stat: Journal Article,

Personal sampler for nitrogen dioxide
Palmes ED; Gunnison AF; DiMattio J; Tomczyk C
1976 Oct;37(10):570-577, American Industrial Hygiene Association journal
A new type of personal sampler for gases in air, originally reported from this laboratory, has been adapted to measurement of NO2. The sampler depends on the transfer of NO2 by diffusion to a triethanolamine coated collector at the sealed end of a tube; the open end of the tube is exposed to the test environment. The devices are accurate, light, simple to use and have very good shelf life before and after sampling
— id: 17598, year: 1976, vol: 37, page: 570, stat: Journal Article,

PERSONAL SAMPLER FOR NITROGEN-DIOXIDE
Palmes, ED; Gunnison, AF; Dimattio, J; Gunnison, J; Tomczyk, C
1975 ;36(8):A15-A15, American Industrial Hygiene Association journal
— id: 28520, year: 1975, vol: 36, page: A15, stat: Journal Article,

S-sulfonates in human plasma following inhalation of sulfur dioxide
Gunnison AF; Palmes ED
1974 May;35(5):288-291, American Industrial Hygiene Association journal
— id: 17600, year: 1974, vol: 35, page: 288, stat: Journal Article,

INTERSPECIES VARIABILITY IN METABOLISM OF INGESTED SULFITE
Gunnison, AF; Gunnison, JT; Palmes, ED
1974 ;29(1):150-150, Toxicology & applied pharmacology
— id: 28359, year: 1974, vol: 29, page: 150, stat: Journal Article,

Persistence of plasma S-sulfonates following exposure of rabbits to sulfite and sulfur dioxide
Gunnison AF; Palmes ED
1973 Feb;24(2):266-278, Toxicology & applied pharmacology
— id: 17601, year: 1973, vol: 24, page: 266, stat: Journal Article,

Personal monitoring device for gaseous contaminants
Palmes ED; Gunnison AF
1973 Feb;34(2):78-81, American Industrial Hygiene Association journal
— id: 17602, year: 1973, vol: 34, page: 78, stat: Journal Article,

Sulfur dioxide: Sulfite. Interaction with mammalian serum and plasma
Gunnison, A F; Benton, A W
1971 Mar;22(3):381-388, Archives of environmental health
— id: 17603, year: 1971, vol: 22, page: 381, stat: Journal Article,

Biological effects of sulfur dioxide on animals, emphasizing the interaction of sulfite with noncellular fraction of blood
Gunnison, Albert F
[S.l. : s.n.], 1971,
Thesis -- Pennsylvania State University, 1971
— id: 1269, year: 1971, vol: , page: , stat: ,

Source of the ether-soluble organies of stings of the honey bee, Apis mellifera (Hymenoptera: Apidae)
Gunnison AF; Morse RA
1968 Jan;61(1):5-8, Annals of the Entomological Society of America
— id: 17604, year: 1968, vol: 61, page: 5, stat: Journal Article,

Sevin and Sticker tests in gypsy moth spray plots and resulting effects on honey bees, Saratoga and Washington Counties, New York : 1965 experiments
Morse, Robert A; Gunnison, Albert F
[S.l. : Cornell University Dept. of Entomology], 1965,
— id: 1268, year: 1965, vol: , page: , stat: ,

BEE VENOM TOLERANCE IN WHITE MICE IN RELATION TO DIET
BENTON, A W; MORSE, R G; GUNNISON, A F
1964 Sep 25;145:1448-1449, Science
— id: 72351, year: 1964, vol: 145, page: 1448, stat: Journal Article,