prior to their use in an experiment. The risk of toxic effects is related to both the extent of exposure and the inherent toxicity of a chemical. As discussed in detail below, extent of exposure is determined by the dose, the duration and frequency of exposure, and the route of exposure. Exposure to even large doses of chemicals with little inherent toxicity, such as phosphate buffer, presents low risk. In contrast, even small quantities of chemicals with high inherent toxicity or corrosivity may cause significant adverse effects. The duration and frequency of exposure are also critical factors in determining whether a chemical will produce harmful effects. A single exposure to some chemicals is sufficient to produce an adverse health effect; for other chemicals repeated exposure is required to produce toxic effects. For most substances, the route of exposure (through the skin, the eyes, the gastrointestinal tract, or the respiratory tract) is also an important consideration in risk assessment. For chemicals that are systemic toxicants, the internal dose to the target organ is a critical factor. Exposure to acute toxicants can be guided by well-defined toxicity parameters based on animal studies and often human exposure from accidental poisoning. The analogous quantitative data needed to make decisions about the neurotoxicity and immunogenicity of various chemicals is often unavailable.

When considering possible toxicity hazards while planning an experiment, recognizing that the combination of the toxic effects of two substances may be significantly greater than the toxic effect of either substance alone is important. Because most chemical reactions produce mixtures of substances with combined toxicities that have never been evaluated, it is prudent 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 trained laboratory personnel in cases where the reactants are mixed unintentionally. For example, inadvertent mixing of formaldehyde (a common tissue fixative) and hydrogen chloride results in the generation of bis(chloromethyl)ether, a potent human carcinogen.

All laboratory personnel must understand certain basic principles of toxicology and 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 6, section 6.D.) Box 4.1 provides a quick guide for performing a toxicity-based risk assessment for laboratory chemicals.

4.C.1.1 Dose-Response Relationships

Toxicology is the study of the adverse effects of chemicals on living systems. The basic tenets of toxicology are 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. As mentioned in Chapter 2, Paracelsus noted that the dose makes the poison and is perhaps the most important concept for all trained laboratory personnel to know. For example, water, a vital substance for life, results 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, produces no permanent (acute) effects if a living system is exposed to a sufficiently low dose. The single most important factor that determines whether a substance is harmful (or, conversely, safe) to an individual is the relationship between the amount (and concentration) of the chemical reaching the target organ, 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 range 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 similar types of chemicals, the dose-response relationships are often similar. (See Figure 4.2.) Among the thousands of laboratory chemicals, a wide spectrum of doses exists that are required to produce toxic effects and 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 to most individuals.

In these curves, dosage is plotted against the percent of the population affected by the dosage. Curve A represents a compound that has an effect on some percent of the population even at small doses. Curve B represents a compound that has an effect only above a dosage threshold.

Some chemicals (e.g., dioxin) produce death in laboratory animals exposed to microgram doses and therefore are extremely toxic. Other substances, however, 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 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 kills one-half (50%) of the animals. The LD50 is usually expressed in milligrams or grams per kilogram of body weight. For volatile chemicals (i.e., chemicals with sufficient

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