Gallium: Environmental Pollution and Health Effects

G Gallium: Environmental Pollution and Health Effects H-S Yu and W-T Liao, Kaohsiung Medical University, Kaohsiung, Taiwan & 2011 Elsevier B.V. All rights reserved.

Abbreviations ACGIH BEI CD DNA Ga IARC ICs IFN IL LED MDA NIOSH PBMC PHA TF TNF US EPA USGS

American Conference of Governmental Industrial Hygienists biological exposure indices cluster of differentiation deoxyribonucleic acid gallium International Agency for Research on Cancer integrated circuits interferon interleukin light-emitting diode malondialdehyde The National Institute for Occupational Safety and Health peripheral blood mononuclear cells phytohemagglutinin transferrin tumor necrosis factor United States Environmental Protection Agency United States Geological Survey

like aluminum in its physical properties, which proved to be quite accurate. Geologically, the abundance of gallium is 19 ppm in crustal rocks and 0.03 ppb in seawater. On the basis of this average number, gallium is not considered as a rare element. Indeed, gallium is the 30th most abundant element on earth. Elemental gallium does not occur in nature, but is present in trace amounts in bauxite and zinc ores as the Ga (III) salt. However, gallium has not been selectively concentrated into minerals by geological process; therefore, there is almost no mineral identified as a primary source of gallium, and the few high-gallium minerals such as gallite (CuGaS2) are too rare to serve as a primary source of the element or its compounds. Gallium tends to be widely dispersed in nature settings but does not exist in pure form. Several ores contain small amounts of gallium, such as bauxite, coal, diaspore, germanite, and sphalerite. Most of pure gallium is extracted as a trace byproduct from these ores. For example, gallium is normally a by-product of the aluminum manufacturing process. Solid gallium has a bluish-gray color, and ultrapure gallium has a stunning silvery white color. Gallium is one of the metals (with cesium, rubidium, francium, and mercury) that are liquid at or near normal room temperature. Solid gallium is soft and stable in air and water, but it can react with acids and alkalis very slowly.

Introduction Applications Gallium (Ga) is a metallic element in group 13 (IIIa), atomic number 31 with the standard atomic weight of 69.72. Gallium has very wide liquid ranges: the melting point of gallium is quite low (303 K, 30 1C, 86 1F) and the boiling point is up to 2477 K (2204 1C, 39991 F). The name gallium comes from the Latin word for France, Gallia. Another theory, however, says that its discoverer, Paul-Emile Lecoq de Boisbaudran, in 1875 may have taken the name from the Latin word gallum, which means ‘the cock,’ a reference to his own name (Lecoq). The existence of gallium was predicted in 1871 by the chemist Mendeleev who said that gallium would be very much

Gallium can be liquefied near room temperature. Coating liquid gallium on glass forms a reflective surface that can be used to create brilliant mirrors. Gallium can also be used to form low-melting alloys since gallium easily alloys with most metals. For example, gallium can be alloyed with plutonium to stabilize the allotropes of plutonium in the nuclear weapons. The low-temperature liquid eutectic alloy and the high boiling temperature of gallium are also used in thermometers designed to measure very high temperatures. However, the most popular usage of gallium currently is the applications of

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Gallium: Environmental Pollution and Health Effects

gallium in the semiconductor and light-emitting diode (LED) industries. Gallium has semiconductor properties. Gallium is used in the semiconductor industry due to its superior electronic and optical properties as compared to the silicon-based semiconductors. Nowadays, gallium arsenide (GaAs) is undoubtedly the most used, representing the majority of annual gallium consumption. Gallium arsenide (GaAs) is able to change electricity directly into laser light. Analog integrated circuits (ICs) are the most common application for gallium, with optoelectronic devices (mostly laser diodes and LEDs) as the second largest end use. GaAs and gallium nitride (GaN) are two of the major materials in these electronic components. Gallium is important in some sophisticated physics experiments. Gallium is one of the few elements of the periodic table, having the capacity to ‘absorb solar electron neutrinos.’ Such experiments used a total of 90 tons of gallium in the quest to detect these particles. In biomedicine, radioactive gallium (67Ga) is used in the field of nuclear medicine imaging procedure, commonly referred to as a gallium scan, to detect and localize malignant tumor cells. Gallium also has the potential to be used as therapeutic agents. Gallium nitrate (Ga(NO3)3) exhibits favorable therapeutic efficacy in lymphoproliferative disorders, urothelial tract tumors, and cancer-related hypercalcemia. Gallium maltolate is used in clinical and preclinical trials as a potential treatment for cancer, infectious disease, and inflammatory disease. Ga is a potentially promising new therapeutic for Pseudomonas aeruginosa infections. Gallium alloys have been proposed as dental restorative material and substitutes for mercury and silver amalgams, but these compounds have yet to see wide acceptance. Nanotechnology and nanosciences are the key technologies of twenty-first century to create innovative materials with new and unique properties and benefits for life. Applications for gallium oxide (Ga2O3) nanocrystals include as a flame retardant in coatings, plastics, fiber and textiles, and in certain alloy and catalyst applications. Not only gallium arsenide but also gallium nitride, gallium phosphide, gallium sulphide, and gallium selenide nanoparticles have been manufactured for their potential electrical, magnetic, optical, and bioscience properties and as a potential candidate for photodetection in the solar-blind region.

Environmental Sources and Possible Exposure Routes Sources Gallium is widely separated on earth but not concentrated in nature, so that gallium compounds are not a primary source of extraction. Industrial usage of

gallium is a potential concentrated source of gallium. On the basis of data from U.S. Geological Survey (USGS) in 2008, approximately 66% of the gallium consumed was used in ICs. Approximately 20% of gallium was used in optoelectronic devices, including LEDs, laser diodes, photodetectors, and solar cells. Approximately 14% was used in research and development. In 2007, estimated world primary production of gallium was approximately 80 metric tons; China, Germany, Japan, and Ukraine were the leading producers. Owing to the economic value, gallium is recycled in some industries. World recycling capacity in 2007 was estimated to be 78 tons. Possible Exposure Routes The gallium-associated waste may pollute the air and water. However, gallium levels in ambient water quality and air quality are not standardized at present. The study of the fates and the routes of gallium from environment to human are still limited. It was summarized that the solubility of solid gallium (as GaO(OH)) is approximately 106 M at pH 7.4 and 25 1C. The minimum solubility is 107.2 M at pH 5.2. Both high and low pH values increase the solubility of gallium. At pH 2, the solubility is 102 M, and at pH 10 it is 103.3 M. The ionized gallium is trivalent in aqueous solution (Ga3þ). Ga3þ bonds to OH strongly in solution; therefore, the dissolved gallium mostly exist as Ga(OH)4 or Ga(OH)3. Since gallium is geologically widely dispersed and its solubility is low, the background concentration of gallium in the aquatic environment is low. The average concentrations of gallium are 0.03 ppb in seawater, 0.15 ppb in stream water, and lower than 1 ppb in groundwater. A study reported that the groundwater levels of gallium were higher in the semiconductor manufacturing area (19.34 ppb) than in control area (0.02 ppb). Therefore, a polluting potential is suspected, and humans may be exposed to gallium via water. The indoor air of gallium-associated working space is another possible exposure source. A study in Taiwan showed that the gallium levels in inhalable air samples were 12.25 and 10.27 mg m3 from working space for semiconductor manufacturing industry operators and engineers, respectively. It was significantly higher than that in working space for administrators (2.59 mg m3). These results indicated that workers might be exposed to relatively high-level gallium, as well as other inhalable metals, through inhalation in working space. However, inhalable gallium has not spread to nonmanufacturing (referent) areas of the factory based on detecting the air samples. The urinary gallium seems to be better correlated with exposure environment as compared with blood gallium levels. The urinary gallium levels are different between studies. To summarize, the range of gallium

Gallium: Environmental Pollution and Health Effects

concentrations is 0.24–9.60 mg l1 in urine from exposed groups and 0.15–1.32 mg l1 in urine from reference groups. Aside from the indoor condition in semiconductor factories, fossil fuels may partially contribute to the emission of gallium to the environment since coal contains 1–35 ppm of gallium, and oil contains 0.01– 1.2 ppm of gallium.

Health Effects of Gallium Tissue Distribution The human body contains very small amounts of gallium, but there are insufficient evidence about the normal biological and nutritional function of gallium in humans. In a person with a mass of 70 kg, there is 0.7 mg of gallium in the body. If this amount of gallium is condensed into a cube, the cube would only be 0.49 mm long on one side. Widespread use of gallium radioisotope (67Ga) scan in humans can provide referable information for gallium localization and accumulation in tissue. Aside from the tumor, gallium (67Ga) accumulates avidly at sites of inflammation and infection. In addition, gallium concentrations are commonly observed in the liver, spleen, kidneys, lactating breasts, and bone. Significant amounts of gallium were present in commercial pharmaceutical product aluminum–phosphate binder (Maalox). However, the intestinal absorption of gallium in rats was not enhanced by the aluminum matrix of Maalox. Biological Activity of Gallium Edwards and Hayes found that gallium accumulated in tumor tissues after injection. On the basis of this, radioactive gallium (67Ga) has been introduced for determining the location of tumors in human. Hoffer et al. further found that 67Ga activity was seen in the breasts of a patient with galactorrhea after intravenous injection. The 67Ga was contained primarily in the lactoferrin, as well as transferrin (TF). Evidence strongly suggested that gallium acts as an analog of ferric ion and, therefore, replaces the ferric ion in human ferric proteins. More specifically, gallium can bind to the iron transport protein, TF. Gallium ions can bind to the two metal sites of TF with binding constants log K1 ¼ 20.3 and log K2 ¼ 19.3 at normal plasma conditions. Once they are occupied by Ga3þ, the replacement is found very difficult to reverse, although the affinity of TF for Fe3þ is approximately 400 times higher than for Ga3þ. This TF–Ga complex can be uptaked by cells via TF receptor. Malignant cells generally have very high TF receptor expression. Dividing cells require iron for ribonucleotide reductase production, which is essential for DNA synthesis. Erythrocyte precursors also require iron for the synthesis of hemoglobin. Gallium is able to convert intracellular TF–Fe to TF–Ga and deprives usable iron

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for cells. Additionally, as cells uptake TF–Ga, gallium is released and subsequently interacts with the iron-containing M2 subunit of the ribonucleotide reductase, which results in functional loss of the enzyme. In summary, these biological activities of gallium result in an antiproliferative effect. Therefore, gallium potentially has an antitumor activity. Gallium complexes are potent proteasome inhibitors with a great potential to be developed into novel anticancer drugs. Gallium can interfere with calcium uptake; the element is a potent inhibitor of protein synthesis and the heme pathway enzyme, aminolevulinic acid dehydratase. Gallium also appears to inhibit DNA synthesis by action on ribonucleotide reductase. Toxicity At present, gallium is not recognized to have inhalation nor ingestion cancer risks by US EPA. Pure gallium is not very harmful substance to human skin. However, some gallium compounds are dangerous; for example, acute exposure to gallium (III) chloride can cause throat irritation, difficulty breathing, chest pain, and its fumes can cause very serious conditions such as pulmonary edema and partial paralysis. Low gallium assimilation can be observed from the gastrointestinal tract, and the toxicity from ingestion is considered to be low. However, inhaled Ga2O3 particles produce considerable toxicity. In animal experiments, gallium causes bone, kidney, and testis injuries and has toxic effects on muscle and nerve. Embryo/fetal toxicity in mice was evidenced by a decrease in the number of viable implants, a reduction in fetal weight, and an increase in the number of skeletal variations. Blindness and paralysis have been reported in rats, and aplastic changes have been reported in dogs. In human, kidney and lung toxicity regarding the use of different gallium compounds for therapeutic purposes is available but not directly applicable to explain gallium toxicity. Gallium sulfate is a toxic substance in carp, with severe hepatic cytopathological alterations and elevated enzyme activities in serum of fish exposed to various concentrations. Effects on Immune System Gallium is shown to accumulate in inflammatory tissue by binding to the TF and acid mucopolysaccharide. Many in vitro or animal studies indicate that gallium can affect immune system. In animal models, gallium treatment (30 mg kg1 in rats or mice) has been shown to suppress immune activation in autoimmune disease such as adjuvant-induced arthritis and experimental allergic encephalomyelitis. Further studies demonstrated that lower concentrations of gallium (1–10 mg ml1) stimulated cytokines release in vitro from human peripheral blood mononuclear cells (PBMC), including tumor necrosis

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factor-alpha (TNF-a), interleukin (IL)-1b, and interferon-gamma (IFN-g), suggesting that gallium can modulate lymphocyte functions. Gallium is able to modulate T-cell immune reactivity. Gallium inhibited the mitogen-induced proliferative response of PBMC in a dose-dependent fashion. Alloantigen-induced proliferation was also potently suppressed. TF–Ga induced a significant reduction in the density of IL-2 receptors on activated T cells and a slight reduction in the number of CD3þ/CD25þ T cells in phytohemagglutinin (PHA)stimulated cultures. Neither secretion of IL-2 nor the induction of IL-2-stimulated lymphokine-activated killer activity, however, was inhibited by TF–Ga. In contrast, higher concentrations of gallium (50–100 mg ml1) were reported to induce cytotoxic effects, which induce human immune cells apoptosis, especially in T and B cells. Carcinogenicity Although there are no data on the induction of cancer in humans by gallium arsenide (inadequate evidence) and limited evidence that this compound is a weak carcinogen in experimental animals, gallium arsenide has been classified by the International Agency for Research on Cancer (IARC) carcinogenic to humans (Group 1). The working group noted the potential for gallium arsenide to cause cancer through two separate mechanisms of action. Once in the body, gallium arsenide releases a small amount of its arsenic, which behaves as inorganic arsenic at the sites where it is distributed. (Arsenic and arsenic compounds have been evaluated as IARC Group 1, carcinogenic to humans.) At the same time, the gallium moiety may be responsible for the lung cancers observed in the study of female rats due to the apparent resistance of rats to the carcinogenic potential of arsenic that is manifest in humans. The similarity of toxicochemical responses observed in subchronic studies with gallium arsenide and gallium oxide adds weight to the finding that the gallium moiety is active and suggests that a carcinogenic response might be observed with other gallium compounds. The observed findings may also be a result of the combination of the two moieties. On the basis of limited data, gallium arsenide does not show genotoxic activity. Human Exposure and Health Effects Industrial usage of gallium is considered to be the most important source for human exposure; however, no standard limit for gallium in biological exposure indices (BEI) has been suggested (by American Conference of Governmental Industrial Hygienists, ACGIH; or other occupational institutes). The only occupational exposure limit for gallium arsenide in the available literature was reported by The National Institute for Occupational Safety and Health (NIOSH). NIOSH recommended a

ceiling value of 0.002 mg m3 for gallium arsenide. Few additional data regarding the toxicology of gallium or the effects related to exposure from working environment were found. Gallium levels in the human body are low in the general population. The researches in semiconductor and LED industries indicated that the blood and urine gallium concentrations are higher in potentially exposed population (such as operators and engineers), as compared with the reference groups (such as office workers and administrators). There is a correlation between the urinary gallium concentrations and inhalable gallium exposure levels. Further study indicated that the urinary levels of gallium were positively and significantly correlated with plasma malondialdehyde (MDA, an index of lipid peroxidation) levels. Plasma MDA levels were significantly higher in the occupationally exposed workers than in the referents. These results suggested that exposure to gallium might initiate lipid peroxidation in humans. The increased lipid peroxidation may associate with chemical characteristic of gallium since gallium acts as an analog of ferric ion and may change cellular antioxidant capacities. AsGa is the major compound for industrial usage, but most of the occupational health hazards are imparted by arsenic and less by gallium. Although some studies suggest that gallium may share certain risks (such as carcinogenetic risk) imposed by arsenic, more and further epidemiology and biomedical investigations are needed to clarify the role of gallium exposure in human health. At present, it is still unknown whether the gallium concentrations found among the workers of risk population are high enough to cause adverse human heath effects.

Further Reading ACGIH Worldwide (2003) Documentation of the TLVss and BEIss with other Worldwide Occupational Exposure Values F CD-ROM F 2003, Cincinnati, OH. Bernstein LR (1998) Mechanisms of therapeutic activity for gallium. Pharmacological Reviews 50: 665--682. Chang KL, Liao WT, Yu CL, Lan CC, Chang LW, and Yu HS (2003) Effects of gallium on immune stimulation and apoptosis induction in human peripheral blood mononuclear cells. Toxicology and Applied Pharmacology 193: 209--217. Chen D, Frezza Ml, Shakya R, et al. (2007) Inhibition of the proteasome activity by gallium(III) complexes contributes to their anti-prostate tumor effects. Cancer Research 67: 9258--9265. Chen HW (2006) Gallium, indium, and arsenic pollution of groundwater from a semiconductor manufacturing area of Taiwan. Bulletin of Environmental Contamination and Toxicology 77: 289--296. Chen HW (2007) Exposure and health risk of gallium, indium, and arsenic from semiconductor manufacturing industry workers. Bulletin of Environmental Contamination and Toxicology 78: 123--127. Chepesiuk R (1999) Where the chips fall: Environmental health in the semiconductor industry. Environmental Health Perspectives 107: 1--8. Chitambar CR (2004) Apoptotic mechanisms of gallium nitrate: Basic and clinical investigations. Oncology (Williston Park) 18(13 Supplement 10): 39--44.

Gallium: Environmental Pollution and Health Effects

Chua MZ, Bernstein LR, Li R, and So SK (2006) Gallium maltolate is a promising chemotherapeutic agent for the treatment of hepatocellular carcinoma. Anticancer Research 26: 1739--1743. Edwards CL and Hayes RL (1969) Tumor scanning with 67Ga citrate. Journal of Nuclear Medicine 10: 103--105. Fowler BA, Yamauchi H, Conner EA, and Akkerman M (1993) Cancer risks for humans from exposure to semiconductor metals. Scandinavian Journal of Work, Environment & Health 19: 101--103. Go´mez M, Sa´nchez DJ, Domingo JL, and Corbella J (2005) Developmental toxicity evaluation of gallium nitrate in mice. Archives of Toxicology 66: 188--192. Harris WR and Pecoraro VL (1983) Thermodynamic binding constants for gallium transferrin. Biochemistry 22: 292--299. Hoffer PB, Huberty J, and Khayam-Bashi H (1977) The association of Ga-67 and lactoferrin. Journal of Nuclear Medicine 18: 713--717. Hoyes KP, Hider RC, and Porter JB (1992) Cell cycle synchronization and growth inhibition by 3-hydroxypyridin-4-one iron chelators in leukemia cell lines. Cancer Research 52: 4591--4599. IARC (2006) Monographs on the Evaluation of Carcinogenic Risks to Human, vol. 86: Cobalt in Hard Metals and Cobalt Sulfate, Gallium Arsenide, Indium Phosphide and Vanadium Pentoxide. Lyon, France: IARC. Kaneko Y, Thoendel M, Olakanmi O, Britigan BE, and Singh PK (2007) The transition metal gallium disrupts Pseudomonas aeruginosa iron metabolism and has antimicrobial and antibiofilm activity. The Journal of Clinical Investigation 117: 877--888. Kirsten TA (1999) Solar neutrino experiments: Results and implications. Review of Modern Physics 71: 1213--1232. Kramer DA (2008) US Geological Survey Mineral Commodity Summaries: Gallium. Reston, VA: US Geological Survey. pp. 64–65. http://minerals.usgs.gov/minerals/pubs/mcs/ (accessed July 2010). Liao YH, Hwang LC, Kao JS, et al. (2006) Lipid peroxidation in workers exposed to aluminium, gallium, indium, arsenic, and antimony in the optoelectronic industry. Journal of Occupational and Environmental Medicine 48: 789--793. Liao YH, Yu HS, Ho CK, et al. (2004) Biological monitoring of exposures to aluminium, gallium, indium, arsenic, and antimony in

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