ARSENIC: deficiency/toxicity health impact

1. ARSENIC: deficiency/toxicity health impact FCS 308 California State University of Northridge Amanda Grigg Dana Sutherland Yelena Tkachenko Professor Darmanyan 05/08/2012

2. ARSENIC: Mineral Characteristics • Chemical symbol: As • A metalloid, ultratrace¹ essential mineral • Atomic # 33, atomic mass 74.92 • Concentration: 2 mg/kg (earth crust) • Best natural food sources: seafoods, meats, cereal and grain products, dairy. • Natural chemical forms: crystalline, powder, amorphous or vitreous (glass) in all rock, soil, water and air. • Recommended Intake: 12-25 µg • Estimated Dietary Intake: <30µg/day • No Tolerable Upper Intake Level (UL) or Adequate Intake (AI) is determined yet ¹Estimated, established or suspected requirements of <1 mg/day (Gropper at al. 2009)

3. ARSENIC: Mineral Characteristics • Inorganic: occur in their pure, metallic form, or when combined in compounds with O, Cl, S as trivalent arsenite (AsO2) or pentavalentarsenate (AsO4) to other non-carbon elements. Most toxic, human poison. • Organic: organic (i.e. carbon based) compounds that contain covalently bonded arsenic atoms such as pentavalent, methylated arsenic. Less toxic. 4-Hydroxy-3-nitrobenzenearsonic acid: organic compound that is widely used agriculturally as a chicken-feed additive. (Gropper at al. 2009)

4. ARSENIC: Mineral Characteristics • Mechanism of Absorption: varies with chemical form and solubility • Mostly simple diffusion across intestinal mucosa, transported in the blood to liver. • Metabolism: •Organic - little or none in liver •Inorganic - reduced, methylated or both in liver •Concentrates in skin, hair, nails • Excretion: via kidneys in urine (<50µg/day) (Gropper at al. 2009)

5. ARSENIC: Mineral Characteristics • Function: formation and utilization of methyl groups, generated in methionine metabolism to SAM (S-adenosylmethionine) • Interactions: • Se and As (oxyanions that inhibit uptake and tissue retention); • I and As (As antagonizes the mechanism of iodine uptake by thyroid) (Gropper at al. 2009)

6. ARSENIC: Mineral Characteristics Deficiency: • impairs methionine metabolism • curtailed growth • reduced conception rate • increased neonatal mortality Toxicity: 1mg > anemia, hepatotoxicity; 10mg > encephalopathy, GI problems. 70mg>fatal • GI problems • hyperkeratosis • neuropathy • delirium • cancer • Blackfoot disease (peripheral vascular condition in Taiwanwhen drinking arsenic-containing drinking water) • Supplements: traditional Chinese medicine formulas, herbal kelp. (Gropper at al. 2009)

7. Commercial Supplements Facts • Serving Size: One capsule daily with food • Amount of Minerals per serving: • Iron 390 mcg • Iodide 400 mcg • Sodium 20mg • Kelp(whole thallus) 660mg

8. Commercial Supplements Facts • According to our research, although arsenic is not included on the kelp supplement label, kelp supplements contain arsenic. • Kelp supplements are considered an Arsenic supplement. • Amount of Arsenic per serving: 5.61 µg • Chemical Form: trivalent arsenic in the form of inorganic arsenious acid (arsenite), or an organic arsenoxide

9. Commercial Supplements Facts • Claims on Label: • “Natural Iodide Source” • “Certified 660mg” • “Premium Herbal”

10. Natural Food Equivalent • Foods of marine origin are rich in arsenic. • Oysters contain up to 10 µg/g of Arsenic • One serving of oysters (6 medium)= 84 g • 84g * (10µg/g)= 840 µg of Arsenic • Kelp supplement contains 5.61 µg • A serving of 0.561 grams of oysters is the equivalent to one serving of kelp supplement. (Gropper et. al., 2009)

11. Possible Mechanism of Supplement Absorption • Concentration of As in the Kelp supplement is 5.61 µg in one serving; relatively low As concentration • Mechanism of absorption: simple diffusion • Most As is absorbed through the intestinal walls, then transported to the liver • Inorganic As absorption does not depend on concentration, but rather its lipid solubility (Gropper at al. 2009)

12. Health Impact: Potential Arsenic Toxicosisin Herbal Kelp • Article: “Case Report: Potential Arsenic Toxicosis Secondary to Herbal kelp Supplement” • Authors: Eric Amster, AsheeshTiwaryand Marc B. Schenker (USC Davis) • Journal: Environmental Health Perspectives • Year: 2007 (Amster et al., 2007)

13. Health Impact: Potential Arsenic Toxicosis in Herbal Kelp Introduction: • Commercially available herbal kelp supplements may contain higher levels of arsenic contamination than previously known. • Chronic use of the supplement may lead to manifestation of arsenic toxicity symptoms. • This study was performed in order to find out if there is a link between both and to inform clinicians about a potential heavy metal toxicity. Objective: Medicinal use of dietary herbal supplements can cause inadvertent arsenic toxicosis. (Amster et al., 2007)

14. Health Impact: Potential Arsenic Toxicosis in Herbal Kelp Case Presentation: • 54 year old woman with symptoms of alopecia, memory loss, fatigue, rash on legs, GI problems, vomiting, later disabled (USC Davis). • Duration of symptoms: october 2002 to october 2003 with progression of worsening • Urine sample = 83.6 μg/g creatinine (normal < 50 μg/g creatinine). A sample of kelp supplements = 8.5 mg/kg (ppm)¹ arsenic (normal: 0-50µg) • Consumption of kelp supplement: 2 to 4 pills a day (1 pill contains 41mg kelp, 66mg Ca, 225 µg I) • Tests included: MRI, blood count, chemistry panel, thyroid studies, diet (seafood:less than one serving), water analysis, other supplements = all normal levels. • When discontinued the supplements, symptoms resolved and arsenic blood and urine levels were undetectable within few weeks. ¹parts per million, dilute concentrations of substances. (ex:1 ppm is equivalent to 1 milligram of something per liter of water (mg/l) or 1 milligram of something per kilogram soil (mg/kg). (Amster et al., 2007)

15. Health Impact: Potential Arsenic Toxicosis in Herbal Kelp Methods: • 9 samples of random kelp supplements (OTC) including 3 of patient’s supplements (same brand not the same bottle). • None of the supplements contained information regarding the possibility of contamination of arsenic • Determination of total arsenic by inductively coupled argon plasma (ICP) using the identical hydride vapor generation method (demonstrates statistical control for samples of biological interest and is especially well suited to analysis of small samples). • A 1 g sample is wet washed in a 16 x 150 mm 10 mL volumetric test tube on a programmed heating block with nitric, sulfuric, and perchloric acids at up to 310 degrees C. After treatment with hydrochloric acid and potassium iodide, arsenic is reduced by sodium borohydride to arsine in a simplified continuous flow manifold. A standard pneumatic nebulizer affects the gas-liquid separation of AsH3, which is quantified by ICP atomic emission at 193.756 nm. The instrument detection limit for the method has been determined to be 0.4 microgram/L. For a 10:1 dilution of a nominal 1 g sample, the detection limit is 4 micrograms/kg and the linear range is up to 4 mg/kg. Recoveries from 3 matrixes were 99-104%, with a typical RSD of 2%. • Analysis: Random blind-folded manner • Outcome Measures: majority of samples showed detectable arsenic levels (Amster et al., 2007 & Tracy, 1991)

16. Health Impact: Potential Arsenic Toxicosis in Herbal Kelp Results: • 8 out of 9 had higher levels (1.59 to 65.5 ppm) than FDA tolerance level (0.5 to 2 ppm) • 1 out of 9 was below the detection limit (0.010 ppm) • 3 patient samples arsenic concentration were 34.8, 2.28, 1.59 ppm. • Patient’s blood arsenic levels on February 2004 were 8µg/L (normal) Conclusion: • Given the nature of patients symptoms and tests performed the study showed a causal associations between her ingestion and symptoms. • Majority of kelp supplements contain higher levels of arsenic • Consumers are misinformed and aren’t aware of the metal intoxication exposures. • Cause of concerns when consistency varies batch to batch (same brand variability) • Improper labeling of supplements. • Concentrations of materials contained in preparations, expected benefits and side-effects should be studied, standardized, monitored and accurately labeled. (Amster et al., 2007)

17. Health Impact:Drinking-Water Arsenic Exposure Modulates Gene Expression • Article: Drinking-Water Arsenic Exposure Modulates Gene Expression in Human Lymphocytes from a U.S. Population • Authors: Angeline S. Andrew, David A. Jewell, Rebecca A. Mason, Michael L. Whitfield, Jason H. Moore, Margaret R. Karagas • Journal: Environmental Health Perspectives • Year: 2008 (Andrew et. al., 2008)

18. Health Impact:Drinking-Water Arsenic Exposure Modulates Gene Expression Introduction: • Arsenic exposure impairs development and can lead to cancer, cardiovascular diseases, and diabetes. • In the northeastern, western, and north central regions of the United States, arsenic levels in drinking-water exceed the maximum contaminant level of 10ug/L. (Andrew et. al., 2008)

19. Health Impact:Drinking-Water Arsenic Exposure Modulates Gene Expression Objectives: • The purpose of this study was to research the effects of arsenic exposure on gene expression. • The effects of arsenic exposure was determined by internal biomarkers at levels relevant to the United States and populations with similar arsenic exposure. (Andrew et. al., 2008)

20. Health Impact:Drinking-Water Arsenic Exposure Modulates Gene Expression Methods: • Subjects: Selection of 21control subjects who did not have cancer were used in this study. • Route of Adminitration: Oral • Doses of Administration: • Unregulated private wells used for drinking-water • High Exposure: (n=11) Averaged 32 ug/L (range: 10.4ug/L-74.7ug/L) • Low Exposure: (n=10) Averaged 0.7ug/L (range: 0.0007ug/L-5.3ug/L) (Andrew et. al., 2008)

21. Health Impact:Drinking-Water Arsenic Exposure Modulates Gene Expression Methods continued: • Outcome Measures: • Subject selection, gene expression analysis, and biological function analysis were performed. • Analysis of Internal Biomarkers: Toenail clippings, and urine samples, venous blood sample. (Andrew et. al., 2008)

22. Health Impact:Drinking-Water Arsenic Exposure Modulates Gene Expression Results: • High arsenic: 82% male, 18% female • Low arsenic: 80% male, 20% female • The SAM test identified 259 genes that were significantly different in the high vs. low arsenic exposure statuses. • Defense and immune response pathways had the most statistically significant level of modified transcripts associated with arsenic exposure. • Arsenic exposure was also associated with an increase in expression of the killer cell immunoglobin-like inhibitory receptors (KIR). (Andrew et. al., 2008)

23. Health Impact:Drinking-Water Arsenic Exposure Modulates Gene Expression Results continued: • 38 genes were identified to be significantly different in those with high urinary arsenic levels versus low urinary arsenic levels. • A substantial trend was identified towards increased transcript abundance for PRF1, IL2RB, and KIR3DL1 with increasing urinary exposure concentration. (Andrew et. al., 2008)

24. Health Impact:Drinking-Water Arsenic Exposure Modulates Gene Expression Conclusion: • Gene expression is modulated because of arsenic exposure. • Chronic arsenic exposure modulates immune function by decreasing defense response genes. (Andrew et. al., 2008)

25. Health Impact: Low Level Arsenic Exposure Is Associated with Poorer Neuropsychological Functioning • Title Long-term Low Level Arsenic Exposure Is Assiciated with Poorer Neuropsychological Functioning: A Project FRONTIER Study • Authors Sid E. O’Bryant, Melissa Edwards, Chloe V. Menon, Gordon Gong, & Robert Barber • Journal International Journal of Environmental Research and Public Health • Year 2011 (O’Bryant et al., 2011)

26. Health Impact: Low Level Arsenic Exposure Is Associated with Poorer Neuropsychological Functioning • Introduction • The health impact of high-level exposure to arsenic has been well established, however there is little reasearch conducted that documents the health impact of prolonged exposure to groundwater arsenic at levels below the current U.S. standard of 10 µg/L. • Arsenic exposure has been associated with an increase in the production of ß amyloid, hyperphoshoralation of tau protein, oxidative stress, inflammation, endothelial cell dysfunction and angiogenesis, all of which have been linked to cognitive dysfunction and are proposed mechanisms underlying Alzheimer's disease. • Objective • The purpose of the current study was to examine the potential association between current and long-term arsenic exposure and neuropsychological functioning in a sample of rural-dwelling adults and elders (O’Bryant et al., 2011)

27. Health Impact: Low Level Arsenic Exposure Is Associated with Poorer Neuropsychological Functioning Methods • Subjects: 434 adults ages 40 and up (133 male, 301 female) • Route of Administration: oral • Doses of Administration: • Parmer County: 3.06 µg/L (15 year average) • Cochran County: 7.39 µg/L (15 year average) • Duration of Experiment: 15 years • Outcome Measures: • Texas Water Development Board (TWDB) • Geographic Information System (GIS) • Project FRONTIER • Mini-Mental state Examination (MMSE), Exit Interview (EXIT25), Repeatable Battery for the Assessment of Neuropsychological Status (BRANS), Trails Making test (TMT-A & B), and Controlled Oral Word association Test (COWAT) (O’Bryant et al., 2011)

28. Health Impact: Low Level Arsenic Exposure Is Associated with Poorer Neuropsychological Functioning • Results • Current estimated groundwater arsenic exposure level was significantly associated with poorer scores in language, visuospatial skills and executive functioning. • Long-term low level exposure to arsenic was significantly associated with poorer scores in global cognition, visuospatial skills, language skills, processing speed and immediate memory • Conclusion • It cannot be concluded that long-term-low-level arsenic consumption through water is causally related to poorer cognition from the current data. • These finding were the first direct evidence that low-level arsenic exposure is associated with poorer neuropsychological functioning among community-dwelling adults and elders in the U.S. • Further research is needed, but this study provides ample justification for a re-evaluation of current policy to acceptable groundwater arsenic levels. (O’Bryant et al., 2011)

29. Conclusion Symbol for Arsenic: As Best natural food source: seafood Recommended Daily Intake: 12-25µg Mechanism of absorption: simple diffusion Function: formation and utilization of methyl groups Deficiency: impairs methionine metabolism Toxicity: Blackfoot Disease Commercial supplement: Kelp

30. Conclusion As from supplements is associated with various symptoms that effect health, such as alopecia, memory loss, fatigue, rash on legs, GI problems, vomiting Gene expression is modulated because of As exposure and chronic arsenic exposure modulates immune function by decreasing defense response genes. Long-term low level exposure to arsenic was significantly associated with poorer scores in global cognition, visuospatial skills, language skills, processing speed and immediate memory

31. References • Amster, E., Tiwary, A. & Schenker, M. (2007). Case Report: Potential arsenic toxicosis secondary to herb kelp supplement. Environ Health Perspect, 115:606-608. http://dx.doi.org/10.1289/ehp.9495 • Gropper, S., Smith, J & Groff, J. (2009). Advanced nutrition and human metabolism, 5th edition. Belmont, CA: Wadsworth, Cengage Learning. • Tracy, M., Littlefield, E. & Moller, G. (1991). Continuous flow vapor generation for inductively coupled argon plasma spectrometric analysis. Part 2. Arsenic. J Assoc Off Anal Chem74:516-521. • Rose, M., Lewis, J., Langford, N., Baxter, M., Origgi, S., Barber, M., MacBane, S., & Thomas, K. (2007, January 17). Arsenic in seaweed--forms, concentration and dietary exposure. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17336439 • O’Bryant, S., Edwards, M., Menton, C., Gong, G., & Barber, R. (2011, March 15). Long-term low-level arsenic exposure is associated with poorer neurological functioning: a project FRONTIER study.International journal of Environmental public health, 8, 861-874.

32. References • Andrew, A. S., Jewell, D. A., Mason, R. A., Whitfield, M. L., Moore, J. H., & Karagas, M. R. (2008). Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a u.s. population. Environmental Health Perspectives, 116(4), 524-531. • Gropper, S. S., Smith, J. L., & Groff, J. L. (2005). Advanced nutrition and human metabolism. (4 ed., pp. 489-492). Belmont, CA: Thomson Wadsworth.