Pulmonary Toxicity and Environmental Contamination: Radicals, Electron Transfer, and Protection by Antioxidants

Part of the Reviews of Environmental Contamination and Toxicology book series (RECT, volume 201)


The pulmonary system is one of the main targets for toxicity. In the industrial age, there has been a large increase in atmospheric pollutants, including industrial products, particulates (asbestos and silica), cigarette smoke, ozone, nitrogen oxides, and substantial number of miscellaneous materials. In lung tissues, many adverse reactions result from exposure to these pollutants; some principal ones include asthma, chronic obstructive pulmonary disease (COPD), and cancer.

The emphasis of this review is on three mechanisms by which many pulmonary toxicants, usually as derived metabolites, induce their effects: electron transfer (ET) (electron movement from one site to another), reactive oxygen species (ROS), and oxidative stress (OS), involving cellular insults. The preponderance of bioactive substances or their metabolites have chemical groups that we believe may play an important role in the physiological responses connected with induction of pulmonary toxicity. Such chemical functionalities include quinones (or their phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced hydroxylamine and nitroso derivatives), and conjugated imines (or iminium species).


Reactive Oxygen Species Chronic Obstructive Pulmonary Disease Electron Transfer Adult Respiratory Distress Syndrome Pulmonary Toxicity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We are grateful to Angelica Ruiz and Thelma Chavez for editorial assistance.


  1. Adachi J, Ishii K, Tomita M, Fujita T, Nurhantari Y, Nagasaki Y, Ueno Y (2003) Consecutive administration of paraquat to rats induces enhanced cholesterol peroxidation and lung injury. Arch Toxicol 77:353–357.Google Scholar
  2. Ahamad, S, Ahamad A, White AW (2006) Purinergic signaling and kinase activation for survival in pulmonary oxidative stress and disease. Free Rad Biol Med 41:29–40.Google Scholar
  3. Andreadis AA, Hazen SL, Comhair SAA, Erzurum SC (2003) Oxidative and nitrosative events in asthma. Free Rad Biol Med 35:213–225.Google Scholar
  4. Attene-Ramos MS, Wagner ED, Gaskin HR, Plewa MJ (2007) Hydrogen sulfide induces direct radical-associated DNA damage. Mol Cancer Res 5:455–459.Google Scholar
  5. Baldwin RM, Shultz MA, Buckpitt AR (2005) Bioactivation of the pulmonary toxicants naphthalene and 1-nitronaphthalene by rat CYP2F4. J Pharmacol Exp Ther 312:857–865.Google Scholar
  6. Barchowsky A, O‗Hara KA (2003) Metal-induced cell signaling and gene activation in lung disease. Free Rad Biol Med 34:1130–1135.Google Scholar
  7. Barnes PJ, Shapiro SD, Pauwels RA (2003) Chronic obstructive pulmonary disease: Molecular and cellular mechanisms. Eur Respir J 22:672–688.Google Scholar
  8. Barreiro E, de la Puente B, Minguella J, Corominas JM, Serrano S, Hussain SNA, Gea J (2005) Oxidative stress and respiratory muscle dysfunction in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 171:1116–1124.Google Scholar
  9. Barroso-Moguel R, Villeda-Hernández J, Méndez-Armenta M, Santamaría A, Galván-Arzate S (1999) Alveolar lesions induced by sytemic administration of cocaine to rats. Toxicol Lett 110:113–118.Google Scholar
  10. Barthel E (1981) Increased risk of lung cancer in pesticide-exposed male agricultural workers. J Toxicol Environ Health 8:1027–1040.Google Scholar
  11. Baskar R, Li L, Moore PK (2007) Hydrogen sulfide-induces DNA damage and changes in apoptotic gene expression in human lung fibroblast cells. FASEB J 21:247–255.Google Scholar
  12. Battacharya R, Kumar P, Sachan AS (1994) Cyanide induced changes in dynamic pulmonary mechanics in rats. Indian J Physiol Pharmacol 38:281–284.Google Scholar
  13. Bebok Z, Varga K, Hicks JK, Venglarik CJ, Kovacs T, Chen L, Hardiman KM, Collawn JF, Sorscher EJ (2002) Reactive oxygen-nitrogen species decrease cystic fibrosis transmembrane conductance regulator expression and cAMP-mediated Cl secretion in airway epithelia. J Biol Chem 227:43041–43049.Google Scholar
  14. Beck-Speier I, Dayal N, Karg E, Kondrad L, Schumann G, Schulz H, Semmler M, Takenaka S, Stettmaier K, Bors W, Ghio A, Samet JM, Heyder J (2005) Oxidative stress and lipid mediators induced in alveolar macrophages by ultrafine particles. Free Rad Biol Med 38:1080–1092.Google Scholar
  15. Beeh KM, Beier J, Haas IC, Kornmann O, Micke P, Buhl R (2002) Glutathione deficiency of the lower respiratory tract in patients with idiopathic pulmonary fibrosis. Eur Resp J 19:1119–1123.Google Scholar
  16. Beltron R, Lee A (2001) Respiratory disorders. In: Lee A (ed) Adverse drug reactions. Pharmaceutical Press, London, pp. 137–155.Google Scholar
  17. Bond JA (1983) Bioactivation and biotransformation of 1-nitropyrene in liver, lung and nasal tissue of rats. Mutat Res 124:315–324.Google Scholar
  18. Bowler RP, Crapo JD (2002) Oxidative stress in allergic respiratory diseases. J Allergy Clin Immunol 110:345–356.Google Scholar
  19. Boysen G, Georgieva NI, Upton PB, Jayaraj K, Li Y, Walker VE, Swenberg JA (2004) Analysis of diepoxide-specific cyclic N-terminal globin adducts in mice and rats after inhalation exposure to 1,3-butadiene. Cancer Res 64:8517–8520.Google Scholar
  20. Briede JJ, Godschalk RWL, Emans MTG, de Kok TMC, van Agen E, van Maanen JMS, van Schooten F-J, Kleinjans JCS (2004) In vitro and in vivo studies on free radical and DNA adduct formation in rat lung and liver during benzo[a]pyrene metabolism. Free Rad Res 38:995–1002.Google Scholar
  21. Brown DM, Donaldson K, Borm PJ, Schins PR, Denhart M, Gilmour P, Jimenez LA, Stone V (2004a) Calcium and reactive oxygen species-mediated activation of transcription factors and TNFa cytokine gene expression in macrophages exposed to ultrafine particles. Am J Physiol 286:L344–L353.Google Scholar
  22. Brown LAS, Harris FL, Ping X-D, Gauthier TW (2004b) Chronic ethanol ingestion and the risk of acute lung injury: A role for glutathione availability? Alcohol 33:191–197.Google Scholar
  23. Casalino-Matsuda SM, Monzon ME, Conner GE, Salathe M, Forteza RM (2004) Role of hyaluronan and reactive oxygen species in tissue kallikrein-mediated EGF receptor activation in human airways. J Biol Chem 279:21606–21616.Google Scholar
  24. Castranova V (2004) Signaling pathways controlling the production of inflammatory mediators in response to crystalline silica exposure: Role of reactive oxygen/nitrogen species. Free Rad Biol Med 37:916–925.Google Scholar
  25. Chang LW, Lo W-S, Lin P (2005) Trans, trans-2,4-decadienal, a product found in cooking oil fumes, induces cell proliferation and cytokine production due to reactive oxygen species in human bronchial epithelial cells. Toxicol Sci 87:337–343.Google Scholar
  26. Chen F, Vallyathan V (2005) Molecular mechanisms of asbestos- and silica-induced lung cancer. In: Bachi D, Preuss HG (eds) Phytopharmaceuticals in cancer chemoprevention. CRC Press, Boca Raton, FL, pp. 41–62.Google Scholar
  27. Chen WJ, Chi EY, Smuckler EA (1977) Carbon tetrachloride-induced changes in mixed function oxidases and microsomal cytochromes in the rat lung. Lab Invest 36:388–394.Google Scholar
  28. Chen SJ, Wang JL, Chen JH, Huang RN (2002) Possible involvement of glutathione and p53 in trichloroethylene-and perchloroethylene-induced lipid peroxidation and apoptosis in human lung cancer cells. Free Rad Biol Med 15:464–472.Google Scholar
  29. Chen W, Bochmann F, Sun Y (2007) Effects of work related confounders on the association between silica exposure and lung cancer: A nested case-control study among Chinese miners and pottery workers. Int Arch Occup Environ Health 80:320–326.Google Scholar
  30. Cho H-Y, Kleeberger SR (2007) Genetic mechanisms of susceptibility to oxidative lung injury in mice. Free Rad Biol Med 42:433–445.Google Scholar
  31. Cho JH, Yang DK, Kim L, Ryu JS, Lee HL, Lim CM, Koh YS (2005) Inhaled nitric oxide improves the survival of the paraquat-injured rats. Vasc Pharmacol 42:171–178.Google Scholar
  32. Comhair SAA, Erzurum SC (2002) Antioxidant responses to oxidant-mediated lung diseases. Am J Physiol Lung Cell Mol Physiol 283:L246–L255.Google Scholar
  33. Cruzan G, Carlson GP, Turner M, Mellert W (2005). Ring-oxidized metabolites of styrene contribute to styrene-induced Clara-cell toxicity in mice. J Environ Toxicol Environ Health A 68:229–237.Google Scholar
  34. Csanady GA, Kessler W, Hoffmann HD, Filser JG (2003) A toxicokinetic model for styrene and its metabolite styrene-7,8-oxide in mouse, rat and human with special emphasis on the lung. Toxicol Lett 138:75–102.Google Scholar
  35. Daga MK, Chhabra R, Sharma B, Mishra TK (2003) Effects of exogeneous vitamin E supplementation on the levels of oxidants and antioxidants in chronic obstructive pulmonary disease. J Biosci 28:7–11.Google Scholar
  36. Dazy A-C, Auger F, Bailbe D, Blouquit S, Lombet A, Marano F (2003) The toxicity of H2O2 on the ionic homeostasis of airway epithelial cells in vitro. Toxicol In Vitro 17:575–580.Google Scholar
  37. Dietrich M, Block G, Hudes M, Morrow JD, Norkus EP, Traber MG, Cross CE, Packer L (2002) Antioxidant supplementation decreases lipid peroxidation biomarker F2-isoprostanes in plasma of smokers. Cancer Epidemiol Biomarkers Prev 11:7–13.Google Scholar
  38. Dobson AW, Weber S, Dorman DC, Lash LK, Erikson KM, Aschner M (2003) Oxidative stress is induced in the rat brain following repeated inhalation exposure to manganese sulfate. Biol Trace Elem Res 93:113–125.Google Scholar
  39. Donaldson K, Borm P (2007) Particle toxicology. CRC Press/Taylor & Francis, Boca Raton, FL, pp. 1–434.Google Scholar
  40. Donaldson K, Jimenez LA, Rahman I, Faux SP, MacNee W, Gilmour PS, Borm PJA, Schins RPF, Shi T, Stone, V (2004) Resiratory health effects of ambient air pollution particles: Role of reactive species. Lung Biol Health Dis 187:257–288.Google Scholar
  41. Dorman DC, Moulin FJ, McManus BE, Mahle KC, James RA, Struve MF (2002) Cytochrome oxidase inhibition induced by acute hydrogen sulfide inhalation: Correlation with tissue sulfide concentration in the rat brain, liver, lung, and nasal epithelium. Toxicol Sci 65:18–25.Google Scholar
  42. Durak, I, Güven T, Birey M, Oztürk HS, Kurtipek O, Yel M, Dikmen B, Canbolat O, Kavutcu M, Kaçmaz M (1996) Halothane hepatotoxicity and hepatic free radical metabolism in guinea pigs: The effects of vitamin E. Can J Anaesth 43:741–748.Google Scholar
  43. Elsayed NM, Omaye ST (2004) Biochemical changes in mouse lung after subcutaneous injection of the sulfur mustard 2-chlroethyl-4- chlorobutyl sulfide. Toxicol 199:195–206.Google Scholar
  44. Emmler J, Hermanns MI, Steinritz D, Kreppel H, Kirkpatrick CJ, Bloch W, Szinicz L (2007) Assessment of alterations in barrier functionality and induction of proinflammatory and cytotoxic effects after sulfur mustard exposure of an in vitro coculture model of the human alveolo-capillary barrier. Inhal Toxicol 19:657–665.Google Scholar
  45. Ergonul Z, Erdem A, Balkanci ZD, Kilinc K (2007) Vitamin E protects against lipid peroxidation due to cold-SO2 coexposure in mouse lung. Inhal Toxicol 19:161–168.Google Scholar
  46. Erikson KM, Dorman DC, Lash LH, Dobson AW, Aschner M (2004) Airborne manganese exposure differently affects end point of oxidative stress in age- and sex- dependent manner. Biol Trace Elem Res 100:49–62.Google Scholar
  47. Fakhrzadeh L, Laskin JD, Gardner CR, Laskin DL (2004a) Superoxide dismutase-overexpressing mice are resistant to ozone-induced tissue injury and increases in nitric oxide and tumor necrosis factor-α. Respir Cell Mol Biol 30:280–287.Google Scholar
  48. Fakhrzadeh L, Laskin JD, Laskin DL (2004b) Ozone-induced production of nitric oxide and TNF-α and tissue injury are dependent on NF-kB p50. Am Physiol Soc 287:L279–L285.Google Scholar
  49. Fedan JS, Fedan KB, Hubbs AF (2006) Popcorn workers lung: In vitro exposure to diacetyl, an ingredient in microwave butter flavoring, increases reactivity to methacholine. Toxicol Appl Pharmacol 215:17–22.Google Scholar
  50. Fubini B, Hubbard A (2003) Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis. Free Rad Biol Med 34:1507–1516.Google Scholar
  51. Giovanetti A, Rossi L, Mancuso M, Lombardi CC, Marasco MR, Manna F, Altavista P, Massa EM (1998) Analysis of lung damage induced by trichoroethylene inhalation in mice fed diets with low, normal, and high copper content. Toxicol Pathol 26:628–635.Google Scholar
  52. Gonzales-Flecha B (2004) Oxidant mechanisms in response to ambient air particles. Mol Aspects Med 25:169–182.Google Scholar
  53. Grasemann H, Tschiedel E, Groch M, Klepper J, Ratjen F (2007) Exhaled nitic oxide in chlorine after accidental exposure to chlorine gas. Inhal Toxicol 19:895–898.Google Scholar
  54. Green FH, Schürch S, de Sanctis, GT, Wallace JA, Cheng S, Prior M (1991) Effects of hydrogen sulfide exposure on surface properties of lung surfactant. J Appl Physiol 70:1943–1949.Google Scholar
  55. Hadjiivanova NB, Salovski PZ, Groseva MM, Charakchieva SB, Nechev CK (1987) Early effects of n-hexane and irradiation on the lung surfactant system. Acta Physiol Pharmacol Bulg 13:25–29.Google Scholar
  56. Hagiwara S-I, Ishii Y, Kitamura S (2000) Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice. Am J Respir Crit Care Med 162:225–231.Google Scholar
  57. Halliwell B, Gutteridge JMC (1999) Free radicals in biology and medicine. Oxford University Press, New York, (a) pp. 1–897, (b) pp. 679–684, (c) pp. 27, 581, (d) p. 576, (e) pp. 27, 55, 86, 91.Google Scholar
  58. Hammerschmidt S, Wahn H (2004) The oxidants hypochorite and hydrogen peroxide induce distinct patterns of acute lung injury. Biochim Biophys Acta Mol Basis Dis 1690:258–264.Google Scholar
  59. Henderson RF, Belinsky SA (1993) Biological markers of respiratory tract exposure. In: Gardner DE, Crapo JD, McClellan RO (eds) Toxicology of the lung. Raven Press, New York, pp. 253–282.Google Scholar
  60. Hessel PA, Herbert FA, Melenka LS, Yoshida K, Nakaza M (1997) Lung health in relation to hydrogen sulfide exposure in oil and gas workers in Alberta, Canada. Am J Ind Med 31:554–557.Google Scholar
  61. Hickman-Davis JM, Fang FC, Nathan C, Shepherd VL, Voelker DR, Wright JR (2001) Lung surfactant and reactive oxygen-nitrogen species: Antimicrobial activity and host–pathogen interactions. Am J Physiol Cell Mol Physiol 281:L517–L523.Google Scholar
  62. Hong HH, Houle CD, Ton TV, Sills RC (2007) K-ras mutations in lung tumors and tumors from other organs are consistent with a common mechanism of ethylene oxide tumorigenesis in the B6C3F1 mouse. Toxicol Pathol 35:81–85.Google Scholar
  63. Hoppin JA, Ulmer R, London SJ (2004) Phthalates exposure and pulmonary function. Environ Health Perspect 112:571–574.Google Scholar
  64. IIgazli A, Sengul C, Maral H, Ozden M, Ercin C (2004) The effects of thinner inhalation on superoxide dismutase activities, malondialdehyde and glutathione levels in rat lungs. Clin Chim Acta 343:141–144.Google Scholar
  65. Ikeda K, Kumagai Y, Nagano Y, Matsuzawa N, Kojo S (2003) Change in the concentration of vitamins C and E in rat tissues by paraquat administration. Biosci Biotechnol Biochem 67:1130–1131.Google Scholar
  66. Ito K, Sumiko H, Yusuke K, Kawaishi S (2005) Mechanism of site-specific DNA damage induced by ozone. Mutat Res Gen Toxicol Environ Mutagen 585:60–70.Google Scholar
  67. Jacintho JD, Kovacic P (2003) Neurotransmission and neurotoxicity by nitric oxide, catecholamines and glutamate: Unifying themes of reactive oxygen species and electron transfer. Curr Med Chem 10: 2693–2704.Google Scholar
  68. Jurczyk AS, Barzdo M, Jankowska B, Meissner E, Berent J, Kordel K, Szram S (2003) Influence of selected alcohols on oxidative stress parameters in rat lungs. Z Zagadnien Nauk Sadowych 55:50–59.Google Scholar
  69. Kaufmann W, Mellert W, van Ravenzwaay B, Landsiedel R, Poole A (2005) Effects of styrene and its metabolites on different lung compartments of the mouse-cell proliferation and histomorphology. Regul Toxicol Pharmacol 42:24–36.Google Scholar
  70. Kelly FJ, Mudway IS (2003) Protein oxidation at the air–lung interface. Amino Acids 25:375–396.Google Scholar
  71. Kim D-H, Suh Y-S, Mun K-C (2004) Tissue levels of malondialdehyde alter passive smoke exposure of rats for a 24-week period. Nicotine Tob Res 6:1039–1042.Google Scholar
  72. King LC, Kohan MJ, Ball LM, Lewtas J (1984) Mutagenicity of 1-nitropyrene metabolites from lung-S9. Cancer Lett 22:255–262.Google Scholar
  73. Knaapen AM, Borm PJA, Albrecht C, Schins RPF (2004) Inhaled particles and lung cancer, Part A: Mechanisms. Int J Cancer 109:799–809.Google Scholar
  74. Kovacic P (2003) Mechanism of organophosphates (nerve gases and pesticides) and antidotes: Electron transfer and oxidative stress. Curr Med Chem 10:2705–2710.Google Scholar
  75. Kovacic P (2005) Role of oxidative metabolites of cocaine in toxicity and addiction: Oxidative stress and electron transfer. Med Hypotheses 64:350–356.Google Scholar
  76. Kovacic P (2006) Novel electrochemal approach to enhanced toxicity of 4-oxo-2-nonenal ve. 4-hydroxy-2-nonenal (role of imine): Oxidative stress and therapeutic modalities. Med Hypotheses 67:151–156.Google Scholar
  77. Kovacic P (2007) What is the basic cause of diacetyl toxicity in popcorn lung disease? Possible remedies, submitted.Google Scholar
  78. Kovacic P, Becvar LE (2000) Mode of action of anti-infective agents: Emphasis on oxidative stress and electron transfer. Curr Pharm Des 6:143–167.Google Scholar
  79. Kovacic P, Cooksy AL (2005) Unifying mechanism for toxicity and addiction by abused drugs: Electron transfer and reactive oxygen species. Med Hypotheses 64:366–367.Google Scholar
  80. Kovacic P, Jacintho JD (2001a) Mechanisms of carcinogenesis: Focus on oxidative stress and electron transfer. Curr Med Chem 8:773–796.Google Scholar
  81. Kovacic P, Jacintho JD (2001b) Reproductive toxins: Pervasive theme of oxidative stress and electron transfer. Curr Med Chem 8:863–892.Google Scholar
  82. Kovacic P, Jacintho JD (2003) Systemic lupus erythematosus and other autoimmune diseases from endogenous and exogenous agents: Unifying theme of oxidative stress. Mini Rev Med Chem 3:568–575.Google Scholar
  83. Kovacic P, Osuna JA (2000) Mechanisms of anticancer agents: Emphasis on oxidative stress and electron transfer. Curr Pharm Des 6:277–309.Google Scholar
  84. Kovacic P, Pozos RS (2006) Cell signaling (mechanism and reproductive toxicity): Redox chains, electrons, relays, conduit, electrochemistry, and other medical implications. Birth Defects Res C 8:333–344.Google Scholar
  85. Kovacic P, Somanathan R (2005) Neurotoxicity: The broad framework of electron transfer, oxidative stress and protection by antioxidants. Curr Med Chem Cent Nerv Syst Agents 5:249–258 (and references therein).Google Scholar
  86. Kovacic P, Somanathan R (2006a) Beneficial effects of antioxidants in relation to carcinogens, toxins and various illnesses. In: Panglossi HV (ed) Frontiers in antioxidants research. Nova Science, Hauppauge, NY, Ch. 1, pp. 1–38.Google Scholar
  87. Kovacic P, Somanathan R (2006b) Alcohol mechanisms, cell signaling, toxicity, addiction, prevention, therapy and beneficial effects. In: Brozner EY (ed) New research on alchohol abuse and alcoholism. Nova Science, Hauppauge, NY, Ch. 4, pp. 40–101.Google Scholar
  88. Kovacic P, Somanathan R (2007) Mechanism of tumorigenesis: Focus on oxidative stress, electron transfer and antioxidants. In: Wong DK (ed), Tumorigenesis research advances. Nova Science, Hauppauge, NY, Ch. 2.Google Scholar
  89. Kovacic P, Thurn LA (2005) Cardiovascular toxins from the perspective of oxidative stress and electron transfer. Curr Vasc Pharmacol 3:107–117.Google Scholar
  90. Kovacic P, Sacman A, Wu-Weis M (2002) Nephrotoxins: Widespread role of oxidative stress and electron transfer. Curr Med Chem 9:823–847.Google Scholar
  91. Kovacic P, Pozos, RS, Somanathan R, Shangari R, O‗Brien PJ (2005) Mechanism of mitochondrial uncouplers, inhibitors, and toxins: Focus on electron transfer, free radicals, and structure–activity relationships. Curr Med Chem 5:2601–2623.Google Scholar
  92. Lai C-H, Liou S-H, Lin H-C, Shih T-S, Tsai P-J, Chen J-S, Yang T, Jaakkola JJK, Stickland PT (2005) Exposure to traffic exhausts and oxidative DNA damage. Occup Environ Med 62:216–222.Google Scholar
  93. Lame MW, Jones AD, Wilson DW, Segall HJ (2003) Protein targets of 1,4-benzoquinone and 1,4-naphthaquinone in human bronchial epithelial cells. Proteomics 3:479–495.Google Scholar
  94. Lang SA, Maron MB (1991) Hemodynamic basis for cocaine-induced pulmonary edema in dogs. J Appl Physiol 71:1166–1170.Google Scholar
  95. Langen RCJ, Korn SH, Wouters EFM (2003) ROS in the local and systemic pathogenesis of COPD. Free Rad Biol Med 35:226–235.Google Scholar
  96. Laskin DL, Gardner CR, Gerecke DR, Laskin JD (2004) Ozone-induced lung injury: Role of macrophages and inflammatory mediators. Lung Biol Health Dis 187:289–316.Google Scholar
  97. Lee KS, Kim SR, Park SJ, Park HS, Min KH, Jin SM, Lee MK, Kim UH, Lee YC (2006) Peroxisome proliferators activated receptor-γ modulates reactive oxygen species generation and activation of nuclear factor-kB and hypoxia-inducible factor 1α in allergic airway disease of mice. J Allergy Clin Immunol 118:120–127.Google Scholar
  98. Leikauf G, Driscoll K (1993) Cellular approaches in respiratory tract toxicology. In: Gardner DE, Crapo JD, McClellan RO (eds) Toxicology of the lung. Raven Press, New York, pp. 335–370.Google Scholar
  99. Levitt JD (1975) The biochemical basis of anesthetic toxicity. Surg Clin North Am 55:801–818.Google Scholar
  100. Lewis AB, Taylor MD, Roberts JR, Leonard SS, Shi X, Antonini JM (2003) Role of metal-induced reactive oxygen species generation in lung responses caused by residual oil fly ash. J Biosci 28:13–18.Google Scholar
  101. Li N, Hao M, Phalen RF, Hinds WC, Nel AE (2003) Particulate air pollutants and asthma. A paradigm for the role of oxidative stress in PM-induced adverse health effects. Clin Immunol 109:250–265.Google Scholar
  102. Liang X, Wang P-H (2004) Phosgene-induced oxidative injury in rats and effects of NaHCO3 buffer. Disi Jumji Daxue Xuebao 25:1235–1237.Google Scholar
  103. Lungarella G, Barni-Comparini I, Fonzi L (1984) Pulmonary changes in rabbits by long-term exposure to n-hexane. Arch Toxicol 55:224–228.Google Scholar
  104. Luo JC, Cheng TJ, Kuo HW, Chang MJ (2004) Decreased lung function associated with occupatoional exposure to epichlorohydrin and the modification effects of glutathione S-transferase polymorphism. J Occup Environ Med 46:280–286.Google Scholar
  105. Machado RF, Nerker, M-VL, Dweik RA, Hammel J, Janocha A, Pyle J, Laskowski D, Jennings C, Arroliga AA, Erzurum SC (2004) Nitric oxide and pulmonary arterial pressures in pulmonary hypertension. Free Rad Biol Med 37:1010–1017.Google Scholar
  106. MacNee W (2005) Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2:50–60.Google Scholar
  107. Manoury B, Nenan S, Leclerc O, Guenon I, Boichot E, Planquois J-M, Bertrand CP, Lagente V (2005) The absence of reactive oxygen species production protects mice against bleomycin-induced pulmonary fibrosis. Respir Res 6:11.Google Scholar
  108. Mazzullo M, Colacci A, Grilli S, Prodi G, Arfellini G (1984) In vivo and in vitro binding of epichlorohydrin to nucleic acids. Cancer Lett 23:81–90.Google Scholar
  109. Meier BW, Gomez JD, Kirichenko OV, Thompson JA (2007) Mechanistic basis for inflammation and tumor promotion in lungs of 2,6-di-tert-butyl-4-methylphenol-treated mice: Electrophilic metabolites alkylate and inactivate antioxidant enzymes. Chem Res Toxicol 20:199–207.Google Scholar
  110. Meng Z, Liu Y (2007) Cell morphological ultrastructural changes in various organs from mice exposed by inhalation to sulfur dioxide. Inhal Toxicol 19:543–551.Google Scholar
  111. Meng Z, Qin G, Zhang, B, Geng H, Bai Q, Bai W, Liu, C (2003) Oxidative damage of sulfur dioxide inhalation on lungs and hearts of mice. Environ Res 93:285–292.Google Scholar
  112. Mikhaĭlova A, Petrova S, Donchev N (1987) Biochemical and histological research on lung tissue in experimental carbon disulfide exposure. Probl Khig 12:103–108.Google Scholar
  113. Miller FJ, Overton JH, Kimbell JS, Russell ML (1993) Regional respiratory tract absorption of inhaled reactive gases. In: Gardner DE, Crapo JD, McClellan RO (eds) Toxicology of the lung. Raven Press, New York, pp. 485–525.Google Scholar
  114. Mossman BT, Gee JBL (1993) Pulmonary reactions and mechanisms of toxicity of inhaled fibers. In: Gardner DE, Crapo JD, McClellan RO (eds) Toxicology of the lung. Garden Press, New York, pp. 371–387.Google Scholar
  115. Munoz X, Cruz MJ, Orriols R, Torres F, Espuga M, Morell F (2004) Validation of specific inhalation challenge for the diagnosis of occupational asthma due to persulfate salts. Occup Environ Med 61:861–866.Google Scholar
  116. Neal RA, Halpert J (1982) Toxicology of thiono-sulfur compounds. Annu Rev Pharmacol Toxicol 22:321–339.Google Scholar
  117. Nistal de Paz F, Fernández JJO, González JA, Colubi LC (1984) Pulmonary complications related to cocaine consumption. Ann Med Int 16:371–379.Google Scholar
  118. Ortega R, Fayard B, Salomé M, Devés G, Susini J (2005) Chromium oxidation state imaging in mammalian cells exposed in vitro to soluble or particulate chromate compounds. Chem Res Toxicol 18:1512–1519.Google Scholar
  119. Pääkkö P, Anttila S, Sormunen R, Ala-kokko L, Peura, R, Ferrans VJ, Ryhänen L (1996) Biochemical and morphological characterization of carbon tetrachloride-induced lung fibrosis in rats. Arch Toxicol 70:540–552Google Scholar
  120. Pant SC, Vijayaraghavan R, Das Gupta S (1993) Sarin induced lung pathology and protection by standard therapy regime. Biomed Environ Sci 6:103–111.Google Scholar
  121. Phimister A J, Lee MG, Morin D, Buckpitt AR, Plopper CG (2004) Glutathione depletion is a major determinant of inhaled naphthalene respiratory toxicity and naphthalene metabolism in mice. Toxicol Sci 82:268–278.Google Scholar
  122. Phimister AJ, Nagasawa HT, Buckpitt AR, Plopper CG (2005) Prevention of naphthalene-induced pulmonary toxicity by glutathione prodrugs: Roles for glutathione depletion in adduct formation and cell injury. J Biochem Mol Toxicol 19:42–51.Google Scholar
  123. Pinho RA, Chiesa D, Mezzomo KM, Andrades ME, Bonatto F, Gelain D, Pizzol F, Knorst MM, Moreira JC (2002) Oxidative stress in chronic obstructive pulmonary disease patients submitted to rehabilitation program. Resp Med 101:1830–1835.Google Scholar
  124. Pluzhnikov N, Tyaptin A, Zemlyanoy A, Varlashova M, Torkounov P, Lupachyov Yu (2004) The state of antioxidant system in brain of rats in the toxic pulmonary edema. Biomed Khim 50:57–63Google Scholar
  125. Poli G, Cheesman KH, Dianzani MU, Slater TF (1989) Free Radicals in the pathogenesis of liver injury. Pergamon, New York, pp. 1–330.Google Scholar
  126. Porter DW, Millecchia L, Robinson VA, Hubbs A, Willard P, Pack D, Ramsay D, McLaurin J, Khan A, Landsittel D, Teass A, Castranova V (2002) Enhanced nitric oxide and reactive oxygen species production and damage after inhalation of silica. Am J Physiol Lung Cell Mol Physiol 283:L485–L493.Google Scholar
  127. Proudfoot AT (2003) Pentachlorophenol poisoning. Toxicol Rev 22:3–11.Google Scholar
  128. Prows DR, McDowell SA, Aronow BJ, Leikauf GD (2003) Genetic susceptibility to nickel-induced acute lung injury. J Chemosphere 51:1139–1148.Google Scholar
  129. Pryor WA, Houk KN, Foote CS, Fukuto JM, Ignarro LJ, Squadrito GL, Davies KJ (2006) Free radical biology and medicine: It‗s a gas, man! Free Rad Biol Med 291:R491–R511.Google Scholar
  130. Puhakka A (2005) Nitric oxide synthases and reactive oxygen species damage in pleural and lung tissues and neoplasia. University of Helsinki, Oulu.Google Scholar
  131. Pyykkö K (1983) Time-course of effects of toluene on microsomal enzymes in rat liver, kidney and lung during and after inhalation exposure. Chem Biol Interact 44:299–310.Google Scholar
  132. Qiu R, Jiang Y, Fan W-C (2004) Mechanism of smoke nitrogen oxides on inhalation lung mediated by peroxynitrite. Xiaofang Kexue Yu Jishu Bianjibu 23:421–424.Google Scholar
  133. Rahman I (2002) Oxidative stress and gene transcription in asthma and chronic obstructive pulmonary disease: Antioxidant therapeutic targets. Curr Drug Targets Inflamm Allergy 1:291–315.Google Scholar
  134. Rahman I (2003) Oxidative stress, chromatin remodeling and gene transcription in inflammation and chronic lung diseases. J Biochem Mol Biol 36:95–109.Google Scholar
  135. Rahman I, MacNee W (2000) Regulation of redox glutathione levels and gene transcription in lung inflammation: Therapeutic approaches. Free Rad Biol Med 28:1405–1420.Google Scholar
  136. Rahman I, Swarska E, Henry M, Stolk J, MacNee W (2000) Is there any relationship between plasma antioxidant capacity and lung function in smokers and in patients with chronic obstructive pulmonary disease? Thorax 55:189–193.Google Scholar
  137. Reed M, Monske M, Lauer F, Meserole S, Born J, Burchiel S (2003) Benzo[a]pyrene diones are produced by photochemical and enzymatic oxidation and induce concentration-dependent decreases in the proliferative state of human pulmonary epithelial cells. J Toxicol Environ Health A 66:1189–1205.Google Scholar
  138. Rhoden CR, Lawrence J, Godleski JJ, Gonzalez-Flecha B (2004) N-Acetylcysteine prevents lung inflammation after short-term inhalation exposure to concentrated ambient particles. Toxicol Sci 79:296–303.Google Scholar
  139. Risch A, Ramroth H, Raedts V, Rajaee-Behbahani N, Schmezer P, Bartsch H, Becher, H, Dietz A (2003) Laryngeal cancer risk in Caucasians is associated with alcohol and tobacco consumption but not modified by genetic polymorphisms in class I alcohol dehydrogenases ADH1B and ADH1C, and glutathione-S-transferases GSTM1 and GSTT1. Pharmacogenetics 13:225–230.Google Scholar
  140. Robin ED, Wong RJ, Ptashne KA (1989) Increased lung water and ascites after massive cocaine overdosage in mice and improved survival related to beta-adrenergic blockage. Ann Intern Med 110:202–207.Google Scholar
  141. Romieu I, Trenga C (2001) Diet and obstructive lung diseases. Epidemiol Rev 23:268–287.Google Scholar
  142. Ryter SW, Otterbein LE (2004) Carbon monoxide in biology and medicine. Bioessays 26:270–280.Google Scholar
  143. Sadowska AM, Manuel-Keenoy B, De Backer WA (2007) Antioxidant and anti-inflammatory efficacy of NAC in the treatment of COPD: Discordant in vitro and in vivo dose-effects: A review. Pulmon Pharmcol Ther 20:9–22.Google Scholar
  144. Sahu SC, Lowther DK, Jones SL (1982) Biochemical response of rat lung to inhaled n-hexane. Toxicol Lett 12:13–17.Google Scholar
  145. Salnikow K, Su W, Blagosklonny MV, Costa M (2000) Carcinogenic metals induce hypoxia-inducible factor-stimulated transcription by reactive oxygen species independent mechanism. Canc Res 60:3375–3378.Google Scholar
  146. Schmiederer M, Knutson E, Muganda P, Albrecht T (2005) Acute exposure of human lung cells to 1.3-butadiene diepoxide results in G1 and G2 cell cycle arrest. Environ Mol Mutagen 45:354–364.Google Scholar
  147. Sciuto AM, Cascio MBM, Moran TS, Forster JS (2003) The fate of antioxidant enzymes in bronchoalveolar lavage fluid over 7 days in mice with acute lung injury. Inhal Toxicol 15:675–685.Google Scholar
  148. Seguy N, Hildebrand HF, Haguenoer JM (1994) Toxic action of ethylene oxide on pulmonary cells (L132) cultured under aerobic conditions. Toxicol Lett 70:23–32.Google Scholar
  149. Shaheen SO, Sterne JAC, Thompson RL, Songhurst CE, Margetts BM, Burney,PGJ (2001) Dietery antioxidants and asthma in adults. Am J Crit Care Med 164:1823–1828.Google Scholar
  150. Shi H, Hudson LG, Ding W, Wang S, Cooper KL, Liu S, Chen Y, Shi X, Liu KJ (2004) Arsenite causes DNA damage in keratinocytes via generation of hydroxyl radicals. Chem Res Toxicol 17:871–878.Google Scholar
  151. Shukla A, Gulumian M, Hei TK, Kamp D, Rahman Q, Mossman BT (2003a) Multiple roles of oxidants in the pathogenesis of asbestos-induced diseases. Free Rad Biol Med 34:1117–1119.Google Scholar
  152. Shukla A, Ramos-Nino M., Mossman B (2003b) Cell signaling and transcription factor activation by asbestos in lung injury and disease. Int J Biochem Cell Biol 35:1198–1209.Google Scholar
  153. Smit HA (2001) Chronic obstructive pulmonary disease, asthma and protective effects of food intake: From hypothesis to evidence? Respir Res 2:261–264.Google Scholar
  154. Sosenko IR (1993) Antenatal cocaine exposure produces accelerated surfactant maturation without stimulation of antioxidant enzyme development in the late gestation rat. Pediatr Res 33:327–331.Google Scholar
  155. Sugimoto R, Kumagai Y, Nakai Y, Ishii T (2005) 9,10-Phenanthroquinone in diesel exhaust particles down regulates Cu, Zn-SOD and HO-1 in human pulmonary epithelial cells: Intracellular iron scavenger 1,10-phenanthroline affords protection against apoptosis. Free Rad Biol Med 38:388–395.Google Scholar
  156. Susskind H, Weber DA, Volkow ND, Hitzemann R (1991) Increased lung permeability following long-term use of free-base cocaine (crack). Chest 100:903–909.Google Scholar
  157. Tabak C, Arts ICW, Smit HA, HeederikD, Kromhout D (2001) Chronic obstructive pulmonary disease and intake of catechins, flavonols, and flavones. Am J Respir Crit Care Med 164:61–64.Google Scholar
  158. Tokunaga I, Gotohda T, Ishigami A, Kitamura, O, Kubo S-I (2003) Toluene inhalation induced 8-hydroxy-2′-deoxyguanosine formation as the peroxidative degeneration in rat organs. Legal Med 5:34–41.Google Scholar
  159. Tomasi A, Billing S, Garner A, Slater TF, Albano E (1983) The metabolism of halothane by hepatocytes: A comparison between free radical spin trapping and lipid peroxidation in relation to cell damage. Chem Biol Interact 46:353–368.Google Scholar
  160. Torkelson TR, Oyen F, Rowe VK (1976) The toxicity of chloroform as determined by single and repeated exposure of laboratory animals. Am Ind Hyg Assoc 37:697–705.Google Scholar
  161. Turi JL, Yang F, Garrick MD, Piantadosi CA, Ghio, AJ (2004) The iron cycle and oxidative stress in the lung. Free Rad Biol Med 36:850–857.Google Scholar
  162. Upadhyay D, Kamp DW (2003) Asbestos-induced pulmonary toxicity: Role of DNA damage and apoptosis. Exp Biol Med 228:650–659.Google Scholar
  163. Valacchi G, Pagnin E, Corbacho AM, Olano E, Davis PA, Packer L, Cross CE (2004) In vivo ozone exposure induces antioxidant/stress-related responses in murine lung and skin. Free Rad Biol Med 36:673–681.Google Scholar
  164. Valavanidis A, Fiotakis K, Bakea E, Vlahogianni T (2005) Electron paramagnetic resonance of the generation of reactive oxygen species catalyzed by transition metals and quinoid redox cycling by inhalable ambient particulate matter. Redox Rep 10:37–51.Google Scholar
  165. van der Vliet A, Eiserich JP, Shigenaga MK, Cross CE (1999) Reactive nitrogen species and tyrosine nitration in the respiratory tract. Am J Respir Crit Care Med 160:1–9.Google Scholar
  166. Van Helden HPM, Kuijpers WC, Diemel RV (2004) Asthmalike symptoms following intratracheal exposure of guinea pigs to sulfur mustard aerosol: Therapeutic efficacy of exogenous lung surfactant curosurf and salbutamol. Inhal Toxicol 16:537–548.Google Scholar
  167. Vassilakopoulos T, Hussain, SNA (2007) Ventilatory muscle activation and inflammation: Cytokines, reactive oxygen species, and nitric oxide. J Appl Physiol 102:1687–1695.Google Scholar
  168. Vettori MV, Caglieri A, Goldoni M, Catoldi AF, Dare E, Alinovi R, Ceccatelli S, Mutti A (2005) Analysis of oxidative stress in SK-N-MC neurons exposed to styrene-7,8-oxide. Toxicol In Vitro 19:11–20.Google Scholar
  169. Vujaskovic Z, Batinic-Haberle I, Rabbani ZN, Feng Q-F, Kang SK, Spasojevic I, Samulski TV, Fridovich I, Dewhirst MW, Anscher MS (2002) A small molecular weight catalytic metalloporphyrin antioxidant with superoxide dismutase (SOD) mimetic properties protects lungs from radiation-induced injury. Free Rad Biol Med 33:857–863.Google Scholar
  170. Waldman WJ, Kristovich R, Knight DA, Dutta PK (2007)Inflammatory properties of iron-containing carbon nanoparticles. Chem Res Toxicol 20:1149–1154.Google Scholar
  171. Wang L, Medan D, Mercer R, Overmiller D, Leonard S, Castranova V, Shi X, Ding M, Huang C, Rojanasakul Y (2003) Vanadium-induced apoptosis and pulmonary inflammation in mice: Role of reactive oxygen species. J Cell Physiol 195:99–107.Google Scholar
  172. Wang Q-S, Zheng Y-M, Dong L, Ho Y-S, Guo Z, Wang Y-X (2007) Role of mitochondrial reactive oxygen species in hypoxia-dependent increase in intracellular calcium in pulmonary artery myocytes. Free Rad Biol Med 42:642–653.Google Scholar
  173. Watt BE, Proudfoot AT, Vale JA (2004) Hydrogen peroxide poisoning. Toxicol Rev 23:51–57.Google Scholar
  174. Wedgwood S, Black SM (2003) Role of reactive oxygen species in vascular remodeling associated with pulmonary hypertension. Antioxid Redox Signal 5:759–769.Google Scholar
  175. Willis RJ, Recknagal RO (1979) Potentiation by carbon tetrachloride of NADPH-dependent lipid peroxidation in lung microsomes. Toxicol Appl Pharmacol 47:89–94.Google Scholar
  176. Witschi H (1997) Selected examples of free-radical mediated lung injury. In: Wallace KB (ed) Free radical toxicology. Taylor & Francis, London, pp. 279–293.Google Scholar
  177. Woo C-H, Yoo M-H, You H-J, Cho S-H, Mun, Y-C, Seong C-M, Kim J-H (2003) Transepithelial migration of neutrophils in response to leukotriene B4 is mediated by a reactive oxygen species-extracellular signal-regulated kinase-linked cascade. J Immunol 170:6273–6279.Google Scholar
  178. Wu KY, Ranasinghe A, Upton PB, Walker VE, Swenbwerg JA (1999) Molecular dosimetry of endogenous and ethylene oxide-induced N7-(2-hydroxyethyl) guanine formation in tissues of rodents. Carcinogenesis 20:1787–1792.Google Scholar
  179. Xi Z, Chao F, Yang, D, Sun Y, Li G, Zhan H, Zhan W, Yang Y, Liu H (2004) Experimental study of the DNA damage induced by formaldehyde. Huanjiing Kexue Xuebao 24:719–722.Google Scholar
  180. Xia T, Korge P, Weiss JN, Li N, Venkatesen MI, Sioutas C, Nel A (2004) Quinones and aromatic chemical compounds in particulate matter induce mitochondrial dysfunction: Implications for ultrafine particle toxicity. Environ Health Perspect 112:1347–1358.Google Scholar
  181. Xie J, Fan R (2007) Protein oxidation and DNA–protein crosslink induced by sulfur dioxide in lungs, livers, and hearts from mice. Inhal Toxicol 19:759–765.Google Scholar
  182. Yang H-B, Peng K-L, Zhao S-L, Chu Q-L, Lu C-R, Liu Y, Liu C, Yang L (2005) Exploring the effects of ammonium perchlorate on pulmonary fibrosis. Huanjing Yu Zhiye Yixue 22:43–45.Google Scholar
  183. Yang YG, Huang ZX, Cheng X (2006) Lung, liver and kidney impairment caused by inhalation of normal hexane. Chin J Ind Hyg Occup Dis 24:292–294.Google Scholar
  184. Yin XJ, Ma JYC, Antonini JM, Castranova VM, Ma JKH (2004) Roles of reactive oxygen species and heme oxygenase-1 in modulation of alveolar macrophage-mediated pulmonary immune responses to Listeria monocytogenes by diesel exhaust particles. Toxicol Sci 82:143–153.Google Scholar
  185. Yoon BI, Hirabayashi Y, Kawasaki Y, Tsuboi I, Ott T, Kodama Y, Kanno J, Kim DY, Willecke K, Inoue T (2004) Exacerbation of benzene pneumotoxicity in connexin 32 knockout mice: Enhanced proliferation of CYP2E1-immunoreactive alveolar epithelial cells. Toxicology 195:19–29.Google Scholar
  186. Yu G, Liu J, Li T, Li L, Li W, Zhu J, Li X (2004) Effects of formaldehyde on lung histomorphology and level of lipid peroxide in mice. Jilin Daxue Xuebao Yixueban 30:888–889.Google Scholar
  187. Yuan Z, Schellekens H, Warner L, Janssen-Heininger J, Burch P, Heintz NH (2003) Reactive nitrogen species block cell re-entry through sustained production of hydrogen peroxide. Am J Res Cell Mol Biol 26:705–712.Google Scholar
  188. Zaher TE, Miller EJ, Morrow DMP, Javdan M, Mantell LL (2007) Hyperoxia-induced signal transduction pathways in pulmonary epithelial cells. Free Rad Biol Med 42:897–908.Google Scholar
  189. Zhang Q, Sun S, Wang Z, Yang D (2004) Effects of formaldehyde on activities of antioxidase by subchronic inhalation in mice. Disi Junyi Daxue Xuebao 24:2206–2207.Google Scholar
  190. Zhang S, Villalta PW, Wang M, Hecht S (2007) Detection and quantitation of acrolein-derived 1,N2-propanodeoxyguanosine adducts in human lung by liquid chromatography-electrospray ionization-tandem mass spectrometry. Chem Res Toxicol 20:565–571.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Department of ChemistrySan Diego State UniversitySan DiegoUSA
  2. 2.Centro de Graduados e Investigación delInstituto Tecnológico de TijuanaB.C. Mexico

Personalised recommendations