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 6–7 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 1’126 424 161 11 263 263 58 15 1 2’586 (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 1’642 650 242 15 457 463 80 26 1 3’926 (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
15- 21- 31- 41- 51- 61- 71- 81- TOTAL 15- 21- 31- 41- 51- 61- 71- 81- TOTAL RAL
ETIOLOGIE
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

 CAUSE
CAUSE DISTRIBUTION
DISTRIBUTION OF
OF ICU
ICU
HOSPITALIZED
HOSPITALIZED POISENED
POISENED PATIENTS
PATIENTS
 STATISTICS - 1995
Total Patients: 5 627

Hospitalized: 3 357

Internal
Medicine Total STI: 1 000 Patients
70%

2 357 Patients
 PATIENTS
PATIENTS HOSPITALIZED
HOSPITALIZED IN
IN
ICU
ICU
TOTAL HOSPITALIZED
PATIENTIS IN ICU 1000

70 PATIENTS DIED
DRUG INTOXICATION
 NON-DRUG
INTOXICATION
 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)
 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
1000’s visits

Poisoning by other and unspecified drugs and 977 200 169,23 20,7 18.1,
medicinal substances 2 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% 8%
2% 2% 2% 2% 2% 2% 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 1–5g
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 letalã 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
CATEGORIA DL50
DL50

▪▪ SUPERTOXICE
SUPERTOXICE 55 mg/kg
mg/kg sausau <<
▪▪ EXTREM
EXTREM DE
DE TOXICE
TOXICE 55 –– 50
50 mg/kg
mg/kg
▪▪ FOARTE
FOARTE TOXICE
TOXICE 50
50 –– 500
500 mg/kg
mg/kg
▪▪ MODERAT
MODERAT TOXICE
TOXICE 0.5
0.5 –– 55 g/kg
g/kg
▪▪ CU
CU TOXICITATE
TOXICITATE REDUSA
REDUSA 55 –– 15
15 g/kg
g/kg
▪▪ PRACTIC
PRACTIC NETOXICE
NETOXICE >> 15
15 g/kg
g/kg
 ENDOBIOTICE

METABOLISM
XENOBIOTICE

•PREDICTIA CONSECINTELOR METABOLICE

•DETERMINAREA POTENTIALULUI TOXIC

METABOLISM – DETERMINANTA A TOXICITATII

DETOXIFIEREA
ECHILIBRU FRAGIL PLURIFACTORIAL

BIOACTIVAREA

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

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

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

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

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

•• GLUCURONILTRANSFERAZA
GLUCURONILTRANSFERAZA (GLUCURONIDAREA)
(GLUCURONIDAREA)

•• SULFOTRANSFERAZA
SULFOTRANSFERAZA (SULFOCONJUGAREA)
(SULFOCONJUGAREA)

•• GLUTATION
GLUTATION S-TRANSFERAZA
S-TRANSFERAZA (GLUTATION
(GLUTATION -- CONJUGAREA)
CONJUGAREA)

•• TIOLTRANSFERAZA
TIOLTRANSFERAZA

•• METILTRANSFERAZA
METILTRANSFERAZA (METILAREA)
(METILAREA)

•• N-ACETILTRANSFERAZA
N-ACETILTRANSFERAZA (ACETILAREA)
(ACETILAREA)

•• SULFTRANSFERAZA
SULFTRANSFERAZA (RODANAZA)
(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