INTENTIONAL THALLIUM INTENTIONAL THALLIUM POISONING – VERIFICATION POISONING – VERIFICATION

AND TREATMENTAND TREATMENT

Pelclová D (1), Šenholdová Z (1), Lukáš E (1), Urban P (2), Lacina L (3), Vlček K (1), Pelclová D (1), Šenholdová Z (1), Lukáš E (1), Urban P (2), Lacina L (3), Vlček K (1), Fenclová Z (1), Kitzlerová, E (4).Fenclová Z (1), Kitzlerová, E (4).

1. Department of Occupational Medicine, Charles University, Prague 1. Department of Occupational Medicine, Charles University, Prague 2. National Institute of Public Health, Prague2. National Institute of Public Health, Prague

3. Department of Dermatology; 3. Department of Dermatology; 4. Psychiatric Department, 4. Psychiatric Department,

General University Hospital and First Medical faculty, General University Hospital and First Medical faculty, Charles University, Prague, Czech RepublicCharles University, Prague, Czech Republic

THALLIUM

discovered in 1861 by Sir Williams Crooks 1862 by French chemist Claude-Auguste Lamy In Greek, thallos "green twig."

Using spectroscopy, the brightest lines in the spectrum of thallium are green

melting point 300º C (576º F) boiling point 1480º C (2,655º F)

elementary thallium non-toxic monovalent and threevalent salts very toxic LD about 900 mg

THALLIUM

rather uncommon element world production 12 tons/year semiconductors,

photocells, optic glass, thermometers in medicine – Tl201radioactive tracer in heart

scintigraphy to detect myocardial ischaemia occurrence in minerals emissions 1500 tons/year granite, coal

THALLIUM – IN THE PAST

Tl2SO4 has long been used as

rodenticide, insecticide Colorless and tasteless Tl acetate : treatment of veneric diseases, ringworm Depilatory agent Low therapeutic index Banned in the 1970ies in most countries

Toxicokinetics – inorganic salts

absorption by all ways, oral about 90% distribution to all tissues greatest concentration in the intestines, liver,

kidney, heart, brain and muscles excretion by faeces and urine, the proportion 2:1 enterohepatic circulation half-lives 1-30 days

Pathophysiology - 1 Similarities in charge and ionic radius between K+ and Tl+

ions), Tl substitutes for K:

1. blocks energy utilization by Na-K-ATPase channel = (active transport of monovalent ions - K+ across cell membrane)

Thallium disturbs maintaining of a resting potential across the membrane of active cells - Tl has 10-fold greater affinity.

Neuronal, cardiac and skeletal muscle cells 2. blocks energy production from glucose: ADP to ATP by

pyruvate kinase = K requiring enzyme - links anaerobic glycolysis to the Krebs cycle)

inhibition by binding with 50-fold affinity comparing to K.

Pathophysiology - 2

3. damages riboflavin, precursor of FAD forming an insoluble complex and intracellular sequestration of vit. B6

decrease of riboflavin disrupts metabolism by reducing activity of Krebs cycle

4. binds to SH groups and interferes with formation of disulphide bonds in keratin - structural damage to hair, nails

5. causes activation or inhibition of other enzymes (ALA synthetase, B12 metabolism…)

2 Case reports

2 patients, mother and daughter, living in the same household

Very probably intentional poisoning by one member of the family

Oral intake Chronic

Patient Amother

44years old PH: no serious disease OH: super-market manager 1. poisoning November 2004 sudden strong chest pain, following 3

days severe pain with paresthesias in both lower limbs Symptoms disappeared within 3 weeks, following 3 weeks

persisted mild paresthesias and discomfort in the lower limbs

2. poisoning

In March 2005 she developed suddenly a strong muscular pain in the lower limbs. The gait was painful „as on a broken glass“.

within 5 days she became bald. In April – one month stayed at neurology dept. With

suspicion on LI syndrome and posttraumatic stress disorder (anxious, depressive, had work overload and home conflict environment)

EMG, evoked potentials, MRI normal In June improvement, returned to work

3. poisoning

August 2005 Progressive pain in lower limbs with paresthesias Blurred vision – she could differentiate only dark

and light spots in the periphery of the visual field After 3 weeks her condition improved a little Mild pain in the feet and knees persisted several

weeks Vision difficulties persisted Eye fundus : n. opticus atrophy

HospitalizationDept. Occupat. Medicine

Admitted on January 31,2006 5 months after last intoxication 1) attempt to prove the poisoning 2) attempt to improve vision damage – she still could not

read

EMG: mild motor and sensoric damage, EEG borderline

Visual evoked potentials: severe damage with visus BIOLOGICAL HALF-LIFE of thallium broad range of 1-30 days Hoffman RS. Toxicol Rev 2003

Patient B: Historydaughter

22years old woman PH: no serious disease OH: high school,1 year maternity leave FH: mother treated for symptoms of unknown etiology,

father probably psychopathic personality, no treatment, daughter 1 year old, healthy

1 poisoning

In December 2005 suddenly strong pain in lower limbs,

maximum in the stockings distribution, ache in the skin of lower extremities

Anorexia 3rd week symptoms deteriorated, treated with analgesics

(tramadol) 4th week lost all body hair (except eyebrow and eyelashes) She developed blurred vision, weakness of lower limbs,

unable to walk Hospitalized at neurology dept.

Hospitalization at Neurology Dept.

Blood and urine sent to toxicology screening (drugs, metals incl. Cd, Pb, Hg, Se, Zn, Tl,)

5th week: vision damage with maximum in the central area, right and left eye

Shortly also speaking difficulties and feeling of heavy tongue Positive results for thallium in blood and urine

Hospitalization atDept. Occup. Medicine

Admitted on January 26, 2006 7th week of symptoms On admission: On a wheel chair, paraparesis, motor weakness Bald (only eyebrow and lashes left) Could distinguished fingers from 30 cm complained of

strong pain in lower limbs Altered mental status, depressive, anxious Slow speech, low voice

Antidote

Prussian blue - Fe4[Fe(CN)6]3 (ferric hexacyanoferrate), Radiogardase, Heyl CAS 14038-43-8 discovered 1704 by a Berlin color maker Diesbach since the 1960s used to treat Cs and Tl poisonings Binds thallium by ion exchange, adsorption and

mechanical trapping within the crystal structure

Specific treatment

Insoluble, low absorption from the GIT (?) stops enterohepatic circulation of thallium Increases elimination both to faeces and urine Advantage: rare side effects, bluish sweat and

tears Reduces half-life from 8 to 3 days First dose after arrival 6g /12 hours Continued with 12 g/day in 4 doses

Supportive therapy

10% mannitol as cathartic Charcoal (Carbosorb) 2x 25 g/day Analgesics Vit. B12, B6 Topical dermatological treatment supporting hair growth

Thallium concentration in urine µg/l in the daughter Total excretion 8.4 mg in 32 days, further Tl in faeces

Antidotal treatment 22 days

Toxicological analysis in daughter

Thallium found in all biological materials – blood, urine, faeces, hair

Examinations

Neurological (incl. needle EMG, VEP, BAEP, EEG, MRI of the brain)

Ophthalmological (visus, fundus, perimeter) Dermatological Further: ECG, psychiatric, blood biochemical analysis, urinalysis,

kidney functions

January 20052nd month

Unable to walk Severe polyneuropathy Verified by needle EMG sensory, motoric and autonomic Symmetrical Low extremities only

April 20065th month

Able to walk with a walker leg support. Severe motor polyneuropatie. Mild improvement,

esp. Sensitive and autonomic nerves. MRI of the brain: normal finding incl. optic nerves,

tracts, chiasma and visual cortex Atrophy of both optic nerves on the ocular fundus

August 20069th month

Still severe motor polyneuropathy She could walk without support Unstable gait Pathology in EEG, VEP, BAEP Vision of fingers from 0.75 m

EEG, BAEP VEP

Slightly abnormal entrance findings

Control: slow improvement

2nd month: no response due to severe vision damage

5th month: Low peak at right side, no response left side.

9th month: Bilaterally abnormal finding low reproducibility and low VEP, worse left side

FURTHER FINDINGS

ECG – non-specific ST segment and T wave changes during a febrile state with tachycardia

Transthoracic echocardiography – diffuse hypokinesis of the left ventricle, markers normal

Psychiatric examination Neuropsychological testing not possible – visual

problems USG of the abdomen normal Kidney functions normal

Total alopeciadaughter

Reversible Highest value 36.1 μg/g (5th week) Sequential analysis of 1.5 cm hair segments = 6 months Thallium 5.61- 6.24 – 7.41 – 7.81 – 6.67 μg/g hair New hair 6th week of poisoning and 8th day of antidote

treatment– drop to 1.6 μg/g) Daniel J Am Acad Dermatol 2004

Trichological analysis of the acute hair loss of the daughter Normal hair

Light microscopy - The proximal end hair fibre tapered and distorted.  Rough surface of the proximal end Amorphous cuticular and cortical cells as a sign of the

pathological keratinisation. (Metter and Vock 1984)

Trichological analysis of the acute hair loss of the daughter

Under transmitted-light microscopy the cortex dark discolorisation and disorganized on the widened club-shaped end.

Gaseous inclusions under the phase contrast microscopy.

Trichological analysis of the new hair of the mother

Hair of the acute loss not available Recent hair – normal finding, smooth surface

of keratinocytes

Thallium in urine (μg/l) Optical Emission Spectrometer - Inductively Coupled Plasma (OES-ICP)

daughter mother normal range

Initial

measurement urine 580.00Jan.15

8.50Jan. 25

0.018-0.021

Thallium in urine (μg/l) voltammetry

daughter mother control subject

before antidote 580 neg. neg.

maximum after antidote/

12 h sample

urine 1170.0 21.0 4.0

end of treatment

12 h sample

urine 2.0 5.4 -

after 6 months urine neg. neg. -

Thallium in blood and faecesOptical Emission Spectrometer - Inductively Coupled Plasma (OES-ICP)

μg/l daughter mother normal range

(OES-ICP)

First

measurement

blood 770.00Jan. 15

0.30Jan. 21

0.049-0.013

mg daughter mother Voltammetry

maximum with antidote

faeces 13 mg/250g 0.25 mg/40g ?

3 days after the end of treatment

faeces 0.1mg/100g 0.05 mg/70g neg.

CONCLUSION - mother

Treatment with Prussian blue produced a higher excretion of thallium in urine

And a measurable amount in faeces In mother the clinical effect was negligible – 1¼ year after last poisoning: EMG: Residual mild axonal sensory neuropathy,

mild improvement after 6 months. Autonomic fibers without damage.

Opthalmologic examination: scotomas of upper and central parts of both visual fields

Visual evoked potentials: prologed latency, lower amplitude

CONCLUSION - daughter

1 year after intoxication EMG examination - Severe damage in motor and

sensory fibers, autonomic normalized already Ophthalmologic examination – mild improvement right eye - scotomas in central and medium

periphery left eye – scotomas in central area

SUMMARY Thallium typically causes damage of

peripheral nerves of lower extremities, vision and hair.

Combination of these symptoms suggests thallium poisoning

Late treatment has low effect Prognosis of hair loss is good Polyneuropathy improves within months till

years Vision damage has the worst prognosis

THANK YOU

3rd victim – dog of the family