2. WHAT IS TOXICOLOGY

1. What is toxicology?

The work is carried out in two phases: first by collecting data on the properties of chemicals, results of studies and accidental misuse of chemicals, second by predicting the effects of chemicals in different situations.

To make relevant predictions there must be information available on: 

• the substance and its chemical and physical properties 
• the biological system affected 
• the effects or response caused by the substance 
• the exposure (dose, time, situation) 

Large amounts of toxicological information are collected into data bases and data banks.

2. Exposure

2.1 Routes

For many substances the greatest effects and the most rapid responses occurs when the substance is inserted directly into the blood circulation. In toxicological animal experiments the routes of exposure may be: 

• Inhalation (breathing in) 
• Absorption (through the skin or eyes) 
• Ingestion, oral (eating, swallowing) 
• Transfer across the placenta to the unborn baby 
• Intravenous (injection into the vein) 
• Intramuscular (injection into the muscle) 
• Subcutaneous (injection under the skin) 
• Intraperitoneal (injection inside the membrane that lines the interior wall of the abdomen) 

2.2 LD50 and LC50

Classification may be based on the LD50 and LC50 values (see Annex 8A in 'Identification, Classification and Labelling of Chemicals' and 'Major Hazard Chemicals'). The assessment of the effects is tested in laboratories using animals, mainly rats, mice and rabbits.

The test substance or preparation may be applied to the animal orally, under the skin, by inhalation, into the abdomen or into the vein. LD50 and LC50 are the parameters used to quantify the results of different tests so that they may be compared.

LD50 is the abbreviation used for the dose which kills 50% of the test population.

LC50 is the abbreviation used for the exposure concentration of a toxic substance lethal to half of the test animals.

LD50 is expressed in milligrams per kilogram of body weight of the test animal (which must be mentioned).

LC50 is expressed in millilitres per kilogram of body weight of the test animal (which must be mentioned), exposed to the substance by inhalation during a specified period. The variation in the numerical values of LD50 and LC50 is wide.

The following list describes the variation in LD50 values measured in ingestion studies on the rat: 

________________________________________
Substance                  LD50 (mg/kg,
                           oral, rat)
________________________________________
Vitamin C                  11 900
Ethyl alcohol ('alcohol')  7 060
Citric acid                5 040
Sodium chloride (table     3 000
salt)
Ferrous sulphate           320
Dieldrin                   38
Parathion                  2
Dioxin (contaminant in     0.02
herbicide)
________________________________________

The assessment of how a human system would react is not straightforward estimation from the animal tests. However, the animal test gives an idea of the level of the toxic effects.

2.3 Limit values

There are different kinds of limit values. The TLVs (Threshold Limit Values) are published by the American Conference of Governmental Industrial Hygienists (ACGIH) and concern the airborne concentrations of hazardous substances. They set a limit concentration below which it is believed that nearly all workers can be repeatedly exposed day after day without adverse effect. The TLVs are regularly reviewed and corrected when new information becomes available. 

TLV-TWA (Threshold Limit Value - Time Weighted Average) is a time-weighted average concentration for an eight hour working day or 40 hours a week to which nearly all workers may be repeatedly exposed without adverse effect. 

TLV-STEL (Threshold Limit Value - Short Term Exposure Limit) is the concentration to which workers may be exposed for a short time (usually 15 minutes) without suffering from irritation, long-term or irreversible tissue damage or impairment likely to increase accidental injury, affect self-rescue or reduce work efficiency. Daily TLV-TWA values should not be exceeded. 

TLV-C (Threshold Limit Value - Ceiling) is a concentration that should not be exceeded at all during work exposure. 

3. What are the responses of a system when exposed to poisons?

3.1 Human body

Local/systemic toxicity

There are two main ways in which chemicals may exert their effects. Local effects occur at the area of the body which has been in contact with the chemical. Examples are injuries from acids or lung injuries from inhaled reactive gases. Systemic effects occur after the chemical has been absorbed and distributed from the entry point to other parts of the body. Most substances produce systemic effects, but some substances may cause both types of effects. An example is tetraethyl lead, which is a gasoline additive and produces skin effects at the contact site. It is absorbed and transported into the body causing typical effects on the central nervous system and on other organs.

Target organs

The degree of the toxic effect is not the same in all organs. Usually there are one or two organs which show the major toxic effect. These are referred as target organs of toxicity of the particular substance. The central nervous system is the target organ of toxicity most frequently involved in systemic effects. The blood circulation system, liver, kidneys, lungs and skin follow in frequency of systemic effects. Muscle and bones are the target organs for a few substances. The male and female reproduction systems are vulnerable to many substances. 

• Skin is the largest organ in the human body, 1.5-2 m² in area. It provides a protective cover to the body but can fail if the load is overwhelming. A number of substances can penetrate healthy intact skin and enter the blood circulation. Phenol is a substance that may even result in death after exposure and penetration through the skin. The vast majority of work-related skin diseases are contact eczemas, irritation and inflammation of the skin. This condition can be either a non-allergic or allergic reaction to exposure to chemical substances. Examples of common contact sensitizers are several colorants and dyes, metals such as nickel and its salts, chromium and cobalt salts and organomercuric compounds, monomers of a number of acrylates and methacrylates, rubber additives and pesticides. In practice chemical skin injury is also influenced by environmental conditions such as humidity and heat. 
• The lung is the major route through which toxic substances in the workplace enter the body. It is also the first organ to be affected by dusts, metal fumes, solvent vapours and corrosive gases. Allergic reactions may be caused by substances such as cotton dust, TDI (toluene diisocyanate, used in the manufacture of polyurethane plastics), and MIC (methylisocyanate, used in production of carbaryl insecticide). In a catastrophic chemical accident in Bhopal, India, in 1984, more than 2000 people died from exposure to MIC. Allergic reactions may result from exposure to bacteria or fungi: this is the case in allergies from handling stocked hay (`farmer's lung') or dried sugar cane. When dust particles of a certain size of some substances are inhaled the lungs are unable to remove them. They become embedded in the lung causing a condition called pneumoconiosis. Pneumoconiosis is mainly a problem for workers exposed to the dust of silica (quartz) and asbestos, and is the commonest non-malignant occupational lung disease throughout the world. Other substances, such as formaldehyde, sulphur dioxide, nitrogen oxides and acid mists may cause irritation and reduce the breathing capacity. 
• The nervous system, the `mystery of matter and mind', is sensitive to the hazardous effects of organic solvents. Some metals affect the nervous system, especially heavy metals such as lead, mercury and manganese. Organophosphate insecticides such as malathion and parathion interfere severely with information transmission (chemical neurotransmitter function) in the nervous system, leading to weakness, paralysis and sometimes death. 
• The blood circulation is a target for the adverse effects of solvents. Blood cells are mainly produced in the bone marrow. Benzene affects the bone marrow; the first sign is mutation in the blood cells called lymphocytes. To study mutation, lymphocytes are cultured in the laboratory to observe specific types of cellular changes. Lead, in the form of the metal or its compounds, is another classic example of a chemical that may cause blood problems. Lead in the blood may inhibit certain enzyme activities involved in the production of hemoglobin in red blood cells. Chronic lead poisoning may result in a reduced ability of the blood to distribute oxygen through the body, a condition known as anaemia. 
• The liver is the largest of the internal organs in the body and has several important functions. It is a purification plant which breaks down unwanted substances in the blood. The liver has a considerable reserve capacity; symptoms of liver disorder appear only in serious diseases. Solvents such as carbon tetrachloride, chloroform and vinyl chloride, as well as alcohol, are hazardous to the liver. 
• The kidneys are part of the body's urinary system. They have the task of excreting the waste products that the blood has transported from various organs of the body, of keeping the fluids in balance and of ensuring that they contain an adequate blend of various necessary salts. They also maintain the acidity of the blood at a constant level. Solvents may irritate and impair kidney function. The most hazardous to the kidneys is carbon tetrachloride. Turpentine in large quantities is also harmful to the kidneys: `painter's kidney' is a known condition related to occupational exposure. Other well-known kidney- damaging substances are lead and cadmium. 

An allergic reaction, or sensitization as it is also called, may appear after repeated contact to a substance. Once the sensitization has bee produced, even very low doses can provoke a reaction. The different allergies are numerous, varying from minor skin irritation to very severe or even fatal reactions.

The pattern of sensitization varies according to the species. In humans, the skin and the eyes are the most common areas of allergic response, whereas, for example, in the guinea pigs reactions are more common in the respiratory system.

Interactions

The effect of simultaneous exposure to two or more substances may differ from a simple additive effect (1+1=2). Organophosphate pesticides, such as dialiphos, naled and parathion, are examples of chemicals where the combined effect is the sum of the effects observed when the chemicals act individually.

The effect can be more than the sum of the individual effects of two chemicals (e.g., 1+1=4). An example of an increase in risk is with asbestos fibres and cigarette smoking. They act together: the risk of developing lung cancer after exposure to asbestos fibres is forty times greater for a smoker than for a non-smoker. Another pair of the chemicals where the combined risk is greater than a mere additive effect are the solvents, trichloroethylene and styrene.

The adverse effects of two substances may counteract one another (1+1=0). This effect is used to find an antidote to a poison.

In other cases, a substance may not cause harm on its own but may make the effect of another chemical much worse (0+1=3). For example, two commonly used solvents isopropanol and carbon tetrachloride have this kind of joint effect. Isopropanol, at concentrations which are not harmful to the liver, increases the liver damage caused by carbon tetrachloride.

In some cases, when the exposure to a substance is repeated the body may decrease its sensitivity to the substance, i.e. it increases its tolerance to it.

3.2 The environment

In the natural environment, large numbers of potentially toxic substances are present. In some cases, when the substance is on its own it would cause no harm but it may interact with other toxic substances or under specific conditions it may be concentrated or transformed to a more dangerous compound.

An example of an air pollution reaction is the production of photochemical smog. Chlorinated hydrocarbons such as DDT and dieldrin have similar chemical and biological effects. When present together they lead to more serious effects than when acting separately.

To assess the effects of toxic substances in the environment some indicators of ecotoxicity are used.

In laboratory, fish and insects called Daphnia (water-flea) are used to test acute toxic effects in the aquatic environment. Green algal species are also used in the assessment of water pollution.

ANNEX 1. Factors that may influence the human reproduction system and the effects
ANNEX 2. Substances able to produce occupational lung diseases
ANNEX 3. Route of absorption, distribution and excretion of potentially toxic substances
ANNEX 4. Pregnant woman at work

BIBLIOGRAPHY

CLAYTON G.D. and CLAYTON F.E., ed., Patty's Industrial Hygiene and Toxicology, 3rd Revised Ed., John Wiley & Sons Inc., USA 1978

East African Newsletter on Occupational Health and Safety, Supplement 2/ 1989, Institute of Occupational Health, Finland 1989

ILO, International Labour Organisation, Encyclopedia of Occupational Health and Safety, Vol I - III, Geneva 1983

IPCS, International Programme on Chemical Safety, Chemical Safety, Fundamentals of Applied Toxicology, Training Module No 1, Geneva 1992

IPCS, International Programme on Chemical Safety, How to use the IPCS Health and Safety Guides

KLAASSEN C.D., AMDUR M.O. and DOULL J., ed., Casarett and Doull's Toxicology, The Basic Science of Poisons, 3rd Ed., Macmillan Publishing Company, New York 1986

NIOSH, RTECS Database, CCINFO Disc, Canadian Centre for Occupational Health and Safety, Hamilton 1993

SAX N.I. and LEWIS R.J.Sr, Dangerous Properties of Industrial Materials, VII ed., Nostrand Reinhold Co., New York 1988

SEILER H.G. and SIGEL H., Handbook of Toxicity of Inorganic Compounds, Marcel Dekker, Inc., New York 1988 

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