Zinc Toxicology Following Particulate Inhalation

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mechanical ventilation for eight Ross G. Cooper Abstract days).[3] The patient left hospital 10 Division of Physiology, The current mini-review describes the toxic effects of zinc days after extubation. Spirometry at Birmingham City University, inhalation principally in the workplace and associated this time revealed a restrictive defect 704 Baker Building complications with breathing and respiration. The [3] (vital capacity 50% predicted). Franchise Street, Perry International ClassiÞ cation of Functioning, Disability and Barr, Birmingham B42 Health Criteria were used to speciÞ cally select articles. Acute metal fume fever is commonly 2SU, UK. Most of the commercial production of zinc involves the associated with zinc inhalation via E-mail: rgcooperuk@ galvanizing of iron and the manufacture of brass. The welding, galvanizing, brass plating, yahoo.com recommended daily allowance for adults is 15 mg zinc/ dyes and electroplating.[4] Zinc severely day. Metal fume fever associated with inhalation of fumes impedes mitochondrial functions of ZnO is characterized by fatigue, chills, fever, myalgias, attenuating ATP production.[5] Potential cough, dyspnea, leukocytosis, thirst, metallic taste and health risks to workers exposed to salivation. ZnCl inhalation results in edema in the 2 zinc oxide (ZnO) and zinc chloride alveolar surface and the protein therein the lavage ß uid (ZnCl ) are significant.[6] is elevated. Particular pathological changes associated 2 with zinc intoxication include: pale mucous membranes; The aim of this mini-review was to jaundice; numerous Heinz bodies; and marked anemia. describe the toxic effects of zinc Adequate ambient air monitors for permissible exposure limits, excellent ventilation and extraction systems, inhalation principally in the workplace and approved respirators are all important in providing and associated complications with adequate protection. breathing and respiration.

METHODS Key words: Breathing, exposure, fumes, occupation, respiration, zinc. The criteria used in the current mini-review for selecting articles to be included were both theoretically INTRODUCTION and practically motivated and adopted from the proposed criteria Zinc is an essential mineral in cellular metabolism. It is a in The International Classification of cofactor for the activity and folding of proteins.[1] Because of Functioning, Disability and Health – the pleiotropic effects of zinc on every aspect of cell physiology, ICF.[7] These criteria were as follows: zinc deficiency or excessive rise in its cellular concentration, • Articles were chosen only with can have catastrophic consequences and are linked to major internationally recognized impact patho-physiologies including diabetes and stroke.[1] factors greater than 0.10 • Articles were chosen based upon The plasma concentration of zinc is about 15 µmol/L, the impact of lifestyle, stress principally bound to albumin and a third of which is bound and/or environmental factor/s to α2-macroglobulin.[2] Zinc occupies 10-20 % of plasma, is predisposing zinc exposure a constituent of the human genome, acts as a site-specific • Criteria for selection of literature antioxidant, acts as an active site in enzymes, and is essential used included yes-no responses for the action of insulin.[2] to: the appropriateness of methodology; adequacy of subject Initial symptoms following exposure to concentrated hexite numbers; specificity of sex and/or smoke, vomiting, cough and dyspnea, disappear after a few age of subjects; and statistically hours .[3] Thereafter, 48h later, acute respiratory distress significant response rates to syndrome appears requiring tracheal intubation and survey questionnaires

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• The time frame used was principally 1990-2007 inclusive, recommended threshold limit value of 5 mg/m3 ZnO.[18] although articles of extreme importance from earlier decades were used where appropriate ZnO is a common constituent of particulate air pollution and • A multi-factorial overview of the factors eschewed if inhaled in fine or ultra-fine fractions at a concentration concerning zinc exposure was elucidated. It was presumed exceeding 500 µg/m3 for 2h can induce acute systemic that collective articles detailing known factors of usage effects.[19] There may be rapid production and secretion of were not necessarily correlated with functionality and metalloproteinases in the lung following heavy metal particle health. deposition including zinc.[20] Concurrent exposure to zinc • Compilation of materials for the mini-review started and copper will result in significantly greater epithelial with published literature or easily accessible academic toxicity and stress.[21] Reduced glutathione levels have been research associated with zinc-induced cytotoxicity.[22] Inhalation of • The articles were accessible from on-line sources including ZnO at concentrations equal to and below a recommended PubMed and Medline. threshold value of 5 mg/m3 results in the induction of target haeme oxygenase gene expression.[18] Significant changes in RESULTS lavage fluid parameters have been described in guinea pigs and rats exposed to 2.5 mg/m3 ZnO.[23,24] Exposure of guinea Zinc inhalation and respiratory distress pigs at three hr/day for five consecutive days to ultrafine ZnO The respiratory tract can be a significant port for heavy at 7 mg/m3 resulted in a gradual decrease in total lung capacity metal toxicity, inhalants often associated with lung cancer.[8] and vital capacity.[25] Vital capacity, functional residual Most of the commercial production of zinc involves the capacity, alveolar volume and diffusing capacity for carbon galvanizing of iron and the manufacture of brass.[9] Others monoxide decrease following exposure to ZnO, although suggest exposure to zinc via fume inhalation during the active increases in flow resistance and decreases in compliance gas welding of steel coated with zinc protective layers.[10] and total lung capacity return to normal by 72h.[26] Total lung One study demonstrated that exposure to fumes of silver capacity, vital capacity, functional residual volume, alveolar solder containing cadmium was more likely to induce fever volume and diffusing capacity for carbon monoxide decrease [11] than fumes of zinc. The recommended daily allowance following exposure to ZnO-SO2 mixtures and did not return for adults is 15 mg zinc/day. Ingestion of 1-2 g zinc sulphate to normal by 72h after the last exposure.[27] Further exposure

(ZnS04) produces emesis. Inhalation of high concentrations resulted in greater decrements in functional residual capacity of ZnCl2 from smoke bombs detonated in close spaces may and residual volume. result in chemical pneumonitis and adult respiratory distress [9] syndrome. Metal fume fever linked with inhalation of fumes ZnCl2 inhalation results in oedema in rats and measurements of ZnO is characterized by fatigue, chills, fever, myalgias, of alveolar surface protein in lavage fluid is variable, dose- cough, dyspnea, leukocytosis, thirst, metallic taste and dependent and maximal at three days, although at sub-lethal salivation. One study asked 12 healthy volunteers to inhale doses it regresses after seven days.[28] zinc oxide fumes through a mask for two hours at 0, 2.5 and 5 mg/m3 on separate days.[12] All but two developed a mild Zinc toxicity fever between 6 and 12 hours after exposure and all but one Zinc compounds can produce irritation and corrosion reported more symptoms (particularly fatigue, muscle ache of the gut, acute renal tubular necrosis and interstitial and cough) after zinc oxide exposure at 5 mg/m3 than after nephritis.[9] Inhalation would presumably contribute partially exposure to the control furnace gas.[12] Another case study of to pathological effects on the kidneys. Zinc toxicity can be a 25-year-old male welder with metal fume fever showed that treated with calcium disodium ethylenediaminetetraacetate, he was suffering from aseptic meningitis with pericarditis, a chelator.[9] Zinc administration is able to attenuate some pleuritis and pneumonitis.[13] The condition is associated with neurochemical, morphological and behavioral effects induced invasion of neutrophils into the airways through stimulation of by pesticides like malathion.[29] Particular pathological changes oxygen free radicals possibly associated with the associated associated with zinc intoxication include: pale mucous pathogenesis.[14-16] In another study, ZnO welding fumes membranes; jaundice; the presence of numerous Heinz were associated with a marked dose-dependent increase in bodies; and marked anemia.[30] the number of polymorphonuclear leukocytes recovered in bronchoalveolar lavage fluid 22h following exposure, although Influence on enzyme activity it was not associated with a clinically significant change Zinc-induced activation of epidermal growth factor in pulmonary function or airway reactivity.[17] The authors receptor in human airway epithelial cells involves a loss suggest a cytokine-mediated mechanism. Haeme oxygenase of tyrosine phosphatase activities, potentially disrupting gene expression occurs following inhalation of ZnO in welding dephosphorylation reactions in cellular protein metabolism.[31] fumes at concentrations equal to and below the current Cardiovascular blood coagulation impairments are likely

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CMYK 11 Cooper: Breathing zinc vapors following pulmonary zinc exposure and associated pulmonary 5. Lemire J, Mailloux R, Appanna VD. Zinc toxicity alters mitochondrial injury and inflammation.[32] Concentrated ambient particle metabolism and leads to decreased ATP production in hepatocytes. J Appl Toxicol 2008;28:175-82. inhalation leads to tissue-specific increases in the activities 6. Bodar CW, Pronk ME, Sijm DT. The European Union risk assessment of antioxidant enzymes including superoxide dismutase and on zinc and zinc compounds: The process and the facts. Integr. Environ catalase, suggesting that episodes of increased particulate Assess Manag 2005;1:301-19. air pollution trigger oxidant injurious effects and adaptive 7. International classifi cation of functioning, disability and health. Geneva: responses.[33] Zinc-induced toxicity has been linked to World Health Organization; 2001. p. 1-11. glutathione metabolism and cellular reduced glutathione 8. Neuberger JS, Hollowell, JG. Lung cancer excess in an abandoned lead- zinc mining and smelting area. Sci Total Environ 1982;25:287-94. [34] activity. Inhibition of glutathione reductase activity and 9. Barceloux DG. Zinc. J Toxicol Clin Toxicol 1999;37:279-92. the associated increase of oxidized glutathione may be 10. Matczak W, Chmielnicka J. Evaluation of exposure to fumes arising responsible for zinc-mediated toxic cellular effects.[35] during welding of non-alloyed and low-alloyed steel by various methods Reduction of glutathione is reduced in zinc-exposed cells [Article in Polish]. Med Pr 1988;39:253-61. and protection of glutathione (reduced) (GSH) oxidation 11. Johnson JS, Kilburn KH. Cadmium induced metal fume fever: Results of inhalation challenge. Am J Indian Med 1983;4:533-40. by antioxidants and enhancement of cellular GSH content 12. Fine JM. Zinc oxide and metal fume fever Food Chem Toxicol are mechanisms for diminishing the toxic cellular effects 1997;35:1230. [36] after exposure to zinc. Exposure to 25-250 µmol ZnCl2 for 13. Hassaballa HA, Lateef OB, Bell J, Kim E, Casey L. Metal fume fever 2h diminished protein synthesis and the decrease in total presenting as aseptic meningitis with pericarditis, pleuritis and pneu- cellular glutathione is accompanied by an increased ratio of monitis. Occup Med (Lond) 2005;55:638-41. 14. Nemery B. Metal toxicity and the respiratory tract. Eur Respir J oxidized: reduced glutathione that was more pronounced in 1990;3:202-19. [37] cells with low glutathione content. Suppression of RNA and 15. Lindahl M, Leanderson P, Tagesson C. Novel aspect on metal fume protein synthesis is due to the direct effect of zinc on these fever: Zinc stimulates oxygen radical formation in human neutrophils. pathways.[38] Hum Exp Toxicol 1998;17:105-10. 16. Kodavanti UP, Schladweiler MC, Ledbetter AD, Hauser R, Christiani DISCUSSION DC, Samet JM, et al. Pulmonary and systemic effects of zinc-containing emission particles in three rat strains: Multiple exposure scenarios. Toxicol Sci 2002;70:73-85. Zinc forms a significant heavy metal occupational toxin, 17. Blanc P, Wong H, Bernstein MS, Boushey HA. An experimental human especially, within the metal processing industry. The lungs model of metal fume fever. Ann Intern Med 1991;114:930-6. act as a trap for dust and therefore facilitate the diffusion of 18. Cosma G, Fulton H, DeFeo T, Gordon T. Rat lung metallothionein zinc into the blood stream. Workers need adequate protection and heme oxygenase gene expression following ozone and zinc oxide from the vapors produced during metal working. It is in the exposure. Toxicol Appl Pharmacol 1992;117:75-80. 19. Beckett WS, Chalupa DF, Pauly-Brown A, Speers DM, Stewart JC, interests of companies to provide very efficient protective Frampton MW, et al. Comparing inhaled ultrafi ne versus fi ne zinc oxide measures in order to avoid litigation. In order to determine the particles in healthy adults: A human inhalation study. Am J Respir Crit Short-Term Exposure Limit Evaluation, a 15 min analysis of air Care Med 2005;171:1129-135. within the workplace with a minimum of three measurements, 20. Adamson Y, Vincent R, Bakowska J. Differential production of metal- the highest concentration recorded being taken as the loproteinases after instilling various urban air particle samples to rat estimate of the worker’s exposure. Adequate ambient air lung. Exp Lung Res 2003;29:375-88. 21. Pagan I, Costa DL, McGee JK, Richards JH, Dye JA. Metals mimic monitors for permissible exposure limits, excellent ventilation airway epithelial injury induced by in vitro exposure to Utah Val- and extraction systems, and approved respirators are all ley ambient particulate matter extracts. J Toxicol Environ Health A important in providing adequate protection. Although there 2003;66:1087-112. is nothing published on the long-term exposure to ZnO fumes 22. Walther UI, Czermak A, Muckter H, Walther SC, Fichtl B. Decreased and the EU does not regard zinc dust as a human carcinogen, GSSG reductase activity enhances cellular zinc toxicity in three human it does not negate the fact that adequate precautions need to lung cell lines. Arch Toxicol 2003;77:131-7. 23. Conner MW, Flood WH, Rogers AE, Amdur MO. Lung injury in guinea be taken to prevent exposure. pigs caused by multiple exposures to ultrafi ne zinc oxide: Changes in pulmonary lavage fl uid. J Toxicol Environ Health 1988;25:57-69. REFERENCES 24. Gordon T, Chen LC, Fine JM, Schlesinger RB, Su WY, Kimmel TA, et al. Pulmonary effects of inhaled zinc oxide in human subjects, guinea 1. Sekler I, Sensi S, Hershfi nkel M, Silverman WF. Mechanism and regula- pigs, rats, and rabbits. Am Indian Hyg Assoc 1992;53:503-9. tion of cellular zinc transport. Mol Med 2007;13:337-43. 25. Lam HF, Chen LC, Ainsworth D, Peoples S, Amdur MO. Pulmonary 2. Samman S. Trace elements. In: Mann J, Truswell AS, editors. Essentials function of guinea pigs exposed to freshly generated ultrafi ne zinc of human nutrition. 3rd ed. Oxford: Oxford University Press; 2007. p. oxide with and without spike concentrations. Am Indian Hyg Assoc 138-62. 1988;49:333-41. 3. Freitag A, Caduff B. ARDS caused by military zinc fumes exposure 26. Lam HF, Conner MW, Rogers AE, Fitzgerald S, Amdur MO. Functional [Article in German]. Schweiz Med Wochenschr 1996;126:1006-10. and morphological changes in the lungs of guinea pigs exposed to freshly 4. Aw TC, Gardiner K, Harrington JM. Chapter 5. Occupational toxicology. generated ultrafi ne zinc oxide. Toxicol Appl Pharmacol 1985;78:29- In: Pocket consultant. Occupational health. 5th ed. Oxford: Blackwell 38. Publishing; 2007. p. 71-114. 27. Conner MW, Lam HF, Rogers AE, Fitzgerald S, Amdur MO. Lung injury

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in guinea pigs caused by multiple exposures to submicron zinc oxide 33. Gurgueira SA, Lawrence J, Coull B, Murthy GG, Gonzalez-Flecha B. mixed with sulphur dioxide in a humidifi ed furnace. J Toxicol Environ Rapid increases in the steady-state concentration of reactive oxygen Health 1985;16:101-14. species in the lungs and heart after particulate air pollution inhalation. 28. Richards RJ, Atkins J, Marrs TC, Brown RF, Masek L. The biochemi- Environ Health Perspect 2002;110:749-55. cal and pathological changes produced by the intratracheal instillation 34. Walther UI, Muckter H, Wallner B, Bergen U, Duggen S, Unsinn G, et of certain components of zinc-hexachloroethane smoke. Toxicology al. Effect of low level zinc pre-treatment on zinc-mediated toxicity in 1989;54:79-88. different lung cell lines. Biol Trace Elem Res 2002;88:45-57. 29. Brocardo PS, Assini F, Franco JL, Pandolfo P, Müller YM, Takahashi 35. Wilhelm B, Walther UI, Fichtl B. Effects of zinc chloride on glutathione RN, et al. Zinc attenuates malathion-induced depressant-like behavior and glutathione synthesis rates in various lung cell lines. Arch Toxicol and confers neuroprotection in the rat brain. Toxicol Sci 2007;97:140- 2001;75:388-94. 8. 36. Walther UI, Wilhelm B, Walther S, Muckter H, Fichtl B. Zinc toxicity in 30. Bexfi eld N, Archer J, Herrtage M. Heinz body haemolytic anaemia various lung cell lines is mediated by glutathione and GSSG reductase in a dog secondary to ingestion of a zinc toy: A case report. Vet J activity. Biol Trace Elem Res 2000;78:163-77. 2007;174:414-7. 37. Walther UI, Muckter H, Fichtl B, Forth W. Infl uence of glutathione on 31. Tal TL, Graves LM, Sibajoris R, Bromberg PA, Wu, W, Samet JM. Inhibi- zinc-mediated cellular toxicity. Biol Trace Elem Res 1999;67:97-107. tion of protein tyrosine phosphatase activity mediates epidermal growth 38. Walther UI, Schulze J, Forth W. Inhibition of protein synthesis by zinc: factor receptor signalling in human airway epithelial cells exposed to Comparison between protein synthesis and RNA synthesis. Hum Exp Zn2+. Toxicol Appl Pharmacol 2006;214:16-23. Toxicol 1998;17:661-7. 32. Gilmour PS, Nyska A, Schladweiler MC, McGee JK, Wallenborn JG, Richards JH, et al. Cardiovascular and blood coagulative effects of Source of Support: Nil, Confl ict of Interest: None declared. pulmonary zinc exposure. Toxicol Appl Pharmacol 2006;211:41-52.

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