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OCR for page 171
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
OCR for page 172
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.
OCR for page 173
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.
OCR for page 174
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.
Representative terms from entire chapter:
physiologically based
