Toksikologi Zat Kimia

Andriyanto, Drh, Msi

Perencanaan Hidup

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Toxicology Concepts

RiskThe likelihood of injury or

disease resulting from

exposure to a potential

hazardhazard

Evaluation of risk

embodies all the basic

concepts of toxicology

The science of Toxicology helps people make informed decisions and balance

RISKS vs. BENEFITS

The study found the highest levels of pesticide residues in peaches, apples,

AND Spinach.

pears…….

Exposure

• Environmental, including home and school

Sources of exposure to chemicals

school• Occupational

• Therapeutic

• Dietary

• Accidental

Exposure• In order for a chemical to produce a biological effect, it must first reach

a target individual (exposure pathway).

• Then the chemical must reach a target site within the body (toxicokinetics).

• Toxicity is a function of the effective dose (how much) of a foreign chemical (xenobiotic) at its target site, integrated over time (how long).

• Individual factors such as body weight will influence the dose at the target site

X =

Exposure

Route of Exposure

• The route (site) of exposure is an important determinant of the ultimate dose—different routes may result in different rates of absorption.

– Dermal (skin)

– Inhalation (lung)

– Oral ingestion (Gastrointestinal)

– Injection

• The route of exposure may be important if there are tissue-specific toxic responses.

• Toxic effects may be local or systemic

ExposureTime of Exposure

• How long an organism is exposed to a chemical is important

Duration and frequencycontribute to dose. Both may alter toxic effects.– Acute Exposure = usually entails a single

exposure

– Chronic Exposures = multiple exposures over time (frequency)

Father of Modern ToxicologyFather of Modern Toxicology

Paracelsus——1564

DoseTHE KEY CONCEPT in Toxicology

Paracelsus——1564

“All things are poisonous, only the dose makes it non-poisonous.”

Dose alone determines toxicityAll chemicals—synthetic or natural—have the

capacity to be toxic

All Interactions between chemicals and biological systems follow a

Dose-Response Relationship

Dose

SACRAMENTO, California—A woman who competed in a radio station’s contest to see how much water she

Woman Dies after Water-drinking Contest: WaterIntoxication eyed in ‘Hold Your Wee for a Wii’ contest Death

Dose

could drink without going to the bathroom died of water intoxication, the coroner’s office said Saturday.

Updated: 10:24 p.m. ET Jan 13, 2007

Dose-Response Relationship

• A key concept in Toxicology is the quantitative relationship between the concentration of a xenobiotic in the body and the magnitude of the biological effect it produces.

• The magnitude of the effect of a xenobiotic is usually a function of the amount of xenobiotic to which a person is exposed (i.e., “The Dose Makes which a person is exposed (i.e., “The Dose Makes the Poison”).

• In any given population, there will be a range of sensitivities to a xenobiotic. It is extremely useful to know what is the average sensitivity of a population to a xenobiotic, and what the average dose required to elicit a toxic response will be.

Dose

• The magnitude of the toxic response is proportional to the concentration (how much) of the chemical at the target site.

• The concentration of a chemical at the target site is proportional to the dose.

• Four important processes control the amount of a chemical that reaches the target site.

– Absorption

– Tissue distribution

– Metabolism

– Excretion

Dose

Determines Whether a Chemical Will Be Beneficial or Poisonous

Beneficial Dose Toxic Dose

Aspirin 300 – 1,000 mg 1,000 – 30,000 mg

Vitamin A 5000 units/day 50,000 units/day

Oxygen 20% (Air) 50 – 80% (Air)

Keracunan Zat Kimia (1)

Pursani ParidjoM. Iskandar

Huda S D

Referensi

• Casarett and Doull’s, 2003, Essential of Toxicology

• Clark & Humprey, 1997, Veterinary Toxicology

• Lu, C. F, 1995, Toksikologi Dasar (translasi Edy Nugroho)

• Bartik & Piskac, 1981, Veterinary Toxicology

Kata Kunci

• Solvent (pelarut), Cairan kimia organik dengan: • a. Keragaman kemampuan lipofilik dan volatil• b. ukuran molekul kecil• c. polaritas rendah

• Absorpsi zat kimia organik volatil (vapors) per inhalasi via paru(alveol)

• Pelarut diabsorbsi via GI s.d. kulit

• Kebanyakan pelarut menyebabkan gangguan SSP

Toxicology• Study of the adverse effect of xenobiotics/ chemical on

living systems

• Racun/ poison: any agent capable of producing a deleterious response in a biological system

• Toksin: refers to toxic substances that are produced by biological system

• Toksikan: ~ by or by-products of anthropogenic (human) activities

Pendahuluan

• Solvent Petroleum based (Naphthalene, Benzene)

• Used for water insoluble material

• Kelarutan (lipophilicty) Penguapan (Volatility)

• Klasifikasi : Struktur Kimia & Grup Fungsional

Klasifikasi

• Hidrokarbon alifatik- halocarbon (N-Heksan)• Hidrokarbon alifatik- berklor (kloroform)• Hidrokarbon aromatik (Benzen)• Alkohol• Alkohol• Ethers• Esters/ asetat• Amides/ Amines• Aldehid• Keton

Paparan

• Hampir semua organisme terpapar zat kimia• Gabungan beberapa senyawa, jarang tunggal

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Intoksikasi

• Toksisitas bersifat additive, sinergis & antagonis

• Bahaya beberapa solvent lebih tinggiSeluruh solvent berpotensi toksik

• Secara keseluruhan menginduksi narkose (neurologik) dan iritasi kulit & membran mukosa

• Beberapa karsinogen, hanya sedikit yg sudah teridentifikasi

Neurological Syndrome-Man

• Painter’s synd, organic solvent’s synd, psychoorganic synd & chronic solvent encephalopathy (CSE)

• Abuse “menginginkan” efek sedasi, euphoria, audio & visual halusinasivisual halusinasi

• Intoksikasi umumnya karena cemaran lingkungan via evaporasi oleh Volatile Organic Compound (VOC)-aerosol propellants, thinner, cleaner, dll

Toksikokinetik - Absorpsi

• Alveol & sal resp atas. Lipofilik PC (Partition Coeff) Kenaikan Darah- Udara uptake meningkat

• GI 100% efek sistemik

• Kulit sistemik & lokal (diffusi pasif).

• Laju absorpsi kulit tgt: konsentrasi, luas permukaan terpapar, durasi, integritas& ketebalan str.korneum, MW zat

Distribusi

• Hepatic first pass elimination

• Pulmonary first pass elimination

• GI tract vena porta eksresi via paru tidak masuk • GI tract vena porta eksresi via paru tidak masuk arteri (jika solvent volatil dimetabolisme dengan baik)

• Solvent lipofilik arteri berikatan dengan hidrofobik sites (memb. Fosfolipid, kolesterol) depo di jaringan adiposa

Tgt Blood Flow & kandungan lipid…obese??

Metabolisme & Eksresi

• Biotransformasi• Modulasi toksisitas solven megubahnya

menjadi relatif larut air eliminasi/ eksresi lebih banyak via urin dan atau empedu lebih banyak via urin dan atau empedu (lemak)

• Bioaktifasi solven metabolit reaktif sitotoksik & mutagenik

Populasi yang berpotensi terpapar

Faktor Endogen• Usia Anakan• Hewan tua• Genetik• Genetik

Faktor Eksogen• Sitokrom P450 inhibitor & inducer• Aktifitas Fisik- olah raga- ventilasi alveolar• Diet- banyak isi GI – absorpsi lebih lambat

Hidrokarbon BerKlorNo Nama Zat Kegunaan Rute

ToxCNS -

NeurologikUro

genitalOrgan Interna

Metabolit Keterangan Tambahan

1 Trichloroethyele (TCE)

Pelarut oli I, O, D

Depresan, Myeloma

Kanker Prostat

Kanker hati, paru & ginjal

TCOH to P450

Karsinogenik, Hodgkin’s

2 Tetrachloroethylene (PERC)

Dry cleaner, Stainer

I, O - - Esofagus, ginjal

TCAcetic to P450

Rokok& minum alkohol

3 Methylene Chlorid (MC)

Preparasi makanan, aerosol propellan

I - - Gangguan ringan & reversibel

- Efek sistemik terbatas - low carsinogenitas

4 Carbon Tetraklorida (CCl4)

- O, IV - - Hepatoseluler injury

- Hepatotoxin klasik, manusiaginjal

5 Chloroform (CHCl3)

Refrigerant O SubAnesthetic

- Hepato & nephro necrosis

Phosgene to lipid

Carcinogen (rodent), probable (man)

Hidrokarbon Aromatik

06.Benzene BBM

(tanpa Pb)I - - Hematopoietik

(anemia, leukopenia, trombositope, Marrow aplasia

Benzene to GSH, DNA,RNA

perokok (benzene level 6-10x)Myelodisplasia acutemyelogenous leukaemia (AML)

07.Toluene (alkylbenzene)

Cat, lem, thinners, campuran bensin

I, O Depresi,nystagmus, atropi cerebral

- Depresi respirasi

- Target utama CNS (toluene & alkilbenzen), exhaled unchanged

08.Xylene & Ethylbenzene

Komponen utama bensin & BBM

I Depresi - Hati, ginjal Xylene to P450

Karsinogenik (ethyllbenzen & styrene)

Alkohol

9. Alkohol -Ethanol

Industri, farmasi, minuman

O Alcoholism-retardasi mental-FAS

- Nekrosis hati, Cardiomyopathy,

Asetaldehid dehidrognase (ALDH)

Fetal Alcohol Syndrome (FAS)-maternal alkohol saat hamil, microcephaly,

ALDH kaukasus >> Asia>> Asia

10. Methanol Pembuatan formalin, BBM

I, O Iritasi sensori, narcosis (I), koma

- Formic acidemia, okuler toxicity

- Gangguan visual (per os) retina,

Glikol’s

11. Glikol-Ethylene Glikol

Kriopreservatif, cairan hidrolik, tinta

O, D

Hypocalcemia (kelasi kristal CaOxalat)

- Cardiac failure, pulmonary edema, nekrosis ginjal

Asam glikolik

Metabolik asidosis (akumulasi asam glikolik), kristal kelat kapiler otak& ginjal

12. Propylene Glikol (PG)

Pelarut, pendingin, antifreeze

O, D

Depresi, encephalopathy

- Hemolisis-Lactic acidosis

Lactal-dehyde-laktat

FDA approved, toksisitas jika ekstrim tinggi

13. Glikol Ethers

s.d.a O Hydrocephalus, spina bifida (defek neural tube), cleft lip (sumbing)

- Hemolisis 2 Methoxy-Ethanol

Toksisitas utama pada reproduksi, pertumbuhkembangan dan hematopoietik,Sperma-toxicity, atrophy testis, abnormal akrosom

BBM & BBM AditifBBM otomotif

• Hydrokarbon rantai panjang (C4-C12)• Karsinogen (benzene, 1,3 butadiene)• Occupational Toxicities encephalopathy• Oral nausea, vomit, diare• Inhalasi rusak epitel pulmoner, edema, pneumonia• Inhalasi rusak epitel pulmoner, edema, pneumonia

Methyl Tertier- Butil Ether-MTBE (Octane booster)• Menyempurnakan pembakaran, reduksi emisi polusi• Simptom akut: iritasi mata, hidung, nausea, batuk (mukosa surface)• Grup C human carcinogen (tumor testis, lymphoma, adenoma hati)

Pengaturan

• Occupational Safety& Health Administration (OSHA)

• Permissible Exposure Limits (PEL’s) – 100 • Permissible Exposure Limits (PEL’s) – 100 pelarut

• Threshold Limit Values (TLVs), published by American Conference of Governmental Industrial Hygiene (ACGIH)

Sekian & Trims