Arsenic Toxicity

Arsenic and many of its compounds are especially potent poisons. Arsenic disrupts ATP production through several mechanisms. At the level of the citric acid cycle, arsenic inhibits pyruvate dehydrogenase and by competing with phosphate it uncouples oxidative phosphorylation, thus inhibiting energy-linked reduction of NAD+, mitochondrial respiration, and ATP synthesis. Hydrogen peroxide production is also increased, which might form reactive oxygen species and oxidative stress.
These metabolic interferences lead to death from multi-system organ failure
Arsenic poisoning is a medical condition caused by elevated levels of arsenic in the body. The dominant basis of arsenic poisoning is from ground water that naturally contains high concentrations of arsenic. A 2007 study found that over 137 million people in more than 70 countries are probably affected by arsenic poisoning from drinking water

1. toxicology Arsenic toxicity

2. Sources​ Moods of exposure Toxicokinetics Mechanisms of toxicity Symptoms of acute and chronic toxicity Diagnosis T reatment Notable cases of arsenic poisoning References outlines

3. Sources

4. You can get arsenic in to youer system by ingestion of food or inhalation during manufacture. In some countries, such as Bangladesh, Argentina, Chile and India, considerable amounts of arsenic are taken up by the general population with the drinking water from contaminated wells

5. organic arsenic found in : Water , soil , grains planted in this contaminated soil. Inorganic arsenic found in : apple juice, orange juice, in vinegars , in milk and dairy products, beef, and in cereal The organic compounds are less toxic than the inorganic compounds.

6. Moods of exposure

7. The primary routes of arsenic entry into the body are via ingestion and inhalation . Dermal exposure can occur, but is not considered a primary route of exposure. Exposure dose is the cumulative exposure by all routes.

8. 1- Ingestion: main source of arsenic exposure is via ingestion of food containing arsenic. Intake from air, soil, and drinking water is usually much less. It has been estimated that the average daily dietary intake of arsenic by adults in the United States is 40 micrograms per day.

9. Arsenic Containing Foods : Meat, fish, and poultry account for 80% of dietary arsenic intake, shellfish, seaweed , and algae also contain arsenic , sometimes referred to as "fish arsenic." Fish arsenic has low toxicity to humans and is rapidly excreted in urine .

10. 2- Inhalation: Major sources of inhaled arsenic may come from air emissions from: burning of fossil fuels that contain arsenic, cotton gins, glass manufacturing operations, pesticide manufacturing facilities, smelters, and tobacco smoke

11. 3- Skin : Dermal contact when handling preserved wood products containing arsenic could result in arsenic exposure. Toxic effects have been reported in the occupational literature from splashes of arsenic trichloride or arsenic acid on worker’s skin.

12. Toxicokinetics

13. Arsenic is a normal component of the human body. Once ingested; soluble forms of arsenic are readily absorbed from the gastrointestinal tract, absorption rate range from 40 % to 100 % for humans. Arsenate As(V) whether inorganic or organic, is better absorbed than As(III) arsenite because arsenate is less reactive with membranes of the gastrointestinal tract. Arsenic in drinking water is mostly in the arsenate form, and complete absorption of arsenic from water may occur . Absorption

14. Arsenic enters the human body through ingestion, inhalation, or skin absorption. Most ingested and inhaled arsenic is well absorbed through the gastrointestinal tract and lung into the blood stream. After absorption through lungs and the gastro-intestinal tract, 95 to 99 % of the arsenic is located in erythrocytes, bound to the globin of hemoglobin and is then transported to the other parts of the body.

15. Distribution Arsenite (trivalent Arsenic) levels in the human body are 2–25 times higher than that of arsenate ( pentavalent form). Arsenic is transported by blood which distributes it to muscles, bones, kidneys, lungs and across the placenta. However larger amounts are concentrated in keratin-rich tissues such as skin nails and hair. Arsenite (trivalent Arsenic) Arsenate ( pentavalent form)

16. Metabolism Methylation is considered the main route of arsenic detoxification; arsenate is redused to arsenite by glutathione. A percentage of arsenite is methylated in the liver by enzymatic transfer of the methyl group from SAM to methyl arsonate and dimethyl arsenate producing monomethylarsonic acid and dimethylarsinic acid. When methylating capacity of the liver is exceeded, exposure to excess levels of inorganic arsenic results in increased retention of arsenic in tissues.

17. Recently additional detoxification mechanisms are suggested such as Antioxidant defenses, Resistance to apoptosis, or Transport.

18. About 70% of the arsenic are excreted mainly through urine. Most arsenic absorbed into the body is converted by the liver to less toxic methylated form that is efficiently excreted in the urine. The rate of decrease of arsenic in the skin appears to be especially low compared with the rate for other organs. Excretion

19. Some of the inorganic arsenic is excreted primarily via urine as the parent form of the ingested arsenic. After methylation, it is also excreted as monomethyarsonous acid (MMA) and dimethylarsinous acid (DMA). Humans rapidly excrete most blood arsenic, with 50 to 90% cleared in two to four days. The remainder is cleared more slowly.

20. Mechanisms of toxicity

21. ARSENIC-INDUCED CARDIOVASCULAR DYSFUNCTION . ARSENIC-INDUCED DIABETES MELLITUS . ARSENITE-INDUCED NEUROTOXICITY . ARSENIC-INDUCED NEPHROTOXICITY AND HEPATOTOXICITY . ARSENIC-INDUCED CARCINOGENICITY . ARSENIC induce toxicity in varies mechanisms depending on the target :

22. ARSENIC-INDUCED CARDIOVASCULAR DYSFUNCTION ROS generated during arsenite exposure increases the expression of atherosclerosis related genes such as heme oxygenase-1 (HO-1), monocyte chemo-attractant protein (MCP-1), and interleukin-6 (IL-6) and thus its exposure promotes the attachment, penetration, and migration of monocytes in VSMC.

23. Chronic exposure to arsenic induces oxidative stress and alters the release of vasoactive mediators in blood vessel leading to elevation of blood pressure. Taken together, it may be suggested that arsenic induces cardiovascular dysfunction by inducing high oxidative stress, reducing the activation of eNOS and enhancing the phosphorylation of MLCK, which may be targeted for preventing arsenic exposure-associated cardiovascular complications.

24. ARSENIC-INDUCED DIABETES MELLITUS The prolonged exposure to arsenic causes decreased expression of PPAR-γ, interference in ATP-dependent insulin secretion, altered glucocorticoid receptor mediated transcription, and inhibition of PDK-1 are involved in the induction of arsenic-associated diabetes, which can serve as potential targets to modulate arsenic-induced diabetes .

25. ARSENITE-INDUCED NEUROTOXICITY Brain is a soft target for arsenic toxicity as it freely crosses blood-brain barrier. The deficiency of thiamine (vitamin B1) is well known to induce neuronal complications. It is worthwhile to note that arsenic causes thiamine deficiency and inhibits pyruvate decarboxylase, which elevates blood pyruvate and hence causes encephalopathy .

26. The chronic arsenic exposure is associated with morphological changes in axons and nerve fibers of the striatum which disturbs central structural organization. Hence, oxidative stress, induction of thiamine deficiency, and inhibitions of pyruvate decarboxylase, acetyl cholinesterase, reduction in biogenic monoamines seem to play a pivotal role in arsenic-induced neurotoxicity.

27. ARSENIC-INDUCED NEPHROTOXICITY AND HEPATOTOXICITY Arsenic concentrates in the kidney during its urinary elimination that affects the function of proximal convoluted tubules. Arsenite -induced apoptotic progression is aggravated by folate deficiency. Arsenic exposure leads to the incidence of hepatotoxicity as manifested by increase in the levels of total bilirubin, alanine aminotransferase, aspartate aminotransferase, and malionaldehyde . Hence, oxidative stress, apoptosis, and upregulation of transcription factors such as AP-1, ATF-2, and Elk-1 are the prospective target sites for arsenite -induced nephrotoxicity and hepatotoxicity.

28. ARSENIC-INDUCED CARCINOGENICITY The trivalent form of arsenic exhibits greater genotoxic effects than the pentavalent counterparts as it could be easily taken up by the cells. Oxidative stress seems to be the main culprit for arsenic-induced carcinogenicity, which can be prevented by antioxidants such as vitamin E, melatonin, and curcumin . Taken together, various possible modes of carcinogenic action of arsenic proposed till date are increased oxidative stress, direct genotoxic effects, altered expression of growth factors, and altered DNA repairing mechanisms.

29. Symptoms of acute and chronic toxicity

30. symptoms of chronic arsenic poisoning Affected organ Features Skin Excessive darkening of skin (hyperpigmentation) in areas that are not exposed to sunlight Excessive formation of scaly skin on the palms and soles (arsenical keratosis) Exfoliative dermatitis Arsenic-induced skin cancers (especially Bowen disease , Squamous cell carcinoma) Nails Transverse white bands of arsenic deposits across the bed of the fingernails ( Mee's lines)

31. Hair Arsenic deposits in hair Nervous system Sensory changes, numbness and tingling in a “stocking-glove” distribution (sensory peripheral neuropathy) Headache, drowsiness, confusion Distal weakness of small muscles e.g. hands and feet Blood and urine Haemolytic anaemia (moderate) Leukopaenia (low white cell count) Proteinuria (protein in urine)

32. Other Inflammation of respiratory mucosa Peripheral vascular insufficiency Increased risk of cancer of lung, liver, bladder, kidney and colon

33. Features of acute arsenic poisoning Symptoms usually start within 30 minutes to 2 hours. Acute arsenic ingestion is typically followed by a severe gastroenteritis, garlic odour and hypersalivation . There is a characteristic sequence of multi-organ failure, with: neurological symptoms (within hours) and cardiac features, succeeded by adult  respiratory distress syndrome   and renal/liver dysfunction. Marrow suppression develops after a few days to weeks in survivors, as does alopecia and an ascending motor neuropathy.

34. Diagnosis

35. Diagnostic criteria of Chronic arsesnicosis: 1. At least 6 months exposure to arsenic levels of greater than 50 mg/L or exposure of high arsenic level from food and air. 2. Dermatological features characteristic of chronic arsenicosis. 3. Non carcinomatous manifestations : Weakness, chronic lung disease, non cirrhotic portal fibrosis of liver with/without portal hypertension, peripheral neuropathy, peripheral vascular disease, non pitting edema of feet/ hand. 4. Cancers : Bowens disease, Squamous cell carcinoma, Basal cell carcinoma at multiple sites, occurring in unexposed parts of the body. 5. Arsenic level in hair and nail above 1 mg/kg and 1.08 mg/kg respectively and/or arsenic level in urine, above 50 mg/L (without any history of taking seafood).

36. Dermatological criteria and grading of severity of chronic arsenic toxicity: Grade I Mild a) Diffuse melanosis. b) Suspicious spotty depigmentation / pigmentation over trunk /limbs . c) Mild diffuse thickening of soles and palms. Grade II Moderate a) Definite spotty pigmentation / depigmentation on the trunk ands limbs, bilaterally distributed. b) Severe diffuse thickening Grade III. Severe a) Definite spotty pigmentation/depigmentation as above with few blotchy pigmented/depigmented macular patches over trunks or limbs. b) Pigmentation involving the undersurface of tongue and/or buccal mucosa. c) Larger nodules over thickened palms and soles occasionally over dorsal aspect of hands and feet. Diffuse verrucous lesions of the soles with cracks and fissures and keratotic horns over palms/soles.

37. Biomarkers with special focus exclusively on diagnosis: 1. Urine 2. Hair and Nail 3. Blood

38. Treatment

39. 1-Treatment of acute arsenic: 1-Gastric lavage 2-Activated charcoal does not bind well inorganic arsenic 3-Whole bowel irrigation with polyethylene glycol

40. 4-Skin decontamination in dermal exposure 5-Supportive care 6-Chelation therapy should be instituted promptly (minutes to hours) 1. BAL (British anti-Lewisite)- IM 2. Succimer (DMSA)- PO 3. DMPS – PO, IV 4. D- Penicillamine - less effective

41. 2-treatment of chronic arsenic For chronic poisoning, chelator therapy has not proven effective in relieving symptoms

42. 1-Chelation 2-Nutrition 3-Removal Chemical and synthetic methods are used to treat arsenic poisoning. Dimercaprol and dimercaptosuccinic acid are chelating agents that sequester the arsenic away from blood proteins and are used in treating acute arsenic poisoning. The most important side effect is hypertension. Dimercaprol is considerably more toxic than succimer .[citation needed]DMSA monoesters, e.g. MiADMSA , are promising antidotes for arsenic poisoning. Calcium sodium edetate is also used. Supplemental potassium decreases the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide. Various techniques have been evolved for arsenic removal, most frequently using absorbents such as activated carbon, aluminium oxide, co-operative with iron oxide to form sludges , adsorption onto iron-oxide-coated polymeric materials, and electrocoagulation by nanoparticle. To remove the stress of heavy and toxic metals, an environment-friendly approach must be applied and the use of naturally occurring microbe must be emphasized. Bacteria, yeast, fungi, algae—all of them can be used for remediation processes and it is always recommended that microbe used for bioremediation must have natural decontamination process and the method should be cost-effective.

43. Notable cases of arsenic poisoning

44. Napoleon Bonaparte Simón Bolívar Van Gogh King Faisal I of Iraq

45. The Largest Mass Poisoning in History Up to 77 million people in Bangladesh are being exposed to toxic levels of arsenic, potentially taking years or decades off their lives. it takes 20 years for the negative morbidity effects of arsenic poisoning to dissipate, even after they stopped using contaminated wells. http://www.youtube.com/watch?v=W3Hvexu5SqM

46. strain GFAJ-1 of the Halomonadaceae, isolated from Mono Lake, California, that is able to substitute arsenic for phosphorus to sustain its growth . Mono lake bacteria

47. Reference http:// www.atsdr.cdc.gov/csem/arsenic/docs/arsenic.pdf http :// toxsci.oxfordjournals.org/content/123/2/305.full Agency for Toxic Substances and Disease Registry (2007) ToxGuide for Arsenic, USA: Centers for Disease Control and Prevention. Agency for Toxic Substances and Disease Registry (2009) Case Studies in Environmental Medicine; Arsenic Toxicity, USA: Centers for Disease Control and Prevention. WHO (2000) Air Quality Guidelines, 2 edn ., Copenhagen, Denmark: WHO Regional Office for Europe. American Conference of Governmental Industrial Hygienists (ACGIH). Documentation of the threshold limit values and Biological Exposure Indics . 5th ed. ACGIH, Cincinnati, OH, 1986. Armstrong, C. W., Stroube , R. B., Rubio, T., and Beckett, W. S. Outbreaks of fatal arsenic poisoning caused by contaminated drinking water. Arch. Environ. Health 39, pp 274-279, 1984. Axelson , O., Dahlgren, E., Jansson , C. D., and Rehnlund , S. O. Arsenic exposure and mortality. Acase reference study from a Swedish copper smelter. Br. J. Ind. Med. 35, pp 8-15, 1978. Dr. D.n . Guha Mazumder , Chapter 4 : Diagnosis and treatment of chronic arsenic poisoning By. In editor. Diagnosis and treatment of chronic arsenic poisoning, : Institute of Post Graduate Medical; 2000. p.20 Steven Marcus. Medscape. Arsenic Toxicity treatment [serial on the Internet]. 2012 [cited 2014 Nov 23]. Available from: Copyright © 1994-2014 by WebMD LLC, MEDLINE database Web site: http://http://emedicine.medscape.com/article/812953-overview Dr. D.n . Guha Mazumder , Chapter 4 : Diagnosis and treatment of chronic arsenic poisoning By. In editor. Diagnosis and treatment of chronic arsenic poisoning, : Institute of Post Graduate Medical; 2000. p.20 Steven Marcus. Medscape. Arsenic Toxicity treatment [serial on the Internet]. 2012 [cited 2014 Nov 23]. Available from: Copyright © 1994-2014 by WebMD LLC, MEDLINE database Web site: http://http:// emedicine.medscape.com/article/812953-overview