PRINCIPLES OF TOXICOLOGY - Biology East Borneo

1.3 THE IMPORTANCE OF DOSE AND THE DOSE–RESPONSE RELATIONSHIP 9TABLE 1.2 Cross-Matching Exercise: Occupational Exposure Limits—Aspirin and Vegetable OilVersus Industrial SolventsThe chemicals listed in this table are not correctly matched with their allowable workplace exposure levels.Rearrange the list so that they correctly match. The correct order can be found in the answer table at the end ofthe chapter.NAllowable Workplace Exposure Level(mg/m 3 ) Chemical (use) Correct Order1 0.1 Aspirin (pain reliever) ____________2 5 Gasoline (fuel) ____________3 10 Iodine (antiseptic) ____________4 55 Naphtha (rubber solvent) ____________5 170 Perchloroethylene (dry-cleaning fluid) ____________6 188 Tetrahydrofuran (organic solvent) ____________7 269 Trichloroethylene (solvent/degreaser) ____________8 590 1,1,1-Trichloroethane (solvent/degreaser) ____________9 890 1,1,2-Trichloroethane (solvent/degreaser) ____________10 1590 Toluene (organic solvent) ____________11 1910 Vegetable oil mists (cooking oil) ____________4. The test duration (observation period)5. A series of doses to testPossible test organisms range from isolated cellular material or selected strains of bacteria throughhigher-order plants and animals. The response or biological endpoint can range from subtle changes inorganism physiology or behavior to death of the organism, and exposure periods may vary from a few hoursto several years. Clearly, tests are sought (1) for which the response is not subjective and can be consistentlydetermined, (2) that are conclusive even when the exposure period is relatively short, and (3) (for predictingeffects in humans) for which the test species responds in a manner that mimics or relates to the likely humanresponse. However, some tests are selected because they yield indirect measurements or special kinds ofresponses that are useful because they correlate well with another response of interest; for example, thedetermination of mutagenic potential is often used as one measure of a chemical’s carcinogenic potential.Fortunately or unfortunately, each of the five basic components of a toxicity test protocol maycontribute to the uniqueness of the dose–response curve that is generated. In other words, as onechanges the species, dose, toxicity of interest, dosage rate, or duration of exposure, the dose–responserelationship may change significantly. So, the less comparable the animal test conditions are to theexposure situation you wish to extrapolate to, the greater the potential uncertainty that will exist in theextrapolation you are attempting to make. For example, as can be seen in Table 1.3, the organ toxicityobserved in the mouse and the severity of that toxic response change with the air concentration ofchloroform to which the animals are exposed. Both of these characteristics of the response—organtype and severity—also change as one changes the species being tested from the mouse to the rat.In the mouse the liver is apparently the most sensitive organ to chloroform-induced systemictoxicity; therefore, selecting an air concentration of 3 ppm to prevent liver toxicity would also eliminatethe possibility of kidney or respiratory toxicity. If the concentration of chloroform being tested isincreased to 100 ppm, severe liver injury is observed, but still no injury occurs in the kidneys orrespiratory tract of the mouse. If test data existed only for the renal and respiratory systems, an exposurelevel of 100 ppm might be selected as a no-effect level with the assumption that an exposure limit atthis concentration would provide complete safety for the mouse. In this case the assumption would beincorrect, and this allowable exposure level would produce an adverse exposure condition for themouse in the form of severe liver injury.Note also that a safe exposure level for kidney toxicity in the mouse, 100 ppm, would not preventkidney injury in a closely related species like the rat. This illustrates the problem in assuming that two