October copyright W.Crinnion 2015

Transcription

1 October

2 2 Specie Type Half life Primary Arsenic types source Arsenate V Inorganic 2-4 days Water Arsenite III Inorganic 2 4 days Water MMA Inorganic hrs Food DMA Inorganic hrs Food Arsenobetaine Organic 4-6 hrs Seafood

3 3 Relative Specie toxicity Toxicity LD-50 LD-50 MMA 2 mg/kg Arsenate (ASV) Arsenite (ASIII) DMA Arsenobetaine 8 mg/kg 26 mg/kg 648 mg/kg >4,000 mg/kg Hughes MF. Toxicol Lett. 2002;133(1):1-16. PMID:

4 Arsenic Absorp,on Inorganic arsenic well absorbed in GI and Respiratory. Does not biomagnify Inorganic ½ life 2-4 days Widely distributed in the body Reduced to arsenite (+3) Then methylated to MMA and DMA Copyright WCrinnion 2010

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7 7 US rice consumption varies, averaging ~0.5 cup/d, with Asian Americans consuming an average of >2 cups/d.

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9 Sources 9 World arsenic groundwater map: US Arsenic groundwater map: US state-by-state groundwater: SubstanceMap.asp

10 Groundwater contamination with inorganic Arsenic is greatest source, persons in areas of high groundwater arsenic- 300ppm and higher- (Bangladesh, Africa, Chile, etc.) who drink an average of 3.3L/d have chronic As poisoning, those drinking 1.9L do not.

11 11 EPA Groundwater Arsenic Rules n Groundwater arsenic is primarily Arsenite (ASIII) and Arsenate (ASV) [pentavalent] n Maximum Contaminant Level in parts per million (ppm) n MCL = ppm = 10 PPB n 10 ug/liter n Water systems were to comply with this standard by January 23,

12 Arsenic in groundwater 12

13 By County 13

14 14 Relative Specie toxicity Toxicity LD-50 LD-50 MMA 2 mg/kg Arsenate (ASV) Arsenite (ASIII) DMA Arsenobetaine 8 mg/kg 26 mg/kg 648 mg/kg >4,000 mg/kg Hughes MF. Toxicol Lett. 2002;133(1):1-16. PMID:

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16 Food 16 Frequency Found Mean mg/kg (PPM) Haddock pan cooked 100% 5.54 Tuna canned in water 100% Shrimp boiled 100% Fast food fish sandwich on bun 100% Salmon steaks 99% New England Clam Chowder 99% Tuna noodle casserole 95% copyright W.Crinnion

17 Food 17 Frequency Found Mean mg/kg (PPM) Fried Rice Chinese takeout 100% Baby food rice cereal 100% Rice cereal infant 60% Baby food rice cereal w/ apples 20% Granola bar w/ raisin 20% Chicken leg fried fast food 20% Fried Chicken fast food 20% 0.024

18 PMID:

19 19 Based on TOTAL arsenic, consumption of 0.56 cups per day of cooked rice was comparable to drinking 1 L/d of 10ug As/L water, the current US maximum contamination limit PMID:

20 20 Based on TOTAL arsenic, Rice arsenic content and speciation consumption of 0.56 cups per day also vary, with some strains of cooked rice was comparable to predominated by dimethylarsinic acid, drinking 1 L/d of 10ug As/L water, particularly those grown in the United the current US maximum States contamination limit PMID:

21 Non- toxic Toxic

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24 24 Sources summary Groundwater with high ias levels Living in old orchards (lead arsenate residue) Cigarette smoke Glass blowing Seafood Rice Chicken

25 25 Avg. consumption Average daily arsenic intake for US residents is estimated to be 3.2 ug/day (range of 1 20 ug/day) Arsenic Exposure and Health, Elsevier Science pub. Amsterdam, The Netherlands. Page

26 26 Sources summary Washing rice in high As water increases As content, while washing with low As water decreases content of As. Chicken conventionally raised avg. 1.8 ug/kg, organic chicken avg. 0.6 ug/kg. PMID: , PMID: , PMID:

27 27 Metabolism of i-arsenic Inorganic arsenics are methylated and reduced. III valence more toxic than V valence More affinity for thiol groups More cytotoxicity and genotoxicity S adenosylmethionine is essential for As methyltransferase. SNPs in MTHFR, AS3MT, and GSTO1 increase MMAlll, and decrease DMAV High homocysteine found in MMA dominance

28 28 PMID:

29 29 When transferases don t work The presence of the following will methylate i-as without transferase activity Methylcobalamine Enhanced substantially by the presence of DMPS or sodium selenite (more if both are present with CH3B12 Glutathione Zahkaryan R, Aposhian V. Toxicol Appl Pharmacol 1999;154: PMID:

30 30 What enhances methylation? S-adenosyl methionine Folate Methylcobalamine L-methionine, cysteine and protein (all increased As excretion) PMIHeck JE EHP PMID:

31 31 Bowel flora methylation Bowel flora also methylate i-as Methylation is enhanced with the presence of: L-methionine Methylcobalamine Glutathione Selenite inhibited methylatioin Hall L, et al. Toxicol Appl Pharmacol 1997;147: PMID

32 32 As Health Effects Skin lesions found in areas with groundwater arsenic levels exceed 300ppm: hyperpigmentation, hypopigmentation, basal and squamous cell cancers. Cancers of the bladder, lung and liver with chronic ingestion of water with arsenic levels above 300ppm. No increased risk found in Nevada residents (avg. >85ppm) PMID:

33 33 Cardiovascular risk High levels of MMA increase risk of CVD (while higher DMA and lower MMA reduce the risk). Areas with avg. groundwater As of only 7.58ppm showed a 19% increased risk of CVD. But increased rates for MI due to chronic consumption of higher As groundwater can range from 26% more for women, 48%more for men and even higher for those who consumed it since childhood during high As years. High groundwater As is also associated with greater risk of hypertension. PMID: , PMID: , PMID: , PMID:

34 PMID:

35 35 Urinary As in Native Americans 3575 Native Americans ages From Az, OK, ND, SD STRONG heart study Baseline visits Follow-up through /3575 developed fatal and nonfatal cardiovascular disease.

36 36 Water & uas Concentrations Arizona <10 to 61ug/L Avg. uas of 14.2 ug/g creatinine Oklahoma <10ug/L Avg. uas of 5.6 ug/g creatinine Dakotas <1 ug/l to 21 ug/l Avg. uas of 10.6 ug/g creatinine

37 37 Arsenic in groundwater

38 38 Findings Low mean uas 5.8 ug/g creatinine High mean uas 15.7 ug/g creatinine 65% more likely to have CVD 71% more likely to have CHD 3.03X more likely to have stroke (mortality) For cardiovascular and coronary heart disease mortality, the associations were positive for all subgroups but stronger among participants from Arizona, those with diabetes and those with higher DMA levels

39 39 More Urinary arsenobetaine was not associated with any of the cardiovascular end points.

40 40 More health effects Diabetes mellitus risk goes up by 28% in areas where the groundwater averages only 7.58 ppm. Pro-oxidant and genotoxic especially MMA which inhibits glutathione reductase enzyme function. Mitochondrial damage: As uncouples ATP formation cellular apoptosis PMID:

41 persons in West Bengal, India Groundwater As averaged 3-6 ug/l Rice content of As averaged >200ug/kg Avg. amount of rice intake 1.3 pounds (of cooked rice) DAILY Urinary As range: ug/l (avg. 50 ug/l) Increase in micronuclei in renal cells PMID: Banerjee M, et al.

42 42 As microsomal damage Reversed nicely in animals by supplementation with: ascorbic acid 200 mg/kg 14,000mg for a 70 kg persons alpha tocopherol 400mg/kg 28,000mg for a 70kg person 42,000 iu PMID: Ramanathan Hum Exp Toxicol 2003.

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44 44 BCC and SCC Non-melanoma skin cancers Most common malignancy among caucasians Incident rates rising dramatically in US SCC has greater tendency to metastasize Increased risk from: Sunlight exposure Male Older

45 45 Associations SCC associated with high-arsenic water (over 100ppm) in Taiwan. Toenail arsenic levels in US associated with SCC (some of the same authors).

46 46 This study 470 persons with newly diagnosed SCC (between 7/2003 and 6/2009) and 447 controls From dermatologist and pathologists in NH. Seafood and rice consumption 2 days prior to urine collection similar in both groups. Seafood associated with higher total AS (primarily DMA) 4 oz serving increases AS by 53%

47 47 Findings Those who did not consume fish w/in 2 days of UA Linear association of SCC and total AS, MMA & DMA. After adjustment for sex, age, BMI, education, smoking, skin rxn to sun, the OR for SCC is 1.33 for each 1 ug/l increase in urinary MMA. Persons in tertile 3 of U-MMA had 76% greater risk of SCC than those in tertile 1. (Only found in those above the 90 th % for non-asians)

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49 49 As- source in this study Urinary As positively associated with water-as Rice consumption was not a significant predictor of urinary inorganic As But was for DMA Seafood consumption was a significant predictor of urinary DMA

50 PMID:

51 51 Zoster Common in elderly and in any immunocompromised person. Increased in those with diabetes, trauma and stress. Noted in those with acute As poisoning and in persons with Acute Promyelocytic Leukemia treated with arsenic trioxide.

52 52 NHANES 2003/4 & 2009/10 TUA1 grouping AsBet, AsChol, arsenite (As3), arsenate (As5), MMA, DMA TUA2 grouping Only inorganic arsenics (no arseno sugars) Seropositive or negative for VZV IgG Positive finding indicates vaccine or disease-induced immunity

53 53 As Exposure As of million Americans were drinking water with an avg. As of > 50 ug/ L WHO limit for water As is 10ug/L Exceeded by 11-19% of private US wells

54 54 Results As total for TUA1 group: 6.57 ug/l As total for TUA2 group: 5.64 ug/l Elevated TUA1 and TUA2 were associated with greater incidence of seronegativity (non-immune to zoster). OR 1.87

55 PMID:

56 56 Conclusion: In this systematic review we identified an association between arsenic and the prevalence of hypertension PMID:

57 57 Botanical help Both Green and Black tea reverse Asinduced cytotoxicity and genotoxicity EGCG Theaflavin Curcumin Both protects against and repairs DNA oxidative damage from As. PMID: , , ,

58 58 Bowel flora methylation Bowel flora also methylate i-as Methylation is enhanced with the presence of: L-methionine Methylcobalamine Glutathione Selenite inhibited methylatioin Hall L, et al. Toxicol Appl Pharmacol 1997;147: PMID

59 59 PMID:

60 60 This study In vivo with mice Given water with 10ppm As daily for 4 weeks Over 25 million US residents drink water with that level or higher Hundreds of millions worldwide Arsenic associated illnesses Skin, bladder, lung and liver cancers Diabetes

61 61 Results Mice fed 10ppm As water had significant changes in microbiome and changes in microflora-related metabolites Reduction in four Firmicutes families Including several important butyrate producers Fatty acid carnitines also significantly reduced Used to transport FFA into mitochondria Elevated indoles Probable increase in Clostridium sporogenes Elevated bile acids and intermediates Impairing synthesis and recycling of bile acids Possible reduction of EFA, PUFA and fat-soluble vitamin depletion

62 Arsenic Cardiovascular disease Hypertension Diabetes Squamous cell carcinoma Shingles High homocysteine and elevated 8 OHdG

63 63 Lab testing Baseline urinary As >15 increased CVD risk High homocysteine levels associated with higher MMA and lower DMA. 8-OHdG levels are elevated with arsenic showing oxidative DNA damage. PMID: , PMID:

64 64 Reducing exposure RO water purification is best for arsenic removal upload/ 2005_11_10_arsenic_treatments_and_costs.pdf Check with your local water utility for the arsenic level in your water. Avoid cigarette smoke Identify and avoid/reduce exposures Haddock is commonly used for fish & chips and fish sandwiches

65 65 EL Foust om

66 66 PMID:

67 67 Background GSH in critical for arsenic excretion from each cell. Inorganic arsenic binds with GSH to form arsenic triglutathione which is then pumped into the intracellular space by MRP1. MRP1 is activated by Nrf2 GSH blockers accelerate As accumulation in the cells

68 68 This study Sulforaphane is a potent Nrf2 activator Sulforaphane pretreatment, 24 hrs before arsenite exposure: 33% reduction in As accumulation in hepatocytes Reduction in As toxicity

69 69 Summary BE aware of areas with higher groundwater arsenic. Only drink filtered water (charcoal is not sufficient to clear out As.) Supplements: Methylation S-adenosyl methionine, methylfolate, methylcobalamine, L-methionine. Antioxidants Vit E and C Probiotics Protein (increases excretion) Glutathione, sulforaphanes and curcumin Green or black tea