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Toxic Metals: Arsenic
TOXIC METALS
Contents Arsenic Cadmium Lead Mercury Trace Metals – Chromium, Nickel, Copper, and Aluminum
Arsenic SS-H Tao, FDA Center for Food Safety and Applied Nutrition, College Park, MD, USA PM Bolger, Senior Managing Scientist, Exponent, Washington, USA r 2014 Elsevier Inc. All rights reserved.
Glossary Benchmark dose – hlower confidence limit (BMDL) The lower boundary of the confidence interval on the benchmark dose (BMD). The BMD is the dose of a substance associated with a specified low incidence of risk, generally in the range of 1-10% of a health effect. Bioavailability The degree or rate at which a substance is absorbed into a living system or is made available at the site of physiological activity. Biomarkers Indicators of signaling events in biological systems or samples. They have been used as markers of exposure, effect, and susceptibility.
Chemical Arsenic (CAS no. 7440-38-2), arsenic trioxide (As2O3, CAS no. 1327-53-3), arsenic pentoxide (As2O5, CAS no. 1303–28-2), sodium arsenite (NaAsO2, CAS no. 7784-46-5), disodium arsenate (Na2HAsO4, CAS no. 7778-43-0).
Background Arsenic is a naturally occurring element that is released from volcanoes and the erosion of arsenic-containing mineral deposits. Human activities such as mining; burning of coal, oil, gasoline, and wood; and the use of arsenic compounds, primarily chromate copper arsenate (CCA), as medicines, pesticides, herbicides, and wood preservatives, also contribute to its environmental contamination. Arsenic exists in many chemical forms and valency states ( 3, 0, þ 3, and þ 5). Low concentrations can be found in air, water, soil, and food. The background soil content of arsenic varies widely, typically ranging from 1 to 40 ppm, with an average of 5 ppm. Arsenic
342
Carcinogen A chemical capable of inducing cancer. Minimal risk level (MRL) An estimate of daily human exposure to a hazardous substance that is likely to be without an appreciable risk of adverse noncancer health effects over a specified route and duration of exposure. Provisional tolerable weekly intake (PTWI) The endpoint used by the Joint FAO/WHO Expert Committee on Food Additives that represents the permissible human weekly exposure to those contaminants unavoidably associated with the consumption of otherwise wholesome and nutritious food.
concentration in natural surface and groundwater is generally approximately 1 ppb, but may exceed 1 ppm in contaminated areas or areas with high soil arsenic. For example, naturally occurring arsenic-contaminated groundwater has severely affected people in Bangladesh where 35–70 million people have been chronically exposed to elevated arsenic in drinking water. This is the result of tube wells installed more than 30 years ago to tap groundwater as a source of pathogen-free drinking water to prevent infectious diseases. The primary forms of arsenic found in drinking water are arsenite ( þ 3) and arsenate ( þ 5), the inorganic forms. Sea water typically contains 1–2 ppb arsenic. Ambient air arsenic background concentrations generally range from less than 1 to 3 ng m–3, but concentrations in an urban area may go up to 100 ng m–3. Food arsenic levels usually range from 20 to 140 mg kg–1. However, higher total arsenic levels are found in seaweed, seafood, mushroom, rice and rice products, and some meat. Most arsenic present in seafood is as the organic form (arsenobetaine and arsenocholine) which is considered to be nontoxic. In general, inorganic arsenic is the most toxic form with trivalent arsenic being more toxic than pentavalent arsenic.
Encyclopedia of Food Safety, Volume 2
doi:10.1016/B978-0-12-378612-8.00201-8
Toxic Metals: Arsenic
Hazard Identification and Characterization Arsenobetaine, the major form of arsenic in most seafood and fish, is considered to be of no toxicological concern because it is not metabolized and is excreted intact by humans. Arsenosugars and arsenolipids are metabolized to dimethylarsinate in humans, but no specific toxicological information is available. Soluble inorganic arsenic is rapidly and well absorbed (80–90%) after ingestion, distributed throughout the body, metabolized by methylation, and excreted mainly in urine. Organic arsenic is also well absorbed, generally by more than 70%. Two basic processes are involved in the metabolism of inorganic arsenic: (1) reduction/oxidation reactions that interconvert As þ 3 and As þ 5 and (2) methylation reaction, which converts arsenite to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). The latter facilitates the excretion of inorganic arsenic from the body as both MMA and DMA are more readily excreted in urine. Inorganic arsenic can also be excreted directly in the urine. In contrast, with the exception of arsenosugars, ingested organic arsenicals such as MMA, DMA, and arsenobetaine, do not readily enter the cell, undergo limited metabolism, and are excreted unchanged in the urine. High variability of arsenic metabolism and toxicokinetics has been reported among different species, populations, and individuals. Some species (marmoset monkey, guinea-pig, chimpanzee) have minimal or no arsenic methylation capability. In humans, inorganic arsenic is extensively methylated and its metabolites are excreted primarily in the urine. Age, gender, and smoking contribute only minimally to the large individual variations in arsenic methylation in humans. The relative proportions of arsenic metabolites in human urine are usually 40–75% DMA, 20–25% inorganic arsenic, and 15–25% MMA. Similar urinary metabolic profiles were reported among family members. An increase in DMA excretion was observed in individuals with a specific allele on a gene, suggesting its possible association with a genotype that protects against arsenic toxicity. Other than genetic polymorphisms and wide differences in methyltransferase activities, nutritional status (protein, selenium, and folate) can also influence methylation capacity. Urine arsenic is commonly used as a measure of recent exposure. Arsenic levels in hair and nails have been shown to provide reliable biomarkers for long-term chronic exposure to arsenic in humans. Inorganic arsenic binds to the sulfhydryl groups of cellular proteins, inhibiting the pyruvate and succinate oxidative pathways. It also competes with phosphorus in the oxidative phosphorylation process. Although chronic exposure to inorganic arsenic has been associated with cancers in humans, the exact underlying molecular mechanisms are not clear. Several modes of action (MOA) of inorganic arsenic in carcinogenesis have been proposed, including: induction of oxidative stress; genotoxicity as induction of mutations and chromosomal aberrations; modulation of signal transduction and apoptosis (growth factors, cell proliferation, and promotion); and alterations in gene expressions via hyper- and hypomethylation of DNA. Arsenic does not directly react with DNA, and it is also probable that more than one of these mechanisms are involved. Recent evidence has proved that arsenic activates Hedgehog signaling, a key oncogenic signaling pathway, and also showed that there is a strong positive
343
correlation between arsenic exposure and high levels of Hedgehog activity in a cohort of bladder cancer patients. This is the first report to suggest that activation of Hedgehog signaling may be in part involved in arsenic-induced cancer. Ingestion of large doses of arsenic can be fatal. The oral lethal dose of arsenic trioxide is reported to be between 70 and 180 mg day–1. The estimated minimum lethal dose in humans ranges from 1 to 3 mg As per kg of bodyweight (bw) per day. Poisoning may appear with daily doses of inorganic arsenic as low as a few mg for a short period of time, for example, weeks. An estimated daily exposure of 1.3–3.6 mg arsenic from the consumption contaminated dried milk for a few weeks resulted in fever, insomnia, and anorexia in more than 12 000 infants (130 deaths) in Japan. Many hospitalized patients also showed liver swelling, anemia, and changes in electrocardiograms. In another episode, more than 200 adults were poisoned by contaminated soy sauce with an estimated daily exposure of 3 mg of arsenic for 2–3 weeks. Depending on dose and duration of exposure, adverse health effects caused by inorganic arsenic can occur in many organs. Symptoms of acute exposure to arsenic in drinking water at doses of 0.2 mg kg–1 day–1 or above usually occur within the first several hours. Essentially, all cases of short-term high-dose exposure to inorganic arsenic show clinical signs of gastrointestinal effects. Short-term exposure (weeks/months) to elevated arsenic (0.06 mg–1day–1) in drinking water can result in gastrointestinal effects, such as abdominal pain, vomiting, diarrhea, and muscular cramping; hematological effects, such as anemia and leucopenia; and peripheral neuropathy, such as numbness, burning or tingling sensations, or pain in the extremities. A metallic taste, garlic odor in breath and feces, and salvation may also be present. These short-term effects are generally reversible when the exposure is terminated. For chronic exposure, lower lethal doses of 0.014– 0.05 mg As kg–1day–1 in drinking water have been reported. Chronic exposure to arsenic in drinking water typically causes specific dermal effects. Diffuse or spotted hyperpigmentation followed by palmer–planter hyperkeratosis occurs after 6 months to 36 months of ingestion of high doses of arsenic (0.04 mg kg–1day–1) or 5–15 years of ingestion of low doses of arsenic (0.01 mg kg–1day–1 or higher). Chronic exposure to 0.02 mg kg–1day–1 or higher has been shown to cause perturbed porphyrin metabolism and irreversible hypertension. In addition to skin lesions, chronic exposure to arsenic is also associated with other health outcomes including peripheral vascular, cardiovascular, diabetes mellitus, peripheral neuropathy, diseases of the respiratory system, negative impacts on fetal and infant development (low birth weight), and cancers (skin and internal organs). Inorganic arsenic is a listed as a human carcinogen by many national agencies and international organizations. It is a multisite carcinogen; numerous epidemiologic studies provide evidence associating of oral exposure to inorganic arsenic via drinking water with different types of cancers including the skin, urinary bladder, lung, kidney, liver, and prostate. This link between these cancers and arsenic exposure in drinking water was observed in many populations of the world, including Taiwan, Japan, Chile, Argentina, Bangladesh, India, and China. In 2010, The International Agency for Research on Cancer (IARC) concluded that there was sufficient evidence to show
344
Toxic Metals: Arsenic
that skin lesions and cancers of the urinary bladder, lung, and skin were caused by arsenic in drinking water, and limited evidence for cancers of the kidney, liver, and prostate. Assessment of human cancer risk related to the exposure of total inorganic arsenic is limited. Because only drinking water arsenic was measured in most available epidemiological studies the information on total dietary exposure was lacking. In 2010, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) withdrew its provisional tolerable weekly intake (PTWI) for arsenic because evidence from human epidemiology data indicated that it did not protect human health. Therefore, using a range of assumptions to extrapolate drinking water arsenic concentration to total dietary inorganic arsenic exposure, JECFA has determined the 95% confidence limit of the benchmark dose (BMDL005) for 0.5% increased incidence of lung cancer over background for inorganic arsenic to be 3.0 mg kg–1 day–1 (2–7 mg kg–1 day–1 based on the range of estimated total dietary exposure). Similarly, based on the studies showing statistically significant association of drinking water arsenic concentration below 100 mg l–1 and its adverse effects in humans, the European Food Safety Authority (EFSA) panel on Contaminants in the Food Chain (CONTAM Panel) selected a benchmark response of 1% extra risk and calculated a range of values of the BMDL01 instead of a single reference point for inorganic arsenic. The BMDL01 values for the various health endpoints, skin lesions, cancers of the skin, urinary bladder, and lung ranged from 0.3 to 8 mg kg–1day–1. Based on animal studies, Agency for Toxic Substances and Disease Registry (ATSDR) has derived an intermediate oral minimal risk level (MRL) of 0.1 mg kg–1 day–1 for MMA for diarrhea in rats exposed to dietary MMA for 13 weeks, a chronic oral MRL of 0.01 mg kg–1 day–1 for MMA for increased incidence of progressive nephropathy in male mice exposed to dietary MMA for 2 years, and a chronic oral MRL of 0.02 mg kg–1 day–1 for DMA for increased vacuolization of the urothelium in the urinary bladder of female mice exposed to dietary DMA for 2 years. In a 2-year rat bioassay, DMA has been shown to promote carcinogenesis in the urinary bladder but not in other tissues. Cytotoxicity and increased cell proliferation were involved rather than direct DNA damage. However, the relevance of these findings to humans has not been established especially because the rats eliminate DMA much slower than other species, including humans.
Methods of Analysis Sample preparation is required for the determination of arsenic in food. Acid digestion is usually used for total arsenic determination, whereas milder extraction combined with chemical separation of inorganic and organic arsenic, or chromatographic separation of arsenic species with on-line selective detector of arsenic are needed for the determination of arsenic species from food. A variety of instrumental techniques for the determination of arsenic are available. These include hydride generation atomic absorption spectrometry (HG-AAS), high-performance liquid chromatography (HPLC)–HG-AAS, HPLC combined with hydride generation atomic fluorescence spectrometry (HPLC–HG-AFS), inductively coupled plasma atomic emission spectrometry (ICP-AES), inductively coupled
plasma mass spectrometry (ICP-MS), HPLC–ICP-MS, neutron activation analysis (NAA), and electro-thermal atomization laser-excited atomic fluorescence spectrometry (ETA-LEAFS). For arsenic species determination in food, HPLC–ICP-MS is by far the most common and useful method.
Exposure For the general population who do not smoke, the most common route of exposure to arsenic is through ingestion, and drinking water and food are the major sources. Depending on arsenic levels in drinking water and food, exposure can vary greatly in different regions. In regions with high natural arsenic levels, drinking water can be the major contributor of inorganic arsenic in the diet. Whereas, in regions where arsenic concentration in the drinking water is low, less than 50 mg l–1, food can be the major contributor. Seafood/fish products contribute the most to dietary total arsenic exposure while cereal and grain products contribute the most of inorganic arsenic. Because rice is generally grown in paddy soil under flooded conditions, it accumulates arsenic from the soil and water more than other cereal grains; its arsenic content is approximately 10 times higher than that of other grains. The predominant arsenic species in rice are inorganic arsenic and DMA. The bioavailability of greenhouse-grown rice in which approximately 86% arsenic is present as DMA was determined to be low: only 33% of total rice arsenic was absorbed in an in vivo swine model. Total and inorganic arsenic content in rice varies greatly, ranging from 0.03 to 0.54 and 0.01 to 0.41 mg kg–1, respectively, and can be influenced by geographic location, cultivar, arsenic levels in irrigation water, soil arsenic, use of arsenic-containing fertilizer and pesticides, etc. The percentage of inorganic arsenic as total arsenic in rice ranged from 11% to 90% or 100%. A recent report indicated that even though Chinese rice has lower inorganic arsenic content than that from other countries, it can contribute significantly to human inorganic arsenic exposure due to high consumption of rice as a staple food. Dietary exposure to inorganic arsenic has been estimated to be 0.13–0.56 mg kg–1day–1 for average consumers and 0.37–1.22 mg kg–1day–1 for 95th percentile consumers across 19 European countries. This was calculated based on the assumption that the overall average of the proportion of inorganic arsenic to total arsenic for food other than fish and seafood was 70% and a fixed inorganic value of 0.03 mg g–1 in fish and 0.1 mg kg–1 in seafood, and using the lower bound and upper bound concentrations. Recently, Xue et al. using a probabilistic modeling with the Stochastic Human Exposure and Dose Simulation Dietary model (SHEDS-Dietary) and based on data from the National Health and Nutrition Examination Survey, reported that in the US, the estimated dietary exposures to total and inorganic arsenic were 0.36 and 0.05 mg kg–1day–1, respectively for the mean, and 1.40 and 0.19 mg kg–1day–1, respectively for the 95th percentile.
Risk Characterization Inorganic arsenic has been identified as a human carcinogen based on numerous epidemiological studies associated with
Toxic Metals: Arsenic
arsenic levels in drinking water. Food can contribute significantly to total dietary inorganic arsenic exposure in people who are high consumers of rice or algae-based products. Water, depending on arsenic levels, used in food, cooking/ preparation and possibly irrigation of crops, particularly rice, can also contribute to arsenic in food. More information on bioavailability and speciation data for different food is needed for improving exposure estimation and for more accurate risk assessment. The estimated mean background dietary exposures to inorganic arsenic in the US and various European and Asian countries were reported to vary from 0.1 to 3.0 mg kg–1day–1 that are near or at the range of the BMDL01 and BMDL005 values identified by EFSA and JECFA, respectively. This suggests that certain populations may have an increase in risk depending on their particular dietary habits.
See also: Disciplines Associated with Food Safety: Epidemiology; Food Safety Toxicology. Foodborne Diseases: Overview of Chemical, Physical, and Other Significant Hazards. Institutions Involved in Food Safety: World Health Organization (WHO). Public Health Measures: Monitoring of Contaminants. Risk Analysis: Risk Assessment: Chemical Hazards; Risk Assessment: Principles, Methods, and Applications. Veterinary Drugs Residues: Control of Helminths
Further Reading Agency for Toxic Substances and Disease Registry (ATSDR) (2007) Toxicological Profile for Arsenic (Update). Atlanta, GA: US Department of Health and Human Services, Public Health Service. European Food Safety Authority (EFSA) (2009) Scientific opinion on arsenic in food. EFSA Journal 7(10): 1351. 199 pp.
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Food and Agriculture Organization/World Health Organization (FAO/WHO) (2010) Evaluation of Certain Food Contaminants | Summary Report of the 72nd Meeting of Joint FAO/WHO Expert Committee on Food Additives (JECFA). http:// www.who.int/foodsafety/chem/summary72_rev.pdf. Heikens A (2006) Arsenic contamination of irrigation water, soil and crops in Bangladesh: Risk implications for sustainable agriculture and food safety in Asia RAP PUBLICATION 2006/20. Bangkok, Thailand: Food and Agriculture Organization, Regional Office for Asia and the Pacific. International Agency for Research on Cancer (IARC) (2004) Overall Evaluations of Carcinogenicity to Humans: As Evaluated in IARC Monographs Volumes 1–82 (At Total of 900 Agents, Mixtures and Exposures). Lyon, France: IARC http:// monographs.iarc.fr/. Juhasz AL, Smith E, Weber J, et al. (2006) In vivo assessment of arsenic bioavailability in rice and its significance for human health risk assessment. Environmental Health Perspectives 114(12): 1826–1831. Liang F, Li Y, Zhang G, et al. (2010) Total and speciated arsenic levels in rice from China. Food Additives and Contaminants, Part A 27(6): 810–816. Meharg A, Williams PN, Adomako E, et al. (2009) Geographical variation in total and inorganic arsenic content of polished (white) rice. Environmental Science Technology 43(5): 1612–1617. National Research Council (NRC) (1999) Arsenic in Drinking Water. National Research Council. Washington, DC: National Academy Press. National Research Council (NRC) (2001) Arsenic in drinking water 2001 Update. National Research Council. Washington, DC: National Academy Press. Nishimura T, Hamano-Nagaoka M, Sakakibara N, Abe T, Maekawa Y, and Maitani T (2010) Determination method for total arsenic and partial-digestion method with nitric acid for inorganic arsenic speciation in several varieties of rice. Food Hygiene and Safety Science 51(4): 178–181. U.S. Environmental Protection Agency (2010) U.S. EPA IRIS Toxicological Review of Inorganic Arsenic (Cancer) (External Review Draft). EPA/635/R-10/001. Washington, DC: U.S. Environmental Protection Agency. http://www.epa.gov/iris/ index.html. World Health Organization (WHO) (2001) Arsenic and Arsenic Compounds, Environmental Health Criteria 224. Geneva, Switzerland: World Health Organization. Xue J, Zartarian V, Wang S-W, Liu SV, and Georgopoulos P (2010) Probabilistic modeling of dietary arsenic exposure and dose and evaluation with 2003–2004 NHANES data. Environmental Health Perspectives 118(3): 345–350.
Contents Arsenic Cadmium Lead Mercury Trace Metals – Chromium, Nickel, Copper, and Aluminum
Arsenic SS-H Tao, FDA Center for Food Safety and Applied Nutrition, College Park, MD, USA PM Bolger, Senior Managing Scientist, Exponent, Washington, USA r 2014 Elsevier Inc. All rights reserved.
Glossary Benchmark dose – hlower confidence limit (BMDL) The lower boundary of the confidence interval on the benchmark dose (BMD). The BMD is the dose of a substance associated with a specified low incidence of risk, generally in the range of 1-10% of a health effect. Bioavailability The degree or rate at which a substance is absorbed into a living system or is made available at the site of physiological activity. Biomarkers Indicators of signaling events in biological systems or samples. They have been used as markers of exposure, effect, and susceptibility.
Chemical Arsenic (CAS no. 7440-38-2), arsenic trioxide (As2O3, CAS no. 1327-53-3), arsenic pentoxide (As2O5, CAS no. 1303–28-2), sodium arsenite (NaAsO2, CAS no. 7784-46-5), disodium arsenate (Na2HAsO4, CAS no. 7778-43-0).
Background Arsenic is a naturally occurring element that is released from volcanoes and the erosion of arsenic-containing mineral deposits. Human activities such as mining; burning of coal, oil, gasoline, and wood; and the use of arsenic compounds, primarily chromate copper arsenate (CCA), as medicines, pesticides, herbicides, and wood preservatives, also contribute to its environmental contamination. Arsenic exists in many chemical forms and valency states ( 3, 0, þ 3, and þ 5). Low concentrations can be found in air, water, soil, and food. The background soil content of arsenic varies widely, typically ranging from 1 to 40 ppm, with an average of 5 ppm. Arsenic
342
Carcinogen A chemical capable of inducing cancer. Minimal risk level (MRL) An estimate of daily human exposure to a hazardous substance that is likely to be without an appreciable risk of adverse noncancer health effects over a specified route and duration of exposure. Provisional tolerable weekly intake (PTWI) The endpoint used by the Joint FAO/WHO Expert Committee on Food Additives that represents the permissible human weekly exposure to those contaminants unavoidably associated with the consumption of otherwise wholesome and nutritious food.
concentration in natural surface and groundwater is generally approximately 1 ppb, but may exceed 1 ppm in contaminated areas or areas with high soil arsenic. For example, naturally occurring arsenic-contaminated groundwater has severely affected people in Bangladesh where 35–70 million people have been chronically exposed to elevated arsenic in drinking water. This is the result of tube wells installed more than 30 years ago to tap groundwater as a source of pathogen-free drinking water to prevent infectious diseases. The primary forms of arsenic found in drinking water are arsenite ( þ 3) and arsenate ( þ 5), the inorganic forms. Sea water typically contains 1–2 ppb arsenic. Ambient air arsenic background concentrations generally range from less than 1 to 3 ng m–3, but concentrations in an urban area may go up to 100 ng m–3. Food arsenic levels usually range from 20 to 140 mg kg–1. However, higher total arsenic levels are found in seaweed, seafood, mushroom, rice and rice products, and some meat. Most arsenic present in seafood is as the organic form (arsenobetaine and arsenocholine) which is considered to be nontoxic. In general, inorganic arsenic is the most toxic form with trivalent arsenic being more toxic than pentavalent arsenic.
Encyclopedia of Food Safety, Volume 2
doi:10.1016/B978-0-12-378612-8.00201-8
Toxic Metals: Arsenic
Hazard Identification and Characterization Arsenobetaine, the major form of arsenic in most seafood and fish, is considered to be of no toxicological concern because it is not metabolized and is excreted intact by humans. Arsenosugars and arsenolipids are metabolized to dimethylarsinate in humans, but no specific toxicological information is available. Soluble inorganic arsenic is rapidly and well absorbed (80–90%) after ingestion, distributed throughout the body, metabolized by methylation, and excreted mainly in urine. Organic arsenic is also well absorbed, generally by more than 70%. Two basic processes are involved in the metabolism of inorganic arsenic: (1) reduction/oxidation reactions that interconvert As þ 3 and As þ 5 and (2) methylation reaction, which converts arsenite to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). The latter facilitates the excretion of inorganic arsenic from the body as both MMA and DMA are more readily excreted in urine. Inorganic arsenic can also be excreted directly in the urine. In contrast, with the exception of arsenosugars, ingested organic arsenicals such as MMA, DMA, and arsenobetaine, do not readily enter the cell, undergo limited metabolism, and are excreted unchanged in the urine. High variability of arsenic metabolism and toxicokinetics has been reported among different species, populations, and individuals. Some species (marmoset monkey, guinea-pig, chimpanzee) have minimal or no arsenic methylation capability. In humans, inorganic arsenic is extensively methylated and its metabolites are excreted primarily in the urine. Age, gender, and smoking contribute only minimally to the large individual variations in arsenic methylation in humans. The relative proportions of arsenic metabolites in human urine are usually 40–75% DMA, 20–25% inorganic arsenic, and 15–25% MMA. Similar urinary metabolic profiles were reported among family members. An increase in DMA excretion was observed in individuals with a specific allele on a gene, suggesting its possible association with a genotype that protects against arsenic toxicity. Other than genetic polymorphisms and wide differences in methyltransferase activities, nutritional status (protein, selenium, and folate) can also influence methylation capacity. Urine arsenic is commonly used as a measure of recent exposure. Arsenic levels in hair and nails have been shown to provide reliable biomarkers for long-term chronic exposure to arsenic in humans. Inorganic arsenic binds to the sulfhydryl groups of cellular proteins, inhibiting the pyruvate and succinate oxidative pathways. It also competes with phosphorus in the oxidative phosphorylation process. Although chronic exposure to inorganic arsenic has been associated with cancers in humans, the exact underlying molecular mechanisms are not clear. Several modes of action (MOA) of inorganic arsenic in carcinogenesis have been proposed, including: induction of oxidative stress; genotoxicity as induction of mutations and chromosomal aberrations; modulation of signal transduction and apoptosis (growth factors, cell proliferation, and promotion); and alterations in gene expressions via hyper- and hypomethylation of DNA. Arsenic does not directly react with DNA, and it is also probable that more than one of these mechanisms are involved. Recent evidence has proved that arsenic activates Hedgehog signaling, a key oncogenic signaling pathway, and also showed that there is a strong positive
343
correlation between arsenic exposure and high levels of Hedgehog activity in a cohort of bladder cancer patients. This is the first report to suggest that activation of Hedgehog signaling may be in part involved in arsenic-induced cancer. Ingestion of large doses of arsenic can be fatal. The oral lethal dose of arsenic trioxide is reported to be between 70 and 180 mg day–1. The estimated minimum lethal dose in humans ranges from 1 to 3 mg As per kg of bodyweight (bw) per day. Poisoning may appear with daily doses of inorganic arsenic as low as a few mg for a short period of time, for example, weeks. An estimated daily exposure of 1.3–3.6 mg arsenic from the consumption contaminated dried milk for a few weeks resulted in fever, insomnia, and anorexia in more than 12 000 infants (130 deaths) in Japan. Many hospitalized patients also showed liver swelling, anemia, and changes in electrocardiograms. In another episode, more than 200 adults were poisoned by contaminated soy sauce with an estimated daily exposure of 3 mg of arsenic for 2–3 weeks. Depending on dose and duration of exposure, adverse health effects caused by inorganic arsenic can occur in many organs. Symptoms of acute exposure to arsenic in drinking water at doses of 0.2 mg kg–1 day–1 or above usually occur within the first several hours. Essentially, all cases of short-term high-dose exposure to inorganic arsenic show clinical signs of gastrointestinal effects. Short-term exposure (weeks/months) to elevated arsenic (0.06 mg–1day–1) in drinking water can result in gastrointestinal effects, such as abdominal pain, vomiting, diarrhea, and muscular cramping; hematological effects, such as anemia and leucopenia; and peripheral neuropathy, such as numbness, burning or tingling sensations, or pain in the extremities. A metallic taste, garlic odor in breath and feces, and salvation may also be present. These short-term effects are generally reversible when the exposure is terminated. For chronic exposure, lower lethal doses of 0.014– 0.05 mg As kg–1day–1 in drinking water have been reported. Chronic exposure to arsenic in drinking water typically causes specific dermal effects. Diffuse or spotted hyperpigmentation followed by palmer–planter hyperkeratosis occurs after 6 months to 36 months of ingestion of high doses of arsenic (0.04 mg kg–1day–1) or 5–15 years of ingestion of low doses of arsenic (0.01 mg kg–1day–1 or higher). Chronic exposure to 0.02 mg kg–1day–1 or higher has been shown to cause perturbed porphyrin metabolism and irreversible hypertension. In addition to skin lesions, chronic exposure to arsenic is also associated with other health outcomes including peripheral vascular, cardiovascular, diabetes mellitus, peripheral neuropathy, diseases of the respiratory system, negative impacts on fetal and infant development (low birth weight), and cancers (skin and internal organs). Inorganic arsenic is a listed as a human carcinogen by many national agencies and international organizations. It is a multisite carcinogen; numerous epidemiologic studies provide evidence associating of oral exposure to inorganic arsenic via drinking water with different types of cancers including the skin, urinary bladder, lung, kidney, liver, and prostate. This link between these cancers and arsenic exposure in drinking water was observed in many populations of the world, including Taiwan, Japan, Chile, Argentina, Bangladesh, India, and China. In 2010, The International Agency for Research on Cancer (IARC) concluded that there was sufficient evidence to show
344
Toxic Metals: Arsenic
that skin lesions and cancers of the urinary bladder, lung, and skin were caused by arsenic in drinking water, and limited evidence for cancers of the kidney, liver, and prostate. Assessment of human cancer risk related to the exposure of total inorganic arsenic is limited. Because only drinking water arsenic was measured in most available epidemiological studies the information on total dietary exposure was lacking. In 2010, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) withdrew its provisional tolerable weekly intake (PTWI) for arsenic because evidence from human epidemiology data indicated that it did not protect human health. Therefore, using a range of assumptions to extrapolate drinking water arsenic concentration to total dietary inorganic arsenic exposure, JECFA has determined the 95% confidence limit of the benchmark dose (BMDL005) for 0.5% increased incidence of lung cancer over background for inorganic arsenic to be 3.0 mg kg–1 day–1 (2–7 mg kg–1 day–1 based on the range of estimated total dietary exposure). Similarly, based on the studies showing statistically significant association of drinking water arsenic concentration below 100 mg l–1 and its adverse effects in humans, the European Food Safety Authority (EFSA) panel on Contaminants in the Food Chain (CONTAM Panel) selected a benchmark response of 1% extra risk and calculated a range of values of the BMDL01 instead of a single reference point for inorganic arsenic. The BMDL01 values for the various health endpoints, skin lesions, cancers of the skin, urinary bladder, and lung ranged from 0.3 to 8 mg kg–1day–1. Based on animal studies, Agency for Toxic Substances and Disease Registry (ATSDR) has derived an intermediate oral minimal risk level (MRL) of 0.1 mg kg–1 day–1 for MMA for diarrhea in rats exposed to dietary MMA for 13 weeks, a chronic oral MRL of 0.01 mg kg–1 day–1 for MMA for increased incidence of progressive nephropathy in male mice exposed to dietary MMA for 2 years, and a chronic oral MRL of 0.02 mg kg–1 day–1 for DMA for increased vacuolization of the urothelium in the urinary bladder of female mice exposed to dietary DMA for 2 years. In a 2-year rat bioassay, DMA has been shown to promote carcinogenesis in the urinary bladder but not in other tissues. Cytotoxicity and increased cell proliferation were involved rather than direct DNA damage. However, the relevance of these findings to humans has not been established especially because the rats eliminate DMA much slower than other species, including humans.
Methods of Analysis Sample preparation is required for the determination of arsenic in food. Acid digestion is usually used for total arsenic determination, whereas milder extraction combined with chemical separation of inorganic and organic arsenic, or chromatographic separation of arsenic species with on-line selective detector of arsenic are needed for the determination of arsenic species from food. A variety of instrumental techniques for the determination of arsenic are available. These include hydride generation atomic absorption spectrometry (HG-AAS), high-performance liquid chromatography (HPLC)–HG-AAS, HPLC combined with hydride generation atomic fluorescence spectrometry (HPLC–HG-AFS), inductively coupled plasma atomic emission spectrometry (ICP-AES), inductively coupled
plasma mass spectrometry (ICP-MS), HPLC–ICP-MS, neutron activation analysis (NAA), and electro-thermal atomization laser-excited atomic fluorescence spectrometry (ETA-LEAFS). For arsenic species determination in food, HPLC–ICP-MS is by far the most common and useful method.
Exposure For the general population who do not smoke, the most common route of exposure to arsenic is through ingestion, and drinking water and food are the major sources. Depending on arsenic levels in drinking water and food, exposure can vary greatly in different regions. In regions with high natural arsenic levels, drinking water can be the major contributor of inorganic arsenic in the diet. Whereas, in regions where arsenic concentration in the drinking water is low, less than 50 mg l–1, food can be the major contributor. Seafood/fish products contribute the most to dietary total arsenic exposure while cereal and grain products contribute the most of inorganic arsenic. Because rice is generally grown in paddy soil under flooded conditions, it accumulates arsenic from the soil and water more than other cereal grains; its arsenic content is approximately 10 times higher than that of other grains. The predominant arsenic species in rice are inorganic arsenic and DMA. The bioavailability of greenhouse-grown rice in which approximately 86% arsenic is present as DMA was determined to be low: only 33% of total rice arsenic was absorbed in an in vivo swine model. Total and inorganic arsenic content in rice varies greatly, ranging from 0.03 to 0.54 and 0.01 to 0.41 mg kg–1, respectively, and can be influenced by geographic location, cultivar, arsenic levels in irrigation water, soil arsenic, use of arsenic-containing fertilizer and pesticides, etc. The percentage of inorganic arsenic as total arsenic in rice ranged from 11% to 90% or 100%. A recent report indicated that even though Chinese rice has lower inorganic arsenic content than that from other countries, it can contribute significantly to human inorganic arsenic exposure due to high consumption of rice as a staple food. Dietary exposure to inorganic arsenic has been estimated to be 0.13–0.56 mg kg–1day–1 for average consumers and 0.37–1.22 mg kg–1day–1 for 95th percentile consumers across 19 European countries. This was calculated based on the assumption that the overall average of the proportion of inorganic arsenic to total arsenic for food other than fish and seafood was 70% and a fixed inorganic value of 0.03 mg g–1 in fish and 0.1 mg kg–1 in seafood, and using the lower bound and upper bound concentrations. Recently, Xue et al. using a probabilistic modeling with the Stochastic Human Exposure and Dose Simulation Dietary model (SHEDS-Dietary) and based on data from the National Health and Nutrition Examination Survey, reported that in the US, the estimated dietary exposures to total and inorganic arsenic were 0.36 and 0.05 mg kg–1day–1, respectively for the mean, and 1.40 and 0.19 mg kg–1day–1, respectively for the 95th percentile.
Risk Characterization Inorganic arsenic has been identified as a human carcinogen based on numerous epidemiological studies associated with
Toxic Metals: Arsenic
arsenic levels in drinking water. Food can contribute significantly to total dietary inorganic arsenic exposure in people who are high consumers of rice or algae-based products. Water, depending on arsenic levels, used in food, cooking/ preparation and possibly irrigation of crops, particularly rice, can also contribute to arsenic in food. More information on bioavailability and speciation data for different food is needed for improving exposure estimation and for more accurate risk assessment. The estimated mean background dietary exposures to inorganic arsenic in the US and various European and Asian countries were reported to vary from 0.1 to 3.0 mg kg–1day–1 that are near or at the range of the BMDL01 and BMDL005 values identified by EFSA and JECFA, respectively. This suggests that certain populations may have an increase in risk depending on their particular dietary habits.
See also: Disciplines Associated with Food Safety: Epidemiology; Food Safety Toxicology. Foodborne Diseases: Overview of Chemical, Physical, and Other Significant Hazards. Institutions Involved in Food Safety: World Health Organization (WHO). Public Health Measures: Monitoring of Contaminants. Risk Analysis: Risk Assessment: Chemical Hazards; Risk Assessment: Principles, Methods, and Applications. Veterinary Drugs Residues: Control of Helminths
Further Reading Agency for Toxic Substances and Disease Registry (ATSDR) (2007) Toxicological Profile for Arsenic (Update). Atlanta, GA: US Department of Health and Human Services, Public Health Service. European Food Safety Authority (EFSA) (2009) Scientific opinion on arsenic in food. EFSA Journal 7(10): 1351. 199 pp.
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Food and Agriculture Organization/World Health Organization (FAO/WHO) (2010) Evaluation of Certain Food Contaminants | Summary Report of the 72nd Meeting of Joint FAO/WHO Expert Committee on Food Additives (JECFA). http:// www.who.int/foodsafety/chem/summary72_rev.pdf. Heikens A (2006) Arsenic contamination of irrigation water, soil and crops in Bangladesh: Risk implications for sustainable agriculture and food safety in Asia RAP PUBLICATION 2006/20. Bangkok, Thailand: Food and Agriculture Organization, Regional Office for Asia and the Pacific. International Agency for Research on Cancer (IARC) (2004) Overall Evaluations of Carcinogenicity to Humans: As Evaluated in IARC Monographs Volumes 1–82 (At Total of 900 Agents, Mixtures and Exposures). Lyon, France: IARC http:// monographs.iarc.fr/. Juhasz AL, Smith E, Weber J, et al. (2006) In vivo assessment of arsenic bioavailability in rice and its significance for human health risk assessment. Environmental Health Perspectives 114(12): 1826–1831. Liang F, Li Y, Zhang G, et al. (2010) Total and speciated arsenic levels in rice from China. Food Additives and Contaminants, Part A 27(6): 810–816. Meharg A, Williams PN, Adomako E, et al. (2009) Geographical variation in total and inorganic arsenic content of polished (white) rice. Environmental Science Technology 43(5): 1612–1617. National Research Council (NRC) (1999) Arsenic in Drinking Water. National Research Council. Washington, DC: National Academy Press. National Research Council (NRC) (2001) Arsenic in drinking water 2001 Update. National Research Council. Washington, DC: National Academy Press. Nishimura T, Hamano-Nagaoka M, Sakakibara N, Abe T, Maekawa Y, and Maitani T (2010) Determination method for total arsenic and partial-digestion method with nitric acid for inorganic arsenic speciation in several varieties of rice. Food Hygiene and Safety Science 51(4): 178–181. U.S. Environmental Protection Agency (2010) U.S. EPA IRIS Toxicological Review of Inorganic Arsenic (Cancer) (External Review Draft). EPA/635/R-10/001. Washington, DC: U.S. Environmental Protection Agency. http://www.epa.gov/iris/ index.html. World Health Organization (WHO) (2001) Arsenic and Arsenic Compounds, Environmental Health Criteria 224. Geneva, Switzerland: World Health Organization. Xue J, Zartarian V, Wang S-W, Liu SV, and Georgopoulos P (2010) Probabilistic modeling of dietary arsenic exposure and dose and evaluation with 2003–2004 NHANES data. Environmental Health Perspectives 118(3): 345–350.