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
PLANTE
Zurich Toxicology Information Center, 2000
Adults Children Total
Agent groups/Severity of
poisoning
N Mi Mo S F N Mi Mo S F
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
horticulture
6 19 9 6 1 21 6 - - - 68 (1.7%)
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
VARSTA (ani)/
ETIOLOGIE
FEMEI BARBATI
TOTAL
GENE
RAL 15-
20
21-
30
31-
40
41-
50
51-
60
61-
70
71-
80
81-
90
TOTAL 15-
20
21-
30
31-
40
41-
50
51-
60
61-
70
71-
80
81-
90
TOTAL
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
0 50 100 150 200 250 300 350
BENZODIAZEPINES
UNDETERMINATED
NEUROLEPTICS
ANTIDEPRESIVES
ETHILICS
POLIDRUGS
BARBITURATES
OTHER CAUSES
WOMEN
MEN
STATISTICS - 1995
Hospitalisation
60%
Refuse
hospitalsation
40%
Non-Drug
Intoxications
43%
Drug
Intoxications
57%
Total Patients: 5 627
Total STI: 1 000 Patients
Hospitalized: 3 357
Internal
Medicine
70%
Drug
Intoxications
81%
Non-Drug
Intoxications
19%
2 357 Patients
Men
46%
Women
54%
PATIENTS HOSPITALIZED IN
ICU
Death
7%
Survive
93%
Men
35%
Women
65%
TOTAL HOSPITALIZED
PATIENTIS IN ICU 1000
70 PATIENTS DIED
DRUG INTOXICATION
0 20 40 60 80 100 120 140 160 180 200
Unexplained Substances
Anticonvulsivantes
Izoniazide
Triciclic antidepresive
Neuroleptics
Benzodiazepines
Barbiturates
Polidrug
Total Women Men Death
NON-DRUG INTOXICATION
0
20
40
60
80
100
120
140
B
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Women Men
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)
75
45
47
22
17
6
0
10
20
30
40
50
60
70
80
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
Principal Diagnosis
ICD-9-
CM
Code
Poisoning
Related ED
Visits in
1000s
95%
CI
%
Poisoning-
Related ED
visits
95%
CI
Poisoning by other and unspecified drugs and
medicinal substances
977 200 169,232 20,7 18.1,
23.3
Poisoning by analgesic, antipyretics and
antirheumatics
965 79 53,105 8.2 5.6,
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
nonmedical as to source
989 39 27,51 4.1 2.8, 5.4
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
classified
955 30 16,44 3.1 1.7, 4.5
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)
1
13
59
147
Death
Hospitalizations
Emergency
department visits
Poison exposures
The prevalence of drug addicts (overdose and
withdrawal syndrome) between 1989-2008
6.70%
4%
2.70%
5%
4%
8%
12%
13%
8%
4%
3%
2% 2% 2% 2% 2% 2%
1% 1%
0%
0%
2%
4%
6%
8%
10%
12%
14%
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
PARAMETRII CANTITATIVI AI TOXICITATII
DL 50 (EXPERIMENTAL) mg/kg
mM/kg
mg/m
2
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 5 g
PARATION 25 mg ACID BORIC 12 g
FENOLI 10 ml CAMFOR 2 g
FOSFOR (galben) 0.1 g CLORALHIDRAT 7 g
STRICNINA 50 mg CLORAT DE K 8 g
TALIU 0.8 g FLUORURA DE K 1 g
FORMALDEHIDA 30 ml

Cl 50
CLt 50
CONCENTRATIA ATMOSFERICA EXPUNERI PROFESIONALE
ppm SAU g/m3
Doza (mg/kg)
M
o
r
t
a
l
i
t
a
t
e

(
%
)

Doza medie letal pentru diverse
substante

Compusul Specia Dl50 (mg/kg,
parenteral)
ETANOL SOARECE 10000
CLORURA DE SODIU SOARECE 4000
SULFAT FEROS SOBOLAN 1500
MORFINA SULFAT SOBOLAN 900
FENOBARBITAL
SULFAT
SOBOLAN 150
DDT SOBOLAN 100
PICROTOXINA SOBOLAN 5
STRICNINA SULFAT SOBOLAN 2
NICOTINA SOBOLAN 1
d-TUBOCURARINA SOBOLAN 0.5
HEMICOLINIUM-3 SOBOLAN 0.2
TETRODOTOXIN SOBOLAN 0.1
DIOXINA COBAI 0.001
TOXINA BOTULINICA SOBOLAN 0.00001
Masa moleculara
(g/mol)
DL 50 (mM/kg)
46 0.2173
58.443 0.068
151.908 0.0098
285.34 0.0031
232.235 0.00064
354.49 0.00028
602.583 0.0000082
334.41 0.0000059
162.26 0.0000061
624.765 0.0000008
414.538 0.0000004
319.27 0.0000003
84.07
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
METABOLISM
ENDOBIOTICE
XENOBIOTICE
PREDICTIA CONSECINTELOR METABOLICE
DETERMINAREA POTENTIALULUI TOXIC
METABOLISM DETERMINANTA A TOXICITATII
ECHILIBRU FRAGIL PLURIFACTORIAL
DETOXIFIEREA
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
MONOOXIGENAZE (P450)
XANTINOXIDAZE
PEROXIDAZE
AMINOXIDAZE
MAO
DIOXIGENAZE
REDUCEREA
MONOOXIGENAZE (P450)
CETOREDUCTAZE
GLUTATIONPEROXIDAZE
EPOXIDHIDROLAZE
SOD
HIDROLIZA
HIDROLIZA ESTERILOR
CARBOXILESTERAZE
AMIDAZE
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
(Paracetamol)
Derivat N-hidroxi Legatura covalenta Necroza hepatica
2-Acetilaminofluoren N-acetoxi-AAF
AAF N-sulfat
Legatura covalenta Cancer
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
(flora intestinala)
Formare de cianura Hipoxie citotoxica
Benzen Benzen epoxid Legatura covalenta Depresie maduva hematopetica
Brombenzen Brombenzen Legatura covalenta Necroza hepatica, renala,
bronsiolara
Tetraclorura de carbon Radical liber
triclormetan
Legatura covalenta,
peroxidarea lipidelor
Necroza hepatica,
Cancer hepatic
Alchilnitrosamine
carciogene
Alfa-hidroxilare Alchilare Cancer hepatic
Coloranti amino
carciogeni
Derivati N-hidroxi Legatura covalenta Cancer hepatic
Compusi bioactivi
(modificat dupa Frank Lu, 1991)
Compusul initial Metabolit toxic Mecanismul toxicitatii Consecinte organo-functionale
Hidrocarburi policiclice
carciogene
Epoxizi in diverse
organe
Legatura covalenta Cancer, citotoxicitate
Cloroform Fosgen Legatura covalenta Necroza hepatica, renala
Cicasin Metilazometanol Alchilare Cancer, necroza hepatica
Ciclamat Ciclohexilamina Necunoscut Cancer de vezica
Etanol Acetaldehida in
diverse organe
Complex Diferite
Fluoracetat Fluorocitrat Inhibitie enzimatica Toxicitate generala
Furosemid Epoxid Legatura covalenta Necroza hepatica, renala
Halotan Radical liber Legatura covalenta Necroza hepatica
Amine aromatice
hemolizante
Metaboliti N-hidroxi Necunoscut Hemoliza
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
aromatice
methemoglobinizante
Metaboliti N-hidroxi Oxidare, reducere
ciclica
Methemoglobinemie
Metoxifluran Fluor anorganic Inhibitie enzimatica Insuficienta renala
Naftilamina N-hidroxi naftilamina Legatura covalenta Cancer vezical
Nitriti si amine
secundare si tertiare
Nitrosamine Alchilare Cancer hepatic, pulmonar
Olefine Epoxizi Legatura covalenta Cancer de piele
Paration Paraoxon Legatura covalenta cu
colinesterazele
Paralizie neuromusculara,
insuficienta respiratorie
Analogi baze purinice si
pirimidinice
Mononucleotide,
nucleotizi trifosfat
Sinteza letala,
incorporare letala
Citotoxicitate
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
REDUSA
NECUNOSCUTA
FOARTE MARE
EFECT TERAPEUTIC TOXIC
STEADY STATE UZUAL NU
DATE CLINICE
COROBORANTE
FRECVENT INCOMPLETE
CONCENTRATIE-EFECTE DA INCOMPLETE
TOXICE, RECEPTORI SI CONSECINTA
INTERACTIUNII LOR
RECEPTOR TOXODINAMIC TOXIC MECANISM
COLINESTERAZE COMPUSI ORGANO-
FOSFORICI
BLOCAREA CENTRULUI
ESTERAZIC
CITOCROMOXIDAZA CIANURI BLOCAREA TRANSPORTULUI DE
ELECTRONI IN LANTUL
RESPIRATOR
GRUPARI TIOLICE
ENZIMATICE
METALE GRELE INACTIVAREA GRUPARILOR
TIOLICE
HEMOGLOBINA MONOXID DE
CARBON, NITRITI,
NITRATI
FORMAREA:
CARBOXIHEMOGLOBINEI
METHEMOGLOBINEI
ACIZI NUCLEICI ALCHILANTE
RADIOMIMETICE
BLOCAREA SINTEZEI ACIZILOR
NUCLEICI
LIPIDE STRUCTURALE TETRACLORURA DE
CARBON
BROMTRICLORMETAN
RADICALI LIBERI
PEROXIDARE
RECEPTOR NICOTINIC NICOTINA
CURARIZANTE
STIMULARE DIRECTA
BLOCARE, PARALIZIE
RECEPTOR MUSCARINIC MUSCARINA
(AMANITA MUSCARIA)
STIMULARE INTENSA, SINDROM
MUSCARINIC