Mod2: PRINCIPLES OF TOXICOLOGY

1. Signs
   1. Measurable abnormalities in physiological function, such as raised blood pressure or heart rate, blood in the urine or raised body temperature.
2. Symptoms
   1. the physical complaints of an individual resulting from abnormal physiological function, such as a cough, pain, breathlessness or headache.
3. Types of Effect
   1. Local
      1. manifests at the site of absorption, usual present immediately
   2. Systemic
      1. manifests in multiple sites, remote from site of absorption
   3. Acute
      1. occur soon after exposure, often REVERSIBLE
   4. Chronic
      1. may manifest many yrs after exposure, MAY NOT be reversible
   5. Critical Effect
      1. the point at which an effect becomes harmful

Annotations:

• Dose can be defined as the quantity of chemical in the target organ, ie. in the body organ which is affected by the chemical.
• Critical organ concentration is the dose at which adverse effects occur in the target organ.

1. Estimates of dose - gained from:
   1. Experimental Exposure

      Annotations:

      • Experimental exposure may be via injection, ingestion, inhalation, or the dermal application of a chemical. The dose can be estimated from the concentration or amount applied and the duration of exposure.
   2. Occupational Exposure
      1. toxico-kinetic factors
      2. atmospheric concentration (environmental monitoring)
      3. duration of exposure
      4. rate of lung ventilation
   3. Environmental Exposure

      Annotations:

      • This is the result of exposure to air, food, water, drugs, consumer products, tobacco smoke, and beverages.
2. Dose-Effect Relationship
   1. The dose - effect relationship is the correlation between dose and the magnitude of the effect in a specified proportion of the population

      Annotations:

      • It is important to note that any determined dose-effect relationship only applies to a specified proportion of the exposed population. Within an exposed group of people there will be some who will be exceptionally susceptible to harm from the chemical and others who will be particularly resistant to it.
3. Dose-Response Relationship
   1. The dose - response relationship: The relationship between dose and the proportion of the population which will suffer illness
      1. LD50

         Annotations:

         • LD50 (lethal dose 50%) represents the dose of a substance that produces death in 50% of the population exposed to a toxicant.
      2. LC50

         Annotations:

         • For exposures administered via inhalation the LC50 or lethal concentration 50%, is computed.
4. Combination: Dose-Effect + Dose-Response
   1. Dose - effect and dose - response relations provide fundamental scientific data relating health impairment to the dose of an agent, in terms of both severity of effect and the proportion of the exposed population to suffer harm.

1. toxicology is the study of the characteristics of poisons and the effects they produce in biological systems. The harmful effects produced by a poison and the conditions under which the harmful effects occur are the issues of most concern.

1. Industrial or occupational toxicology addresses the toxicity of chemicals found in the workplace.

1. 1. Inhalation
   1. The absorption rate of inhaled particulates depends on the site of their deposition in the respiratory tract, as well as on their solubility in body fluids and the ventilation rate.
   2. Inhaled gases and vapours are able to penetrate the lungs and pass into the blood stream to be distributed throughout the body.
2. 3. Ingestion
   1. The ingestion of toxicants is usually of minor importance in the occupational setting. However, the mis-labelling of containers or the storage of toxic chemicals in drink bottles may result in accidental ingestion of chemicals at work.
3. 2. Skin Absorption
   1. Some toxic agents can enter the blood and lymphatic circulations of the body via the skin. They are able to pass by passive diffusion directly through the layers of the skin, or through the openings of sebaceous glands, sweat glands or hair follicles.

1. Blood
   1. Depends on RATE of BLOOD FLOW & presence of BINDING sites
   2. Many chemicals are bound to plasma proteins for transport
   3. Blood-Brain Barrier
2. Lymphatics

1. Gases & Vapours readily eliminated
2. Particulates likely to remain
3. Tissue affinity for chemicals affects retention

Annotations:

• In general, biotransformation renders a chemical more water soluble. This prevents it from readily dissolving in cell membranes (cf. lipophilic compounds which have a propensity to localise in membranes) and assists elimination in watery urine.

1. Phase 1
   1. Adds/Exposes functional HYDROPHILLIC groups (assists Phase 2)
   2. ENZYMES-mixed function oxidases
2. Phase 2
   1. Conjugation of chemical into an endogenous molecule

1. KIDNEYS - primary route for elimination of foreign chemicals
2. G.I.T. - gut can return chemicals thru bile
3. -Sweat -Expired Air -Hair
4. Rate of Elimination: BHT - Biological Half-Time

   Annotations:

   • Biological half time is independent of dose and is a useful indicator of the degree to which chemicals are retained in the body.

Annotations:

• Toxico-kinetic models facilitate the study of the time course of toxic substance concentrations in excreta, blood or other fluids and tissues of the body.

1. 1 Compartment

   Annotations:

   • A one compartment model is the simplest case and assumes that the body is effectively a single compartment with a single input and a single output, ie., there is very rapid equilibration between blood and other tissues so that concentration changes in blood mirror those in other tissues.
2. 2+ Compartments

   Annotations:

   • A simple multi compartment model assumes that the single compartment is divided into two and a substance will enter both compartments, either in parallel or in sequence, before being eliminated.

1. 1.Largest constant [C] for 24hrs/day for lifetime
2. 2.Largest constant [C] for 8hrs/day, 5d/wk for working lifetime
3. 3.Largest average [C] for 8hrs/day, 5d/wk for working lifetime

1. 1. Interference with Communication Systems
   1. Nerve signalling and endocrine system functions involve the attachment of transmitters or hormones to receptor sites.

      Annotations:

      • Interference with communication systems: Nerve signalling and endocrine system functions involve the attachment of transmitters or hormones to receptor sites. Many 'foreign' chemicals are believed to act by binding to these types of receptors in the body. They then disturb normal function, either directly or indirectly by preventing normal endogenous chemicals from binding to receptors. Many pharmaceutical agents work in this way, eg., morphine which is used for analgesia and d-tubocurarine, a synthetic form of the plant toxin curare, which is used as a muscle relaxant. Organophosphate pesticides inhibit an enzyme, acetyl cholinesterase, which normally breaks down acetyl choline, an important neurotransmitter at neurone- neurone and neurone-muscle junctions. The inhibition of acetyl cholinesterase interferes with the removal of the transmitter molecules from receptor sites, thereby interfering with nerve impulse transmission. Other chemicals directly disturb the ionic current of nerve impulse generation. An occupational example of a chemical acting in this way is the pesticide DDT. It is believed to interfere with the closing of sodium channels during nerve signal conduction, thereby altering the rate of repolarisation. Lipid soluble organic solvents have a non-specific effect on nerve membranes resulting in a general depression of central nervous system activity.
2. 2. Binding to Important Structural or Functional Biomolecules
   1. Such binding may lead to impairment of fundamental processes of cell respiration, leading to tissue anoxia, or to disturbances in the structural integrity of cells.

      Annotations:

      • This is a broad category of toxic mechanisms underpinning much toxic activity. Such binding may lead to impairment of fundamental processes of cell respiration, leading to tissue anoxia, or to disturbances in the structural integrity of cells. Many chemicals cause tissue damage as a result of anoxia. For example, carbon monoxide has a much greater affinity than oxygen for haemoglobin and readily combines with it to form carboxyhaemaglobin. The result is reduced delivery of oxygen to the tissues. Cyanide binds with and blocks the activity of cytochrome oxidase, which is an essential step in oxidative phosphorylation. The result is impaired use of oxygen by the tissues. Many toxic metals, such as lead, mercury and cadmium, preferentially combine with the sulphydryl groups of protein molecules. Proteins are important structural and functional molecules. Enzymes and many hormones are proteins and proteins are also important components of cell membranes. Chemical binding to proteins therefore clearly has the potential to disturb a wide range of cellular activity. For example, lead binds with enzymes involved in haem synthesis, which ultimately can result in anaemia. In most cases of tissue necrosis, chemical binding is preceded by the formation of reactive free radicals. Formation of free radicals may occur via enzyme mediated oxidation. Free radicals can interact with polyunsaturated fatty acids in cell membranes, resulting in the formation of lipid peroxides and hydroperoxides. Lipid peroxidation tends to 'stiffen' cell membranes and this may result in cell rupture and tissue necrosis. The stiffening is also thought to underpin the pathology of, for example, atherosclerosis, cataract and liver cirrhosis. Free radicals can also interact with and oxidise thiol (sulphur containing) groups in protein molecules. Many proteins contain thiol groups and such oxidative stress can destroy the structure, which may affect critical enzyme activity. Another important group of molecules with which 'foreign' chemicals can combine are the nucleic acids, DNA and RNA. There are many sites in DNA which can bind with chemicals - DNA adduction. DNA adduction potentially can interfere with gene expression necessary for cell survival, but also it can result in mutation that may then lead to carcinogenesis. Binding to RNA can result in RNA adduction and disturbances in protein synthesis.
3. 3. Disturbance of Calcium Homeostasis
   1. Tissue injury is associated with the accumulation of calcium, as a result of enhanced influx, release from intracellular stores, or the inhibition of removal from the cell.

      Annotations:

      • Toxic insult (e.g., aldehydes, dioxins, alkanes, alkenes, nitrophenols) can result in disturbances in intracellular calcium. This directly disturbs membrane structure and the many functions such as muscular contraction that are regulated by calcium.
4. 4. Targeted Toxicity
   1. Some chemicals target specific groups of cells.

      Annotations:

      • Some chemicals target specific groups of cells. For example, manganese is known to damage cells in the basal ganglia in the brain, which normally contribute to the control of muscle contraction by inhibiting activity of motorneurones. Manganese poisoning can result in symptoms that resemble Parkinson's disease. The developing embryo also is very sensitive to toxic substances. The drug thalidomide results in particular patterns of birth defects, chiefly the failure of limb development. Cells for developing limb buds are targeted by thalidomide in the early stages of development.
5. 5. Carcinogenesis
   1. If DNA adductions are not repaired then mutation may result from DNA replication during cell division, which can go on to develop into cancer.

      Annotations:

      • Some carcinogenic chemicals are believed to be genotoxic because they stimulate proto-oncogenes, which regulate growth and differentiation. Other chemicals may be carcinogenic because they promote the growth of mutated cells rather than because they act directly on the genome.

1. Effects on UPTAKE
2. Effects on METABOLISM
3. Effects on BINDING
4. Effects on ELIMINATION

1. Additive Effects - multiple chemicals targeting one organ
2. Potentiation & Synergistic Effects - one chemical increasing the severity/likelihood of adverse effects
3. Antagonistic Effects
4. Indifferent Effects - effect on dependent of the most active chemical
5. The Nature of the Interaction Depends on the Response Measured