1. W507 – Basic toxicokinetics

2. Toxicokinetics
Effect of a hazardous substance depends on the level or concentration of the substance that is present in the body’s systems – this will depend on rates (or kinetics) of
Absorption
Distribution
Metabolism
Elimination
Study of these processes is called toxicokinetics (sometimes referred to as pharmacokinetics)

3. Toxicokinetics Absorption Distribution Metabolism Elimination
Uptake of chemical into the lymph and blood
Distribution
Transport of chemical in blood and accumulation in organs and tissues
Metabolism
Biotransformation into other products (metabolites)
Elimination
Excretion from the organism

4. Routes of Absorption Inhalation – via the lungs
Direct contact – via the skin or eyes
Ingestion – via the gastrointestinal tract (GIT)
Injection – via direct puncture of the skin
In all routes of exposure, except injection, the chemical must cross a biological membrane to enter the body - there are two main ways this can occur
Passive diffusion
Active transport

5. Absorption Inhalation Ingestion Skin
Gases, vapours and particles - solid and liquid (aerosols)
Ingestion
Facial splashing, contaminated food, hand-to-mouth behaviour
Skin
Through or between cells, via sweat glands, sebaceous glands or hair follicles

6. Passive diffusion
Requires a positive concentration gradient i.e. substance tends to diffuse across biological membrane from a high concentration to a lower concentration.
Other factors that influence ability to cross biological membrane include:
Lipid (or fat) solubility
Molecular size
Degree of ionisation
Generally, lipid soluble, small molecules that are non-ionised cross biological membranes more easily.

7. Active transport
Involves a specific ‘carrier’ protein that transfers the xenobiotic across the plasma membrane.
Can move molecules against a concentration gradient – requires energy (ATP).
Mechanism particularly important in elimination of substances via the kidney and liver by enabling active movement of water-soluble substances across the largely fatty nature of the plasma membrane.

8. Inhalation Usually main route of occupational exposure
Lungs have a large surface area
Good blood supply
Thin membrane barrier
High turnover of contents of lungs
Above factors lead to high potential for absorption of airborne contaminants
Once absorbed, distribution around body via bloodstream is rapid
In addition to absorption through lungs, insoluble particles such as silica and asbestos can deposit in lungs and may lead to lung damage

9. Direct contact (skin absorption)
Epidermis (outer layer) of skin is impermeable to water and water-soluble compounds
However, some substances can enter the bloodstream by crossing the external membrane (the skin or eyes) – these tend to be highly lipid soluble compounds such as:
Organic solvents
Organo-phosphorous pesticides
Phenol
Underlying layers of the skin (dermis) are permeable to all substances so damage to the epidermis will decrease the defence to absorption of substances through the skin

10. Source: Tranter 1999 –reproduced with permission

11. Ingestion Not a common problem in the occupational environment.
Usually occurs due to:
Poor personal hygiene – eating at work station or not washing hands.
Carelessness
Poor facilities
Very high inhalable dust levels can result in ingestion via the mucociliary escalator and normal swallowing.

12. Injection
Direct route of entry occurs when a substance is absorbed through cuts, or by injury with contaminated sharp objects such as needles or broken glass
Risk of such injuries should be managed by protecting cuts, correct disposal of broken glass, sharps etc., and safe working practices

13. Distribution
Substances are transported around body predominantly via the blood and lymphatic systems
Substances may attach to red blood cells or proteins in blood plasma and be distributed around the body and may target specific organs
If lipid soluble, of small molecular size and non-ionised it is likely to cross cell membranes and enter body tissues
Water soluble chemicals tend to remain in solution in the plasma
Highly fat soluble substances will deposit and tend to remain in the body’s fat stores

14. Distribution
Lymphatic system is a complex network that produces and transports lymph fluid from tissues to the circulatory system and has three major functions
Removal of excess fluids from body tissues
Absorption of fatty acids and transport of fat to the circulatory system
Production of immune cells

15. Distribution
The ability of a substance to cross the ‘blood-brain barrier’ or the placental barrier is an important factor
Lipid soluble substances can cross the ‘blood-brain barrier’ and are likely to affect the central nervous system
e.g. organic solvents and organo-metal compounds
The placental barrier is easily breached by small or lipid soluble compounds putting developing offspring at particular risk
e.g. lead or organic solvents

16. Storage
Some substances may accumulate in specific tissues, for example:
Liver – acts as a storage organ
Lead in the bones
Solvents in fatty tissues
Carbon monoxide in blood as carboxyhaemoglobin

17. Metabolism (biotransformation)
A major factor influencing absorption and retention of a substance in the body is its lipid solubility
For a substance to be easily eliminated from the body it needs to be in a more water-soluble form
This is achieved via a process of metabolism (or biotransformation)

18. Metabolism (biotransformation)
The main objectives of biotransformation are
Detoxifying a hazardous substance
Making a substance more water soluble to facilitate elimination via the kidney
All tissues are involved to some extent, however the main site is the liver.

19. Metabolism (biotransformation)
Biotransformation of a compound does not always result in detoxification, it may result in the production of toxic metabolites
e.g. n-hexane metabolised to 2,5-hexanedione which can cause peripheral neuropathy
Knowledge of metabolism is also required for biological monitoring as the presence or amount of a particular metabolite may indicate exposure to the hazardous substance
e.g. increased levels of carbon dioxide are found in exhaled breath following dichloromethane exposure

20. Metabolism (biotransformation)
Biotransformation is controlled by complex enzyme systems – metabolism of xenobiotics is generally divided into two ‘phases’
Phase 1 reactions tend to produce a molecule that is more water soluble and more reactive
These reactions often involve Cytochrome P450 enzymes
Types of reactions include oxidation, reduction, hydrolysis
Phase 2 reactions tend to make the phase 1 product highly water soluble
Reaction or conjugation with another endogenous compound

21. Biotransformation of benzene
Major route involves:
Phase 1 oxidation, catalysed by Cytochrome p450 enzyme to phenol
Phase 2 conjugation with a sulphate donor compound to form phenyl sulphate
Biotransformation of benzene also produces other intermediates and metabolites – some of which may be responsible for the carcinogenic properties of benzene
This is an example where the intermediate or metabolite is more toxic than the substance itself

22. Epoxidation
Hydroxylation

23. Biotransformation of dichloromethane
Another example of a substance that undergoes multiple metabolic pathways
Produces products which are more toxic than dichloromethane
e.g. formaldehyde

25. Biotransformation of methanol
Methanol metabolism is regulated by the alcohol dehydrogenase enzyme.
Methanoic acid accumulates in the retina causing the blurred vision and blindness that occurs with methanol poisoning, the continued metabolism to CO2 is slow

26. Excretion
Compounds (metabolised or not) ultimately are eliminated from the body
The rate at which a compound is eliminated has an impact on the toxicity
The longer it is in the body the greater the potential for an adverse effect
Rate of excretion can be described in terms of its half life
Half lives vary greatly e.g. half life of cadmium is years, while carbon monoxide has a half life of a few hours

27. Half-life
Half-life
Time taken for the concentration of a chemical in the body (usually measured in blood) to fall by half
Majority of excretion (~97%) completed within 5 half-lives.

28. Half-life

29. Effect of half-life
Half-life 1h
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30. Effect of half-life
Half-life 20h
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31. Excretion The main routes of excretion are: Renal (via the kidneys)
Main route of excretion for small water-soluble molecules
Biliary (via the liver and gastro-intestinal tract)
Second most important route of elimination for hazardous substances and for some materials, e.g. lipid soluble materials, may be the most important
Pulmonary (exhaled)
May be an important route for volatile substances
Secretory (in body fluids)
Minor route

32. Essential points Toxicokinetics describes:
Absorption
Distribution
Metabolism
and Elimination of chemicals
Recognising routes of absorption:
Inhalation
Skin absorption
Ingestion & injection

33. Essential points
Understanding that metabolism often occurs so that the body can excrete chemicals more easily.
Metabolism can either reduce or increase the toxicity of chemicals.
Excretion half-life can have an influence on the toxicity of chemicals and is important when considering repeated exposures.