arsenic and manganese poisoning

Arsenic and Manganese poisoning

Ratchaneewan Sinitkul, MD.Department of Pediatrics

Faculty of Medicine Ramathibodi HospitalMahidol University

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การแต�งแร�ทองคำ�า

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จิากก�น เพ��อให.ไดิ.เฉพาะทองคำ�าบูร�สุ�ทธ�:

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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