W 507 Basic toxicokinetics Toxicokinetics Effect of a

W 507 – Basic toxicokinetics

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)

Toxicokinetics • Absorption • 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

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

Absorption • Inhalation • 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

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 nonionised cross biological membranes more easily.

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.

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

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

Source: Tranter 1999 –reproduced with permission

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.

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

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

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

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

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

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)

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.

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

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 P 450 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

Biotransformation of benzene • Major route involves: • Phase 1 oxidation, catalysed by Cytochrome p 450 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

Epoxidation Hydroxylation

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

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 CO 2 is slow

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 10 -20 years, while carbon monoxide has a half life of a few hours

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.

Half-life

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

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

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.