22.214.171.124 Measurable abnormalities in
physiological function, such as raised blood
pressure or heart rate, blood in the urine or
raised body temperature.
126.96.36.199 the physical complaints of an individual resulting from
abnormal physiological function, such as a cough, pain,
breathlessness or headache.
1.1.3 Types of Effect
188.8.131.52.1 manifests at the site of absorption, usual
184.108.40.206.1 manifests in multiple sites, remote
from site of absorption
220.127.116.11.1 occur soon after exposure,
18.104.22.168.1 may manifest many yrs after
exposure, MAY NOT be reversible
22.214.171.124 Critical Effect
126.96.36.199.1 the point at which an effect
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.
1.2.1 Estimates of dose -
188.8.131.52 Experimental Exposure
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.
This is the result of exposure to air, food, water, drugs, consumer products, tobacco smoke, and beverages.
184.108.40.206 The dose - effect relationship is the correlation
between dose and the magnitude of the effect in a
specified proportion of the population
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.
220.127.116.11 The dose - response relationship: The
relationship between dose and the proportion of
the population which will suffer illness
LD50 (lethal dose 50%) represents the dose of a substance that produces death in 50% of the population exposed to a toxicant.
For exposures administered via inhalation the LC50 or lethal concentration 50%, is computed.
18.104.22.168 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.
2.1.1 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.
2.2 Occuptional Toxicology
2.2.1 Industrial or occupational toxicology addresses the
toxicity of chemicals found in the workplace.
3.1.1 1. Inhalation
22.214.171.124 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.
126.96.36.199 Inhaled gases and vapours are
able to penetrate the lungs and
pass into the blood stream to be
distributed throughout the body.
3.1.2 3. Ingestion
188.8.131.52 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.
3.1.3 2. Skin Absorption
184.108.40.206 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.
220.127.116.11 Depends on RATE of BLOOD
FLOW & presence of BINDING sites
18.104.22.168 Many chemicals are bound
to plasma proteins for
22.214.171.124 Blood-Brain Barrier
3.3 Accumulation & Retention
3.3.1 Gases & Vapours readily
likely to remain
3.3.3 Tissue affinity for
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.
3.4.1 Phase 1
126.96.36.199 Adds/Exposes functional
(assists Phase 2)
3.4.2 Phase 2
188.8.131.52 Conjugation of
chemical into an
3.5.1 KIDNEYS -
3.5.2 G.I.T. - gut can
3.5.4 Rate of Elimination: BHT
- Biological Half-Time
Biological half time is independent of dose and is a useful indicator of the degree to which chemicals are retained in the body.
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.
3.6.1 1 Compartment
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.
3.6.2 2+ Compartments
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.
3.7 Threshold of
3.7.1 1.Largest constant [C] for
24hrs/day for lifetime
3.7.2 2.Largest constant [C] for
8hrs/day, 5d/wk for
3.7.3 3.Largest average [C]
for 8hrs/day, 5d/wk for
4.1 General Mechanisms
4.1.1 1. Interference with
184.108.40.206 Nerve signalling and endocrine system
functions involve the attachment of
transmitters or hormones to receptor sites.
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.
4.1.2 2. Binding to Important Structural
or Functional Biomolecules
220.127.116.11 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.
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.
4.1.3 3. Disturbance of Calcium
18.104.22.168 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.
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.
4.1.4 4. Targeted Toxicity
22.214.171.124 Some chemicals target specific groups of cells.
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.
4.1.5 5. Carcinogenesis
126.96.36.199 If DNA adductions are not repaired then mutation
may result from DNA replication during cell
division, which can go on to develop into cancer.
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.
5 Interactions of Chemicals:
5.1 Toxico-Kinetic Interactions
5.1.1 Effects on UPTAKE
5.1.2 Effects on METABOLISM
5.1.3 Effects on BINDING
5.1.4 Effects on ELIMINATION
5.2 Toxico-Dynamic Interactions
5.2.1 Additive Effects - multiple
chemicals targeting one organ
5.2.2 Potentiation & Synergistic Effects - one chemical
increasing the severity/likelihood of adverse effects
5.2.3 Antagonistic Effects
5.2.4 Indifferent Effects - effect on dependent
of the most active chemical
5.2.5 The Nature of the Interaction
Depends on the Response Measured