Toxicity, effects of noxious substances

Poisoning – intoxication

 * Interaction of the poison with the organism, effect on metabolic processes, damage to organ functions, morphological changes
 * Processing of the poison in the organism - toxicokinetics
 * Effects of poison on the organism - toxicodynamics
 * Poison metabolism - detoxification or bioactivation
 * Acute intoxication
 * neurotoxic, hepatotoxic, nephrotoxic, cardiotoxic, embryotoxic,...
 * Chronic intoxication: developmental damage, carcinogenicity, genotoxicity, development of allergies, etc.
 * Chronic abuse of drugs, development of tolerance

Poisons and damage mechanism

 * Damaging the function of the target organ. Toxicity is a function of concentration at target organs, receptors.
 * Damaging cells causing cellular lesions
 * The degree of damage depends on reaching the concentration in the target organ (amanitins, mercury,...)
 * Combined mechanisms, e.g. prolonged cellular hypoxia (CO, HCN), formation of cytotoxic metabolites (methanol, glycol,...). Chronic exposure

Toxicity, effects, toxicodynamics

 * toxicity of the original form, chemical structure (QSAR studies)
 * method of administration, application, exposure (bioavailability)
 * exposure time, dose frequency
 * bioavailability
 * Individual susceptibility of the organism – genetic basis, physiological and external influences (age, diseases, diet, smoking, etc.)
 * Inter and intra-individual variability of metabolism, variability of enzyme capacity during biotransformation

Physiological factors

 * Sexual differences – hormonal influences, differences in enzyme capacity (biotransformation of ethanol), isoenzyme representation in women and men (e.g. P450)
 * Age differences, cell changes, cell development, development of enzyme activity in a specific way, increase and decrease (aromatic hydroxylation, N-demethylation, ability to form glucosiduronates....)
 * External influences, diet, lifestyle, diseases
 * Interaction of substances – induction and inhibition of enzymes
 * Chronic doses – cellular changes, receptor adaptation (alcoholism, addictive substances, development of tolerance)

Substance toxicity
Information about the toxicity of substances:
 * Acute
 * Chronic
 * 1) "case studies" - completeness and reliability of anamnestic data, filtering out interfering influences, e.g. mixed poisoning, unknown factors
 * 2) epidemiological studies - side effects of drugs and therapeutic effectiveness - statistical evaluation. Unknown influencing factors
 * 3) controlled experimental studies, clinical studies - strict ethical restrictions

Drugs' Other substances - experimental studies on animals
 * clinical studies on human volunteers
 * Ethical considerations, microdoses, major limitations
 * Informed consent of the volunteer

Testing regulations:
 * Czech pharmacopoeia (drugs, medical supplies)
 * "OECD Guidelines for Testing of Chemicals"
 * Guidelines determine which animals and in what quantity to use for a certain test; what dose and method of application
 * The goal is harmonization, generalization of study results
 * What animal? – as close to the human model as possible
 * Animal size - repeated sampling - study cost

Experimental toxicity studies

 * 1) short term
 * 2) long term
 * Effect versus dose
 * non-linear relationship
 * semi-logarithmic dependence


 * effect vs. log dose
 * toxicity vs. log dose
 * LD50 – median lethal dose

Therapeutic drug index

 * Effective dose ED
 * Toxic dose TD
 * T-INDEX = LD50 / ED50
 * higher value, high toxic dose
 * i.e. safer drug and less risk of poisoning

Short-term toxicity studies

 * Acute toxicity – LD50 – histological examination of organs
 * Subchronic toxicity, includes e.g. accumulation of poison, repeated doses lasting 10% of the life of the laboratory animal
 * Local effects on skin, eyes (soaps, ophthalmology) – rabbit, guinea pig, mouse – irritation tests
 * Teratogenicity, embryotoxicity – administration to females during pregnancy, histological examination of fetal soft tissues, skeletal examination
 * Reproductive toxicity, administration to the parent pair, monitoring of litter size, offspring size, after weaning, parent necropsy, histopathological examination of reproductive organs

Long-term toxicity studies

 * Carcinogenicity - repeated doses, 3 dosages, 18-24 months, haematological examination, necropsy and histopathological examination
 * Chemical structure of the substance vs. carcinogenicity
 * Different sensitivity of animals to chemical induction of tumors
 * Chronic toxicity – minimum period of 12 months
 * Both rodent and non-rodent (dog, primate)

Individual susceptibility to toxicity
Variability - mainly genetically determined (genotypes)
 * between animal species
 * within an animal species
 * physiological and temporal influences (sex, age, diseases,...)
 * variability of the metabolic capacity of enzymes
 * polymorphism of enzymes, alternative forms, isoenzymes

Interspecies variability in benzoic acid conjugation metabolism
Člověk: amfetamin, 4-OH-amfetamin a konjugace, dále oxidativní deaminace až kys. hippurová

Králík: amfetamin, oxidativní deaminace; ale redukce fenylacetonu, výsledný alkohol je vylučován konjugovaný močí

Interspecies variability in methamphetamine metabolism
Human: amphetamine, 4-OH-amphetamine and conjugation, then oxidative deamination to hippuric acid

Rabbit: amphetamine, oxidative deamination; but reduction of phenylacetone, the resulting alcohol is excreted conjugated in urine

Genetic variability of toxicity

 * E.g. isoniazid (treatment for tuberculosis)
 * Genetic polymorphism of N-acetylation, the metabolite is more polar, excreted more quickly
 * Europeans:''' 40% of the population acetylates rapidly
 * Asians: 80% of the population acetylates rapidly
 * Eskimos: 96% of the population acetylates rapidly
 * The acetylation phenotype of an individual determines toxic manifestations:
 * neuropathy with slow acetylation
 * hepatotoxicity with rapid acetylation

Development of toxic manifestations

 * Sequence of processes, interaction with macromolecules, disruption of physiological processes – change in toxicity
 * Factors influencing toxic manifestations, dynamics:
 * Chemical effects, substance structure:
 * Genetic factors
 * Physiological factors (sex, age, state of health)
 * Toxicokinetic factors
 * External factors, diet, environment, lifestyle

Related Articles

 * The fate of xenobiotics in the organism
 * Introduction to Toxicology
 * Abuse and intoxication