Doseresponse Relationships Risk Assessment

There is a graded dose-response relationship in an individual and a quantal dose-response relationship in the population (see Chapters 1 and 5). Graded doses of a drug given to an individual usually result in a greater magnitude of response as the dose is increased. In a quantal dose-response relationship, the percentage of the population affected increases as the dose is raised; the relationship is quantal in that the effect is specified to be either present or absent in a given individual (see Figure 5-4). This quantal dose-response phenomenon is used to determine the median lethal dose (LD50) of drugs and other chemicals.

There are marked differences in the LD50 values of various chemicals. Some result in death at extremely low doses (LD50 for botulinum toxin = 10 pg/kg); others may be relatively harmless in doses of several grams or more (e.g., penicillin). Even a single chemical may be safe at low doses and quite toxic at higher doses, or safe acutely but harmful over time. Thus, it is not possible to categorize all chemicals as either safe or toxic. The real concern is the risk associated with use of the chemical. Depending on the use and disposition of a chemical, a very toxic compound ultimately may be less harmful than a relatively nontoxic one.

There is much concern about the risk from exposure to chemicals that produce cancer in laboratory animals. Whether these chemicals are human carcinogens is generally unknown. Regulatory agencies take one of three approaches to potential chemical carcinogens. For food additives, the U.S. Food and Drug Administration (FDA) is very cautious because large numbers of people are likely to be exposed to the chemicals, and they are not likely to have beneficial effects to individuals. For drugs, the FDA weighs the relative risks and benefits of the drugs for patients. Thus, it is unlikely that the FDA will approve the use of a drug that produces tumors in laboratory animals for a mild ailment, but it may approve its use for a serious disease. In fact, most cancer chemotherapeutic drugs also are chemical carcinogens.

In the regulation of environmental carcinogens, agencies such as the Environmental Protection Agency (EPA) attempt to limit lifetime exposure such that the incidence of cancer due to the chemical is no more than one in a million people. To determine the daily allowable exposure for humans, mathematical models are used to extrapolate doses of chemicals that produce a particular incidence of tumors in laboratory animals (often in the range of 10-20%) to those that should produce cancer in no more than one person in a million in a lifetime. The models used are conservative and are thought to provide adequate protection from undue risks from exposure to potential carcinogens. As discussed in Chapter 3, variations in drug metabolism often result in substantial differences between the biological responses of humans and rodents (the common laboratory test animals).

acute VERSUS chronic exposure Effects of acute exposure to a chemical often differ from those of chronic exposure. Evaluation of cumulative toxic effects is receiving increased attention because of chronic exposure to low concentrations of various natural and synthetic chemical substances in the environment.

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