dent to assume that mixtures of different substances (i.e., chemical reaction mixtures) will be more toxic than their most toxic ingredient. Furthermore, chemical reactions involving two or more substances may form reaction products that are significantly more toxic than the starting reactants. This possibility of generating toxic reaction products may not be anticipated by the laboratory worker in cases where the reactants are mixed unintentionally. For example, inadvertent mixing of formaldehyde (a common tissue fixative) and hydrogen chloride could result in the generation of bis(chloromethyl)ether, a potent human carcinogen.

It is essential that all laboratory workers understand certain basic principles of toxicology and learn to recognize the major classes of toxic and corrosive chemicals. The next sections of this chapter summarize the key concepts involved in assessing the risks associated with the use of toxic chemicals in the laboratory.

(Also see Chapter 5, section 5.D.)

3.C.1.1 Dose-Response Relationships

Toxicology, the science of poisons, is the study of the adverse effects of chemicals on living systems. The basic tenet of toxicology is that no substance is entirely safe and that all chemicals result in some toxic effects if a high enough amount (dose) of the substance comes in contact with a living system. Paracelsus (1493-1541) elegantly articulated this simple concept five centuries ago when he noted, "All substances are poisons; there is none which is not a poison. The right dose differentiates a poison...." This is perhaps the most important concept for all laboratory workers to be cognizant of. For example, ingestion of water, a vital substance for life, can result in death if a sufficiently large amount (i.e., gallons) is ingested at one time. On the other hand, sodium cyanide, a highly lethal chemical, will produce no permanent effects if a living system is exposed to a sufficiently low dose. The single most important factor that determines whether a substance will be harmful (or, conversely, safe) to an individual is the relationship between the amount (or concentration) of the chemical and the toxic effect it produces. For all chemicals, there is a range of concentrations that result in a graded effect between the extremes of no effect and death. In toxicology, this is referred to as the dose-response relationship for the chemical. The dose is the amount of the chemical and the response is the effect of the chemical. This relationship is unique for each chemical, although for many similar types of chemicals, the dose-response relationships are very similar. Among the thousands of laboratory chemicals, there is clearly a wide spectrum of doses that are required to produce toxic effects and, in some cases, even death. For most chemicals, a threshold dose has been established (by rule or by consensus) below which a chemical is not considered to be harmful.

Some chemicals (e.g., dioxin) will produce death in laboratory animals upon exposure to microgram doses and therefore are obviously extremely toxic. Other substances, however, may have no harmful effects following doses in excess of several grams. One way to evaluate the acute toxicity (i.e., the toxicity occurring after a single exposure) of laboratory chemicals involves consideration of their lethal dose 50 (LD50) or lethal concentration 50 (LC50) value. The LD50 is defined as the amount of a chemical that when ingested, injected, or applied to the skin of a test animal under controlled laboratory conditions will kill one-half (50%) of the animals. The LD50 is usually expressed in units of milligrams or grams per kilogram of body weight. For volatile chemicals (i.e., chemicals with sufficient vapor pressure that inhalation is an important route of chemical entry into the body), the LC50 is often reported instead of the LD50. The LD50 is the concentration of the chemical in air that will kill 50% of the test animals exposed to it. The LC50 is usually given in units of parts per million, milligrams per liter, or milligrams per cubic meter. Also reported are LC10, and LD10 values, which are defined as the lowest concentration or dose that causes the death of test animals. In general, the larger the value of the LD50 or LC50, the more chemical it takes to kill the test animals and therefore the lower the toxicity of the chemical. Although lethal dose values may vary among animal species and between animals and humans, the relative toxicity of different substances is usually relatively constant, and chemicals that are highly toxic to animals are generally highly toxic to humans.

3.C.1.2 Duration and Frequency of Exposure

Toxic effects of chemicals can occur after single (acute), intermittent (repeated), or long-term, repeated (chronic) exposure. An acutely toxic substance can cause damage as the result of a single, short-duration exposure. Hydrogen cyanide, hydrogen sulfide, and nitrogen dioxide are examples of acute toxins. In contrast, a chronically toxic substance causes damage after repeated or long-duration exposure or causes damage that becomes evident only after a long latency period. Chronic toxins include all carcinogens, reproductive toxins, and certain heavy metals (e.g., mercury, lead) and their compounds. Many chronic toxins are extremely dangerous because of their long latency periods: the cumulative effect of low exposures to such substances may not become apparent for many years.



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