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APPENDIX A An Approach for Risk Assessment of Volatile Organic Chemicals in Drinking Water That Uses Experimental Inhalation Data and a Physiologically Based Pharmacokinetic Mode' The toxicity of trichloroethylene appears to be associated with its metab- olites, and not with the compound itself (NRC, 19861. Figure A-1 is a plot of AMEFF (the effective concentration of reactive metabolite formed in a compartment of specified volume) against inhalation exposure concentrations obtained from computer simulation of the physiologically based pharmacok- inetic model for trichloroethylene. The lowest dose reported in the literature to produce any effect (a hepatic effect) in rats was 56 parts per million (ppm) (NRC, 1986, p. 1871. Under the conditions of the experiments, that exposure would produce 940 mg of reactive metabolite in the liver per liter of liver volume (called effective concentration, target concentration, or delivered dose). Interroute extrapolation with physiologically based pharmacokinetics results in the information presented in Figure A-2, where four drinking water consumption patterns are simulated to produce four curves for AMEFF versus drinking water exposure concentrations. As shown in Figure A-2, it takes trichloroethylene at 380-594 mg/liter, depending on the drinking water con- sumption pattern, to form the AMEFF of 940 mg/liter in the rat liver. Under the assumption that the effective concentration of the toxic metabolite at the cellular or molecular level is the same for all species, further interspecies extrapolation with physiologically based pharmacokinetics yields the infor- mation in Figure A-3 for humans. The predicted results suggest, for instance, that the toxic AMEFF would result if a human drank 2 liters of water that contained trichloroethylene at 1,528 mg/liter in six equal portions every day for a lifetime. 171

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172 DRINKING WATER AND HEALTH Other important applications are possible for interroute simulation by phys- iologically based pharrnacokinetic modeling, as described above. For in- star~ce, Chapter 2 discussed the issue of exposure to chemicals in contaminated drinking water via multiple routes. In addition to ingestion, inhalation ex- posures to compounds that volatilize indoors from various uses and cutaneous exposures from bathing and washing are important. Physiologically based pharmacokinetic modeling can be used to estimate the intake of one or more compounds under these circumstances. 6,000 a) ._ hi. ~ 3,000 11 LL 940 o 7 5/6 ppm I I I I I - 500 INHALED CONCENTRATION (ppm) (1 ppm = 5.4 mg/m3) 1 ,000 FIGURE A-l AMEFF (effective concentration of reactive metabolite formed in compartment of specified volume) vs. inhalation-exposure concentration of trichloroethylene in rat. Computer sim- ulation from physiologically based pharmacokinetic model. Frorn NRC 1986.

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Appendix A 173 2,500 ~ _ a) - I` 1,250 _ lo o 72 380 mg/liter 940 384 mg/literi' ~ I\\t ~_ _ ,:P __~~~' ''1 o 1 ~ 594 mg/liter 1 J 500 1 ,000 DRINKING WATER CONCENTRATION (mg/liter) FIGURE A-2 Dose-route extrapolation for trichloroethylene from inhalation exposure of rats to drinking water exposure with four patterns of drinking water intake. Computer simulation from same physiologically based pharmacokinetic model as in Figure A-1. Numbers at ends of drinking water curves are numbers of equal doses (drinking water patterns) taken by test animal. From NRC, 1986.

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1~74 DRINKING WATER AND HEALTH 2,000 - a) - Cal _ 1,000 lo 6 72 940 At, ''1 ,,.~; :1 1 o 0 0.66 1.33 2.00 2.67 3.33 4.00 - 1,528 mg/liter I 1 1 ,1 DRINKING WATER CONCENTRATION (mg/liter x 103) FIGURE A-3 Interspecies (rats to humans) extrapolation for trichloroethylene, based on physio- logically based pharmacokinetic model of equivalent target-tissue doses (AMEFF, 940 mg/liter). Numbers at ends of drinking water curves are numbers of equal doses (drinking water patterns) taken by human. From NRC, 1986. REFERENCE NRC (National Research Council). 1986. Drinking Water and Health, Vol. 6. R. Thomas, ed. Washington' D.C.: National Academy Press.