4.1 – Chemical Toxicology Overview

The potential toxicity (harmful action) inherent in a substance is exhibited only when that substance comes in contact with a living biological system. The potential toxic effect increases as the exposure increases. All chemicals will exhibit a toxic effect given a large enough dose. The toxic potency of a chemical is thus ultimately defined by the dose (the amount) of the chemical that will produce a specific response in a specific biological system.

There are three main routes by which hazardous chemicals enter the body:

• Absorption through the respiratory tract via inhalation.
• Absorption through the skin via dermal contact.
• Absorption through the digestive tract via ingestion. (Ingestion can occur through eating or smoking with contaminated hands or in contaminated work areas.)

Most exposure standards, such as the Threshold Limit Values (TLVs) and Permissible Exposure Limits (PELs), are based on the inhalation route of exposure. These limits are normally expressed in terms of either parts per million (ppm) or milligrams per cubic meter (mg/m3) concentration in air. If a significant route of exposure for a substance is through skin contact, the SDS, PEL and/or TLV will have a “skin” notation. Examples of substances where skin absorption may be a significant factor include: pesticides, carbon disulfide, carbon tetrachloride, dioxane, mercury, thallium compounds, xylene and hydrogen cyanide.

Acute poisoning is characterized by sudden and severe exposure and rapid absorption of the substance. Normally, a single large exposure is involved. Adverse health effects are often reversible. Examples: carbon monoxide or cyanide poisoning.

Chronic poisoning is characterized by prolonged or repeated exposures of a duration measured in days, months or years. Symptoms may not be immediately apparent. Health effects are often irreversible. Examples: lead or mercury poisoning.

Local effect refers to an adverse health effect that takes place at the point or area of contact. The site may be skin, mucous membranes, the respiratory tract, gastrointestinal system, eyes, etc. Absorption does not necessarily occur. Examples: strong acids or alkalis on the skin.

Systemic effect refers to an adverse health effect that takes place at a location distant from the body’s initial point of contact and presupposes absorption has taken place. Examples: arsenic affects the blood, nervous system, liver, kidneys and skin; benzene affects bone marrow.

Cumulative poisons are characterized by materials that tend to build up in the body as a result of numerous chronic exposures. The effects are not seen until a critical body burden is reached. Example: heavy metals.

Substances in combination: When two or more hazardous materials are present at the same time, the resulting effect can be greater than the effect predicted based on the additive effect of the individual substances. This is called a synergistic or potentiating effect. Example: exposure to alcohol and chlorinated solvents; or smoking and asbestos.

Rate of entry and route of exposure; that is, how fast is the toxic dose delivered and by what means.

Age can affect the capacity to repair tissue damage.
Previous exposure can lead to tolerance, increased sensitivity or make no difference.

State of health, physical condition and life style can affect the toxic response. Pre-existing disease can result in increased sensitivity.

Environmental factors such as temperature and pressure.

Host factors including genetic predisposition and the sex of the exposed individual.

Gas applies to a substance, which is in the gaseous state at room temperature and pressure.

A vapor is the gaseous phase of a material, which is ordinarily a solid or a liquid at room temperature and pressure.

When considering the toxicity of gases and vapors, the solubility of the substance is a key factor. Highly soluble materials, like ammonia irritate the upper respiratory tract. On the other hand, relatively insoluble materials, like nitrogen dioxide, penetrate deep into the lung. Fat-soluble materials, like pesticides, tend to have longer residence times in the body and be cumulative poisons.

An aerosol is composed of solid or liquid particles of microscopic size dispersed in a gaseous medium.

The toxic potential of an aerosol is only partially described by its airborne concentration. For a proper assessment of the toxic hazard, the size of the aerosol’s particles must be determined. A particle’s size will determine if a particle will be deposited within the respiratory system and the location of deposition. Particles above 10 micrometers tend to deposit in the nose and other areas of the upper respiratory tract. Below 10 micrometers particles enter and are deposited in the lung. Very small particles (<0.2 micrometers) are generally not deposited but exhaled.

Irritants are materials that cause inflammation of mucous membranes with which they come in contact. Inflammation of tissue results from exposure to concentrations far below those needed to cause corrosion. Examples include:

• Ammonia
• Alkaline dusts and mists
• Hydrogen chloride
• Hydrogen fluoride
• Halogens
• Ozone
• Phosgene
• Diethyl/dimethyl sulfate
• Nitrogen dioxide
• Phosphorus chlorides
• Arsenic trichloride

Irritants can also cause changes in the mechanics of respiration and lung function. Examples include:

• Sulfur dioxide
• Acetic acid
• Formaldehyde
• Formic acid
• Sulfuric acid
• Acrolein
• Iodine

Long term exposure to irritants can result in increased mucous secretions and chronic bronchitis.

A primary irritant exerts no systemic toxic action either because the products formed on the tissue of the respiratory tract are non-toxic or because the irritant action is far in excess of any systemic toxic action. Example: hydrogen chloride.

A secondary irritant’s effect on mucous membranes is overshadowed by a systemic effect resulting from absorption. Examples include hydrogen sulfide and aromatic hydrocarbons.

Asphyxiants have the ability to deprive tissue of oxygen.

Simple asphyxiants are inert gases that displace oxygen. Examples include:

• Nitrogen
• Nitrous oxide
• Carbon dioxide
• Hydrogen
• Helium

Chemical asphyxiants reduce the body’s ability to absorb, transport, or utilize inhaled oxygen. They are often active at very low concentrations (a few ppm). Examples include carbon monoxide and cyanides.

Primary anesthetics have a depressant effect upon the central nervous system, particularly the brain. Examples include halogenated hydrocarbons and alcohols.

Hepatotoxic agents cause damage to the liver. Examples include carbon tetrachloride, tetrachloroethane, and nitrosamines.

Neurotoxic agents damage the nervous system. The nervous system is especially sensitive to organometallic compounds and certain sulfide compounds. Examples include:

• Trialkyl tin compounds
• Tetraethyl lead
• Methyl mercury
• Carbon disulfide
• Organic phosphorus insecticides
• Thallium
• Manganese

Some toxic agents act on the blood or hematopoietic system. The blood cells can be affected directly or the bone marrow (which produces the blood cells) can be damaged. Examples include:

• Nitrites
• Aniline
• Toluidine
• Nitrobenzene
• Benzene

There are toxic agents that produce damage of the pulmonary tissue (lungs) but not by immediate irritant action. Fibrotic changes can be caused by free silica and asbestos. Other dusts can cause a restrictive disease called pneumoconiosis. Examples include coal dust, cotton dust, and wood dust.

A carcinogen is an agent that can initiate or increase the proliferation of malignant neoplastic cells or the development of malignant or potentially malignant tumors. Known human carcinogens include:

• Asbestos
• 4-nitrobiphenyl
• Alpha-napthylamine
• Methyl chloromethyl ether
• 3,3′-Dichlorobenzidine
• Bis-chloromethyl ether
• Vinyl chloride
• Inorganic arsenic
• Ethylene oxide
• 1,2-Dibromo-3-chloropropane (DBCP)
• N-nitrosodimethylamine
• Coal tar pitch volatiles

A mutagen interferes with the proper replication of genetic material (chromosome strands) in exposed cells. If germ cells are involved, the effect may be inherited and become part of the genetic pool passed onto future generations.

A teratogen (embryotoxic or fetotoxic agent) is an agent, which interferes with normal embryonic development without causing a lethal effect to the fetus or damage to the mother. Effects are not inherited. Examples include lead and thalidomide.

A sensitizer is a chemical, which can cause an allergic reaction in normal tissue after repeated exposure to the chemical. The reaction may be as mild as a rash (allergic dermatitis) or as serious as anaphylactic shock. Examples include:

• Epoxies
• Toluene diisocyanate
• Nickel compounds
• Chromium compounds
• Poison ivy
• Chlorinated hydrocarbons