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CHEMICAL FACTORS AS CAUSES OF DISEASE

LECTURES FROM GENERAL

PATHOLOGICAL PHYSIOLOGY

OLIVER RÁCZ

CLASSIFICATION OF TOXIC SUBSTANCES

AND INTOXICATIONS

• ANORGANIC (metals, gases, cyanide, nitrites, etc.)

• ORGANIC (almost everything)

• BIOLOGICAL (animal, plants, mycotoxins, bacteria)

• NATURALLY OCCURING & SYNTHETIC

• ACUTE & CHRONIC (CUMULATIVE)

• ACCIDENTAL & VOLUNTARY

• POLLUTION, TERRORISM


Cadmium ( 48 Cd 112 )

• Itai-itai; Japan, 1940 - 1960

– 1 mg Cd/day from rice contaminated by mining waste

– Deficit of vitamin D, Ca, Zn

• Postmenopausal & multiparous women

– Bone deformities, pain in the joints

– Chronic renal disease - hypercalcuria, proteinuria &

glycosuria

(max. permitted 50µg/d; avg ≅ 5 µg; smokers ≅ 10 µg)

Cadmium ( 48 Cd 112 )

• Binding to metallothionein (Cd-Mt)

– 8.5 - 10 kD; rich in Cys; binds 4 - 12 atoms of metalls

• Mechanism of toxicity

– antagonism with Zn

– covalent binding to DNA

– interference with the transport of other Me 2+

– interaction with SH groups

• Nutritional protection

– Zinc


Mercury ( 80 Hg 201 )

• WIDESPREAD USE IN A VARIETY OF PRODUCTS

❊ 5-6*10 6 kg released to the environment every year

❊ accumulation in marine sediment → fish

• HIGHLY TOXIC COMPOUND (lipohilic, volatile)

• Hg 0 vapors - inhalation, lung damage

• Hg salts (sublimate, HgCl 2 - GIT, kidney damage

• Hg in medicine (syfilis, calomel, dermatology,)

• MethylHg - CNS, teratogen

• amalgames used in dentistry ?

❊ Affinity for SH groups & Fenton reaction catalyst → oxidative

stress

❊ inactivation of enzymes, membrane & transport system damage

etc.

Mercury ( 80 Hg 201 )

• MINAMATA BAY, JAPAN

Metallic Hg released from a factory into the sea

transformed to organic mercury compounds.

Consumption of contaminated fish and shellfish →

staggering cats, CNS injury & deaths in fishermen, birth

defects in newborns

• IRAQ, 3 epidemics (50‘s - 70‘s)

Bread made from grain treated with organomercurial

antifungal agents


Lead ( 82 Pb 207 )

• Used throughout modern history of mankind

• XXth Century - gasoline additive

• Current production - 3.8*10 6 tons/year

contribution to history

❋ Nero‘s madness (wine in pewter vases)

❋ The fall of Roman Empire (lead water pipes*)

❋ „Franklin“ expedition to the Northwest Passage, 1845 (lead

seals of tin cans)

❋ Vincent van Gogh‘s illness & madness (paints)

*EPA & WHO standard < 0.05 mg/l

YEAR Pb, µg/m 3

1970 0.91

1978 0.84

1982 0.32

Lead - toxicity

• Lethal dose ≅ 0.5 g

• Harmful > 10 µg/l blood

• accumulation in bones,

replaces Ca

• t 1/2 ≅ 15 - 20 years

• children more sensitive

• organic compounds are

more dangerous

DAMAGE OF

• Brain and nerves

• Liver

• Kidney

• Blood

– synthesis of porphyrins

• Reproductive system

• Digestive system

• Immune system


Cyanide and related compounds

• HCN, KCN - electron transport in mitochondria

(Cytochrome A)

• Increase in respiration, paralysis of all cells (BP fall,

convulsions, coma)

• Sources

– Industry

– Cassava & manioca roots (glycosides)

– stones of bitter almonds, apricots (glycosides)


*and heavy metals!

Baia Mare (RO), 30 th January 2000

Gold reprocessing facility,

leak of a tailing pond

378 500 liters toxic

sludge (8g KCN /l)*

River Lapus Somes

Tisza (February 3, 12 mg/l;

590 km of very sensitive

ecosystem)

Danube (end of February

till higher than 0.1 mg/l )

• More than 100 tons of dead fish,

some of them rare and

endangered species.

• Other water animals killed too -

frogs, crabs, insects, etc.

• Secondary intoxication &

perishing of otters, beavers,

birds, dogs

• Cyanides are unstable

• Danger of ecological

catastrophe

• Monitoring & prevention in the

future

Purvis A.: Deadly Discharge. Time 155, 2000, No 6; February 28, p.26

Bombová E., Kupcová M.: V zápase s kyanidom v riekach život azda celkom neprehrá. SME 22.2.2000

Further examples

• Contergan, thalidomid, 1957 - 1961

– 2625 cases of birth defects (phocomelia)

• Seveso, Italy, 1976 (& in Vietnam war)

– DIOXIN ➡ SKIN, LIVER, BRAIN (CUMULATIVE)

• Bhopal, India, 1984, Union Carbide

– CH 3 -N=C=O (methyl isocyanate)

– 7000 residents died within days, 500 000 affected,

many survivors remain ill or disabled after 15 years

• Asbestos - Lung Ca, bankruptcy of Lloyd‘s


CHERNOBYL, 1986

6 tons of radioactive fuel released = 10 EBq* in two

phases (during the explosion and a week later)

143 cases of acute radiation illness, 28 ✟

(unsuccessful attempts of bone marrow transplantation)

Radioactive fallout and exposition:

600 000 person*sievert

40 % Soviet Union; 50 % Europe

Exa = 10 18


CHERNOBYL 1986 - RELEASE OF SOME

RADIONUCLIDES

NUCLIDE HALF-LIFE ACTIVITY, PBq RELEASE

Xenon 133 5.3 d 6500 6500

Iodine 131 8 d 3200 1760

Cesium 134 2 y 180 54

Cesium 137 30 y 280 85

Tellurium 132 78 h 2700 1150

THYROID CANCER IN CHILDREN BEFORE AND

AFTER CHERNOBYL

AREA 1981-1985 1986-1994

GOMEL 1 164

BELARUS 3 333

NORTHERN

1 118

UKRAINE

UKRAINE 25 209

PREVENTION BY KI DELIBERATELY NEGLECTED


POPULATION DOSE, mSv + DEATHS

200 000

emergency workers

135 000

evacuees (30 km)

270 000

control zone residents

6 800 000

whole area residents

100 2200

10 160

50 1600

7 5000

GREECE: 2.6* Increase of leukemia in children ?!

MAYAK RIVER, PLUTONIUM PLANT

1949 - 1956; 65*10 6 m 3 radioactive waste

1700 times the permitted exposition

28 000 affected people in 28 villages

The effects of alcohol

• Acute alcohol intoxication (Noe)

• Alcoholism (addiction)

– Alcoholic is who drinks more than his doctor

• Withdrawal syndrome (delirium, white mice)

• Diseases associated to alcohol consumption

• Beneficial health effects of moderate drinking

– The French paradox


Alcohol and the western populations

• Absolute abstainers 10 %

• Consistent consumers 20 %

• Nonconsistent consumers 20 %

• Occasional heavy drinkers 27 %

• Regular heavy drinkers 20 %

• Addictive alcoholics 3 %

Alcohol and diseases

• Direct effect (brain, liver)

• Energy content (beer ⇒ obesity)

• Deficient nutrition (B vitamins ⇒neuropathy)

• Toxic compounds (Methanol, Glycols, Cobalt, Thujone

from absynth

♥ The French paradox (CHD in France vs Scotland

♥ ⇑ HDL cholesterol, ⇑ fibrinolysis, ⇓coagulation,

⇑insulin sensitivity

♥ Decreased risk of MI

♥ Antioxidants ? Life style ?

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