arsenic and manganese poisoning
TRANSCRIPT
Arsenic and Manganese poisoning
Ratchaneewan Sinitkul, MD.Department of Pediatrics
Faculty of Medicine Ramathibodi HospitalMahidol University
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แผนท��แสุดิงแหล�งแร�ทองคำ�าในประเทศไทย
1. พ�(นท��ท��อย)�ในแนวพาดิ ผ�านต�(งแต�
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ปราจิ�นบู�ร� สุระแก.ว ชลบู�ร�และระยอง
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เหม�องแร�ทองคำ�าในประเทศไทย• แหล�งแร�ทองคำ�าชาตร�
ข้องบร่�ษั�ทำอ�ค์ร่ไมนิ่��ง จำกั�ด อยู่��ในิ่เข้ต้ร่อยู่ต้�อ ข้องอเภอ ทำ�บค์ล�อ จำ�งหวั�ดพื่�จำ�ต้ร่ และอเภอวั�งโป่(ง จำ�งหวั�ดเพื่ชร่บ�ร่ณ์� ซึ่,�งม-
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การร�อนและเล�ยง เพ��อหาแร�ทองคำ�าบูร�เวณล�าห.วย
โคำรงการสุาราน�กรมไทยสุ�าหร�บูเยาวชน โดิยพระราชประสุงคำ,ในพระบูาทสุมเดิ2จิ พระเจิ.าอย)�ห�ว http://kanchanapisek.or.th/
การแต�งแร�ทองคำ�า
1.การบูดิและแยกแร�2.การสุก�ดิแร�ทองคำ�าโดิยว�ธ�การทางเคำม�
โคำรงการสุาราน�กรมไทยสุ�าหร�บูเยาวชน โดิยพระราชประสุงคำ,ในพระบูาทสุมเดิ2จิ พระเจิ.าอย)�ห�ว http://kanchanapisek.or.th/
สุายพานล�าเล�ยงห�นท��บูดิแล.ว เข.าสุ)�กระบูวนการแยกแร�โดิยการละลายแร�
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จิากก�น เพ��อให.ไดิ.เฉพาะทองคำ�าบูร�สุ�ทธ�:
โคำรงการสุาราน�กรมไทยสุ�าหร�บูเยาวชน โดิยพระราชประสุงคำ,ในพระบูาทสุมเดิ2จิ พระเจิ.าอย)�ห�ว http://kanchanapisek.or.th/
Metals of concern
• Arsenic (As)• Manganese (Mn)• Cyanide: same as adult• Lead (Pb)• Cadmium (Cd)• Others: Cr, Fe, Co, Ni, Cu, Zn, Hg
Arsenic
• Potential uses: effective poison, very effective against acute promyelocytic leukemia
• Antimetabolic and carcinogenic properties• Inorganic forms:
trivalent (arsenite): more toxic and carcinogenic, most industrial uses
pentavalent (arsenate)• Organic forms:
Natural: nontoxicDimethylarsenic acid: pesticides, very toxic
Arsenic
Route of exposure• Ingestion• Inhalation• Placenta
Soil pica behavior: when children ingest large amounts of soil at a time (e.g. up to 1 teaspoon or 5,000mg)
Arsenic
Sources of exposure: common in the environment• Natural
Groundwater Food chain (nontoxic, organic form): Seafood and fish
• AnthropogenicArsenic containing mineral ores Industrial processes
• Semiconductor manufacturing (gallium arsenide)• Fossil fuels• Wood treated with arsenic preservatives• Smelting (copper, zinc, lead) and refining of metals and ores• Glass manufacturing
Commercial products: Wood preservatives, pesticides, herbicides, fungicides Herbal remedies
Food chain
Source Intake*Iron def increase
GI absorption
Metabolism Elimination*:mostly in urine 10% in bile
WaterFoodAirOther
Inorganic arsenicwell absorbed (80–90%) from GI tract
T1/2(blood): 10 hrs
YesInorganic arsenic
Organic arsenic:Methylate arsenic
Total arsenic
Seafood
Organic arsenic T1/2(blood): 30 hrs
ArsenosugarsArsenolipids
Yes Other metabolites
Arsenobetaine No Arsenobetaine
*Humans are able to detoxify small amounts from inorganicorganic forms**Children are less able than adult
* Within 2-4 wks after exposure, the remaining body burden of arsenic is found in hair, skin, and nails.
Arsenic: metabolism
The intermediate metabolites, methylarsonous acid (MMA3+) and dimethylarsinous acid(DMA3+), are generated during this process, and these trivalent methylated arsenicals are now thought to be more toxic than even the inorganic arsenic species
Arsenic: toxicokinetics
As5+ (Arsenate)
As3+ (Arsenite)
Methylarsenite (in liver)
Dimethylarsenite (readily eliminated – urine)
Arsenic: systemic affectedAcute: high dose, inorganic(>3-5 mg/kg) ChronicGI: N/V, hematemesis, diarrhea, abdominal cramping
Fatigue and malaise
Nervous system: CNS: encephalopathyPNS- mimic Guillain-Barré syndrome
IQ
CVS: intractable shock, arrhythmia, heart failure
Bronchiectasis
Bone marrow suppression: pancytopenia Bone marrow suppression: aplastic anemia
Skin: Mee lines (white transverse creases across the fingernails )
Skin: eczematoid eruptions, hyperkeratosis, dyspigmentation, alopecia
Liver: hepatic dysfunction Hepatic dysfunction
Kidneys: proteinuria, hematuria, ARF Kidneys: Cancer
Carcinogen: bladder, lung, skin, kidney, liver, AML
Spontaneous abortion, still birth, preterm birth
Arsenic-associated Change To Epigenome
• Low to moderate dose exposure to inorganic arsenic (iAS)DNA methylationmiRNA abundanceHistone modification
Bailey KA, Fry RC.Curr Environ Health Rep. 2014 Jan 19;1:22-34.
Potential modes of action for Arsenic carcinogenesis
Arsenic exposure
Carcinogenesis
Altered DNA repair
Altered DNA Methylation
Chromosomal abnormality
Oxidative stress
Modification of cell
proliferation
Arsenic: diagnosis
• Urine collection: test of choice*Children: timed urinary collection for 8-24 hrs Some methods does not distinguish organic and
organic formsabstain seafood ingestion > 5 days
• Blood: not recommend (short t1/2)• Hair and fingernail analyses: validity???
Arsenic: treatment
• Decontamination• Chelation therapy:
dimercaprol (BAL) d-penicillamine succimer
Chronic poisoning: chelation therapy has not proven effective in relieving symptoms
Woolf A, Wright R, Amarasiriwardena C, Bellinger D.Environ Health Perspect. 2002 Jun;110(6):613-6.
uncertain howthe water became contaminatedA 10-year-old male:
refer to PEH center with elevated blood, urine, hair [Mn]
PEH center evaluation
Patient• Unremarkable PH and
examination• Patient’s grades and
behavior were excellent• Mother: for the past
several years teachers had consistently noted a difficulty with listening skills and following directions
Home and environment• Boston, Massachusetts, suburb
5years• Well was drilled to supply the
home with water• Water: turbid, metallic taste,
and left an orange-brown residue on clothes, dishes, and appliances
• Parents, 16 and 10 years boy• Only the younger boy had
abnormally high blood [Mn]
Woolf A, Wright R, Amarasiriwardena C, Bellinger D.Environ Health Perspect. 2002 Jun;110(6):613-6.
Normal IQ but unexpectedly poor verbal and visual memory
Woolf A, Wright R, Amarasiriwardena C, Bellinger D.Environ Health Perspect. 2002 Jun;110(6):613-6.
Management
• Advised to discontinue all residential use of the water from the well
• Interceded with town officials on the behalf of the family 3 mo later: a standpipe was dropped from the water main to the family home
• 18 mo later: Still in an age-appropriate grade Teachers: continued to remark on his difficulty in
remaining on task and his inattentiveness in class
Woolf A, Wright R, Amarasiriwardena C, Bellinger D.Environ Health Perspect. 2002 Jun;110(6):613-6.
Manganese
• Light weight and durability• Inorganic: steel alloys, batteries, glass,
ceramics, incendiaries, fungicides, organic compounds , etc.
• Organic: gasoline and fuel oil additive, fungicides
• Essential in human nutrient: bone, metabolism of AA, lipids, CHO, enzyme
Manganese
• Route of exposureIngestedInhaledPlacentaHuman milk
Manganese
• Sources of exposureFoods: whole barley, rye and wheat, nuts, and leafy
green vegetableBeverages: tea, milk (soy> cow’s milk> human milk)Remedy: Chinese herbalPollution: air, water, and soil
Manganese exposure
Blood brain barrier
Circulation
3-5% 100 %
• Children• Female• Iron deficiency• Low protein intake• Genetic modulation
Excretion: t1/2 40 days
• High dietary Ca2+
•High dietary PO4
3-
*esp.Neonate
Manganese: clinical effectsAcute effects Chronic/long-term effects
Lungs: “metal fume fever” or manganese pneumonitis
Neurotoxicity: progressive “Manganese madness” Manganism: mimics Parkinson disease
Skin Pulmonary disease: chronic RS tract inflammation
Hepatic injury Reproductive toxicity: Decrease spermatogenesis (animal) Stillbirths and birth defects (cleft lip, imperforate anus, cardiac defects, and deafness)
IQ and learning problems
Mn exposure and cognitive deficits
From Chang et al., 2010
Both low and high B-Mn levels may have adverseneurological effects
From Claus Henn et al., 2010
Manganese: diagnosis
• Normal rangesBlood: 4-15 µg/dL (bound to RBC)Serum: 0.4-0.85 µg/dLUrine: 1-8 µg/dL
Biomarkers of manganese intoxication
• Biomarkers of exposure• Biomarkers of effect• Biomarkers of host susceptibility
No reliable biomarkers: complete scientific understanding of the mechanism of
toxicity remains undiscovered
Biomarkers of Mn exposure
• Mn concentrations in body fluid: whole blood, plasma, or serum
1) reasonable indicator of exposure on a group basis; 2) reflects recent, active exposure; and 3) appears to be a modest indicator for distinguishing
Mn-exposed workers from control subjects at the individual level
Manganese: treatment
• Chelation therapy Calcium disodium edetate (CaNa2EDTA)
increase urinary excretion
Manganese: prevention
• Air pollution: < 0.05 µg/m3 (EPA)• Water supplies: < 50 µg/L (EPA)
Recommended daily intake• EPA: 0.14 mg/kg/day (adult)• The institute of Medicine(Washington,DC):
Infants 3 µg/day Adolescent males: 2.2 mg/day
Chronic intake of heavy metals
• Carcinogenic hazards• Non-carcinogenic hazards
Neurologic and developmental involvement Endocrine disruptorEpigenetic
Chemical mixtures and children’s health
• Evaluating health effects of single chemical exposures: under estimate the true effects
• Metal mixtures:Children: developmental and neurological effectsMore severe than exposure to each metal aloneLead: increased toxicity in the presence of other
metals e.g., Mn, Cd, Mercury (Hg), As
Claus Henn B, Coull BA, Wright RO.Curr Opin Pediatr. 2014 Apr;26(2):223-9.
Chemical mixtures and children’s health
• Birth defects• Reproductive outcome• Cognitive and motor development
Claus Henn B, Coull BA, Wright RO.Curr Opin Pediatr. 2014 Apr;26(2):223-9.
• Chitwan Valley, Nepal• Hospital-based birth cohort study with 100 pregnant women; 100 infants at 1 day after birth• Pb, As, and Zn concentrations in cord blood• Pb, As inverse neurodevelopment of newborns
• High levels of Pb or As exposure during prenatal induce retardation during in utero neurodevelopment
As, Cd and Mn with neurodevelopment in children
• 50% increase in As levels (urine) 0.4 decrease in the IQ of children• 50% increase in Mn levels (hair)0.7 decrease in the IQ of children
• Mn exposure attention deficit disorder with hyperactivity
Rodríguez-Barranco M,et al. Sci Total Environ. 2013 Jun 1;454-455:562-77.
•2002-2012•As(18), Mn(17), Cd (6)•Neurodevelopmental or behavioral
As (13/18) Mn (14 /17) Cd(2/6)
Proposed biomarkers
Andrade VM, et al..Biol Trace Elem Res. 2015 Feb 20.
Thank you