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Vanadium
Vanadium SC Gad, Gad Consulting Services, Cary, NC, USA T Pham, Charlotte, NC, USA Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous print edition article by Shayne C. Gad, volume 4, pp 416–418, Ó 2005, Elsevier Inc. l
Name: Vanadium Chemical Abstracts Service Registry Number: 7440-62-2 l Synonyms: Vanadium, Vanadium metallicum, Vanadium dust l Molecular Formula: V2þ, V3þ, V4þ, V5þ l
Background Vanadium was discovered in 1830 in Mexico by Andreas Manuel del Rio. It is present at 0.01% in earth’s crust and found in about 65 different minerals. Vanadium is released naturally into the air through the formation of continental dust, marine aerosols, and volcanic emissions. The natural release of vanadium into water and soils occurs primarily as a result of weathering of rocks and soil erosion. Anthropogenic sources include the combustion of fossil fuels, particularly residual fuel oils, which constitute the single largest overall release of vanadium into the atmosphere. Deposition of atmospheric vanadium is also an important source both near and far from industrial plants burning residual fuel oils rich in vanadium. Other anthropogenic sources include leachates from mining tailings, vanadium-enriched slag heaps, municipal sewage sludge, and certain fertilizers. Natural releases to water and soil are far greater overall than anthropogenic releases to the atmosphere.
Uses Vanadium is used as an alloying addition to steel, iron, titanium, copper, and aluminum, with the primary use in the steel industry. Vanadium is also used as a target material for X-rays, as a catalyst for the production of synthetic rubbers, plastics, and chemicals, and in ceramics. Vanadium is an element of pharmacological and nutritional significance; for example, it has increasing therapeutic use in diabetes, and is emerging as a potent anticarcinogenic agent.
Environmental Fate and Behavior Vanadium is a gray metal with a body-centered cubic crystal system. Vanadium has oxidation states of þ2, þ3, þ4, and þ5. Vanadium is released naturally into the atmosphere by the formation of continental dust, marine aerosols, and volcanic emissions. Vanadium cannot be destroyed in the environment, but it can transform or change its form and attach or separate from airborne particulate, soil, water particulate, and sediment. Vanadium particles in the air settle to the ground or are washed out of the air by rain. Smaller particles, such as those emitted from oil-fueled power plants, may stay in the air for longer times and are more likely to be transported farther away
Encyclopedia of Toxicology, Volume 4
from the site of release. The transport and partitioning of vanadium in water and soil is influenced by many factors, including acidity of the water or soil and the presence of particulates. Vanadium can either be dissolved in water as dissolved ions or may become adsorbed to particulate matter. As an element, vanadium cannot be degraded but can undergo various precipitation or ligand exchange reactions. Bioconcentration is insignificant.
Exposure Routes and Pathways The general population is exposed to background levels of vanadium primarily through ingestion of food. Workers in industries processing or using vanadium compounds are commonly exposed to higher than background levels via the inhalation pathway. An estimate by the National Institute for Occupational Safety and Health indicates that in 1980 about 5319 people were exposed to vanadium pentoxide in their workplace. Exposure through inhalation may also be of importance in urban areas, where large amounts of residual fuel oil are burned. Other populations possibly exposed to higher than background levels, include those ingesting foodstuffs contaminated by vanadium-enriched soil, fertilizers, or sludge. Populations in the vicinity of vanadium-containing hazardous waste sites may be exposed under these circumstances. Releases of vanadium to the environment are mainly associated with industrial sources, such as oil refineries and power plants using vanadium-rich fuel oil and coal. Natural releases of vanadium to water and soil are far greater overall than anthropogenic sources released into the atmosphere.
Toxicokinetics In humans, 0.1–1% of orally administered vanadium is absorbed through the gut. Lung and gut absorption increases with the solubility of the vanadium compound. Vanadium pentoxide is w100% absorbed by inhalation. Vanadium is not absorbed through the skin. Vanadium distributes in low levels in human kidney and liver, with less in brain, heart, and breast milk. Higher levels have been detected in hair, bone, and teeth. Vanadium, as an element, does not metabolize. It circulates as a polyvanadate (isopolyanions containing pentavalent vanadium) in oxygenated blood and remains as vanadyl cation (cationic form of tetravalent vanadium) in the tissues. Vanadium is very reactive with oxygen; therefore, depending on the availability of reducing equivalent and oxygen, it may be reduced, reoxidized, or undergo redox cycling. Sixty percent of the vanadium is excreted by the kidneys within 24 h of administration. Elimination is primarily in the urine. Vanadium can pass through the blood–brain barrier.
http://dx.doi.org/10.1016/B978-0-12-386454-3.00960-X
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Vanadium
Mechanism of Toxicity In the consolidated form, vanadium metal and its alloys may pose no particular health or safety hazard; however, the toxicity of vanadium alloys may be a function of other components of the alloy. Vanadium compounds have been proved to be associated with the pathogenesis of some human diseases and also in the maintenance of normal body functions. Salts of vanadium interfere with many enzyme systems, for example, ATPases, protein kinases, ribonucleases, and phosphatases. Vanadium may also be an essential trace element, contributing to glucose balance; however, the importance of this element as a micronutrient is yet to be unequivocally accepted. Vanadium deficiency has been associated with disturbances in physiological functions, for instance, thyroid, glucose, and lipid metabolism. Vanadate (VO3) mimics the action of insulin in target tissues and is a potential inhibitor of the sodium pump. Vanadium toxicity is enhanced by dietary zinc. Several genes are regulated by this element or by its compounds, including those for tumor necrosis factor-alpha, interleukin-8, activator protein-1, ras, c-raf-1, Mitogen activated protein kinase, p53, and nuclear factor kappa B. When inhaled, vanadium is toxic to alveolar macrophages and therefore may impair pulmonary resistance to infection and clearance of particulate matter. An increase in inflammatory cells of the nasal mucosa has been observed in workers exposed to vanadium.
Acute and Short-Term Toxicity (or Exposure)
may result in central nervous system depression with tremors, headache, and tinnitus.
Chronic Toxicity (or Exposure) Animal Chronic inhalation and oral exposure to vanadium in laboratory animals has resulted in kidney and liver changes, decreased erythrocyte count and hemoglobin levels, and increased reticulocyte count in peripheral blood. Chronic oral exposure to vanadium has caused an increase in minor birth defects and fetal death in pregnant rats.
Human Systemic symptoms of exposure to vanadium are extremely rare but could include peripheral vasoconstriction of the lungs, spleen, kidneys, and intestines. Chronic exposure to vanadium may result in arrhythmias and bradycardia.
Immunotoxicity No studies were located regarding immunological effects in humans after oral exposure to vanadium. Minimal information on immunological effects in animals were located as well.
Reproductive Toxicity
Animal Inhalation of vanadium in animals results in lung irritation, coughing, wheezing, chest pain, atrophic rhinitis, and conjunctivitis. Pulmonary edema has been observed in animals after exposure to some vanadium compounds. The acute oral toxicity of vanadium is low. In mice, 1000 mg kg1 causes catarrhal gastritis. Acute oral exposure in rats results in distress, hemorrhagic exudates from the nose, diarrhea, hind limb paralysis, labored respiration, convulsions, organ congestion, fatty degeneration of the liver and kidney, focal hemorrhage of the lung and adrenal cortex, and death. Rat (oral) LDLo ¼ 225 mg kg1 over 5 days.
Studies in animals exposed during pregnancy have shown that vanadium can cause decreases in growth and increases in the occurrence of birth defects. These effects are usually observed at levels that cause effects in the mother. Following inhalation exposure, alterations in estrous cycle were observed in female rats exposed to vanadium pentoxide for the duration of 3 months. No alterations in sperm characteristics were observed. Autopsy data have not provided detectable levels of vanadium in human reproductive organs. It is unlikely that the reproductive system is a sensitive indicator for vanadium toxicity in humans.
Genotoxicity Human In general, vanadium has a very low oral and dermal toxicity and a moderately low toxicity by the inhalation route. The toxicity of vanadium increases with its valence state, with vanadium pentoxide being the most toxic of the vanadium compounds. Vanadium fumes are more toxic than vanadium dust. Acute inhalation exposure has resulted in lung irritation, coughing, wheezing, chest pain, nosebleeds, atrophic rhinitis, pharyngitis, epistaxis, tracheitis, asthma-like diseases, irritation of the eyes, and a metallic taste in the mouth. Symptoms generally disappear within 2 weeks of exposure. A quantity of 2–10 mg m3 has resulted in mild to moderate respiratory effects and no systemic effects in humans. Acute oral exposure results in abdominal cramping, diarrhea, black stools, and a greenish-black coating on the tongue. Skin exposure may result in dermatitis, allergic skin lesions, and a green discoloration of the skin. A fatal dose
An increase in micronuclei formation was observed in lymphocytes in workers exposed to vanadium pentoxide. Increases in the micronuclei formations were also observed in mouse bone marrow cells following oral exposure to vanadyl sulfate.
Carcinogenicity An increase in lung carcinoma incidence has been observed in mice chronically exposed to vanadium pentoxide. However, carcinogenicity has not been adequately assessed in laboratory animals following oral exposure. No studies have examined the carcinogenic potential of vanadium in humans. The US EPA has not classified carcinogenicity of vanadium.
Vanadium
Clinical Management Irrigate exposed skin and eyes with copious amounts of tepid water (with soap for exposed skin). After inhalation exposures, move to fresh air and monitor for respiratory distress. Administer 100% humidified supplemental oxygen with assisted ventilation as required. If coughing or breathing difficulties are noted, the patient should be evaluated for irritation or bronchitis, including chest X-rays and determination of blood gases. For ingestion exposures, emesis may be indicated for recent, substantial ingestion. Activated charcoal may be considered, depending on the form of vanadium ingested. Chelation is not usually indicated since systemic effects are rare.
Ecotoxicology It is unlikely that there is bioaccumulation or biotransformation.
Other Hazards The toxicologically significant compounds are vanadium pentoxide (V2O5), sodium metavanadate (NaVO3), sodium orthovanadate (Na3VO4), vanadyl sulfate (VOSO4), and ammonium vanadate (NH4VO3). Vanadium pentoxide dust is usually encountered in occupational settings, and humans can be exposed via the inhalation route.
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concentrations as low as 0.018 mg m3 may result in irritation, tearing, blurred vision, and a burning sensation of the conjunctiva.
Miscellaneous Vanadium can react violently with bromine trifluoride, chlorine, lithium, and oxidants; for example, powdered vanadium can explode in contact with chlorine.
See also: Metals; Zinc.
Further Reading Dart, R.C. (Ed.), 2004. Medical Toxicology, third ed. Williams and Wilkins, Baltimore, MD. Goyer, R.A., Klaassen, C.D., Waalkes, M.P., 1995. Metal Toxicology. Academic Press, San Diego, CA. Liu, J., Cui, H., Liu, X., Peng, X., Deng, J., Zuo, Z., Cui, W., Deng, Y., Wang, K., 2012 Feb. Dietary high vanadium causes oxidative damage-induced renal and hepatic toxicity in broilers. Biol. Trace. Elem. Res. 145 (2), 189–200. Mukherjee, B., Patra, B., Mahapatra, S., et al., 2004. Vanadium – an element of atypical biological significance. Toxicol. Lett. 150, 135–143. Nordberg, G.F., Fowler, B.A., Nordberg, M., Friberg, L.T., 2007. Handbook on the Toxicology of Metals, third ed. Associated Press, London. Rydzynski, K., 2001. Vanadium, niobium, and tantalum. In: Bingham, E., Cohrssen, B., Powell, C.H. (Eds.), Patty’s Toxicology, fifth ed., vol. 3. Wiley, New York, pp. 1–74. Shafer, M.M., Toner, B.M., Overdier, J.T., Schauer, J.J., Fakra, S.C., Hu, S., Herner, J.D., Ayala, A., 2012 Jan. Chemical speciation of vanadium in particulate matter emitted from diesel vehicles and urban atmospheric aerosols. Environ. Sci. Technol. 46 (1), 189–195.
Exposure Standards and Guidelines The US Occupational Safety and Health Administration permissible exposure limit is 0.5 mg m3 of vanadium pentoxide as a time-weighted average. Direct skin contact with air concentrations of approximately 0.03 mg m3 may result in dermal irritation, eczema, generalized rashes, and contact dermatitis during acute exposures. Direct eye contact with air
Relevant Websites http://www.atsdr.cdc.gov – Agency for Toxic Substances and Disease Registry. Toxicological profile of vanadium (2009). http://www.who.int – Vanadium Pentoxide and Other Inorganic Vanadium Compounds (Concise International Chemical Assessment Document 29 from the International Programme on Chemical Safety).
Name: Vanadium Chemical Abstracts Service Registry Number: 7440-62-2 l Synonyms: Vanadium, Vanadium metallicum, Vanadium dust l Molecular Formula: V2þ, V3þ, V4þ, V5þ l
Background Vanadium was discovered in 1830 in Mexico by Andreas Manuel del Rio. It is present at 0.01% in earth’s crust and found in about 65 different minerals. Vanadium is released naturally into the air through the formation of continental dust, marine aerosols, and volcanic emissions. The natural release of vanadium into water and soils occurs primarily as a result of weathering of rocks and soil erosion. Anthropogenic sources include the combustion of fossil fuels, particularly residual fuel oils, which constitute the single largest overall release of vanadium into the atmosphere. Deposition of atmospheric vanadium is also an important source both near and far from industrial plants burning residual fuel oils rich in vanadium. Other anthropogenic sources include leachates from mining tailings, vanadium-enriched slag heaps, municipal sewage sludge, and certain fertilizers. Natural releases to water and soil are far greater overall than anthropogenic releases to the atmosphere.
Uses Vanadium is used as an alloying addition to steel, iron, titanium, copper, and aluminum, with the primary use in the steel industry. Vanadium is also used as a target material for X-rays, as a catalyst for the production of synthetic rubbers, plastics, and chemicals, and in ceramics. Vanadium is an element of pharmacological and nutritional significance; for example, it has increasing therapeutic use in diabetes, and is emerging as a potent anticarcinogenic agent.
Environmental Fate and Behavior Vanadium is a gray metal with a body-centered cubic crystal system. Vanadium has oxidation states of þ2, þ3, þ4, and þ5. Vanadium is released naturally into the atmosphere by the formation of continental dust, marine aerosols, and volcanic emissions. Vanadium cannot be destroyed in the environment, but it can transform or change its form and attach or separate from airborne particulate, soil, water particulate, and sediment. Vanadium particles in the air settle to the ground or are washed out of the air by rain. Smaller particles, such as those emitted from oil-fueled power plants, may stay in the air for longer times and are more likely to be transported farther away
Encyclopedia of Toxicology, Volume 4
from the site of release. The transport and partitioning of vanadium in water and soil is influenced by many factors, including acidity of the water or soil and the presence of particulates. Vanadium can either be dissolved in water as dissolved ions or may become adsorbed to particulate matter. As an element, vanadium cannot be degraded but can undergo various precipitation or ligand exchange reactions. Bioconcentration is insignificant.
Exposure Routes and Pathways The general population is exposed to background levels of vanadium primarily through ingestion of food. Workers in industries processing or using vanadium compounds are commonly exposed to higher than background levels via the inhalation pathway. An estimate by the National Institute for Occupational Safety and Health indicates that in 1980 about 5319 people were exposed to vanadium pentoxide in their workplace. Exposure through inhalation may also be of importance in urban areas, where large amounts of residual fuel oil are burned. Other populations possibly exposed to higher than background levels, include those ingesting foodstuffs contaminated by vanadium-enriched soil, fertilizers, or sludge. Populations in the vicinity of vanadium-containing hazardous waste sites may be exposed under these circumstances. Releases of vanadium to the environment are mainly associated with industrial sources, such as oil refineries and power plants using vanadium-rich fuel oil and coal. Natural releases of vanadium to water and soil are far greater overall than anthropogenic sources released into the atmosphere.
Toxicokinetics In humans, 0.1–1% of orally administered vanadium is absorbed through the gut. Lung and gut absorption increases with the solubility of the vanadium compound. Vanadium pentoxide is w100% absorbed by inhalation. Vanadium is not absorbed through the skin. Vanadium distributes in low levels in human kidney and liver, with less in brain, heart, and breast milk. Higher levels have been detected in hair, bone, and teeth. Vanadium, as an element, does not metabolize. It circulates as a polyvanadate (isopolyanions containing pentavalent vanadium) in oxygenated blood and remains as vanadyl cation (cationic form of tetravalent vanadium) in the tissues. Vanadium is very reactive with oxygen; therefore, depending on the availability of reducing equivalent and oxygen, it may be reduced, reoxidized, or undergo redox cycling. Sixty percent of the vanadium is excreted by the kidneys within 24 h of administration. Elimination is primarily in the urine. Vanadium can pass through the blood–brain barrier.
http://dx.doi.org/10.1016/B978-0-12-386454-3.00960-X
909
910
Vanadium
Mechanism of Toxicity In the consolidated form, vanadium metal and its alloys may pose no particular health or safety hazard; however, the toxicity of vanadium alloys may be a function of other components of the alloy. Vanadium compounds have been proved to be associated with the pathogenesis of some human diseases and also in the maintenance of normal body functions. Salts of vanadium interfere with many enzyme systems, for example, ATPases, protein kinases, ribonucleases, and phosphatases. Vanadium may also be an essential trace element, contributing to glucose balance; however, the importance of this element as a micronutrient is yet to be unequivocally accepted. Vanadium deficiency has been associated with disturbances in physiological functions, for instance, thyroid, glucose, and lipid metabolism. Vanadate (VO3) mimics the action of insulin in target tissues and is a potential inhibitor of the sodium pump. Vanadium toxicity is enhanced by dietary zinc. Several genes are regulated by this element or by its compounds, including those for tumor necrosis factor-alpha, interleukin-8, activator protein-1, ras, c-raf-1, Mitogen activated protein kinase, p53, and nuclear factor kappa B. When inhaled, vanadium is toxic to alveolar macrophages and therefore may impair pulmonary resistance to infection and clearance of particulate matter. An increase in inflammatory cells of the nasal mucosa has been observed in workers exposed to vanadium.
Acute and Short-Term Toxicity (or Exposure)
may result in central nervous system depression with tremors, headache, and tinnitus.
Chronic Toxicity (or Exposure) Animal Chronic inhalation and oral exposure to vanadium in laboratory animals has resulted in kidney and liver changes, decreased erythrocyte count and hemoglobin levels, and increased reticulocyte count in peripheral blood. Chronic oral exposure to vanadium has caused an increase in minor birth defects and fetal death in pregnant rats.
Human Systemic symptoms of exposure to vanadium are extremely rare but could include peripheral vasoconstriction of the lungs, spleen, kidneys, and intestines. Chronic exposure to vanadium may result in arrhythmias and bradycardia.
Immunotoxicity No studies were located regarding immunological effects in humans after oral exposure to vanadium. Minimal information on immunological effects in animals were located as well.
Reproductive Toxicity
Animal Inhalation of vanadium in animals results in lung irritation, coughing, wheezing, chest pain, atrophic rhinitis, and conjunctivitis. Pulmonary edema has been observed in animals after exposure to some vanadium compounds. The acute oral toxicity of vanadium is low. In mice, 1000 mg kg1 causes catarrhal gastritis. Acute oral exposure in rats results in distress, hemorrhagic exudates from the nose, diarrhea, hind limb paralysis, labored respiration, convulsions, organ congestion, fatty degeneration of the liver and kidney, focal hemorrhage of the lung and adrenal cortex, and death. Rat (oral) LDLo ¼ 225 mg kg1 over 5 days.
Studies in animals exposed during pregnancy have shown that vanadium can cause decreases in growth and increases in the occurrence of birth defects. These effects are usually observed at levels that cause effects in the mother. Following inhalation exposure, alterations in estrous cycle were observed in female rats exposed to vanadium pentoxide for the duration of 3 months. No alterations in sperm characteristics were observed. Autopsy data have not provided detectable levels of vanadium in human reproductive organs. It is unlikely that the reproductive system is a sensitive indicator for vanadium toxicity in humans.
Genotoxicity Human In general, vanadium has a very low oral and dermal toxicity and a moderately low toxicity by the inhalation route. The toxicity of vanadium increases with its valence state, with vanadium pentoxide being the most toxic of the vanadium compounds. Vanadium fumes are more toxic than vanadium dust. Acute inhalation exposure has resulted in lung irritation, coughing, wheezing, chest pain, nosebleeds, atrophic rhinitis, pharyngitis, epistaxis, tracheitis, asthma-like diseases, irritation of the eyes, and a metallic taste in the mouth. Symptoms generally disappear within 2 weeks of exposure. A quantity of 2–10 mg m3 has resulted in mild to moderate respiratory effects and no systemic effects in humans. Acute oral exposure results in abdominal cramping, diarrhea, black stools, and a greenish-black coating on the tongue. Skin exposure may result in dermatitis, allergic skin lesions, and a green discoloration of the skin. A fatal dose
An increase in micronuclei formation was observed in lymphocytes in workers exposed to vanadium pentoxide. Increases in the micronuclei formations were also observed in mouse bone marrow cells following oral exposure to vanadyl sulfate.
Carcinogenicity An increase in lung carcinoma incidence has been observed in mice chronically exposed to vanadium pentoxide. However, carcinogenicity has not been adequately assessed in laboratory animals following oral exposure. No studies have examined the carcinogenic potential of vanadium in humans. The US EPA has not classified carcinogenicity of vanadium.
Vanadium
Clinical Management Irrigate exposed skin and eyes with copious amounts of tepid water (with soap for exposed skin). After inhalation exposures, move to fresh air and monitor for respiratory distress. Administer 100% humidified supplemental oxygen with assisted ventilation as required. If coughing or breathing difficulties are noted, the patient should be evaluated for irritation or bronchitis, including chest X-rays and determination of blood gases. For ingestion exposures, emesis may be indicated for recent, substantial ingestion. Activated charcoal may be considered, depending on the form of vanadium ingested. Chelation is not usually indicated since systemic effects are rare.
Ecotoxicology It is unlikely that there is bioaccumulation or biotransformation.
Other Hazards The toxicologically significant compounds are vanadium pentoxide (V2O5), sodium metavanadate (NaVO3), sodium orthovanadate (Na3VO4), vanadyl sulfate (VOSO4), and ammonium vanadate (NH4VO3). Vanadium pentoxide dust is usually encountered in occupational settings, and humans can be exposed via the inhalation route.
911
concentrations as low as 0.018 mg m3 may result in irritation, tearing, blurred vision, and a burning sensation of the conjunctiva.
Miscellaneous Vanadium can react violently with bromine trifluoride, chlorine, lithium, and oxidants; for example, powdered vanadium can explode in contact with chlorine.
See also: Metals; Zinc.
Further Reading Dart, R.C. (Ed.), 2004. Medical Toxicology, third ed. Williams and Wilkins, Baltimore, MD. Goyer, R.A., Klaassen, C.D., Waalkes, M.P., 1995. Metal Toxicology. Academic Press, San Diego, CA. Liu, J., Cui, H., Liu, X., Peng, X., Deng, J., Zuo, Z., Cui, W., Deng, Y., Wang, K., 2012 Feb. Dietary high vanadium causes oxidative damage-induced renal and hepatic toxicity in broilers. Biol. Trace. Elem. Res. 145 (2), 189–200. Mukherjee, B., Patra, B., Mahapatra, S., et al., 2004. Vanadium – an element of atypical biological significance. Toxicol. Lett. 150, 135–143. Nordberg, G.F., Fowler, B.A., Nordberg, M., Friberg, L.T., 2007. Handbook on the Toxicology of Metals, third ed. Associated Press, London. Rydzynski, K., 2001. Vanadium, niobium, and tantalum. In: Bingham, E., Cohrssen, B., Powell, C.H. (Eds.), Patty’s Toxicology, fifth ed., vol. 3. Wiley, New York, pp. 1–74. Shafer, M.M., Toner, B.M., Overdier, J.T., Schauer, J.J., Fakra, S.C., Hu, S., Herner, J.D., Ayala, A., 2012 Jan. Chemical speciation of vanadium in particulate matter emitted from diesel vehicles and urban atmospheric aerosols. Environ. Sci. Technol. 46 (1), 189–195.
Exposure Standards and Guidelines The US Occupational Safety and Health Administration permissible exposure limit is 0.5 mg m3 of vanadium pentoxide as a time-weighted average. Direct skin contact with air concentrations of approximately 0.03 mg m3 may result in dermal irritation, eczema, generalized rashes, and contact dermatitis during acute exposures. Direct eye contact with air
Relevant Websites http://www.atsdr.cdc.gov – Agency for Toxic Substances and Disease Registry. Toxicological profile of vanadium (2009). http://www.who.int – Vanadium Pentoxide and Other Inorganic Vanadium Compounds (Concise International Chemical Assessment Document 29 from the International Programme on Chemical Safety).