Occupational exposure to hazardous chemicals in laboratories 1990 OSHA Laboratory Standard 29 CFR 1910.1450

The following description of a laboratory chemical hygiene plan corresponds with Section (e:1-4), Chemical hygiene plan-General, of the 1990 OSHA Laboratory Standard. This plan should be made readily available to employees and employee representatives.The chemical hygiene plan shall include each of the following elements and shall indicate specific measures that the employer will take to ensure laboratory employee protection:

1. Stand operating procedures relevant to safety and health considerations to be followed when laboratory work involves the use of hazardous chemicals;
2. Criteria that the employer will use to determine and implement control measures to reduce employee exposure to hazardous chemicals, including engineering controls, the use of personal protective equipment and hygiene practices; particular attention shall be given to the selection of control measures for chemicals that are known to be extremely hazardous;
3. A requirement that fume hoods and other protective equipment are functioning properly, and specific measures that shall be taken to ensure proper and adequate performance of such equipment;
4. Provisions for employee information and training as prescribed [elsewhere in this plan];
5. The circumstances under which a particular laboratory operation, procedure or activity shall require prior approval from the employer or the employer’s designee before implementation;
6. Provisions for medical consultation and medical examinations...;
7. Designation of personnel responsible for implementation of the chemical hygiene plan, including the assignment of a chemical hygiene officer and, if appropriate, establishment of a chemical hygiene committee; and
8. Provision for additional employee protection for work with particularly hazardous substances. These include “select carcinogens”, reproductive toxins and substances which have a high degree of acute toxicity. Specific consideration shall be given to the following provisions, which shall be included where appropriate:

 (a)     establishment of a designated area;

 (b)     use of containment devices such as fume hoods or glove boxes;

 (c)     procedures for safe removal of contaminated waste; and

 (d)     decontamination procedures. 

The employer shall review and evaluate the effectiveness of the chemical hygiene plan at least annually and update it as necessary.

Setting up a Safe and Healthy Laboratory

A laboratory can only be safe and hygienic if the work practices and procedures that are followed there are safe and hygienic. Such practices are fostered by first giving responsibility and authority for laboratory safety and chemical hygiene to a laboratory safety officer who, together with a safety committee of laboratory personnel, decides what tasks must be accomplished and assigns responsibility for carrying out each of them.

The safety committee’s specific tasks include conducting periodic laboratory inspections and summarizing the results in a report submitted to the laboratory safety officer. These inspections are properly done with a checklist. Another important aspect of safety management is periodic inspections of safety equipment to ensure that all equipment is in good working order and in designated locations. Before this can be done, an annual inventory of all the safety equipment must be made; this includes a brief description, including size or capacity and manufacturer. Of no less importance is a semiannual inventory of all laboratory chemicals, including proprietary products. These should be classified into groups of chemically similar substances and also classified according to their fire hazard. Another essential safety classification depends on the degree of hazard associated with a substance, since the treatment a substance receives is directly related to the harm it can cause and the ease with which the harm is unleashed. Each chemical is put into one of three hazard classes chosen on the basis of grouping according to the order of magnitude of risk involved; they are:

1. ordinary hazard substances
2. high-hazard substances
3. extremely hazardous materials.

Ordinary hazard substances are those that are relatively easily controlled, are familiar to laboratory personnel and present no unusual risk. This class ranges from innocuous substances such as sodium bicarbonate and sucrose to concentrated sulphuric acid, ethylene glycol and pentane.

High-hazard substances present much greater hazards than ordinary hazards. They require special handling or, sometimes, monitoring, and present high fire or explosion hazards or severe health risks. In this group are chemicals that form unstable explosive compounds on standing (e.g., hydroperoxides formed by ethers) or substances that have high acute toxicities (e.g., sodium fluoride, which has an oral toxicity of 57 mg/kg in mice), or that have chronic toxicities such as carcinogens, mutagens or teratogens. Substances in this group often have the same kind of hazard as those in the group that follows. The difference is one of degree—those in group 3, the extremely hazardous materials, have either a greater intensity of hazard, or their order of magnitude is much greater, or the dire effects can be released far more easily.

Extremely hazardous materials, when not handled correctly, can very readily cause a serious accident resulting in severe injury, loss of life or extensive property damage. Extreme caution must be exercised in dealing with these substances. Examples of this class are nickel tetracarbonyl (a volatile, extremely poisonous liquid, the vapours of which have been lethal in concentrations as low as 1 ppm) and triethylaluminium (a liquid that spontaneously ignites on exposure to air and reacts explosively with water).

One of the most important of the safety committee’s tasks is to write a comprehensive document for the laboratory, a laboratory safety and chemical hygiene plan, that fully describes its safety policy and standard procedures for carrying out laboratory operations and fulfilling regulatory obligations; these include guidelines for working with substances that may fall into any of the three hazard categories, inspecting safety equipment, responding to a chemical spill, chemical waste policy, standards for laboratory air quality and any recordkeeping required by regulatory standards. The laboratory safety and chemical hygiene plan must be kept in the laboratory or must be otherwise easily accessible to its workers. Other sources of printed information include: chemical information sheets (also called material safety data sheets, MSDSs), a laboratory safety manual, toxicological information and fire hazard information. The inventory of laboratory chemicals and three associated derivative lists (classification of chemicals according to chemical class, fire safety class and the three degrees of hazard) must also be kept with these data.

A file system for records of safety-related activities is also required. It is not necessary that this file either be in the laboratory or be immediately accessible to laboratory workers. The records are mainly for the use of laboratory personnel who oversee laboratory safety and chemical hygiene and for the perusal of regulatory agency inspectors. It should thus be easily available and kept up to date. It is advisable that the file be kept outside the laboratory in order to reduce the possibility of its destruction in the event of a fire. The documents on file should include: records of laboratory inspections by the safety committee, records of inspections by any local regulatory agencies including fire departments and state and federal agencies, records dealing with hazardous waste disposal, records of taxes levied on various classes of hazardous waste, where applicable, a second copy of the inventory of laboratory chemicals, and copies of other pertinent documents dealing with the facility and its personnel (e.g., records of attendance of personnel at annual laboratory safety sessions).

Causes of Illness and Injury in the Laboratory

Measures for the prevention of personal injury, illness and anxiety are an integral part of the plans for the day-to-day operation of a well-run laboratory. The people who are affected by unsafe and unhygienic conditions in a laboratory include not only those who work in that laboratory but also neighbouring personnel and those who provide mechanical and custodial services. Since personal injuries in laboratories stem largely from inappropriate contact between chemicals and people, inappropriate mixing of chemicals or inappropriate supply of energy to chemicals, protecting health entails preventing such undesirable interactions. This, in turn, means suitably confining chemicals, combining them properly and closely regulating the energy supplied to them. The main kinds of personal injury in the laboratory are poisoning, chemical burns and injury resulting from fires or explosions. Fires and explosions are a source of thermal burns, lacerations, concussions and other severe bodily harm.

Chemical attack on the body. Chemical attack takes place when poisons are absorbed into the body and interfere with its normal function through disturbance of metabolism or other mechanisms. Chemical burns, or the gross destruction of tissue, usually occur by contact with either strong acids or strong alkalis. Toxic materials that have entered the body by absorption through the skin, eyes or mucous membranes, by ingestion or by inhalation, can cause systemic poisoning, usually by being spread via the circulatory system.

Poisoning is of two general types—acute and chronic. Acute poisoning is characterized by ill effects appearing during or directly after a single exposure to a toxic substance. Chronic poisoning becomes evident only after the passage of time, which may take weeks, months, years or even decades. Chronic poisoning is said to occur when each of these conditions is met: the victim must have been subjected to multiple exposures over long periods of time and to metabolically significant amounts of a chronic poison.

Chemical burns, usually encountered when liquid corrosives are spilled or splashed on the skin or in the eyes, also occur when those tissues come in contact with corrosive solids, ranging in size from powdery dusts to fairly large crystals, or with corrosive liquids dispersed in the air as mists, or with such corrosive gases as hydrogen chloride. The bronchial tubes, lungs, tongue, throat and epiglottis can also be attacked by corrosive chemicals in either the gaseous, liquid or solid states. Toxic chemicals also, of course, may be introduced into the body in any of these three physical states, or in the form of dusts or mists.

Injury through fires or explosions. Both fires or explosions may produce thermal burns. Some of the injuries caused by explosions, however, are particularly characteristic of them; they are injuries engendered either by the concussive force of the detonation itself or by such of its effects as glass fragments hurled through the air, causing loss of fingers or limbs in the first case, or skin lacerations or loss of vision, in the second.

Laboratory injuries from other sources. A third class of injuries may be caused neither by chemical attack nor by combustion. Rather they are produced by a miscellany of all other sources—mechanical, electrical, high-energy light sources (ultraviolet and lasers), thermal burns from hot surfaces, sudden explosive shattering of screw-capped glass chemical containers from the unexpected build-up of high internal gas pressures and lacerations from the sharp, jagged edges of newly broken glass tubing. Among the most serious sources of injury of a mechanical origin are tall, high-pressure gas cylinders tipping over and falling to the floor. Such episodes can injure legs and feet; in addition, should the cylinder stem break during the fall, the gas cylinder, propelled by the rapid, massive, uncontrolled escape of gas, becomes a deadly, undirected missile, a potential source of greater, more widespread harm.

Injury Prevention

Safety sessions and information dissemination. Injury prevention, dependent on performance of laboratory operations in a safe and prudent manner, is, in turn, dependent on laboratory workers being trained in correct laboratory methodology. Although they have received some of this training in their undergraduate and graduate education, it must be supplemented and reinforced by periodic laboratory safety sessions. Such sessions, which should emphasize understanding the physical and biological bases of safe laboratory practice, will enable laboratory workers to reject questionable procedures easily and to select technically sound methods as a matter of course. The sessions should also acquaint laboratory personnel with the kinds of data needed to design safe procedures and with sources of such information.

Workers must also be provided with ready access, from their work stations, to pertinent safety and technical information. Such materials should include laboratory safety manuals, chemical information sheets and toxicological and fire hazard information.

Prevention of poisoning and chemical burns. Poisoning and chemical burns have a common feature—the same four sites of entry or attack: (1) skin, (2) eyes, (3) mouth to stomach to intestines and (4) nose to bronchial tubes to lungs. Prevention consists in making these sites inaccessible to poisonous or corrosive substances. This is done by placing one or more physical barriers between the person to be protected and the hazardous substance or by ensuring that the ambient laboratory air is not contaminated. Procedures that use these methods include working behind a safety shield or using a fume hood, or utilizing both methods. The use of a glove box, of course, of itself affords a twofold protection. Minimization of injury, should contamination of tissue occur, is accomplished by removing the toxic or corrosive contaminant as quickly and completely as possible.

Prevention of acute poisoning and chemical burns in contrast with the prevention of chronic poisoning. Although the basic approach of isolation of the hazardous substance from the person to be protected is the same in preventing acute poisoning, chemical burns and chronic poisoning, its application must be somewhat different in preventing chronic poisoning. Whereas acute poisoning and chemical burns may be likened to massive assault in warfare, chronic poisoning has the aspect of a siege. Usually produced by much lower concentrations, exerting their influence through multiple exposures over long periods of time, its effects surface gradually and insidiously through sustained and subtle action. Corrective action involves either first detecting a chemical capable of causing chronic poisoning before any physical symptoms appear, or recognizing one or more aspects of a laboratory worker’s discomfort as possibly being physical symptoms connected with chronic poisoning. Should chronic poisoning be suspected, medical attention must be sought promptly. When a chronic poison is found at a concentration exceeding the allowable level, or even approaching it, steps must be taken either to eliminate that substance or, at the very least, to reduce its concentration to a safe level. Protection against chronic poisoning often requires that protective equipment be used for all or much of the workday; however, for reasons of comfort, the use of a glove box or a self-contained breathing apparatus (SCBA) is not always feasible.

Protection against poisoning or chemical burns. Protection against contamination of the skin by a particular splashed corrosive liquid or scattered poisonous airborne solid is best done by the use of safety gloves and a laboratory apron made of a suitable natural or synthetic rubber or polymer. The term suitable here is taken to mean a material which is neither dissolved, swelled nor in any other way attacked by the substance against which it must afford protection, nor should it be permeable to the substance. The use of a safety shield on the laboratory bench interposed between apparatus in which chemicals are being heated, reacted or distilled and the experimenter is a further safeguard against chemical burns and poisoning via skin contamination. Since the speed with which a corrosive or a poison is washed from the skin is a critical factor in preventing or minimizing the damage these substances can inflict, a safety shower, conveniently located in the laboratory, is an indispensable piece of safety equipment.

The eyes are best protected from splashed liquids by safety goggles or face shields. Airborne contaminants, in addition to gases and vapours, include solids and liquids when they are present in a finely subdivided state as dusts or mists. These are most effectively kept out of the eyes by conducting operations in a fume hood or glove box, although goggles afford some protection against them. To afford additional protection while the hood is being used, goggles may be worn. The presence of easily accessible eyewash fountains in the laboratory will often eliminate, and certainly will, at least, reduce eye damage through contamination by splashed corrosives or poisons.

The mouth to stomach to intestines route is usually connected with poisoning rather than with attack by corrosives. When toxic materials are ingested, it usually happens unwittingly through the chemical contamination of foods or cosmetics. Sources of such contamination are food stored in refrigerators with chemicals, food and beverages consumed in the laboratory, or lipstick kept or applied in the laboratory. Prevention of this kind of poisoning is done by avoiding practices known to cause it; this is feasible only when refrigerators to be used exclusively for food, and dining space outside of the laboratory, are made available.

The nose to bronchial tubes to lungs route, or respiratory route, of poisoning and chemical burns deals exclusively with airborne substances, whether gases, vapours, dusts or mists. These airborne materials may be kept from the respiratory systems of people within and outside of the laboratory by the concurrent practices of: (1) confining operations that either use or produce them to the fume hood (2) adjusting the laboratory air supply so that the air is changed 10 to 12 times per hour and (3) keeping the laboratory air pressure negative with respect to that of the corridors and rooms around it. Fume- or dust-producing operations that involve very bulky pieces of apparatus or containers the size of a 218-l drum, which are too large to be enclosed by an ordinary fume hood, should be done in a walk-in hood. In general, respirators or SCBA should not be used for any laboratory operations other than those of an emergency nature.

Chronic mercury poisoning, produced by the inhalation of mercury vapours, is occasionally found in laboratories. It is encountered when a pool of mercury that has accumulated in a hidden location—under floorboards, in drawers or a closet—has been emitting vapours over a long enough period of time to affect the health of laboratory personnel. Good laboratory housekeeping will avert this problem. Should a hidden source of mercury be suspected, the laboratory air must be checked for mercury either by the use of a special detector designed for the purpose or by sending an air sample for analysis.

Preventing fires and explosions and extinguishing fires. The principal cause of laboratory fires is the accidental ignition of flammable liquids. Flammable liquid is defined, in the fire safety sense, as being a liquid having a flashpoint of less than 36.7 °C. Ignition sources known to have caused this kind of laboratory fire include open flames, hot surfaces, electric sparks from switches and motors found in such equipment as stirrers, household-type refrigerators and electric fans, and sparks produced by static electricity. When ignition of a flammable liquid occurs, it takes place, not in the liquid itself, but above it, in the mixture of its vapours with air (when the concentration of vapour falls between certain upper and lower limits).

Preventing laboratory fires is accomplished by confining the vapours of flammables completely within the containers in which the liquids are kept or the apparatus in which they are used. If it is not possible to contain these vapours completely, their rate of escape should be made as low as possible and a continuous vigorous flow of air should be supplied to sweep them away, so as to keep their concentration at any given time well below the lower critical concentration limit. This is done both when reactions involving a flammable liquid are run in a fume hood and when drums of flammables are stored in safety solvent cabinets vented to an exhaust.

A particularly unsafe practice is the storage of such flammables as ethanol in a household-type refrigerator. These refrigerators will not keep vapours of stored flammable liquids from the sparks of its switches, motors and relays. No containers of flammables must ever be put in this type of refrigerator. This is especially true of open vessels and trays containing flammable liquids. However, even flammables in screw-capped bottles, kept in this type of refrigerator, have caused explosions, presumably by vapours leaking through a faulty seal or by the bottles breaking. Flammable liquids that require refrigeration must be kept only in explosion-proof refrigerators.

A significant source of fires that occur when large quantities of flammables are poured or siphoned from one drum to another is sparks produced through the accumulation of electric charge produced by a moving fluid. Spark generation of this sort can be prevented by electrically grounding both drums.

Most chemical and solvent fires that occur in the laboratory and are of manageable size, may be extinguished with either a carbon dioxide or dry-chemical type fire extinguisher. One or more 4.5 kg extinguishers of either kind should be supplied to a laboratory, according to its size. Certain special types of fires require other kinds of extinguishing agents. Many metal fires are put out with sand or graphite. Burning metal hydrides require graphite or powdered limestone.

When clothing is set afire in the laboratory, the flames must be put out quickly to minimize the injury caused by thermal burns. A wall-mounted wrap-around fire blanket extinguishes such fires effectively. It may be used for unassisted smothering of flames by the person whose clothing is on fire. Safety showers may also be used to extinguish these fires.

There are limits to the total volumes of flammable liquids that may be safely kept in a particular laboratory. Such limits, generally written into local fire codes, vary and depend on the materials of construction of the laboratory and on whether it is equipped with an automatic fire-extinguishing system. They usually range from about 55 to 135 litres.

Natural gas is often available from numbers of valves located throughout a typical laboratory. These are the most common sources of gas leaks, along with the rubber tubes and burners leading from them. Such leaks, when not detected soon after their onset, have led to severe explosions. Gas detectors, designed to indicate the level of gas concentration in the air, may be used to locate the source of such leakage quickly.

Prevention of injury from miscellaneous sources. Harm from tall, high-pressure gas cylinders falling, among the most familiar in this group of accidents, is avoided easily by strapping or chaining these cylinders securely to a wall or laboratory bench and putting cylinder caps on all unused and empty cylinders.

Most of the injuries from jagged edges of broken glass tubing are sustained through breakage while the tubing is being put into corks or rubber stoppers. They are avoided by lubricating the tube with glycerol and protecting the hands with leather work gloves.

(a)     General laboratory ventilation. This system should: Provide a source of air for breathing and for input to local ventilation devices; it should not be relied on for protection from toxic substances released into the laboratory; ensure that laboratory air is continually replaced, preventing increase of air concentrations of toxic substances during the working day; direct air flow into the laboratory from non-laboratory areas and out to the exterior of the building.

(b)    Hoods. A laboratory hood with 2.5 linear feet (76 cm) of hood space per person should be provided for every 2 workers if they spend most of their time working with chemicals; each hood should have a continuous monitoring device to allow convenient confirmation of adequate hood performance before use. If this is not possible, work with substances of unknown toxicity should be avoided or other types of local ventilation devices should be provided.

(c)     Other local ventilation devices. Ventilated storage cabinets, canopy hoods, snorkels, etc. should be provided as needed. Each canopy hood and snorkel should have a separate exhaust duct.

(d)    Special ventilation areas. Exhaust air from glove boxes and isolation rooms should be passed through scrubbers or other treatment before release into the regular exhaust system. Cold rooms and warm rooms should have provisions for rapid escape and for escape in the event of electrical failure.

(e)     Modifications. Any alteration of the ventilation system should be made only if thorough testing indicates that worker protection from airborne toxic substances will continue to be adequate.

(f)     Performance. Rate: 4-12 room air changes/hour is normally adequate general ventilation if local exhaust systems such as hoods are used as the primary method of control.

(g)    Quality. General air flow should not be turbulent and should be relatively uniform throughout the laboratory, with no high velocity or static areas; airflow into and within the hood should not be excessively turbulent; hood face velocity should be adequate (typically 60-100 lf/min) (152-254 cm/min).

(h)     Evaluation. Quality and quantity of ventilation should be evaluated on installation, regularly monitored (at least every 3 months), and reevaluated whenever a change in local ventilation is made.

Incompatible Materials

Incompatible materials are a pair of substances that, on contact or mixing, produce either a harmful or potentially harmful effect. The two members of an incompatible pair may be either a pair of chemicals or a chemical and a material of construction such as wood or steel. The mixing or contact of two incompatible materials leads either to a chemical reaction or to a physical interaction that generates a large amount of energy. Specific harmful or potentially harmful effects of these combinations, which can ultimately lead to serious injury or damage to the health, include liberation of large amounts of heat, fires, explosions, production of a flammable gas or generation of a toxic gas. Since a fairly extensive variety of substances is usually found in laboratories, the occurrence of incompatibles in them is quite common and presents a threat to life and health if they are not handled correctly.

Incompatible materials are seldom mixed intentionally. Most often, their mixing is the result of a simultaneous accidental breaking of two adjacent containers. Sometimes it is the effect of leakage or dripping, or results from the mixing of gases or vapours from nearby bottles. Although in many cases in which a pair of incompatibles is mixed, the harmful effect is easily observed, in at least one instance, a not readily detectable chronic poison is formed. This occurs as the result of the reaction of formaldehyde gas from 37% formalin with hydrogen chloride that has escaped from concentrated hydrochloric acid to form the potent carcinogen bis(chloromethyl) ether. Other instances of not immediately detectable effects are the generation of odourless, flammable gases.

Keeping incompatibles from mixing through the simultaneous breaking of adjacent containers or through escape of vapours from nearby bottles is simple—the containers are moved far apart. The incompatible pair, however, must first be identified; not all such identifications are simple or obvious. To minimize the possibility of overlooking an incompatible pair, a compendium of incompatibles should be consulted and scanned occasionally to acquire an acquaintance with less familiar examples. Preventing a chemical from coming in contact with incompatible shelving material, through dripping or through a bottle breaking, is done by keeping the bottle in a glass tray of sufficient capacity to hold all of its contents.

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Adapted from 3rd edition, Encyclopaedia of Occupational Health and Safety

Gases in their compressed state, and particularly compressed air, are almost indispensable to modern industry, and are also used widely for medical purposes, for the manufacture of mineral waters, for underwater diving and in connection with motor vehicles.

For purposes of the present article, compressed gases and air are defined as being those with a gauge pressure exceeding 1.47 bar or as liquids having a vapour pressure exceeding 2.94 bar. Thus, consideration is not given to such cases as natural gas distribution, which is dealt with elsewhere in this Encyclopaedia.

Table 1 shows the gases commonly encountered in compressed cylinders.

Table 1. Gases often found in compressed form

*These gases are flammable.

All the above gases present either an irritant, asphyxiant or highly toxic respiratory hazard and may also be flammable and an explosive when compressed. Most countries provide for a standard colour-coding system whereby different coloured bands or labels are applied to the gas cylinders to indicate the type of hazard to be expected. Particularly toxic gases, such as hydrogen cyanide, are also given special markings.

All compressed gas containers are so constructed that they are safe for the purposes for which they are intended when first put into service. However, serious accidents may result from their misuse, abuse or mishandling, and the greatest care should be exercised in the handling, transport, storage and even in the disposal of such cylinders or containers.

Characteristics and Production

Depending on the characteristics of the gas, it may be introduced into the container or cylinder in liquid form or simply as a gas under high pressure. In order to liquefy a gas, it is necessary to cool it to below its critical temperature and to subject it to an appropriate pressure. The lower the temperature is reduced below the critical temperature, the less the pressure required.

Certain of the gases listed in table 1 have properties against which precautions must be taken. For example, acetylene can react dangerously with copper and should not be in contact with alloys containing more than 66% of this metal. It is usually delivered in steel containers at about 14.7 to 16.8 bar. Another gas that has a highly corrosive action on copper is ammonia, which must also be kept out of contact with this metal, use being made of steel cylinders and authorized alloys. In the case of chlorine, no reaction takes place with copper or steel except in the presence of water, and for this reason all storage vessels or other containers must be kept free from contact with moisture at all times. Fluorine gas, on the other hand, although reacting readily with most metals, will tend to form a protective coating, as, for example, in the case of copper, where a layer of copper fluoride over the metal protects it from further attack by the gas.

Among the gases listed, carbon dioxide is one of the most readily liquefied, this taking place at a temperature of 15 °C and a pressure of about 14.7 bar. It has many commercial applications and may be kept in steel cylinders.

The hydrocarbon gases, of which liquefied petroleum gas (LPG) is a mixture formed mainly of butane (about 62%) and propane (about 36%), are not corrosive and are generally delivered in steel cylinders or other containers at pressures of up to 14.7 to 19.6 bar. Methane is another highly flammable gas that is also generally delivered in steel cylinders at a pressure of 14.7 to 19.6 bar.

Hazards

Storage and transport

When a filling, storage and dispatch depot is being selected, consideration must be given to the safety of both the site and the environment. Pump rooms, filling machinery and so on must be located in fire-resistant buildings with roofs of light construction. Doors and other closures should open outwards from the building. The premises should be adequately ventilated, and a system of lighting with flameproof electrical switches should be installed. Measures should be taken to ensure free movement in the premises for filling, checking and dispatch purposes, and safety exits should be provided.

Compressed gases may be stored in the open only if they are adequately protected from the weather and direct sunlight. Storage areas should be located at a safe distance from occupied premises and neighbouring dwellings.

During the transport and distribution of containers, care must be taken to ensure that valves and connections are not damaged. Adequate precautions should be taken to prevent cylinders from falling off the vehicle and from being subjected to rough usage, excessive shocks or local stress, and to prevent excessive movement of liquids in large tanks. Every vehicle should be equipped with a fire extinguisher and an electrically conductive strip for earthing static electricity, and should be clearly marked “Flammable liquids”. Exhaust pipes should have a flame-control device, and engines should be halted during loading and unloading. The maximum speed of these vehicles should be rigorously limited.

Use

The main dangers in the use of compressed gases arise from their pressure and from their toxic and/or flammable properties. The principal precautions are to ensure that equipment is used only with those gases for which it was designed, and that no compressed gases are used for any purpose other than that for which their use has been authorized.

All hoses and other equipment should be of good quality and should be examined frequently. The use of non-return valves should be enforced wherever necessary. All hose connections should be in good condition and no joints should be made by forcing together threads that do not exactly correspond. In the case of acetylene and combustible gases, a red hose should be used; for oxygen the hose should be black. It is recommended that for all flammable gases, the connection-screw thread shall be left-handed, and for all other gases, it shall be right-handed. Hoses should never be interchanged.

Oxygen and some anaesthetic gases are often transported in large cylinders. The transfer of these compressed gases to small cylinders is a hazardous operation, which should be done under competent supervision, making use of the correct equipment in a correct installation.

Compressed air is widely used in many branches of industry, and care should be taken in the installation of pipelines and their protection from damage. Hoses and fittings should be maintained in good condition and subjected to regular examinations. The application of a compressed air hose or jet to an open cut or wound through which air can enter the tissues or the bloodstream is particularly dangerous; precautions should also be taken against all forms of irresponsible behaviour which could result in a compressed air jet coming in contact with any openings in the body (the result of which can be fatal). A further hazard exists when compressed air jets are used to clean machined components or workplaces: flying particles have been known to cause injury or blindness, and precautions against such dangers should be enforced.

Labelling and marking

4.1.1.  The competent authority, or a body approved or recognized by the competent authority, should establish requirements for the marking and labelling of chemicals to enable persons handling or using chemicals to recognize and distinguish between them, both when receiving and when using them, so that they may be used safely (see paragraph 2.1.8 (criteria and requirements)). Existing criteria for marking and labelling established by other competent authorities may be followed where they are consistent with the provisions of this paragraph and are encouraged where this may assist uniformity of approach. 

4.1.2.  Suppliers of chemicals should ensure that chemicals are marked and hazardous chemicals are labelled, and that revised labels are prepared and provided to employers whenever new relevant safety and health information becomes available (see paragraphs 2.4.1 (suppliers’ responsibilities) and 2.4.2 (classification)). 

4.1.3.  Employers receiving chemicals that have not been labelled or marked should not use them until the relevant information is obtained from the supplier or from other reasonably available sources. Information should be obtained primarily from the supplier but may be obtained from other sources listed in paragraph 3.3.1 (sources of information), with a view to marking and labelling in accordance with the requirements of the national competent authority, prior to use. ...

4.3.2.   The purpose of the label is to give essential information on:

1. (a) the classification of the chemical;
2. (b) its hazards;
3. (c) the precautions to be observed.

The information should refer to both acute and chronic exposure hazards.

4.3.3.     Labelling requirements, which should be in conformity with national requirements, should cover:

(a) the information to be given on the label, including as appropriate:

1. trade names;
2. identity of the chemical;
3. name, address and telephone number of the supplier;
4. hazard symbols;
5. nature of the special risks associated with the use of the chemical;
6. safety precautions;
7. identification of the batch;
8. the statement that a chemical safety data sheet giving additional information is available from the employer;
9. the classification assigned under the system established by the competent authority;

(b)     the legibility, durability and size of the label;

(c)     the uniformity of labels and symbols, including colours.

Source: ILO 1993, Chapter 4.

Labelling and marking should be in accordance with standard practice in the country or region in question. The use of one gas for another by mistake, or the filling of a container with a gas different from that which it previously contained, without the necessary cleaning and decontamination procedures, may cause serious accidents. Colour marking is the best method of avoiding such errors, painting specific areas of containers or piping systems in accordance with the colour code stipulated in national standards or recommended by the national safety organization.

Gas Cylinders

For convenience in handling, transportation and storage, gases are commonly compressed in metal gas cylinders at pressures that range from a few atmospheres overpressure to 200 bar or even more. Alloy steel is the material most commonly used for the cylinders, but aluminium is also widely used for many purposes—for example, for fire extinguishers.

The hazards met with in handling and using compressed gases are:

• normal hazards entailed in handling heavy objects
• hazards connected with pressure (i.e., the amount of stored energy in the gases)
• hazards from the special properties of the gas content, which may be flammable, poisonous, oxidizing and so on.

Cylinder manufacture. Steel cylinders may be seamless or welded. The seamless cylinders are made from high-quality alloy steels and carefully heat-treated in order to obtain the desired combination of strength and toughness for high-pressure service. They may be forged and hot-drawn from steel billets or hot-formed from seamless tubes. Welded cylinders are made from sheet material. The pressed top and bottom parts are welded to a cylindrical seamless or welded tube section and heat-treated to relieve material stresses. Welded cylinders are extensively used in low-pressure service for liquefiable gases and for dissolved gases such as acetylene.

Aluminium cylinders are extruded in large presses from special alloys that are heat-treated to give the desired strength.

Gas cylinders must be designed, produced and tested according to strict norms or standards. Every batch of cylinders should be checked for material quality and heat treatment, and a certain number of cylinders tested for mechanical strength. Inspection is often aided by sophisticated instruments, but in all cases the cylinders should be inspected and hydraulically tested to a given test pressure by an approved inspector. Identification data and the inspector’s mark should be permanently stamped on the cylinder neck or another suitable place.

Periodic inspection. Gas cylinders in use may be affected by rough treatment, corrosion from inside and outside, fire and so on. National or international codes therefore require that they shall not be filled unless they are inspected and tested at certain intervals, which mostly range between two and ten years, depending on the service. Internal and external visual inspection together with a hydraulic pressure test is the basis for the approval of the cylinder for a new period in a given service. The test date (month and year) is stamped on the cylinder.

Disposal. A large number of cylinders are scrapped every year for various reasons. It is equally important that these cylinders be disposed of in such a way that they will not find their way back into use through uncontrolled channels. The cylinders should therefore be made completely unserviceable by cutting, crushing or a similar safe procedure.

Valves. The valve and any safety attachment must be regarded as a part of the cylinder, which must be kept in good working condition. Neck and outlet threads should be intact, and the valve should close tight without the use of undue force. Shut-off valves are often equipped with a pressure-relief device. This may be in the form of a resetting safety valve, bursting disc, fuse plug (melt plug) or a combination of bursting disc and fuse plug. The practice varies from country to country, but cylinders for low-pressure liquefied gases are always equipped with safety valves connected to the gas phase.

Hazards

Different transport codes classify gases as compressed, liquefied or dissolved under pressure. For the purpose of this article, it is useful to use the type of hazard as a classification.

High pressure. If cylinders or equipment burst, damage and injuries may be caused by flying debris or by the gas pressure. The more a gas is compressed, the higher is the stored energy. This hazard is always present with compressed gases and will increase with temperature if the cylinders are heated. Hence:

• Mechanical damage to the cylinder (dents, cuts and so on) should be avoided.
• Cylinders should be stored away from heat and not in direct sun.
• Cylinders should be removed from fires.
• Cylinders should only be connected to equipment suitable for the intended use.
• The cylinder valve should be protected with the cap during transport.
• Cylinders should be secured in use against falling, which may knock off the valve.
• Tampering with safety devices should be avoided.
• Cylinders should be handled with care to avoid mechanical shocks in very cold climates, since steel may become brittle at low temperature.
• Corrosion, which reduces the strength of the shell, should be avoided.

Low temperature. Most liquefied gases will evaporate rapidly under atmospheric pressure, and may reach very low temperatures. A person whose skin is exposed to such liquid may sustain injuries in the form of “cold burns”. (Liquid CO₂ will form snow particles when expanded.) Correct protective equipment (e.g., gloves, goggles) should therefore be used.

Oxidation. The hazard of oxidation is most evident with oxygen, which is one of the most important compressed gases. Oxygen will not burn on its own, but is necessary for combustion. Normal air contains 21% oxygen by volume.

All combustible materials will ignite more easily and burn more vigorously when the oxygen concentration is increased. This is noticeable with even a slight increase in oxygen concentration, and utmost care must be taken to avoid oxygen enrichment in the working atmosphere. In confined spaces small oxygen leaks may lead to dangerous enrichment.

The danger with oxygen increases with increasing pressure to the point where many metals will burn vigorously. Finely divided materials may burn in oxygen with explosive force. Clothing that is saturated with oxygen will burn very rapidly and be difficult to extinguish.

Oil and grease have always been regarded as dangerous in combination with oxygen. The reason is that they react readily with oxygen, their existence is common, the ignition temperature is low and the developed heat may start a fire in the underlying metal. In high-pressure oxygen equipment the necessary ignition temperature may easily be reached by the compression shock that may result from rapid valve opening (adiabatic compression).

Therefore:

• Valves should be operated slowly.
• All oxygen equipment should be kept clean and free from oil and dirt.
• Only materials that are proven to be safe with oxygen should be used.
• Workers should refrain from lubricating oxygen equipment.
• Entering confined spaces where oxygen may exist in higher concentration should be avoided.
• The atmosphere should be checked and the use of oxygen instead of compressed air or some other gas should be strictly avoided.

Flammability. The flammable gases have flashpoints below room temperature and will form explosive mixtures with air (or oxygen) within certain limits known as the lower and upper explosion limits.

Escaping gas (also from safety valves) may ignite and burn with a shorter or longer flame depending on the pressure and amount of gas. The flames may again heat nearby equipment, which may burn, melt or explode. Hydrogen burns with an almost invisible flame.

Even small leaks may cause explosive mixtures in confined spaces. Some gases, such as liquefied petroleum gases, mostly propane and butane, are heavier than air and are difficult to vent away, as they will concentrate in the lower parts of buildings and “float” through channels from one room to another. Sooner or later, the gas may reach an ignition source and explode.

Ignition may be caused by hot sources, but also by electrical sparks, even very small ones.

Acetylene takes a special place among the combustible gases because of its properties and wide use. If heated, the gas may start to decompose with the development of heat even without the presence of air. If allowed to proceed, this may lead to cylinder explosion.

Acetylene cylinders are, for safety reasons, filled with a highly porous mass which also contains a solvent for the gas. Outside heating from a fire or welding torch, or in certain cases internal ignition by strong backfires from welding equipment, may start a decomposition within the cylinder. In such cases:

• The valve should be closed (using protective gloves if necessary) and the cylinder should be removed from fire.
• If part of the cylinder becomes hotter, it should be put into a river, canal or the like to cool down or cooled with water sprays.
• If the cylinder is too hot to be handled, it should be sprayed with water from a safe distance.
• Cooling should continue until the cylinder stays cool by itself.
• The valve should be kept closed, because gas flow will accelerate decomposition.

Acetylene cylinders in several countries are equipped with fuse (melting) plugs. These will release the gas pressure when they melt (usually at about 100 °C) and prevent cylinder explosion. At the same time there is a risk that the released gas may ignite and explode.

Common precautions to observe in respect of combustible gases are as follows:

• Cylinders should be stored separately from other gases in a well ventilated area above ground level.
• Leaking cylinders or equipment should not be used.
• Liquid gas cylinders should be stored and used in an upright position. Larger quantities of gas will come out if liquid is expelled through the safety valves instead of gas. The pressure will be reduced more slowly. Very long flame will result if the gas ignites.
• In case of leaks, any possible ignition source should be avoided.
• Smoking where flammable gases are stored or used should be prohibited.
• The safest way of extinguishing a fire is usually to stop the supply of gas. Merely extinguishing the flame may cause the formation of an explosive cloud, which may re-ignite in contact with a hot object.

Toxicity. Certain gases, if not the most common, may be toxic. At the same time, they may be irritating or corrosive to the skin or eyes.

Persons who handle these gases should be well trained and aware of the danger involved and the necessary precautions. The cylinders should be stored in a well ventilated area. No leaks should be tolerated. Suitable protective equipment (gas masks or breathing equipment) should be used.

Inert gases. Gases such as argon, carbon dioxide, helium and nitrogen are widely used as protective atmospheres to prevent unwanted reactions in welding, chemical plants, steel works and so on. These gases are not labelled as being hazardous, and serious accidents may happen because only oxygen can support life.

When any gas or gas mixture displaces the air so that the breathing atmosphere becomes deficient in oxygen, there is a danger of asphyxiation. Unconsciousness or death may result very rapidly when there is little or no oxygen, and there is no warning effect.

Confined spaces where the breathing atmosphere is deficient in oxygen must be ventilated before entering. When breathing equipment is used, the person entering must be supervised. Breathing equipment must be used even in rescuing operations. Normal gas masks give no protection against oxygen deficiency. The same precaution must be observed with large, permanent firefighting installations, which are often automatic, and those who may be present in such areas should be warned of the danger.

Cylinder filling. Cylinder filling involves the operation of high-pressure compressors or liquid pumps. The pumps may operate with cryogenic (very low-temperature) liquids. The filling stations may also incorporate large storage tanks of liquid gases in a pressurized and/or deeply refrigerated state.

The gas filler should check that the cylinders are in acceptable condition for filling, and should fill the correct gas in not more than the approved amount or pressure. The filling equipment should be designed and tested for the given pressure and type of gas, and protected by safety valves. Cleanliness and material requirements for oxygen service must be observed strictly. When filling flammable or toxic gases, special attention should be given to the safety of the operators. The primary requirement is good ventilation combined with correct equipment and technique.

Cylinders which are contaminated with other gases or liquids by the customers constitute a special hazard. Cylinders with no residual pressure may be purged or evacuated before filling. Special care should be taken to ensure that medical gas cylinders are free from any harmful matter.

Transport. Local transport tends to become more mechanized through the use of fork-lift trucks and so on. Cylinders should be transported only with the caps on and secured against falling from the vehicles. Cylinders must not be dropped from trucks directly onto the ground. For hoisting with cranes, suitable lifting cradles should be used. Magnetic lifting devices or caps with uncertain threads should not be used for lifting cylinders.

When cylinders are manifolded into larger packages, great care should be taken to avoid strain on the connections. Any hazard will be increased because of the greater amount of gas involved. It is good practice to divide larger units into sections and to place shut-off valves where they can be operated in any emergency.

The most frequently occurring accidents in cylinder handling and transport are injuries caused by the hard, heavy and difficult-to-handle cylinders. Safety shoes should be worn. Trolleys should be provided for longer transport of single cylinders.

In international transport codes, compressed gases are classified as dangerous goods. These codes give details about which gases may be transported, cylinder requirements, allowed pressure, marking and so on.

Identification of content. The most important requirement for safe handling of compressed gases is the correct identification of the gas content. Stamping, labelling, stencilling and colour marking are the means that are used for this purpose. Certain requirements for marking are covered in International Organization for Standardization (ISO) standards. The colour marking of medical gas cylinders follows the ISO standards in most countries. Standardized colours are also used in many countries for other gases, but this is not a sufficient identification. In the end only the written word can be regarded as a proof of the cylinder content.

Standardized valve outlets. The use of a standardized valve outlet for a certain gas or group of gases strongly reduces the chance of connecting cylinders and equipment made for different gases. Adapters should therefore not be used, as this sets aside the safety measures. Only normal tools and no excessive force should be used when making connections.

Safe Practice for Users

The safe use of compressed gases entails applying the safety principles outlined in this chapter and the ILO Code of Practice Safety in the Use of Chemicals at Work (ILO 1993). This is not possible unless the user has some basic knowledge of the gas and the equipment that he or she is handling. In addition the user should take the following precautions:

• Gas cylinders should only be used for the purpose for which they are intended and not as rollers or work supports.
• The cylinders should be stored and handled in such a way that their mechanical strength is not reduced (e.g., by severe corrosion, sharp dents, cuts and so on).
• The cylinders should be removed from fires or excessive heat.
• Only the necessary number of gas cylinders should be kept in working areas or occupied buildings. It is preferable for them to be kept near doors and not in emergency escape routes or difficult-to-reach areas.
• Any cylinders that have been exposed to fires should be clearly marked and returned to the filler (owner), since the cylinders may have become brittle or lost their strength.
• Cylinders should be stored in a well-ventilated place, away from rain or snow and any combustible storage.
• Cylinders in use should be secured against falling.
• Gas content should be positively identified before use.
• Labels and instructions should be carefully read.
• Cylinders should only be connected to equipment meant for the particular service.
• Connections should be kept clean and in good order; their condition should be checked at regular intervals.
• Good tools (e.g., normal length, fixed wrenches) should be used.
• Loose valve keys should be left in place when the cylinder is in use.
• Valves should be kept closed when cylinders are not in use.
• Cylinders or connected equipment should be removed from confined spaces when not in use (even during short breaks).
• The atmosphere should be checked for oxygen content and, if possible, for flammable gases before confined spaces are entered and during prolonged working periods.
• It should be kept in mind that heavy gases may concentrate in lower areas and that they may be difficult to remove by ventilation.
• Cylinders should be protected against contamination from pressurized equipment, since backflow of other gases may lead to serious accidents. Proper non-return valves, block-and-bleed arrangements and the like should be used.
• Empty cylinders should be returned to the filler with the valves closed and the caps in place. A little residual pressure should always be left in the cylinder to prevent contamination with air and moisture.
• The filler should be notified of any faulty cylinders.
• Acetylene should only be used at a correctly reduced pressure.
• Flame arrestors should only be used in acetylene lines where acetylene is used with compressed air or oxygen.
• Fire extinguishers and heat-protecting gloves should be available with gas welding equipment.
• Liquid gas cylinders should be stored and used in an upright position.
• Poisonous and irritating gases, such as chlorine, should be handled only by well-informed operators with personal safety equipment.
• Unidentified cylinders should not be kept in stock. Fixed installations, with the gas cylinders connected in separate gas centrals, are safest where gases are used regularly.

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Adapted from 3rd edition, Encyclopaedia of Occupational Health and Safety

Before a new hazardous substance is received for storage, information concerning its correct handling should be provided to all users. Planning and maintaining of storage areas are necessary to avoid material losses, accidents and disasters. Good housekeeping is essential, and special attention should be paid to incompatible substances, suitable location of products and climatic conditions.

Written instructions of storage practices should be provided, and the chemicals’ material safety data sheets (MSDSs) should be available in storage areas. Locations of the different classes of chemicals should be illustrated in a storage map and in a chemical register. The register should contain the maximum allowed quantity of all chemical products and the maximum allowed quantity of all chemical products per class. All substances should be received at a central location for distribution to the storerooms, stockrooms and laboratories. A central receiving area is also helpful in monitoring substances that may eventually enter the waste-disposal system. An inventory of substances contained in the storerooms and stockrooms will give an indication of the quantity and nature of substances targeted for future disposal.

Stored chemicals should be examined periodically, at least annually. Chemicals with expired shelf lives and deteriorated or leaking containers should be disposed of safely. A “first in, first out” system of keeping stock should be used.

The storage of dangerous substances should be supervised by a competent, trained person. All workers required to enter storage areas should be fully trained in appropriate safe work practices, and a periodic inspection of all storage areas should be carried out by a safety officer. A fire alarm should be situated in or near the outside of the storage premises. It is recommended that persons should not work alone in a storage area containing toxic substances. Chemical storage areas should be located away from process areas, occupied buildings and other storage areas. In addition, they should not be in proximity of fixed sources of ignition.

Labelling and Relabelling Requirements

The label is the key to organizing chemical products for storage. Tanks and containers should be identified with signs indicating the name of the chemical product. No containers or cylinders of compressed gases should be accepted without the following identifying labels:

• identification of contents
• description of principal hazard (e.g., flammable liquid)
• precautions to minimize hazards and prevent accidents
• correct first aid procedures
• correct procedures for cleaning up spills
• special instructions to medical personnel in case of an accident.

The label may also offer precautions for correct storage, such as “Keep in a cool place” or “Keep container dry”. When certain dangerous products are delivered in tankers, barrels or bags and repackaged at the workplace, each new container should be relabelled so that the user will be able to identify the chemical and recognize the risks immediately.

Explosive Substances

Explosive substances include all chemicals, pyrotechnics and matches which are explosives per se and also those substances such as sensitive metallic salts which, by themselves or in certain mixtures or when subject to certain conditions of temperature, shock, friction or chemical action, may transform and undergo an explosive reaction. In the case of explosives, most countries have stringent regulations regarding safe storage requirements and precautions to be taken in order to prevent theft for use in criminal activities.

The storage places should be situated far away from other buildings and structures so as to minimize damage in case of an explosion. Manufacturers of explosives issue instructions as to the most suitable type of storage. The storerooms should be of solid construction and kept securely locked when not in use. No store should be near a building containing oil, grease, waste combustible material or flammable material, open fire or flame.

In some countries there is a legal requirement that magazines should be situated at least 60 m from any power plant, tunnel, mine shaft, dam, highway or building. Advantage should be taken of any protection offered by natural features such as hills, hollows, dense woods or forests. Artificial barriers of earth or stone walls are sometimes placed around such storage places.

The storage place should be well ventilated and free from dampness. Natural lighting or portable electric lamps should be used, or lighting provided from outside the storehouse. Floors should be constructed of wood or other non-sparking material. The area surrounding the storage place should be kept free of dry grass, rubbish or any other material likely to burn. Black powder and explosives should be stored in separate storehouses, and no detonators, tools or other materials should be kept in an explosive store. Non-ferrous tools should be used for opening cases of explosives.

Oxidizing Substances

Oxidizing substances provide sources of oxygen, and thus are capable of supporting combustion and intensifying the violence of any fire. Some of these oxygen suppliers give off oxygen at storage-room temperature, but others require the application of heat. If containers of oxidizing materials are damaged, the contents may mix with other combustible materials and start a fire. This risk can be avoided by storing oxidizing materials in a separate storage place. However, this practice may not always be available, as, for example, in dock warehouses for goods in transit.

It is dangerous to store powerful oxidizing substances near liquids that even have a low flash point or even slightly flammable materials. It is safer to keep all flammable materials away from a place where oxidizing substances are stored. The storage area should be cool, well ventilated and of fire-resisting construction.

Flammable Substances

A gas is deemed to be flammable if it burns in the presence of air or oxygen. Hydrogen, propane, butane, ethylene, acetylene, hydrogen sulphide and coal gas are among the most common flammable gases. Some gases such as hydrogen cyanide and cyanogen are both flammable and poisonous. Flammable materials should be stored in places which are cool enough to prevent accidental ignition if the vapours mix with the air.

Vapours of flammable solvents may be heavier than air and may move along the floor to a distant ignition source. Flammable vapours from spilled chemicals have been known to descend into stairwells and elevator shafts and ignite at a lower storey. It is therefore essential that smoking and open flames be prohibited where these solvents are handled or stored.

Portable, approved safety cans are the safest vessels for storing flammables. Quantities of flammable liquids greater than 1 litre should be stored in metal containers. Two-hundred-litre drums are commonly used to ship flammables, but are not intended as long-term storage containers. The stopper should be removed carefully and replaced by an approved pressure-relief vent to avoid increased internal pressure from heat, fire or exposure to sunlight. When transferring flammables from metal equipment, the worker should use an enclosed transfer system or have adequate exhaust ventilation.

The storage area should be situated away from any source of heat or fire hazard. Highly flammable substances should be kept apart from powerful oxidizing agents or from materials which are susceptible to spontaneous combustion. When highly volatile liquids are stored, any electric light fittings or apparatus should be of certified flameproof construction, and no open flames should be permitted in or near the storage place. Fire extinguishers and absorbent inert materials, such as dry sand and earth, should be available for emergency situations.

The walls, ceilings and floors of the storage room should consist of materials with at least a 2-hour fire resistance. The room should be fitted with self-closing fire doors. The storage-room installations should be electrically grounded and periodically inspected, or equipped with automatic smoke- or fire-detection devices. Control valves on storage vessels containing flammable liquids should be clearly labelled, and pipelines should be painted with distinctive safety colours to indicate the type of liquid and the direction of flow. Tanks containing flammable substances should be situated on ground sloping away from the main buildings and plant installations. If they are on level ground, protection against fire spread can be obtained by adequate spacing and the provision of dykes. The dyke capacity should preferably be 1.5 times that of the storage tank, as a flammable liquid may be likely to boil over. Provision should be made for venting facilities and flame arrestors on such storage tanks. Adequate fire extinguishers, either automatic or manual, should be available. No smoking should be allowed.

Toxic Substances

Toxic chemicals should be stored in cool, well ventilated areas out of contact with heat, acids, moisture and oxidizing substances. Volatile compounds should be stored in spark-free freezers (–20 °C) to avoid evaporation. Because containers may develop leaks, storerooms should be equipped with exhaust hoods or equivalent local ventilation devices. Open containers should be closed with tape or other sealant before being returned to the storeroom. Substances which can react chemically with each other should be kept in separate stores.

Corrosive Substances

Corrosive substances include strong acids, alkalis and other substances which will cause burns or irritation of the skin, mucous membranes or eyes, or which will damage most materials. Typical examples of these substances include hydrofluoric acid, hydrochloric acid, sulphuric acid, nitric acid, formic acid and perchloric acid. Such materials may cause damage to their containers and leak into the atmosphere of the storage area; some are volatile and others react violently with moisture, organic matter or other chemicals. Acid mists or fumes may corrode structural materials and equipment and have a toxic action on personnel. Such materials should be kept cool but well above their freezing point, since a substance such as acetic acid may freeze at a relatively high temperature, rupture its container and then escape when the temperature rises again above its freezing point.

Some corrosive substances also have other dangerous properties; for example, perchloric acid, in addition to being highly corrosive, is also a powerful oxidizing agent which can cause fire and explosions. Aqua regia has three dangerous properties: (1) it displays the corrosive properties of its two components, hydrochloric acid and nitric acid; (2) it is a very powerful oxidizing agent; and (3) application of only a small amount of heat will result in the formation of nitrosyl chloride, a highly toxic gas.

Storage areas for corrosive substances should be isolated from the rest of the plant or warehouses by impervious walls and floor, with provision for the safe disposal of spillage. The floors should be made of cinder blocks, concrete that has been treated to reduce its solubility, or other resistant material. The storage area should be well ventilated. No store should be used for the simultaneous storage of nitric acid mixtures and sulphuric acid mixtures. Sometimes it is necessary to store corrosive and poisonous liquids in special types of containers; for example, hydrofluoric acid should be kept in leaden, gutta percha or ceresin bottles. Since hydrofluoric acid interacts with glass, it should not be stored near glass or earthenware carboys containing other acids.

Carboys containing corrosive acids should be packed with kieselguhr (infusorial earth) or other effective inorganic insulating material. Any necessary first-aid equipment such as emergency showers and eyewash bottles should be provided in or immediately close to the storage place.

Water-reactive Chemicals

Some chemicals, such as sodium and potassium metals, react with water to produce heat and flammable or explosive gases. Certain polymerization catalysts, such as alkyl aluminium compounds, react and burn violently on contact with water. Storage facilities for water-reactive chemicals should not have water in the storage area. Non-water automatic sprinkler systems should be employed.

Legislation

Detailed legislation has been drawn up in many countries to regulate the manner in which various dangerous substances may be stored; this legislation includes the following specifications:

• type of building, its location, the maximum amounts of various substances that may be stored in one place
• type of ventilation required
• precautions to be taken against fire, explosion and the release of dangerous substances
• type of lighting (e.g., flameproof electrical equipment and light fixtures when explosive or flammable materials are stored)
• number and location of fire exits
• security measures against entry by unauthorized persons and against theft
• labelling and marking of storage vessels and pipelines
• warning notices to workers as to the precautions to be observed.

In many countries there is no central authority concerned with the supervision of the safety precautions for the storage of all dangerous substances, but a number of separate authorities exist. Examples include mine and factory inspectorates, dock authorities, transport authorities, police, fire services, national boards and local authorities, each of which deals with a limited range of dangerous substances under various legislative powers. It is usually necessary to obtain a licence or permit from one of these authorities for the storage of certain types of dangerous substances such as petroleum, explosives, cellulose and cellulose solutions. The licensure procedures require that storage facilities comply with specified safety standards.

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Hazard classification and labelling systems are included in legislation covering the safe production, transport, use and disposal of chemicals. These classifications are designed to provide a systematic and comprehensible transfer of health information. Only a small number of significant classification and labelling systems exist at the national, regional and international levels. Classification criteria and their definitions used in these systems vary in the number and degree of hazard scales, specific terminology and test methods, and the methodology for classifying mixtures of chemicals. The establishment of an international structure for harmonizing classification and labelling systems for chemicals would have a beneficial impact on chemical trade, on the exchange of information related to chemicals, on the cost of risk assessment and management of chemicals, and ultimately on the protection of workers, the general public and the environment.

The major basis for classification of chemicals is the assessment of exposure levels and environmental impact (water, air and soil). About half of the international systems contain criteria related to a chemical’s production volume or the effects of pollutant emissions. The most widespread criteria used in chemical classification are values of median lethal dose (LD₅₀) and median lethal concentration (LC₅₀). These values are evaluated in laboratory animals via three main pathways—oral, dermal and inhalation—with a one-time exposure. Values of LD₅₀ and LC₅₀ are evaluated in the same animal species and with the same exposure routes. The Republic of Korea considers LD₅₀ with intravenous and intracutaneous administration as well. In Switzerland and Yugoslavia chemical management legislation requires quantitative criteria for LD₅₀ with oral administration and adds a provision which specifies the possibility of different hazard classifications based on the route of exposure.

In addition, differences in the definitions of comparable hazard levels exist. While the European Community (EC) system utilizes a three-level acute toxicity scale (“very toxic”, “toxic” and “harmful”), the US Occupational Safety and Health Administration (OSHA) Hazard Communication Standard applies two acute toxicity levels (“highly toxic” and “toxic”). Most classifications apply either three categories (United Nations (UN), World Bank, International Maritime Organization (IMO), EC and others) or four (the former Council for Mutual Economic Assistance (CMEA), the Russian Federation, China, Mexico and Yugoslavia).

International Systems

The following discussion of existing chemical classification and labelling systems focuses primarily on major systems with long application experience. Hazard assessments of pesticides are not covered in general chemical classifications, but are included in the Food and Agricultural Organization/World Health Organization (FAO/WHO) classification as well as in various national legislation (e.g., Bangladesh, Bulgaria, China, the Republic of Korea, Poland, the Russian Federation, Sri Lanka, Venezuela and Zimbabwe).

Transport-oriented classifications

Transport classifications, which are broadly applied, serve as a basis for regulations governing labelling, packaging and transport of dangerous cargoes. Among these classifications are the UN Recommendations on the Transport of Dangerous Goods (UNRTDG), the International Maritime Dangerous Goods Code developed within the IMO, the classification established by the Group of Experts on the Scientific Aspects of Marine Pollution (GESAMP) for hazardous chemicals carried by ship, as well as national transport classifications. National classifications as a rule comply with UN, IMO and other classifications within international agreements on transportation of dangerous goods by air, rail, road and inland navigation, harmonized with the UN system.

The United Nations Recommendations on the Transport of Dangerous Goods and related transport modal authorities

The UNRTDG create a widely accepted global system which provides a framework for intermodal, international and regional transport regulations. These Recommendations are increasingly being adopted as the basis of national regulations for domestic transport. The UNRTDG is rather general on issues such as notification, identification and hazard communication. The scope has been restricted to the transport of hazardous substances in packaged form; the Recommendations do not apply to exposed hazardous chemicals or to transport in bulk. Originally the objective was to prevent dangerous goods from causing acute injury to workers or the general public, or damage to other goods or the means of transport employed (aircraft, vessel, railcar or road vehicle). The system has now been extended to include asbestos and substances hazardous to the environment.

The UNRTDG focus primarily on hazard communication based on labels which include a combination of graphic symbols, colours, warning words and classification codes. They also provide key data for emergency response teams. The UNRTDG are relevant for the protection of such transport workers as aircrew, mariners and the crews of trains and road vehicles. In many countries the Recommendations have been incorporated in legislation for the protection of dock workers. Parts of the system, such as the Recommendations on explosives, have been adapted to regional and national regulations for the workplace, generally including manufacturing and storage. Other UN organizations concerned with transport have adopted the UNRTDG. The transport classification systems of dangerous goods of Australia, Canada, India, Jordan, Kuwait, Malaysia and United Kingdom basically comply with the major principles of these Recommendations, for example.

The UN classification subdivides chemicals into nine classes of hazards:

• 1st class—explosive substances
• 2nd class—compressed, liquefied, dissolved under pressure or deeply condensed gases
• 3rd class—easily inflammable liquids
• 4th class—easily inflammable solid substances
• 5th class—oxidizing substances, organic peroxides
• 6th class—poisonous (toxic) and infectious substances
• 7th class—radioactive substances
• 8th class—corrosive agents
• 9th class—other dangerous substances.

The packaging of goods for the purpose of transport, an area specified by the UNRTDG, is not covered as comprehensively by other systems. In support of the Recommendations, organizations such as IMO and International Civil Aviation Organization (ICAO) carry out very significant programmes aimed at training dock workers and airport personnel in the recognition of label information and packaging standards.

The International Maritime Organization

The IMO, with a mandate from the 1960 Conference on Safety of Life at Sea (SOLAS 1960), has developed the International Maritime Dangerous Goods (IMDG) Code. This code supplements the mandatory requirements of chapter VII (Carriage of Dangerous Goods) of SOLAS 74 and those of Annex III of the Maritime Pollution Convention (MARPOL 73/78). The IMDG Code has been developed and kept up to date for more than 30 years in close cooperation with the UN Committee of Experts on Transport of Dangerous Goods (CETG) and has been implemented by 50 IMO members representing 85% of the world’s merchant tonnage.

Harmonization of the IMDG Code with the UNRTDG ensures compatibility with the national and international rules applicable to the transport of dangerous goods by other modes, in so far as these other modal rules are also based on the recommendations of the UNCETG—that is, ICAO Technical Instructions for the Safe Transport of Dangerous Goods by Air and the European Regulations concerning the international carriage of dangerous goods by road (ADR) and by rail (RID).

In 1991 the 17th IMO Assembly adopted a Resolution on the Coordination of Work in Matters Relating to Dangerous Goods and Hazardous Substances, urging, inter alia, UN bodies and governments to coordinate their work in order to ensure the compatibility of any legislation on chemicals, dangerous goods and hazardous substances with established international transport rules.

Basel Convention on the Control of Transboundary Movements of Hazardous Wastes and their Disposal, 1989

The Convention’s Annexes define 47 categories of wastes, including domestic wastes. Although the hazard classification parallels that of the UNRTDG, a significant difference includes the addition of three categories reflecting more specifically the nature of toxic wastes: chronic toxicity, liberation of toxic gases from interaction of wastes with air or water, and capacity of wastes to yield secondary toxic material after disposal.

Pesticides

National classification systems related to the hazard assessment of pesticides tend to be quite comprehensive because of the wide use of these chemicals and the potential long-term damage to the environment. These systems may identify from two to five hazard classifications. The criteria are based on median lethal doses with different routes of exposure. While Venezuela and Poland recognize only one route of exposure, ingestion, the WHO and various other countries identify both ingestion and skin application.

The criteria for hazard assessment of pesticides in East European countries, Cyprus, Zimbabwe, China and others are based on median lethal doses via inhalation. Bulgaria’s criteria, however, include skin and eye irritation, sensitization, accumulation ability, persistence in environmental media, blastogenic and teratogenic effects, embryotoxicity, acute toxicity and medical treatment. Many classifications of pesticides also include separate criteria based on median lethal doses with different aggregative states. For example, criteria for liquid pesticides are usually more severe than those for solid ones.

WHO Recommended Classification of Pesticides by Hazard

This Classification was first issued in 1975 by the WHO and updated subsequently on a regular basis by the United Nations Environment Programme, the ILO and the WHO (UNEP/ILO/WHO) International Programme on Chemical Safety (IPCS) with input from the Food and Agriculture Organization (FAO). It consists of one hazard category or classification criterion, acute toxicity, divided in four classification levels based on LD₅₀ (rat, oral and dermal values for liquid and solid forms) and ranging from extremely to slightly hazardous. Apart from general considerations, no specific labelling rules are provided. The 1996–97 update contains a guide to classification which includes a list of classified pesticides and comprehensive safety procedures. (See the chapter Minerals and agricultural chemicals.)

FAO International Code of Conduct on the Distribution and Use of Pesticides

The WHO Classification is supported by another document, the FAO International Code of Conduct on the Distribution and Use of Pesticides. Although it is only a recommendation, this classification is applied most widely in developing countries, where it is often included into pertinent national legislation. With regard to labelling, the FAO has published Guidelines on Good Labelling Practice for Pesticides as an addendum to these guidelines.

Regional Systems (EC, EFTA, CMEA)

The EC Council Directive 67/548/EEC has been in application for over two decades and has harmonized the pertinent legislation of 12 countries. It has evolved into a comprehensive system which includes an inventory of existing chemicals, a notification procedure for new chemicals prior to marketing, a set of hazard categories, classification criteria for each category, testing methods, and a hazard communication system including labelling with codified risk and safety phrases and hazard symbols. Chemical preparations (mixtures of chemicals) are regulated by Council Directive 88/379/EEC. The definition of the chemical safety data sheet data elements is practically identical to that defined in ILO Recommendation No. 177, as discussed earlier in this chapter. A set of classification criteria and a label for chemicals that are dangerous to the environment have been produced. The Directives regulate chemicals placed on the market, with the goal of protecting human health and the environment. Fourteen categories are divided into two groups related respectively to physico-chemical properties (explosive, oxidizing, extremely flammable, highly flammable, flammable) and toxicological properties (very toxic, toxic, harmful, corrosive, irritant, carcinogenic, mutagenic, toxic to reproduction, properties dangerous to health or the environment).

The Commission of European Communities (CEC) has an extension to the system specifically addressed to the workplace. In addition, these measures on chemicals should be considered within the overall framework of the protection of the health and safety of workers provided for under Directive 89/391/EEC and its individual Directives.

With the exception of Switzerland, the countries in EFTA follow the EC system to a large degree.

Former Council for Mutual Economic Assistance (CMEA)

This system was elaborated under the umbrella of the Standing Commission for Cooperation in Public Health of the CMEA, which included Poland, Hungary, Bulgaria, the former USSR, Mongolia, Cuba, Romania, Vietnam and Czechoslovakia. China still uses a system which is similar in concept. It consists of two classification categories, namely toxicity and hazard, using a four-level ranking scale. Another element of the CMEA system is its requirement for the preparation of a “toxicological passport of new chemical compounds subjected to introduction in the economy and domestic life”. Criteria for irritancy, allergic effects, sensitization, carcinogenicity, mutagenicity, teratogenicity, antifertility and ecological hazards are defined. However, the scientific basis and the testing methodology related to the classification criteria are significantly different from those used by the other systems.

Provisions for workplace labelling and hazard symbols are also different. The UNRTDG system is used for labelling goods for transport, but there does not seem to be any linkage between the two systems. There are no specific recommendations for chemical safety data sheets. The system is described in detail in the UNEP International Register of Potentially Toxic Chemicals (IRPTC) International Survey of Classification Systems. While the CMEA system contains most of the basic elements of the other classification systems, it differs significantly in the area of hazard assessment methodology, and uses exposure standards as one of the hazard classification criteria.

Examples of National Systems

Australia

Australia has enacted legislation for the notification and assessment of industrial chemicals, the Industrial Chemicals Notification and Assessment Act of 1989, with similar legislation enacted in 1992 for agricultural and veterinary chemicals. The Australian system is similar to that of the EC. The differences are mainly due to its utilization of the UNRTDG classification (i.e., the inclusion of the categories compressed gas, radioactive and miscellaneous).

Canada

The Workplace Hazardous Materials Information System (WHMIS) was implemented in 1988 by a combination of federal and provincial legislation designed to enforce the transfer of information about hazardous materials from producers, suppliers and importers to employers and in turn to workers. It applies to all industries and workplaces in Canada. WHMIS is a communication system aimed primarily at industrial chemicals and composed of three interrelated hazard communication elements: labels, chemical safety data sheets and worker education programmes. A valuable support to this system was the earlier creation and commercial distribution worldwide of a computerized database, now available on compact disc, containing over 70,000 chemical safety data sheets voluntarily submitted to the Canadian Centre for Occupational Health and Safety by manufacturers and suppliers.

Japan

In Japan, the control of chemicals is covered mainly by two laws. First, the Chemical Substances Control Law, as amended in 1987, is aimed at preventing environmental contamination by chemical substances that are low in biodegradability and harmful to human health. The law defines a premarket notification procedure and three “hazard” classes:

• Class 1—specified chemical substances (low biodegradation, high bioaccumulation, risk to human health)
• Class 2—specified chemical substances (low biodegradation and bioaccumulation, risk to human health and of contamination of the environment in vast areas)
• Class 3—designated substances (low biodegradation and bioaccumulation, suspicion of risk to human health)

Control measures are defined, and a list of existing chemicals is provided.

The second regulation, the Industrial Safety and Health Law, is a parallel system with its own list of “Specified chemical substances” which require labelling. Chemicals are classified into four groups (lead, tetraalkyl lead, organic solvents, specified chemical substances). The classification criteria are (1) possible occurrence of serious health impairment, (2) possible frequent occurrence of health impairment and (3) actual health impairment. Other laws dealing with the control of hazardous chemicals include the Explosives Control Law; the High Pressure Gas Control Law; the Fire Prevention Law; the Food Sanitation Law; and the Drugs, Cosmetics and Medical Instruments Law.

United States

The Hazard Communication Standard (HCS), a mandatory standard promulgated by OSHA, is a workplace-oriented binding regulation which refers to other existing laws. Its goal is to ensure that all chemicals produced or imported are evaluated, and that information related to their hazards is transmitted to employers and to workers through a comprehensive hazard communication programme. The programme includes labelling and other forms of warning, chemical safety data sheets and training. Label and data sheet minimum contents are defined, but the use of hazard symbols is not mandatory.

Under the Toxic Substances Control Act (TSCA), administered by the Environmental Protection Agency (EPA), an inventory listing approximately 70,000 existing chemicals is maintained. The EPA is developing regulations to complement the OSHA HCS which would have similar hazard evaluation and worker communication requirements for the environmental hazards of chemicals on the inventory. Under TSCA, prior to manufacture or import of chemicals which are not on the inventory, the manufacturer must submit a premanufacture notice. The EPA may impose testing or other requirements based on the premanufacture notice review. As new chemicals are introduced into commerce, they are added to the inventory.

Labelling

Labels on containers of hazardous chemicals provide the first alert that a chemical is hazardous, and should provide basic information about safe handling procedures, protective measures, emergency first aid and the chemical’s hazards. The label should also include the identity of the hazardous chemical(s) and the name and address of the chemical manufacturer.

Labelling consists of phrases as well as graphic and colour symbols applied directly on the product, package, label or tag. The marking should be clear, easily comprehensible and able to withstand adverse climatic conditions. The labelling should be placed against a background that contrasts with the product’s accompanying data or package colour. The MSDS provides more detailed information on the nature of the chemical product’s hazards and the appropriate safety instructions.

While presently there are no globally harmonized labelling requirements, there are established international, national and regional regulations for labelling hazardous substances. Requirements for labelling are incorporated into the Law on Chemicals (Finland), the Act on Dangerous Products (Canada) and EC Directive N 67/548. Minimum label content requirements of the European Union, United States and Canadian systems are relatively similar.

Several international organizations have established labelling content requirements for handling chemicals at the workplace and in transport. The labels, hazard symbols, risk and safety phrases, and emergency codes of the International Organization for Standardization (ISO), the UNRTDG, the ILO and EU are discussed below.

The section on labelling in the ISO/IEC guide 51, Guidelines for Inclusion of Safety Aspects in Standards, includes commonly recognized pictograms (drawing, colour, sign). In addition, short and plain warning phrases alert the user to potential hazards and provide information on preventive safety and health measures.

The guidelines recommend the use of the following “signal” words to alert the user:

• DANGER—high danger
• HANDLE WITH CARE—intermediate danger
• BEWARE—potential danger.

The UNRTDG establish five main pictograms for easy visible recognition of dangerous goods and significant hazard identification:

• bomb—explosive
• flame—flammable
• skull and cross-bones—toxic
• trefoil—radioactive
• liquid pouring out of two test-tubes on a hand and a piece of metal—corrosive.

These symbols are supplemented by other representations such as:

• oxidizing substances—flame above a circle
• non-flammable gases—a gas bottle
• infectious substances—three crescent signs superimposed on a circle
• harmful substances which should be stowed away—St. Andrew’s cross posed on a wheat-ear.

The Chemicals Convention, 1990 (No. 170), and Recommendation, 1990 (No. 177), were adopted at the 77th Session of the International Labour Conference (ILC). They establish requirements for the labelling of chemicals to ensure the communication of basic hazard information. The Convention states that label information should be easily understandable and should convey the potential risks and appropriate precautionary measures to the user. Regarding the transport of dangerous goods, the Convention refers to the UNRTDG.

The Recommendation outlines labelling requirements in accordance with existing national and international systems, and establishes criteria for classification of chemicals including chemical and physical properties; toxicity; necrotic and irritating properties; and allergic, teratogenic, mutagenic and reproductive effects.

The EC Council Directive N 67/548 stipulates the form of label information: graphic hazard symbols and pictograms including risk and safety phrases. Hazards are coded by the Latin letter R accompanied with combinations of Arabic numerals from 1 to 59. For example, R10 corresponds with “flammable”, R23 with “toxic by inhalation”. The hazard code is given with a safety code consisting of the Latin letter S and combinations of numerals from 1 to 60. For example, S39 means “Wear eye/face protection”. The EC labelling requirements serve as a reference for chemical and pharmaceutical companies throughout the world.

Despite significant efforts in chemical hazard data acquisition, evaluation and organization by different international and regional organizations, there is still a lack of coordination of these efforts, particularly in the standardization of assessment protocols and methods and interpretation of data. The ILO, the Organization for Economic Cooperation and Development (OECD), the IPCS and other concerned bodies have initiated a number of international activities aimed toward establishing a global harmonization of chemical classification and labelling systems. The establishment of an international structure to monitor chemical hazard assessment activities would greatly benefit workers, the general public and the environment. An ideal harmonization process would reconcile the transport, marketing and workplace classification and labelling of hazardous substances, and address consumer, worker and environmental concerns.

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The ILO Code of Practice

Much of the information and excerpts in this chapter are taken from the Code of Practice “Safety in the Use of Chemicals at Work” of the International Labour Organization (ILO 1993). The ILO Code provides practical guidelines on the implementation of the provisions of the Chemicals Convention, 1990 (No. 170), and Recommendation, 1990 (No. 177). The object of the Code is to provide guidance to those who may be engaged in the framing of provisions relating to the use of chemicals at work, such as competent authorities, the management in companies where chemicals are supplied or used, and emergency services, which should also offer guidelines to suppliers’, employers’ and workers’ organizations. The Code provides minimum standards and is not intended to discourage competent authorities from adopting higher standards. For more detailed information on individual chemicals and chemical families, see the “Guide to chemicals” in Volume IV of this “Encyclopaedia”.

The objective (section 1.1.1) of the ILO Code of Practice Safety in the Use of Chemicals at Work is to protect workers from the hazards of chemicals, to prevent or reduce the incidence of chemically- induced illnesses and injuries resulting from the use of chemicals at work, and consequently to enhance the protection of the general public and the environment by providing guidelines for:

• ensuring that all chemicals for use at work—including impurities, by-products and intermediates, and wastes that may be formed—are evaluated to determine their hazards
• ensuring that employers are provided with a mechanism for obtaining from their suppliers information about the chemicals used at work to enable them to implement effective programmes to protect workers from chemical hazards
• providing workers with information about the chemicals at their workplaces and about appropriate preventive measures to enable them to participate effectively in safety programmes
• establishing principles for such programmes to ensure that chemicals are used safely
• making special provision to protect confidential information, the disclosure of which to a competitor would be liable to cause harm to an employer’s business, so long as the safety and health of workers are not compromised thereby.

Section 2 of the ILO Code of Practice outlines the general obligations, responsibilities and duties of the competent authority, the employer and the worker. The section also details the general responsibilities of suppliers and the rights of workers, and it offers guidelines regarding special provisions for the employer’s disclosure of confidential information. The final recommendations address the need for cooperation among employers, workers and their representatives.

General Obligations, Responsibilities and Duties

It is the responsibility of the appropriate governmental agency to follow existing national measures and practices, in consultation with the most representative organizations of employers and workers concerned, in order to assure safety in the use of chemicals at work. National practices and laws should be viewed in the context of international regulations, standards and systems, and with the measures and practices recommended by the ILO Code of Practice and the ILO Convention No. 170 and Recommendation No. 177.

The major focus of such measures which provide for safety of workers are, in particular:

• the production and handling of hazardous chemicals
• the storage of hazardous chemicals
• the transport of hazardous chemicals, consistent with national or international transport regulations
• the disposal and treatment of hazardous chemicals and hazardous waste products, consistent with national or international regulations.

There are various means by which the competent authority may achieve this aim. It may enact national laws and regulations; adopt, approve or recognize existing standards, codes or guidelines; and, where such standards, codes or guidelines do not exist, an authority may encourage their adoption by another authority, which can then be recognized. The governmental agency may also require that employers justify the criteria by which they are working.

According to the Code of Practice (section 2.3.1), it is the responsibility of employers to set out, in writing, their policy and arrangements on safety in the use of chemicals, as part of their general policy and arrangements in the field of occupational safety and health, and the various responsibilities exercised under these arrangements, in accordance with the objectives and principles of the Occupational Safety and Health Convention, 1981 (No. 155), and Recommendation, 1981 (No. 164). This information should be brought to the attention of their workers in a language the latter readily understand.

Workers, in turn, should take care of their own health and safety, and that of other persons who may be affected by their acts or omissions at work, as far as possible and in accordance with their training and with instructions given by their employer (section 2.3.2).

The suppliers of chemicals, whether manufacturers, importers or distributors, should ensure that, in accordance with the guidelines in the relevant paragraphs of the Code and in pursuance of the requirements of Convention No. 170 and Recommendation No. 177:

• such chemicals have been classified or their properties assessed
• such chemicals are marked
• hazardous chemicals are labelled
• chemical safety data sheets for hazardous chemicals are prepared and provided to employers.

Operational Control Measures

Certain general principles exist for the operation control of chemicals at work. These are dealt with in Section 6 of the ILO Code of Practice, which prescribes that after reviewing the chemicals being used at work and obtaining information about their hazards and making an assessment of the potential risks involved, employers should take steps to limit exposure of workers to hazardous chemicals (on the basis of the measures outlined in sections 6.4 to 6.9 of the Code), in order to protect workers against hazards from the use of chemicals at work. The measures taken should eliminate or minimize the risks, preferably by substitution of non-hazardous or less hazardous chemicals, or by the choice of better technology. When neither substitution nor engineering control are feasible, other measures, such as safe working systems and practices, personal protective equipment (PPE) and the provision of information and training will further minimize risks and may have to be relied upon for some activities entailing the use of chemicals.

When workers are potentially exposed to chemicals that are hazardous to health, they must be safeguarded against the risk of injury or disease from these chemicals. There should be no exposure which exceeds exposure limits or other exposure criteria for the evaluation and control of the working environment established by the competent authority, or by a body approved or recognized by the competent authority in accordance with national or international standards.

Control measures to provide protection for workers could be any combination of the following:

1. good design and installation practice:

• totally enclosed process and handling systems
• segregation of the hazardous process from the operators or from other processes

2. plants processes or work systems which minimize generation of, or suppress or contain, hazardous dust, fumes, etc., and which limit the area of contamination in the event of spills and leaks:

• partial enclosure, with local exhaust ventilation (LEV)
• LEV
• sufficient general ventilation

3. work systems and practices:

• reduction of the numbers of workers exposed and exclusion of non-essential access
• reduction in the period of exposure to workers
• regular cleaning of contaminated walls, surfaces, etc.
• use and proper maintenance of engineering control measures
• provision of means for safe storage and disposal of chemicals hazardous to health

4. personal protection (where the above measures do not suffice, suitable PPE should be provided until such time as the risk is eliminated or minimized to a level that would not pose a threat to health)

5. prohibition of eating, chewing, drinking and smoking in contaminated areas

6. provision of adequate facilities for washing, changing and storage of clothing, including arrangements for laundering contaminated clothing

7. use of signs and notices

8. adequate arrangements in the event of an emergency.

Chemicals known to have carcinogenic, mutagenic or teratogenic health effects should be kept under strict control.

Record Keeping

Record keeping is an essential element of the work practices which provide a safe use of chemicals. Records should be kept by employers on measurements of airborne hazardous chemicals. Such records should be clearly marked by date, work area and plant location. The following are some elements of section 12.4 of the ILO Code of Practice, which deals with record-keeping requirements.

• Personal sampling measurements, including the exposures calculated, should be recorded.
• The workers and their representatives, and the competent authority, should have access to these records.

Besides the numerical results of measurements, the monitoring data should include, for example:

• the marking of the hazardous chemical
• the location, nature, dimensions and other distinctive features of the workplace where static measurements were made; the exact location at which personal monitoring measurements were made, and the names and job titles of the workers involved
• the source or sources of airborne emissions, their location and the type of work and operations being performed during sampling
• relevant information on the functioning of the process, engineering controls, ventilation and weather conditions with respect to the emissions
• the sampling instrument used, its accessories and the method of analysis
• the date and exact time of sampling
• the duration of the workers’ exposure, the use or non-use of respiratory protection and other comments relating to the exposure evaluation
• the names of the persons responsible for the sampling and for the analytical determinations.

Records should be kept for a specified period of time determined by the competent authority. Where this has not been prescribed, it is recommended that the employer keep the records, or a suitable summary, for:

1. at least 30 years where the record is representative of the personal exposures of identifiable employees
2. at least 5 years in all other cases.

Information and Training

Correct instruction and quality training are essential components of a successful hazard communication programme. The ILO Code of Practice Safety in the Use of Chemicals at Work provides general principles of training (sections 10.1 and 10.2). These include the following:

• Workers should be informed of the hazards associated with chemicals used at their workplace.
• Workers should be instructed about how to obtain and use the information provided on labels and chemical safety data sheets.
• Workers should be trained in the correct and effective use of the control measures, in particular the engineering control measures and measures for personal protection provided, and should be made aware of their significance.
• Employers should use chemical safety data sheets, along with information specific to the workplace, as a basis for the preparation of instruction to workers, which should be in writing if appropriate.
• Workers should be trained on a continuing basis in the working systems and practices to be followed and their significance for safety in the use of chemicals at work, and in how to deal with emergencies.

Review of training needs

The extent of the training and instruction received and required should be reviewed and updated simultaneously with the review of the working systems and practices referred to in section 8.2 (Review of work systems).

The review should include the examination of:

• whether workers understand when protective equipment is required, and its limitations
• whether workers understand the most effective use of the engineering control measures provided
• whether workers are familiar with procedures in the event of an emergency involving a hazardous chemical
• procedures for the exchange of information between shift workers.

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Figure 1. The female reproductive system.

The female reproductive system is controlled by components of the central nervous system, including the hypothalamus and pituitary. It consists of the ovaries, the fallopian tubes, the uterus and the vagina (Figure 1). The ovaries, the female gonads, are the source of oocytes and also synthesize and secrete oestrogens and progestogens, the major female sex hormones. The fallopian tubes transport oocytes to and sperm from the uterus. The uterus is a pear-shaped muscular organ, the upper part of which communicates through the fallopian tubes to the abdominal cavity, while the lower part is contiguous through the narrow canal of the cervix with the vagina, which passes to the exterior. Table 1 summarizes compounds, clinical manifestations, site and mechanisms of action of potential reproductive toxicants.

Table 1. Potential female reproductive toxicants

Source: From Plowchalk, Meadows and Mattison 1992. These compounds are suggested to be direct-acting reproductive toxicants based primarily on toxicity testing in experimental animals.

The Hypothalamus and Pituitary

The hypothalamus is located in the diencephalon, which sits on top of the brainstem and is surrounded by the cerebral hemispheres. The hypothalamus is the principal intermediary between the nervous and the endocrine systems, the two major control systems of the body. The hypothalamus regulates the pituitary gland and hormone production.

The mechanisms by which a chemical might disrupt the reproductive function of the hypothalamus generally include any event that could modify the pulsatile release of gonadotrophin releasing hormone (GnRH). This may involve an alteration in either the frequency or the amplitude of GnRH pulses. The processes susceptible to chemical injury are those involved in the synthesis and secretion of GnRH—more specifically, transcription or translation, packaging or axonal transport, and secretory mechanisms. These processes represent sites where direct-acting chemically reactive compounds might interfere with hypothalmic synthesis or release of GnRH. An altered frequency or amplitude of GnRH pulses could result from disruptions in stimulatory or inhibitory pathways that regulate the release of GnRH. Investigations of the regulation of the GnRH pulse generator have shown that catecholamines, dopamine, serotonin, γ-aminobutyric acid, and endorphins all have some potential for altering the release of GnRH. Therefore, xenobiotics that are agonists or antagonists of these compounds could modify GnRH release, thus interfering with communication with the pituitary.

Prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are three protein hormones secreted by the anterior pituitary that are essential for reproduction. These play a critical role in maintaining the ovarian cycle, governing follicle recruitment and maturation, steroidogenesis, completion of ova maturation, ovulation and luteinization.

The precise, finely tuned control of the reproductive system is accomplished by the anterior pituitary in response to positive and negative feedback signals from the gonads. The appropriate release of FSH and LH during the ovarian cycle controls normal follicular development, and the absence of these hormones is followed by amenorrhoea and gonadal atrophy. The gonadotrophins play a critical role in initiating changes in the morphology of ovarian follicles and in their steroidal microenvironments through the stimulation of steroid production and the induction of receptor populations. Timely and adequate release of these gonadotrophins is also essential for ovulatory events and a functional luteal phase. Because gonadotrophins are essential for ovarian function, altered synthesis, storage or secretion may seriously disrupt reproductive capacity. Interference with gene expression—whether in transcription or translation, post-translational events or packaging, or secretory mechanisms—may modify the level of gonadotrophins reaching the gonads. Chemicals that act by means of structural similarity or altered endocrine homeostasis might produce effects by interference with normal feedback mechanisms. Steroid-receptor agonists and antagonists might initiate an inappropriate release of gonadotrophins from the pituitary, thereby inducing steroid-metabolizing enzymes, reducing steroid half-life and subsequently the circulating level of steroids reaching the pituitary.

The Ovary

The ovary in primates is responsible for the control of reproduction through its principal products, oocytes and steroid and protein hormones. Folliculogenesis, which involves both intraovarian and extraovarian regulatory mechanisms, is the process by which oocytes and hormones are produced. The ovary itself has three functional subunits: the follicle, the oocyte and the corpus luteum. During the normal menstrual cycle, these components, under the influence of FSH and LH, function in concert to produce a viable ovum for fertilization and a suitable environment for implantation and subsequent gestation.

During the preovulatory period of the menstrual cycle, follicle recruitment and development occur under the influence of FSH and LH. The latter stimulates the production of androgens by thecal cells, whereas the former stimulates the aromatization of androgens into oestrogens by the granulosa cells and the production of inhibin, a protein hormone. Inhibin acts at the anterior pituitary to decrease the release of FSH. This prevents excess stimulation of follicular development and allows continuing development of the dominant follicle—the follicle destined to ovulate. Oestrogen production increases, stimulating both the LH surge (resulting in ovulation) and the cellular and secretory changes in the vagina, cervix, uterus and oviduct that enhance spermatozoa viability and transport.

In the postovulatory phase, thecal and granulosa cells remaining in the follicular cavity of the ovulated ovum, form the corpus luteum and secrete progesterone. This hormone stimulates the uterus to provide a proper environment for implantation of the embryo if fertilization occurs. Unlike the male gonad, the female gonad has a finite number of germ cells at birth and is therefore uniquely sensitive to reproductive toxicants. Such exposure of the female can lead to decreased fecundity, increased pregnancy wastage, early menopause or infertility.

As the basic reproductive unit of the ovary, the follicle maintains the delicate hormonal environment necessary to support the growth and maturation of an oocyte. As previously noted, this complex process is known as folliculogenesis and involves both intraovarian and extraovarian regulation. Numerous morphological and biochemical changes occur as a primordial follicle progresses to a pre-ovulatory follicle (which contains a developing oocyte), and each stage of follicular growth exhibits unique patterns of gonadotrophin sensitivity, steroid production and feedback pathways. These characteristics suggest that a number of sites are available for xenobiotic interaction. Also, there are different follicle populations within the ovary, which further complicates the situation by allowing for differential follicle toxicity. This creates a situation in which the patterns of infertility induced by a chemical agent would depend on the follicle type affected. For example, toxicity to primordial follicles would not produce immediate signs of infertility but would ultimately shorten the reproductive lifespan. On the other hand, toxicity to antral or preovulatory follicles would result in an immediate loss of reproductive function. The follicle complex is composed of three basic components: granulosa cells, thecal cells and the oocyte. Each of these components has characteristics that may make it uniquely susceptible to chemical injury.

Several investigators have explored methodology for screening xenobiotics for granulosa cell toxicity by measuring the effects on progesterone production by granulosa cells in culture. Oestradiol suppression of progesterone production by granulosa cells has been utilized to verify granulosa cell responsiveness. The pesticide p,p’-DDT and its o,p’-DDT isomer produce supression of progesterone production apparently with potencies equal to that of oestradiol. By contrast, the pesticides malathion, arathion and dieldrin and the fungicide hexachlorobenzene are without effect. Further detailed analysis of isolated granulosa cell responses to xenobiotics is needed to define the utility of this assay system. The attractiveness of isolated systems such as this is economy and ease of use; however, it is important to remember that granulosa cells represent only one component of the reproductive system.

Thecal cells provide precursors for steroids synthesized by granulosa cells. Thecal cells are believed to be recruited from ovarian stroma cells during follicle formation and growth. Recruitment may involve stromal cellular proliferation as well as migration to regions around the follicle. Xenobiotics that impair cell proliferation, migration and communication will impact on thecal cell function. Xenobiotics that alter thecal androgen production may also impair follicle function. For example, the androgens metabolized to oestrogens by granulosa cells are provided by thecal cells. Alterations in thecal cell androgen production, either increases or decreases, are expected to have a significant effect on follicle function. For example, it is believed that excess production of androgens by thecal cells will lead to follicle atresia. In addition, impaired production of androgens by thecal cells may lead to decreased poestrogen production by granulosa cells. Either circumstance will clearly impact on reproductive performance. At resent, little is known about thecal cell vulnerability to xenobiotics.

Although there is a acuity of information defining the vulnerability of ovarian cells to xenobiotics, there are data clearly demonstrating that oocytes can be damaged or destroyed by such agents. Alkylating agents destroy oocytes in humans and experimental animals. Lead produces ovarian toxicity. Mercury and cadmium also produce ovarian damage that may be mediated through oocyte toxicity.

Fertilization to Implantation

Gametogenesis, release and union of male and female germ cells are all preliminary events leading to a zygote. Sperm cells deposited in the vagina must enter the cervix and move through the uterus and into the fallopian tube to meet the ovum. penetration of ovum by sperm and the merging of their respective DNA comprise the process of fertilization. After fertilization cell division is initiated and continues during the next three or four days, forming a solid mass of cells called a morula. The cells of the morula continue to divide, and by the time the developing embryo reaches the uterus it is a hollow ball called a blastocyst.

Following fertilization, the developing embryo migrates through the fallopian tube into the uterus. The blastocyst enters the uterus and implants in the endometrium approximately seven days after ovulation. At this time the endometrium is in the postovulatory phase. Implantation enables the blastocyst to absorb nutrients or toxicants from the glands and blood vessels of the endometrium.

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Spermatogenesis and spermiogenesis are the cellular processes that produce mature male sex cells. These processes take place within the seminiferous tubules of the testes of the sexually mature male, as shown in Figure 1. The human seminiferous tubules are 30 to 70 cm long and 150 to 300 mm in diameter (Zaneveld 1978). The spermatogonia (stem cells) are ppositioned along the basement membrane of the seminiferous tubules and are the basic cells for the production of sperm.

Figure 1. The male reproductive system

Sperm mature through a series of cellular divisions in which the spermatogonia proliferate and become primary spermatocytes. The resting primary spermatocytes migrate through tight junctions formed by the Sertoli cells to the luminal side of this testis barrier. By the time the spermatocytes reach the membrane barrier in the testis, the synthesis of DNA, the genetic material in the nucleus of the cell, is essentially complete. When the primary spermatocytes actually encounter the lumen of the seminiferous tubule, these undergo a special type of cell division which occurs only in germ cells and is known as meiosis. Meiotic cellular divison results in the splitting up of the chromosomes pairs in the nucleus, so that each resulting germ cell contains only a single copy of each chromosome strand rather than a matched pair.

During meiosis the chromosomes change shape by condensing and becoming filamentous. At a certain point, the nuclear membrane which surrounds them breaks down and microtubular spindles attach to the chromosomal pairs, causing them to separate. This completes the first meiotic division and two haploid secondary spermatocytes are formed. The secondary spermatocytes then undergo a second meiotic division to form equal numbers of X- and Y-chromosome bearing spermatids.

The morphological transformation of spermatids to spermatozoa is called spermiogenesis. When spermiogenesis is complete, each sperm cell is released by the Sertoli cell into the seminiferous tubule lumen by a process referred to as spermiation. The sperm migrate along the tubule to the rete testis and into the head of the epididymis. Sperm leaving the seminiferous tubules are immature: unable to fertilize an ovum and unable to swim. Spermatozoa released into the lumen of the seminiferous tubule are suspended in fluid pproduced primarily by the Sertoli cells. Concentrated sperm suspended within this fluid flow continuously from the seminiferous tubules, through slight changes in the ionic milieu within the rete testis, through the vasa efferentia, and into the epididymis. The epididymis is a single highly coiled tube (five to six metres long) in which sperm spend 12 to 21 days.

Within the epididymis, sperm progressively acquire motility and fertilizing capacity. This may be due to the changing nature of the suspension fluid in the epididymis. That is, as the cells mature the epididymis absorbs components from the fluid including secretions from the Sertoli cells (e.g., androgen binding protein), thereby increasing the concentration of spermatozoa. The epididymis also contributes its own secretions to the suspension fluid, including the chemicals glycerylphosphorylcholine (GPC) and carnitine.

Sperm morphology continues to transform in the epididymis. The cytoplasmic droplet is shed and the sperm nucleus condenses further. While the epididymis is the principal storage reservoir for sperm until ejaculation, about 30% of the sperm in an ejaculate have been stored in the vas deferens. Frequent ejaculation accelerates passage of sperm through the epididymis and may increase the number of immature (infertile) sperm in the ejaculate (Zaneveld 1978).

Ejaculation

Once within the vas deferens, the sperm are transported by the muscular contractions of ejaculation rather than by the flow of fluid. During ejaculation, fluids are forcibly expelled from the accessory sex glands giving rise to the seminal plasma. These glands do not expel their secretions at the same time. Rather, the bulbourethral (Cowper’s) gland first extrudes a clear fluid, followed by the prostatic secretions, the sperm-concentrated fluids from the epididymides and ampulla of the vas deferens, and finally the largest fraction primarily from the seminal vesicles. Thus, seminal plasma is not a homogeneous fluid.

Toxic Actions on Spermatogenesisand Spermiogenesis

Toxicants may disrupt spermatogenesis at several points. The most damaging, because of irreversibility, are toxicants that kill or genetically alter (beyond repair mechanisms) spermatogonia or Sertoli cells. Animal studies have been useful to determine the stage at which a toxicant attacks the spermatogenic process. These studies employ short term exposure to a toxicant before sampling to determine the effect. By knowing the duration for each spermatogenic stage, one can extrapolate to estimate the affected stage.

Biochemical analysis of seminal plasma pprovides insights into the function of the accessory sex glands. Chemicals that are secreted primarily by each of the accessory sex glands are typically selected to serve as a marker for each respective gland. For example, the epididymis is represented by GPC, the seminal vesicles by fructose, and the prostate gland by zinc. Note that this type of analysis pprovides only gross information on glandular function and little or no information on the other secretory constituents. Measuring semen pH and osmolality provide additional general information on the nature of seminal plasma.

Seminal plasma may be analysed for the presence of a toxicant or its metabolite. Heavy metals have been detected in seminal plasma using atomic absorption spectrophotometry, while halogenated hydrocarbons have been measured in seminal fluid by gas chromatography after extraction or protein-limiting filtration (Stachel et al. 1989; Zikarge 1986).

The viability and motility of spermatozoa in seminal plasma is typically a reflection of seminal plasma quality. Alterations in sperm viability, as measured by stain exclusion or by hypoosmotic swelling, or alterations in sperm motility parameters would suggest post-testicular toxicant effects.

Semen analyses also can indicate whether production of sperm cells has been affected by a toxicant. Sperm count and sperm morphology provide indices of the integrity of spermatogenesis and spermiogenesis. Thus, the number of sperm in the ejaculate is directly correlated with the number of germ cells per gram of testis (Zukerman et al. 1978), while abnormal morphology is probably a result of abnormal spermiogenesis. Dead sperm or immotile sperm often reflect the effects of post-testicular events. Thus, the type or timing of a toxic effect may indicate the target of the toxicant. For example, exposure of male rats to 2-methoxyethanol resulted in reduced fertility after four weeks (Chapin et al. 1985). This evidence, corroborated by histological examination, indicates that the target of toxicity is the spermatocyte (Chapin et al. 1984). While it is not ethical to intentionally expose humans to suspected reproductive toxicants, semen analyses of serial ejaculates of men inadvertently exposed for a short time to potential toxicants may provide similar useful information.

Occupational exposure to 1,2-dibromochloropropane (DBCP) reduced sperm concentration in ejaculates from a median of 79 million cells/ml in unexposed men to 46 million cells/ml in exposed workers (Whorton et al. 1979). Upon removing the workers from the exposure, those with reduced sperm counts experienced a partial recovery, while men who had been azoospermic remained sterile. Testicular biopsy revealed that the target of DBCP was the spermatogonia. This substantiates the severity of the effect when stem cells are the target of toxicants. There were no indications that DBCP exposure of men was associated with adverse pregnancy outcome (Potashnik and Abeliovich 1985). Another example of a toxicant targeting spermatogenesis/spermiogenesis was the study of workers exposed to ethylene dibromide (EDB). They had more sperm with tapered heads and fewer sperm per ejaculate than did controls (Ratcliffe et al. 1987).

Genetic damage is difficult to detect in human sperm. Several animal studies using the dominant lethal assay (Ehling et al. 1978) indicate that paternal exposure can produce an adverse pregnancy outcome. Epidemiological studies of large populations have demonstrated increased frequency of spontaneous abortions in women whose husbands were working as motor vehicle mechanics (McDonald et al. 1989). Such studies indicate a need for methods to detect genetic damage in human sperm. Such methods are being developed by several laboratories. These methods include DNA probes to discern genetic mutations (Hecht 1987), sperm chromosome karyotyping (Martin 1983), and DNA stability assessment by flow cytometry (Evenson 1986).

Figure 2. Exposures positively associated with adversely affecting semen quality

Figure 2 lists exposures known to affect sperm quality and table 1 provides a summary of the results of epidemiological studies of paternal effects on reproductive outcomes.

Table 1. Epidemiological studies of paternal effects on pregnancy outcome

¹ – no significant association; (+) marginally significant association; + significant association.
Source: Adapted from Taskinen 1993.

Neuroendocrine System

The overall functioning of the reproductive system is controlled by the nervous system and the hormones pproduced by the glands (the endocrine system). The reproductive neuroendocrine axis of the male involves principally the central nervous systems (CNS), the anterior pituitary gland and the testes. Inputs from the CNS and from the periphery are integrated by the hypothalamus, which directly regulates gonadotrophin secretion by the anterior pituitary gland. The gonadotrophins, in turn, act principally upon the Leydig cells within the interstitium and Sertoli and germ cells within the seminiferous tubules to regulate spermatogenesis and hormone production by the testes.

Hypothalamic–Pituitary Axis

The hypothalamus secretes the neurohormone gonadotrophin releasing hormone (GnRH) into the hypophysial portal vasculature for transport to the anterior pituitary gland. The pulsatile secretion of this decapeptide causes the concomitant release of luteinizing hormone (LH), and with lesser synchrony and one-fifth the potency, the release of follicle stimulating hormone (FSH) (Bardin 1986). Substantial evidence exists to support the presence of a separate FSH releasing hormone, although none has yet been isolated (Savy-Moore and Schwartz 1980; Culler and Negro-Vilar 1986). These hormones are secreted by the anterior pituitary gland. LH acts directly upon the Leydig cells to stimulate synthesis and release of testosterone, whereas FSH stimulates aromatization of testosterone to estradiol by the Sertoli cell. Gonadotropic stimulation causes the release of these steroid hormones into the spermatic vein.

Gonadotrophin secretion is, in turn, checked by testosterone and estradiol through negative feedback mechanisms. Testosterone acts principally upon the hypothalamus to regulate GnRH secretion and thereby reduces the pulse frequency, primarily, of LH release. Estradiol, on the other hand, acts upon the pituitary gland to reduce the magnitude of gonadotrophin release. Through these endocrine feedback loops, testicular function in general and testosterone secretion specifically are maintained at a relatively steady state.

Pituitary–Testicular Axis

LH and FSH are generally viewed as necessary for normal spermatogenesis. Presumably the effect of LH is secondary to inducing high intratesticular concentrations of testosterone. Therefore, FSH from the pituitary gland and testosterone from the Leydig cells act upon the Sertoli cells within the seminiferous tubule epithelium to initiate spermatogenesis. Sperm production persists, although quantitatively reduced, after removing either LH (and presumably the high intratesticular testosterone concentrations) or FSH. FSH is required for initiating spermatogenesis at puberty and, to a lesser extent, to reinitiate spermatogenesis that has been arrested (Matsumoto 1989; Sharpe 1989).

The hormonal synergism that serves to maintain spermatogenesis may entail recruitment by FSH of differentiated spermatogonia to enter meiosis, while testosterone may control specific, subsequent stages of spermatogenesis. FSH and testosterone may also act upon the Sertoli cell to stimulate production of one or more paracrine factors which may affect the number of Leydig cells and testosterone production by these cells (Sharpe 1989). FSH and testosterone stimulate protein synthesis by Sertoli cells including synthesis of androgen binding protein (ABP), while FSH alone stimulates synthesis of aromatase and inhibin. ABP is secreted primarily into the seminiferous tubular fluid and is transported to the proximal portion of the caput epididymis, possibly serving as a local carrier of androgens (Bardin 1986). Aromatase catalyses the conversion of testosterone to estradiol in the Sertoli cells and in other peripheral tissues.

Inhibin is a glycoprotein consisting of two dissimilar, disulphide-linked subunits, a and b. Although inhibin preferentially inhibits FSH release, it may also attenuate LH release in the presence of GnRH stimulation (Kotsugi et al. 1988). FSH and LH stimulate inhibin release with approximately equal potency (McLachlan et al. 1988). Interestingly, inhibin is secreted into the spermatic vein blood as pulses which are synchronous to those of testosterone (Winters 1990). This probably does not reflect direct actions of LH or testosterone on Sertoli cell activity, but rather the effects of other Leydig cell products secreted either into the interstitial spaces or the circulation.

Prolactin, which is also secreted by the anterior pituitary gland, acts synergistically with LH and testosterone to promote male reproductive function. Prolactin binds to specific receptors on the Leydig cell and increases the amount of androgen receptor complex within the nucleus of androgen responsive tissues (Baker et al. 1977). Hyperprolactinaemia is associated with reductions of testicular and prostate size, semen volume and circulating concentrations of LH and testosterone (Segal et al. 1979). Hyperprolactinaemia has also been associated with impotency, apparently independent of altering testosterone secretion (Thorner et al. 1977).

If measuring steroid hormone metabolites in urine, consideration must be given to the potential that the exposure being studied may alter the metabolism of excreted metabolites. This is especially pertinent since most metabolites are formed by the liver, a target of many toxicants. Lead, for example, reduced the amount of sulphated steroids that were excreted into the urine (Apostoli et al. 1989). Blood levels for both gonadotrophins become elevated during sleep as the male enters puberty, while testosterone levels maintain this diurnal pattern through adulthood in men (Plant 1988). Thus blood, urine or saliva samples should be collected at approximately the same time of day to avoid variations due to diurnal secretory patterns.

The overt effects of toxic exposure targeting the reproductive neuroendocrine system are most likely to be revealed through altered biological manifestations of the androgens. Manifestations significantly regulated by androgens in the adult man that may be detected during a basic physical examination include: (1) nitrogen retention and muscular development; (2) maintenance of the external genitalia and accessory sexual organs; (3) maintenance of the enlarged larynx and thickened vocal cords causing the male voice; (4) beard, axillary and pubic hair growth and temporal hair recession and balding; (5) libido and sexual performance; (6) organ specific proteins in tissues (e.g., liver, kidneys, salivary glands); and (7) aggressive behaviour (Bardin 1986). Modifications in any of these traits may indicate that androgen production has been affected.

Examples of Toxicant Effects

Lead is a classic example of a toxicant that directly affects the neuroendocrine system. Serum LH concentrations were elevated in men exposed to lead for less than one year. This effect did not progress in men exposed for more than five years. Serum FSH levels were not affected. On the other hand, serum levels of ABP were elevated and those of total testosterone were reduced in men exposed to lead for more than five years. Serum levels of free testosterone were significantly reduced after exposure to lead for three to five years (Rodamilans et al. 1988). In contrast, serum concentrations of LH, FSH, total testosterone, prolactin, and total neutral 17-ketosteroids were not altered in workers with lower circulating levels of lead, even though the distribution frequency of sperm count was altered (Assennato et al. 1986).

Exposure of shipyard painters to 2-ethoxyethanol also reduced sperm count without a concurrent change in serum LH, FSH, or testosterone concentrations (Welch et al. 1988). Thus toxicants may affect hormone production and sperm measures independently.

Male workers involved in the manufacture of the nematocide DBCP experienced elevated serum levels of LH and FSH and reduced sperm count and fertility. These effects are apparently sequelae to DBCP actions upon the Leydig cells to alter androgen production or action (Mattison et al. 1990).

Several compounds may exert toxicity by virtue of structural similarity to reproductive steroid hormones. Thus, by binding to the respective endocrine receptor, toxicants may act as agonists or antagonists to disrupt biological responses. Chlordecone (Kepone), an insecticide that binds to oestrogen receptors, reduced sperm count and motility, arrested sperm maturation and reduced libido. While it is tempting to suggest that these effects result from chlordecone interfering with oestrogen actions at the neuroendocrine or testicular level, serum levels of testosterone, LH and FSH were not shown to be altered in these studies in a manner similar to the effects of oestradiol therapy. DDT and its metabolites also exhibit steroidal properties and might be expected to alter male reproductive function by interfering with steroidal hormone functions. Xenobiotics such as polychlorinated biphenyls, polybrominated biphenyls, and organochlorine pesticides may also interfere with male reproductive functions by exerting oestrogenic agonist/antagonist activity (Mattison et al. 1990).

Sexual Function

Human sexual function refers to the integrated activities of the testes and secondary sex glands, the endocrine control systems, and the central nervous system-based behavioural and psychological components of reproduction (libido). Erection, ejaculation and orgasm are three distinct, independent, physiological and psychodynamic events which normally occur concurrently in men.

Little reliable data are available on occupational exposure effects on sexual function due to the problems described above. Drugs have been shown to affect each of the three stages xof male sexual function (Fabro 1985), indicating the potential for occupational exposures to exert similar effects. Antidepressants, testosterone antagonists and stimulants of prolactin release effectively reduce libido in men. Antihypertensive drugs which act on the sympathetic nervous system induce impotence in some men, but surprisingly, priapism in others. Phenoxybenzamine, an adrenoceptive antagonist, has been used clinically to block seminal emission but not orgasm (Shilon, Paz and Homonnai 1984). Anticholinergic antidepressant drugs permit seminal emission while blocking seminal ejection and orgasm which results in seminal plasma seeping from the urethra rather than being ejected.

Recreational drugs also affect sexual function (Fabro 1985). Ethanol may reduce impotence while enhancing libido. Cocaine, heroin and high doses of cannabinoids reduce libido. Opiates also delay or impair ejaculation.

The vast and varied array of pharmaceuticals that has been shown to affect the male reproductive system pprovides support for the notion that chemicals found in the workplace may also be reproductive toxicants. Research methods that are reliable and practical for field study conditions are needed to assess this important area of reproductive toxicology.

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Reproductive toxicity has many unique and challenging differences from toxicity to other systems. Whereas other forms of environmental toxicity typically involve development of disease in an exposed individual, because reproduction requires interaction between two individuals, reproductive toxicity will be expressed within a reproductive unit, or couple. This unique, couple- dependent aspect, although obvious, makes reproductive toxicology distinct. For example, it is ppossiblethat exposure to a toxicant by one member of a reproductive couple (e.g., the male) will be manifest by an adverse reproductive outcome in the other member of the couple (e.g., increased frequency of spontaneous abortion). Any attempt to deal with environmental causes of reproductive toxicity must address the couple-specific aspect.

There are other unique aspects that reflect the challenges of reproductive toxicology. Unlike renal, cardiac or pulmonary function, reproductive function occurs intermittently. This means that occupational exposures can interfere with reproduction but go unnoticed during periods when fertility is not desired. This intermittent characteristic can make the identification of a reproductive toxicant in humans more difficult. Another unique characteristic of reproduction, which follows directly from the consideration above, is that complete assessment of the functional integrity of the reproductive system requires that the couple attempt pregnancy.

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Male and female reproductive toxicity are topics of increasing interest in consideration of occupational health hazards. Reproductive toxicity has been defined as the occurrence of adverse effects on the reproductive system that may result from exposure to environmental agents. The toxicity may be expressed as alterations to the reproductive organs and/or the related endocrine system. The manifestations of such toxicity may include:

• alterations in sexual behaviour
• reduced fertility
• adverse pregnancy outcomes
• modifications of other functions that are dependent on the integrity of the reproductive system.

Mechanisms underlying reproductive toxicity are complex. More xenobiotic substances have been tested and demonstrated to be toxic to the male reproductive process than to the female. However, it is not known whether this is due to underlying differences in toxicity or to the greater ease of studying sperm than oocytes.

Developmental Toxicity

Developmental toxicity has been defined as the occurrence of adverse effects on the developing organism that may result from exposure prior to conception (either parent), during pprenatal development or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. The major manifestations of developmental toxicity include:

• death of the developing organism
• structural abnormality
• altered growth
• functional deficiency.

In the following discussion, developmental toxicity will be used as an all-inclusive term to refer to exposures to the mother, father or conceptus that lead to abnormal development. The term teratogenesis will be used to refer more specifically to exposures to the conceptus which produce a structural malformation. Our discussion will not include the effects of postnatal exposures on development.

Mutagenesis

In addition to reproductive toxicity, exposure to either parent prior to conception has the potential of resulting in developmental defects through mutagenesis, changes in the genetic material that is passed from parent to offspring. Such changes can occur either at the level of individual genes or at the chromosomal level. Changes in individual genes can result in the transmission of altered genetic messages while changes at the chromosomal level can result in the transmission of abnormalities in chromosomal number or structure.

It is interesting that some of the strongest evidence for a role for preconception exposures in developmental abnormalities comes from studies of paternal exposures. For example, Prader-Willi syndrome, a birth defect characterized by hypotonicity in the newborn period and, later, marked obesity and behaviour problems, has been associated with paternal occupational exposures to hydrocarbons. Other studies have shown associations between paternal preconception exposures to physical agents and congenital malformations and childhood cancers. For example, paternal occupational exposure to ionizing radiation has been associated with an increased risk of neural tube defects and increased risk of childhood leukaemia, and several studies have suggested associations between paternal preconception occupational exposure to electromagnetic fields and childhood brain tumours (Gold and Sever 1994). In assessing both reproductive and developmental hazards of workplace exposures increased attention must be paid to the ppossibleeffects among males.

It is quite likely that some defects of unknown aetiology involve a genetic component which may be related to parental exposures. Because of associations demonstrated between father’s age and mutation rates it is logical to believe that other paternal factors and exposures may be associated with gene mutations. The well-established association between maternal age and chromosomal non-disjunction, resulting in abnormalities in chromosomal number, suggests a significant role for maternal exposures in chromosomal abnormalities.

As our understanding of the human genome increases it is likely that we will be able to trace more developmental defects to mutagenic changes in the DNA of single genes or structural changes in portions of chromosomes.

Teratogenesis

The adverse effects on human development of exposure of the conceptus to exogenous chemical agents have been recognized since the discovery of the teratogenicity of thalidomide in 1961. Wilson (1973) has developed six “general principles of teratology” that are relevant to this discussion. These principles are:

1. The final manifestations of abnormal development are death, malformation, growth retardation and functional disorder.
2. Susceptibility of the conceptus to teratogenic agents varies with the developmental stage at the time of exposure.
3. Teratogenic agents act in specific ways (mechanisms) on developing cells and tissues in initiating abnormal embryogenesis (pathogenesis).
4. Manifestations of abnormal development increase in degree from the no-effect to the totally lethal level as dosage increases.
5. The access of adverse environmental influences to developing tissues depends on the nature of the agent.
6. Susceptibility to a teratogen depends on the genotype of the conceptus and on the manner in which the genotype interacts with environmental factors.

The first four of these principles will be discussed in further detail, as will the combination of principles 1, 2 and 4 (outcome, exposure timing and dose).

Spectrum of Adverse Outcomes Associatedwith Exposure

There is a spectrum of adverse outcomes potentially associated with exposure. Occupational studies that focus on a single outcome risk overlooking other important reproductive effects.

Figure 1 lists some examples of developmental outcomes potentially associated with exposure to occupational teratogens. Results of some occupational studies have suggested that congenital malformations and spontaneous abortions are associated with the same exposures—for example, anaesthetic gases and organic solvents.

Spontaneous abortion is an important outcome to consider because it can result from different mechanisms through several pathogenic processes. A spontaneous abortion can be the result of toxicity to the embryo or foetus, chromosomal alterations, single gene effects or morphological abnormalities. It is important to try to differentiate between karyotypically normal and abnormal conceptuses in studies of spontaneous abortions.

Figure 1. Developmental abnormalities and reproductive outcomes potentially associated with occupational exposures.

Timing of Exposure

Wilson’s second principle relates susceptibility to abnormal development to the time of exposure, that is, the gestational age of the conceptus. This principle has been well established for the induction of structural malformations, and the sensitive periods for organogenesis are known for many structures. Considering an expanded array of outcomes, the sensitive period during which any effect can be induced must be extended throughout gestation.

In assessing occupational developmental toxicity, exposure should be determined and classified for the appropriate critical period—that is, gestational age(s)—for each outcome. For example, spontaneous abortions and congenital malformations are likely to be related to first and second trimester exposure, whereas low birth weight and functional disorders such as seizure disorders and mental retardation are more likely to be related to second and third trimester exposure.

Teratogenic Mechanisms

The third principle is the importance of considering the potential mechanisms that might initiate abnormal embryogenesis. A number of different mechanisms have been suggested which could lead to teratogenesis (Wilson 1977). These include:

• mutational changes in DNA sequences
• chromosomal abnormalities leading to structural or quantitative changes in DNA
• alteration or inhibition of intracellular metabolism, e.g., metabolic blocks and lack of co-enzymes, precursors or substrates for biosynthesis
• interruption of DNA or RNA synthesis
• interference with mitosis
• interference with cell differentiation
• failure of cell-to-cell interactions
• failure of cell migrations
• cell death through direct cytotoxic effects
• effects on cell membrane permeability and osmolar changes
• physical disruption of cells or tissues.

By considering mechanisms, investigators can develop biologically meaningful groupings of outcomes. This can also provide insight into potential teratogens; for example, relationships between carcinogenesis, mutagenesis and teratogenesis have been discussed for some time. From the perspective of assessing occupational reproductive hazards, this is of particular importance for two distinct reasons: (1) substances that are carcinogenic or mutagenic have an increased probability of being teratogenic, suggesting that particular attention should be paid to the reproductive effects of such substances, and (2) effects on deoxyribonucleic acid (DNA), producing somatic mutations, are thought to be mechanisms for both carcinogenesis and teratogenesis.

Dose and Outcome

The fourth principle concerning teratogenesis is the relationship of outcome to dose. This principle is clearly established in many animal studies, and Selevan (1985) has discussed its potential relevance to the human situation, noting the importance of multiple reproductive outcomes within specific dose ranges and suggesting that a dose-response relationship could be reflected in an increasing rate of a particular outcome with increasing dose and/or a shift in the spectrum of the outcomes observed.

In regard to teratogenesis and dose, there is considerable concern about functional disturbances resulting from the ppossiblebehavioural effects of pprenatal exposure to environmental agents. Animal behavioural teratology is expanding rapidly, but human behavioural environmental teratology is in a relatively early stage of development. At present, there are critical limitations in the definition and ascertainment of appropriate behavioural outcomes for epidemiological studies. In addition it is ppossiblethat low-level exposures to developmental toxicants are important for some functional effects.

Multiple Outcomes and Exposure Timing and Dose

Of particular importance with respect to the identification of workplace developmental hazards are the concepts of multiple outcomes and exposure timing and dose. On the basis of what we know about the biology of development, it is clear that there are relationships between reproductive outcomes such as spontaneous abortion and intrauterine growth retardation and congenital malformations. In addition, multiple effects have been shown for many developmental toxicants (table 1).

Table 1. Examples of exposures associated with multiple adverse reproductive end-points

Relevant to this are issues of exposure timing and dose-response relationships. It has long been recognized that the embryonic period during which organogenesis occurs (two to eight weeks post-conception) is the time of greatest sensitivity to the induction of structural malformations. The foetal period from eight weeks to term is the time of histogenesis, with rapid increase in cell number and cellular differentiation occurring during this time. It is then that functional abnormalities and growth retardation are most likely to be induced. It is ppossiblethat there may be relationships between dose and response during this period where a high dose might lead to growth retardation and a lower dose might result in functional or behavioural disturbance.

Male-Mediated Developmental Toxicity

While developmental toxicity is usually considered to result from exposure of the female and the conceptus—that is, teratogenic effects—there is increasing evidence from both animal and human studies for male-mediated developmental effects. Proposed mechanisms for such effects include transmission of chemicals from the father to the conceptus via seminal fluid, indirect contamination of the mother and the conceptus by substances carried from the workplace into the home environment through personal contamination, and—as noted earlier—paternal preconception exposures that result in transmissible genetic changes (mutations).

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Olav Axelson^*

*Adapted from Axelson 1996.

Early knowledge about the neurotoxic effects of occupational exposures appeared through clinical observations. The observed effects were more or less acute and concerned exposure to metals such as lead and mercury or solvents like carbon disulphide and trichloroethylene. With time, however, more chronic and clinically less obvious effects of neurotoxic agents have been assessed through modern examination methods and systematic studies of larger groups. Still, the interpretation of the findings has been controversial and debated such as the chronic effects of solvent exposure (Arlien-Søborg 1992).

The difficulties met in interpreting chronic neurotoxic effects depend on both the diversity and vagueness of symptoms and signs and the associated problem of defining a proper disease entity for conclusive epidemiological studies. For example, in solvent exposure, the chronic effects might include memory and concentration problems, tiredness, lack of initiative, affect liability, irritability, and sometimes dizziness, headache, alcohol intolerance, and reduced libido. Neurophysiological methods have also revealed various functional disturbances, again difficult to condense into any single disease entity.

Similarly, a variety of neurobehavioural effects also seems to occur due to other occupational exposures, such as moderate lead exposure or welding with some exposure to aluminium, lead, and manganese or exposure to pesticides. Again there are also neurophysiological or neurological signs, among others, polyneuropathy, tremor, and disturbance of equilibrium, in individuals exposed to organochlorine, organophosphorus and other insecticides.

In view of the epidemiological problems involved in defining a disease entity out of the many types of neurobehavioural effects referred to, it has also become natural to consider some clinically, more or less well-defined neuropsychiatric disorders in relation to occupational exposures.

Since the 1970s several studies have especially focused on solvent exposure and the psycho-organic syndrome, when of disabling severity. More recently also Alzheimer’s dementia, multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis, and related conditions have attracted interest in occupational epidemiology.

Regarding solvent exposure and the psycho-organic syndrome (or toxic chronic encephalopathy in clinical occupational medicine, when exposure is taken into diagnostic account), the problem of defining a proper disease entity was apparent and first led to considering en bloc the diagnoses of encephalopathia, dementia, and cerebral atrophy, but neurosis, neurasthenia, and nervositas were also included as not necessarily distinct from each other in medical practice (Axelson, Hane and Hogstedt 1976). Recently, more specific disease entities, such as organic dementia and cerebral atrophy, have also been associated with solvent exposure (Cherry, Labréche and McDonald 1992). The findings have not been totally consistent, however, as no excess of “presenile dementia” appeared in a large-scale case-referent study in the United States with as many as 3,565 cases of various neuropsychiatric disorders and 83,245 hospital referents (Brackbill, Maizlish and Fischbach 1990). However, in comparison with bricklayers, there was about a 45% excess of disabling neuropsychiatric disorders among white male painters, except spray painters.

Occupational exposures also seem to play a role for disorders more specific than the psycho-organic syndrome. Hence, in 1982, an association between multiple sclerosis and solvent exposure from glues was first indicated in the Italian shoe industry (Amaducci et al. 1982). This relationship has been considerably strengthened by further studies in Scandinavia (Flodin et al. 1988; Landtblom et al. 1993; Grönning et al. 1993) and elsewhere, so that 13 studies with some information on solvent exposure could be considered in a review (Landtblom et al. 1996). Ten of these studies provided enough data for inclusion in a meta-analysis, showing about a twofold risk for multiple sclerosis among individuals with solvent exposure. Some studies also associate multiple sclerosis with radiological work, welding, and work with phenoxy herbicides (Flodin et al. 1988; Landtblom et al. 1993). Parkinson’s disease seems to be more common in rural areas (Goldsmith et al. 1990), especially at younger ages (Tanner 1989). More interestingly, a study from Calgary, Canada, showed a threefold risk for herbicide exposure (Semchuk, Love and Lee 1992).

All the case persons who recalled specific exposures reported exposure to phenoxy herbicides or thiocarbamates. One of them recalled exposure to paraquat, which is chemically similar to MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), an inducer of a Parkinson-like syndrome. Paraquat workers have not yet been found to suffer from such a syndrome, however (Howard 1979). Case-referent studies from Canada, China, Spain, and Sweden have indicated a relation with exposure to unspecified industrial chemicals, pesticides, and metals, especially manganese, iron and aluminium (Zayed et al. 1990).

In a study from the United States, an increased risk of motor neuron disease (encompassing amyotrophic lateral sclerosis, progressive bulbar palsy and progressive muscular atrophy) appeared in connection with welding and soldering (Armon et al. 1991). Welding also appeared as a risk factor, as did electricity work, and also work with impregnating agents in a Swedish study (Gunnarsson et al. 1992). Hereditability for neurodegenerative and thyroid disease, combined with solvent exposure and male gender, showed a risk as high as 15.6. Other studies also indicate that exposure to lead and solvents could be of importance (Campbell, Williams and Barltrop 1970; Hawkes, Cavanagh and Fox 1989; Chio, Tribolo and Schiffer 1989; Sienko et al. 1990).

For Alzheimer’s disease, no clear indication of any occupational risk appeared in a meta-analysis of eleven case-referent studies (Graves et al. 1991), but more recently an increased risk was connected with blue-collar work (Fratiglioni et al. 1993). Another new study, which included also the oldest ages, indicated that solvent exposure could be a rather strong risk factor (Kukull et al. 1995). The recent suggestion that Alzheimer’s disease might be related to exposure to electromagnetic fields was perhaps even more surprising (Sobel et al. 1995). Both these studies are likely to stimulate interest in several new investigations along the indicated lines.

Hence, in view of the current perspectives in occupational neuroepidemiology, as briefly outlined, there seems to be a reason for conducting additional work-related studies of different, hitherto more or less neglected, neurological and neuropsychiatric disorders. It is not unlikely that there are some contributing effects from various occupational exposures, in the same manner as we have seen for many cancer types. In addition, as in etiologic cancer research, new clues suggesting ultimate causes or triggering mechanisms behind some of the serious neurological disorders may be obtained from occupational epidemiology.

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