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

• Acute
• Chronic

Information about the toxicity of substances:

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'

• clinical studies on human volunteers
• Ethical considerations, microdoses, major limitations
• Informed consent of the volunteer

Other substances - experimental studies on animals

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

Classification of toxic substances according to LD₅₀ size

Chemical substance	LD50
Super toxic	less than 5 mg/kg
Extremely toxic	5–50 mg/kg
Highly toxic	50–500 mg/kg
Moderately toxic	0.5-5 g/kg
Slightly toxic	5-15 g/kg

LD₅₀ for humans when administered orally – e.g.:

Chemical substance	LD50 (mg/kg)
Ethanol	7000
Sodium Chloride	3000
Morphine	900
Phenobarbital	150
Strychnine	2
Nicotine	1
Dioxin (TCDD)	0.01
Botulotoxin	0.00001

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

Alcohol	Minimal i.v. lethal dose (g/kg)
	Rabbit	Cat
Methanol	15.9	4.7
Ethanol	9.4	3.9
Propanol	4.0	1.6
Isobutanol	2.6	0.72
Isoamyl alcohol	1.6	0.21

Cross-species susceptibility to dichlorophenoxyacetic acid toxicity

LD50 of the herbicide 2,4-D – p.o.
Animal species	(mg/kg)
Mouse	360–710
Rat	900–1500
Guinea pig	400–800
Rabbit	420
Dog	100
Monkey	214

Interspecies variability in phenol conjugation metabolism

	Excreted proportion (%) – glucuronide	Excreted proportion (%) – sulfate
Cat	0	87
Man	23	71
Rat	25	68
Rabbit	46	45
Pig	100	0

Interspecies variability in benzoic acid conjugation metabolism

Animal species	Dose p.o. (mg/kg)	Urine elimination in 24 hours (%)	Proportion of dose in urine in 24 hours
			benzoic acid (%)	hippuric acid (%)	benzoyl glucuronide (%)
Mouse	56	55		95	5
Rat	50	100	1	99
Hamster	52	99	1	97
Rabbit	49	60		100
Pig	50	49	15	85
Cat	51	30		100
Dog	51	94		82	18
Chimpanzee	20	47		100
Human	1	100		100
Human	42			50 – 85

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

Amphetamine 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:

1. Chemical effects, substance structure:
2. Genetic factors
3. Physiological factors (sex, age, state of health)
4. Toxicokinetic factors
5. External factors, diet, environment, lifestyle

Links

Related Articles

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

Sources

• BALÍKOVÁ, Marie. Toxicita, účinky nox [online]. [cit. 2012-03-13]. <https://el.lf1.cuni.cz/p78927861/>
• PROKEŠ, Jaroslav. Základy toxikologie :  obecná toxikologie a ekotoxikologie. 1. vydání. Praha : Galén : Karolinum, c2005. ISBN 80-7262-30-1X