toxicology w9 Flashcards
(22 cards)
toxicology
the study of adverse effects of chemical, physical, or biological agents on living organisms.
applied areas of toxicology
- clinical
- forensic
- analytical
- environmental + ecotoxilogical
- regulatory
types of toxic substances
- drugs: adverse drug reactions (ADRs), overdose, toxic interactions
- food components: intentional, additive, unintentional, contaminant
- industrial chemicals: industrial processes, car exhausts
- natural toxins: bacterial, plant, and animal toxins
- household poisons: cleaning agents, medications
types of toxic exposures:
- intentional ingestion: drugs*, food additives, alcohol, tobacco
- unintentional: chronic exposure, allergic reactions, chronic toxicity
- occupational exposure: usually chronic inhalation (lung disease) and skin (dermatitis) exposure, acute exposure, accidents.
- Environmental exposure: factory effluent (gas, liquid, solid), spillages and dumping, continuous release.
- Accidental poisoning: acute (usually drugs*, pesticides, household products, natural poisons, inhalation of fire fumes
- Intentional poisonings: homicide, suicide
therapeutic index (TI)
TI = LD50/ED50
margin of safety (MoS)
MoS = LD1/ED99
ADI
acceptable daily intake
TRV
toxic reference value
- health based guideline thats used to assess and manage risks associated with chemical exposure
Routes of absorption
Most common routes of absorption:
- Oral (GI tract; for drugs)
- Inhalation (resp. system)
- Dermal (skin)
- Injection (mainly drugs)
rate of absorption depends on:
- Route of exposure: inhalation > oral > dermal
- Lipophilicity of chemical
- Injection: direct delivery into the body (i.v., s.c, i.m, etc.)
XENOBIOTIC METABOLISM (def)
The body’s process of breaking down and eliminating foreign chemicals. It involves phase 1 and phase 2.
Can modify xenobiotic effects in at least 4 ways, by forming:
- An inactive metabolite from an active compound (terminating its bioactivity) – detoxication
- An active metabolite from an initially inactive compound (pro-drug to drug; pro-carcinogen to ultimate carcinogen)
- An active metabolite from an initially active compound
- A toxic metabolite from an initially active compound
Xenobiotic metabolism Phase 1
Catabolic (oxidation, reduction, or hydrolysis)
- Introduces a functional chemical group and increases polarity
- Cytochrome P450 (CYP) is a major pathway for oxidation
- Inducible by many factors (smoking, drinking, drugs, diet)
Compared to the parent xenobiotic, the metabolites are:
- More chemically reactive (sometimes more toxic)’
- More polar from introduction of reactive (functional) group
- More easily eliminated by the kidney.
Oral dose -> gut wall -> liver -> systemic circulation -> target organ for toxicity
Liver is the main organ of metabolism
Processes of xenobiotic metabolism occur within specific cellular sites, in organelles or cytoplasm
3 families of CYP usually involved in xenobiotic reactions: CYP1;2;3
Xenobiotic metabolism Phase 2
- Synthetic, anabolic (conjugation to glutathione (GSH), sulfate, glucuronife, amino acids, etc.)
o Conjugates a highly polar compound to greatly increase excretion - Compared to phase 1 metabolites, the phase 2 conjugate is:
o usually less active or inactive
o much more polar and more easily eliminated by kidney
other protective factors: - antioxidants (vit. E, Vit C, sulfhydryls)
toxic outcome depends on: Activation vs detoxication.
TOXICODYNAMICS
- types of chemical toxicity; sensitivity to toxicity (hyper/hypo)
- acute/immediate (acute overdose) r delayed toxicity (neurotoxicity, teratoxictiy, allergy, cancer)
- local or systemic toxicity
- reversible or irreversible toxicity
- cytotoxicity + cell death pathways: apoptosis/necrosis
- toxicophores; selective toxicity
- toxic interactions (antagonism, potentiation, additivity, synergy)
types of drug toxicity
Adverse effects (‘iatrogenic’ effects) can be classified into 2 broad categories:
Type A (Augmented)
- predictable reactions that are extensions of pharmacological effects, and generally dose – dependent and less severe.
Type B (Bizarre)
- idiosyncratic reactions that are not predicted by pharmacology, occur infrequently, are not related to dose, and can cause significant morbidity or death.
Adverse Drug Reactions (ADR) categories also include types C + D (chronic, delayed)
Cell death pathways
Apoptosis/ Necrosis
Damaged cells are eliminated by apoptosis or necrosis
Apoptosis – cell deletion without inflammation, caused by many toxins at low doses
Necrosis – lysis of damaged cells, infiltrating immune cells, caused by higher doses
Apoptosis kills itself when there’s high levels of p53
Toxicophores
- these structural alerts are molecular functionalities associated with toxicity
- often related to metabolic activation
- used in silico QSAR screening
selective toxicity
“a chemical producing injury to one form (undesirable form) of life without harming another form of life (desirable), even though they may exist in intimate contact”
i.e. host vs parasite/bacteria/virus/ tumour.
Agricultural crops vs. fungi/insects/weeds
Toxic responses to chemical in selected target organs.
1st main mechanism of selective toxicity
- pharmacokinetic difference:
chemical is equitoxic to both economic and uneconomic cells, but is accumulated mainly by uneconomic form
i.e. distribution differences due to: absorption, biotransformation or excretion differences.
2nd main mechanism of selective toxicity
- PharmacoDYNAMIC difference:
Chemical reacts fairly specially with a cytological or biochemical feature absent or unimportant to economic form
e.g. penicillin antibiotics stop bacterial cell wall growth
differences in metabolism
- Toxic metabolites produced in target organism more than in non-target species:
i.e. organophosphate (OP) pesticides - Malathion is rapidly oxidised by insects to toxic anticholinesterase compound malaoxon (slow in mammals); while inactivating hydrolysis pathways are slow in insects (but rapid in mammals)
