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TOXICOLOGIE

CLINICA
Toate substantele sunt
toxice, nu exista nici
una care sa nu fie
toxica.
Numai doza diferentiaza
un toxic de un remediu

Paracelsus
1493-1541
EVOLUTIA TOXICOLOGIEI:
INTERRELATIILE SI APLICATIILE SALE
BIOLOGIE CHIMIE
ZOOLOGIE BIOCHIMIE BOTANICA
GENETICA FIZIOLOGIE
FARMACOLOGIE
TOXICOLOGIE

OCUPATIONALA MEDIULUI VETERINARA


LEGALA CLINICA

TOXICOLOGIE PIROTOXICOLOGIE TOXICOLOGIE


INHALATORIE BIOCHIMICA

TOXICOLOGIE FITOTOXICOLOGIE TOXICOLOGIE


GENETICA ACVATICA
EPIDEMIOLOGIA INTOXICATIILOR ACUTE
1986: 4.8 MILIOANE INTOXICATII
( ASOCIATIA AMERICANA A CENTRELOR CONTRA INTOXICATIILOR)

22% EVALUATI IN CENTRE DE INTOXICATI SAU URGENTA

~ 1% DECESE

80% CALE ORALA

COMPUSI UZUAL IMPLICATI DISTRIBUTIE

ALCOOL ETILIC SEX ACC. SUICID NEC


DIAZEPAM M 40 28 31
MORFINICE F 22 42 36
ASPIRINA
FENCICLIDINA VARSTA
MARIJUANA 67 47 53 _
AMITRIPTILINA
FENOBARBITAL 12 29 40 27 32
HIDANTOINE 30 39 42 24 34
HIPNOTICE > 40 19 46 34
AMFETAMINE
NEUROLEPTICE
DETERGENTI
SOLVENTI
INSECTICIDE
Zurich Toxicology Information Center, 2000
Adults Children Total
Agent groups/Severity of N Mi Mo S F N Mi Mo S F
poisoning
Drugs 264 1126 424 161 11 263 263 58 15 1 2586 (69.9 %)

Household products 28 123 20 4 - 83 89 6 6 - 359 (9.1%)

Technical and industrial products 20 169 46 10 2 24 26 3 1 - 301 (7.7%)

Recreational and abused drugs 9 72 83 50 1 16 19 4 2 - 256 (6.6%)

Plants 8 27 17 - - 25 15 3 - - 95 (2.4%)

Mushrooms 3 17 26 4 - 4 1 3 2 - 60 (1.5%)

Products used in agriculture and 6 19 9 6 1 21 6 - - - 68 (1.7%)


horticulture
Toilet articles and cosmetics 2 19 3 - - 17 10 - - - 51 (1.3%)

Poisonous animals 1 15 4 4 - 2 7 3 - - 36 (0.9%)

Food and beverages 2 4 3 1 - 1 6 - - - 17 (0.4%)

Veterinary drugs 3 1 4 - - - - - - - 8 (0.2%)

Other and unknown agents 4 50 11 2 - 1 21 - - - 89 (2.3%)

Total 350 1642 650 242 15 457 463 80 26 1 3926 (100%)

Severity of poisoning: N=no symptoms, Mi=minor, Mo=moderate, S=severe, F=fatal


INTOXICATII ACUTE INTERNATE IN SECTIA DE TOXICOLOGIE
CLINICA INTRE ANII 2000-2004
INTOXICATII FEMEI BARBATI TOTAL
VARSTA (ani)/ GENE
ETIOLOGIE 15- 21- 31- 41- 51- 61- 71- 81- TOTAL 15- 21- 31- 41- 51- 61- 71- 81- TOTAL RAL
20 30 40 50 60 70 80 90 20 30 40 50 60 70 80 90

POLIMEDICAMENTOASE 270 324 239 220 124 81 51 18 1327 91 218 110 79 29 12 15 1 555 1882

BENZODIAZEPINE 82 116 83 37 31 20 20 9 398 39 54 25 26 11 9 4 3 171 569

BARBITURICE 113 154 89 63 28 10 12 9 478 22 79 23 27 8 1 5 0 165 643

ALCOOL ETILIC 33 44 31 33 20 11 5 0 177 109 103 151 145 88 38 14 2 650 827

ALCOOL+MEDICAMENTE 34 53 47 61 22 9 4 0 230 23 95 84 71 28 11 5 2 319 549

NEUROLEPTICE 13 15 10 6 12 5 0 0 61 7 16 7 3 6 0 0 0 39 100

TUBERCULOSTATICE 4 3 3 3 0 1 0 0 14 2 8 3 1 0 0 0 0 14 28

ANTIDEPRESIVE 26 32 22 30 15 5 2 1 131 5 12 11 9 6 0 3 0 46 177

MONOXID DE CARBON 39 77 44 50 36 31 28 17 322 49 57 57 45 37 25 19 7 296 618

ETILENGLICOL 3 2 0 2 2 1 4 0 14 3 5 8 12 8 8 4 0 48 62

CIUPERCI 14 29 26 25 12 14 4 0 124 10 22 24 17 11 9 2 0 95 219

COF 22 47 39 50 18 15 10 2 203 19 46 55 52 35 19 11 1 238 441

METANOL 1 0 0 1 1 0 0 0 3 1 1 5 4 1 1 0 0 13 16

OPIACEE 40 57 12 6 1 2 1 0 119 127 209 28 5 1 1 0 0 371 490

SDR. INTRERUPERE 20 33 5 2 1 0 0 0 61 70 155 20 6 6 4 0 0 261 322

SOLVENTI 5 18 10 14 7 4 3 3 64 13 34 27 27 19 10 3 4 137 201

COROZIVE / CAUSTICE 4 7 6 4 3 2 0 0 26 0 5 3 1 10 0 1 0 20 46

ANTICONVULSIVANTE 23 18 14 8 6 0 2 2 73 8 21 12 13 2 0 1 0 57 130

ANXIOLITICE 112 108 64 45 16 11 3 1 360 21 48 10 13 7 4 0 0 103 463

BETA-BLOCANTE 2 1 1 1 1 1 0 0 7 1 1 1 3 0 0 0 0 6 13

BLOCANTE DE CALCIU 1 2 1 4 2 4 0 0 14 3 2 4 0 6 3 0 0 18 22

PARACETAMOL 2 1 0 O O O O O 3 0 1 0 0 0 0 0 0 1 4

METALE 1 0 0 0 0 0 0 0 1 2 0 0 0 0 0 0 0 2 3

DIVERSE 116 144 100 131 101 99 109 16 816 30 94 73 92 100 76 71 16 552 1368

NEPRECIZATE 36 39 23 17 7 3 8 3 136 14 36 20 14 6 5 4 0 99 235

DECESE 7 4 2 14 1 12 16 11 67 2 11 15 14 13 18 13 8 94 161
CAUSE DISTRIBUTION OF ICU
HOSPITALIZED POISENED PATIENTS

OTHER CAUSES

BARBITURATES

POLIDRUGS

ETHILICS
WOMEN
ANTIDEPRESIVES
MEN
NEUROLEPTICS

UNDETERMINATED

BENZODIAZEPINES

0 50 100 150 200 250 300 350


STATISTICS - 1995
Total Patients: 5 627
Hospitalisation Non-Drug
60% Intoxications
Refuse
hospitalsation
43%
40%

Hospitalized: 3 357 Drug


Intoxications
57%

Internal
Medicine Total STI: 1 000Women
Patients
70% 54%

Non-Drug

2 357 Patients Intoxications


19%

Men
46%
Drug
Intoxications
PATIENTS HOSPITALIZED IN
ICU
Men
35%
TOTAL HOSPITALIZED
PATIENTIS IN ICU 1000 Women
65%

Death
7%
70 PATIENTS DIED

Survive
93%
DRUG INTOXICATION
Polidrug

Barbiturates

Benzodiazepines

Neuroleptics

Triciclic antidepresive

Izoniazide

Anticonvulsivantes

Unexplained Substances

0 20 40 60 80 100 120 140 160 180 200

Total Women Men Death


NON-DRUG INTOXICATION

Ethanol+Drugs or Nondrugs
Ethanol
Detergents
Aniline
Mushrooms
Men

Insecticides
OPC
Methanol
Women

Solvents
CO
Ethilenglicol
Burns (acids)
Burns (bases)
140

120

100

80

60

40

20

0
Average annual percent distribution of type of poisoning-related
emergency department visits by urgency and hospital admission:
US, 1993 1996
(Source: CDC/NCHS, NHAMCS, 1993 - 1996)

80 75
70
60
45 47
50
40
30 22
17
20
6
10
0
Urgent Admitted

Poisoning Illness Nonpoisoning injury


Number and % of Poisoning Related ED Visits by the 10 Leading
Principal Diagnoses for Poisoning Related Injuries, Averaged over a
4-Year Period: US, 1993-1996
Poisoning %
ICD-9-
Related ED 95% Poisoning- 95%
Principal Diagnosis CM
Visits in CI Related ED CI
Code
1000s visits
Poisoning by other and unspecified drugs and 977 200 169,232 20,7 18.1,
medicinal substances 23.3
Poisoning by analgesic, antipyretics and 965 79 53,105 8.2 5.6,
antirheumatics 10.8
Poisoning by psyhotrops agents 969 52 37,67 5.4 3.9, 6.9
Toxic effect of other gases, fumes or vapors 987 42 27,57 4.4 2.9, 5.9
Toxic effect of other substances, chiefly 989 39 27,51 4.1 2.8, 5.4
nonmedical as to source
Toxic effect of carbon monoxide 986 34 19,49 3.6 2.1, 5.1

Neurotic disorders 300 31 17,44 3.2 1.8, 4.6


Certain adverse effects not elsewhere 955 30 16,44 3.1 1.7, 4.5
classified
Depressive disorder, not elsewhere classified 311 24 13,35 2.5 1.4, 3.6
Nondependent abuse of drugs 305 24 13,35 2.5 1.4, 3.6
The Poisoning Pyramid
(Source: CDC/NCHS, NVSS, 1995; NHDS, 1995; NHAMCS, 1993 1996; and TESS, 1995)

Death
1

Hospitalizations
13

Emergency
59 department visits

Poison exposures
147
The prevalence of drug addicts (overdose and
withdrawal syndrome) between 1989-2008

13%
12%

8% 14%
8%
12%
6.70%
4% 5% 10%
4%
3% 4%
2% 2% 2% 2% 2% 2% 8%
2.70%
0% 1%1% 6%

4%

2%

0%
19 89 19 90 19 91 19 92 19 93 19 94 19 95 19 96 19 97 19 98 19 99 20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08
PARAMETRII CANTITATIVI AI TOXICITATII
DL 50 (EXPERIMENTAL) mg/kg
mM/kg
mg/m2
DML (DOZA MINIMA LETALA OM)

CLORURA MERCURICA 0.5 g ARSENIC 100 mg


METANOL 70 ml
NICOTINA 50 mg ACONITINA 10 mg
PARALDEHIDA 100 ml BARBITURICE 15g
PARATION 25 mg ACID BORIC 12 g
FENOLI 10 ml CAMFOR 2g
FOSFOR (galben) 0.1 g CLORALHIDRAT 7g
STRICNINA 50 mg CLORAT DE K 8g
TALIU 0.8 g FLUORURA DE K 1g
FORMALDEHIDA 30 ml

Cl 50
CLt 50
CONCENTRATIA ATMOSFERICA EXPUNERI PROFESIONALE
ppm SAU g/m3
Mortalitate (%)

Doza (mg/kg)
Doza medie letal pentru diverse
substante
Compusul Specia Dl50 (mg/kg, Masa moleculara DL 50 (mM/kg)
parenteral) (g/mol)
ETANOL SOARECE 10000 46 0.2173

CLORURA DE SODIU SOARECE 4000 58.443 0.068

SULFAT FEROS SOBOLAN 1500 151.908 0.0098

MORFINA SULFAT SOBOLAN 900 285.34 0.0031

FENOBARBITAL SOBOLAN 150 232.235 0.00064


SULFAT

DDT SOBOLAN 100 354.49 0.00028

PICROTOXINA SOBOLAN 5 602.583 0.0000082

STRICNINA SULFAT SOBOLAN 2 334.41 0.0000059

NICOTINA SOBOLAN 1 162.26 0.0000061

d-TUBOCURARINA SOBOLAN 0.5 624.765 0.0000008

HEMICOLINIUM-3 SOBOLAN 0.2 414.538 0.0000004

TETRODOTOXIN SOBOLAN 0.1 319.27 0.0000003

DIOXINA COBAI 0.001 84.07

TOXINA BOTULINICA SOBOLAN 0.00001 149322.7


CLASIFICAREA SUBSTANTELOR TOXICE
CONFORM TOXICITATII RELATIVE

CATEGORIA DL50

SUPERTOXICE 5 mg/kg sau <


EXTREM DE TOXICE 5 50 mg/kg
FOARTE TOXICE 50 500 mg/kg
MODERAT TOXICE 0.5 5 g/kg
CU TOXICITATE REDUSA 5 15 g/kg
PRACTIC NETOXICE > 15 g/kg
ENDOBIOTICE

METABOLISM
XENOBIOTICE

PREDICTIA CONSECINTELOR METABOLICE


DETERMINAREA POTENTIALULUI TOXIC

METABOLISM DETERMINANTA A TOXICITATII

DETOXIFIEREA
ECHILIBRU FRAGIL PLURIFACTORIAL

BIOACTIVAREA

CITOTOXICITATE
CARCINOGENEZA
METABOLIZAREA XENOBIOTICELOR DE
CATRE FLORA INTESTINALA
HIDROLIZA
GLUCURONIZI
GLICOZIZI
SULFAMATI CICLAMAT
AMIDE METOTREXAT
ESTERI ACETILDIGOXINA
NITRATI PENTAERITR. TETRANITRAT

DEHIDROXILARE
DECARBOXILARE AMINOACIZI
DEAMINARE AMINOACIZI
DEHIDROGENARE COLESTEROL, ACIZI BILIARI
DEHALOGENARE DDT

REDUCERE
GRUPARE NITRO ACID P-NITROBENZOIC
LEGATURI DUBLE ACIZI GRASI NESATURATI
ALDEHIDE BENZALDEHIDE
ALCOOLI ALCOOLI BEZILICI

ALTE REACTII
FORMARE NITROZAMINE DIMETILNITROZAMINA
AROMATIZAREA ACID CHINIC
ACETILAREA HISTAMINA
ESTERIFICAREA ACID GALIC
METABOLIZAREA XENOBIOTICELOR
REACTII FAZA I
OXIDAREA HIDROLIZA
MONOOXIGENAZE (P450) HIDROLIZA ESTERILOR
XANTINOXIDAZE CARBOXILESTERAZE
PEROXIDAZE AMIDAZE
AMINOXIDAZE
MAO
DIOXIGENAZE

REDUCEREA
MONOOXIGENAZE (P450)
CETOREDUCTAZE
GLUTATIONPEROXIDAZE
EPOXIDHIDROLAZE
SOD
REACTII FAZA II

GLUCURONILTRANSFERAZA (GLUCURONIDAREA)

SULFOTRANSFERAZA (SULFOCONJUGAREA)

GLUTATION S-TRANSFERAZA (GLUTATION - CONJUGAREA)

TIOLTRANSFERAZA

METILTRANSFERAZA (METILAREA)

N-ACETILTRANSFERAZA (ACETILAREA)

SULFTRANSFERAZA (RODANAZA)
ENTITATI TOXICE CONSECUTIVE
METABOLIZARI UNOR COMPUSI
EPOXIZI COMPUSI N-HIDROXILATI
RADICALI LIBERI NITROZAMINE
AFLATOXINA B1
BENZEN, BROMBENZEN
EPOXIZI FUROSEMID
OLEFINE
BIFENILI POLICLORURATI SI POLIBROMATI
TRICLORETILENA
CLORURA DE VINIL

TETRACLORURA DE CARBON
RADICALI LIBERI HALOTAN
BROMTRICLORMETAN
PARAQUAT
UNELE ALIMENTE
RADIATII IONIZANTE
INFLAMATIE
PROCESE PATOGENICE

PARACETAMOL
COMPUSI N-HIDROXILATI URETAN

AMINE
NITROZAMINE
(tub digestiv) NITRITI
Compusi bioactivi
(modificat dupa Frank Lu, 1991)
Compusul initial Metabolit toxic Mecanismul toxicitatii Consecinte organo-functionale
Acetaminofen Derivat N-hidroxi Legatura covalenta Necroza hepatica
(Paracetamol)
2-Acetilaminofluoren N-acetoxi-AAF Legatura covalenta Cancer
AAF N-sulfat
Aflatoxin B1 Aflatoxin-2,3-epoxid Legatura covalenta Cancer hepatic

Alil formiat Acroleina Legatura covalenta Necroza hepatica

Alilizopropil acetamida Epoxid Necunoscut Distructie citocrom P450


Porfirie
Amigdalina Mandelonitril Formare de cianura Hipoxie citotoxica
(flora intestinala)
Benzen Benzen epoxid Legatura covalenta Depresie maduva hematopetica

Brombenzen Brombenzen Legatura covalenta Necroza hepatica, renala,


bronsiolara
Tetraclorura de carbon Radical liber Legatura covalenta, Necroza hepatica,
triclormetan peroxidarea lipidelor Cancer hepatic
Alchilnitrosamine Alfa-hidroxilare Alchilare Cancer hepatic
carciogene
Coloranti amino Derivati N-hidroxi Legatura covalenta Cancer hepatic
carciogeni
Compusi bioactivi
(modificat dupa Frank Lu, 1991)
Compusul initial Metabolit toxic Mecanismul toxicitatii Consecinte organo-functionale
Hidrocarburi policiclice Epoxizi in diverse Legatura covalenta Cancer, citotoxicitate
carciogene organe
Cloroform Fosgen Legatura covalenta Necroza hepatica, renala

Cicasin Metilazometanol Alchilare Cancer, necroza hepatica

Ciclamat Ciclohexilamina Necunoscut Cancer de vezica

Etanol Acetaldehida in Complex Diferite


diverse organe
Fluoracetat Fluorocitrat Inhibitie enzimatica Toxicitate generala

Furosemid Epoxid Legatura covalenta Necroza hepatica, renala

Halotan Radical liber Legatura covalenta Necroza hepatica

Amine aromatice Metaboliti N-hidroxi Necunoscut Hemoliza


hemolizante
Izoniazida Acetihidrazina Legatura covalenta Necroza hepatica

Meclizina Noroclorciclizina Necunoscut Teratogeneza


Compusi bioactivi
(modificat dupa Frank Lu, 1991)
Compusul initial Metabolit toxic Mecanismul toxicitatii Consecinte organo-functionale
Metanol Formaldehida Complex Toxicitate retiniana si generala

Compusi nitro si amine Metaboliti N-hidroxi Oxidare, reducere Methemoglobinemie


aromatice ciclica
methemoglobinizante
Metoxifluran Fluor anorganic Inhibitie enzimatica Insuficienta renala

Naftilamina N-hidroxi naftilamina Legatura covalenta Cancer vezical

Nitriti si amine Nitrosamine Alchilare Cancer hepatic, pulmonar


secundare si tertiare
Olefine Epoxizi Legatura covalenta Cancer de piele

Paration Paraoxon Legatura covalenta cu Paralizie neuromusculara,


colinesterazele insuficienta respiratorie
Analogi baze purinice si Mononucleotide, Sinteza letala, Citotoxicitate
pirimidinice nucleotizi trifosfat incorporare letala
Alcaloizi pirolizidinici Derivati pirolitici Necunoscut Necroza hepatica si canceroasa

Talidomida Acid ftalil L-glutamic Necunoscut Teratogeneza

Uretan N-hidroxil uretan Alchilare Cancer, citotoxicitate


FARMACOCINETICA TOXOCINETICA

PARAMETRU FARMACOCINETICA TOXOCINETICA

DOZA CUNOSCUTA NECUNOSCUTA


REDUSA FOARTE MARE

EFECT TERAPEUTIC TOXIC

STEADY STATE UZUAL NU


DATE CLINICE FRECVENT INCOMPLETE
COROBORANTE
CONCENTRATIE-EFECTE DA INCOMPLETE
TOXICE, RECEPTORI SI CONSECINTA
INTERACTIUNII LOR
RECEPTOR TOXODINAMIC TOXIC MECANISM
COLINESTERAZE COMPUSI ORGANO- BLOCAREA CENTRULUI
FOSFORICI ESTERAZIC
CITOCROMOXIDAZA CIANURI BLOCAREA TRANSPORTULUI DE
ELECTRONI IN LANTUL
RESPIRATOR
GRUPARI TIOLICE METALE GRELE INACTIVAREA GRUPARILOR
ENZIMATICE TIOLICE
HEMOGLOBINA MONOXID DE FORMAREA:
CARBON, NITRITI, CARBOXIHEMOGLOBINEI
NITRATI METHEMOGLOBINEI
ACIZI NUCLEICI ALCHILANTE BLOCAREA SINTEZEI ACIZILOR
RADIOMIMETICE NUCLEICI
LIPIDE STRUCTURALE TETRACLORURA DE RADICALI LIBERI
CARBON PEROXIDARE
BROMTRICLORMETAN
RECEPTOR NICOTINIC NICOTINA STIMULARE DIRECTA
CURARIZANTE BLOCARE, PARALIZIE
RECEPTOR MUSCARINIC MUSCARINA STIMULARE INTENSA, SINDROM
(AMANITA MUSCARIA) MUSCARINIC