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British Journal of'Industrial Medicine, 1977, 34, 56-63 A pharmacokinetic model to study the excretion of trichloroethylene and its metabolites after an inhalation exposure AKIO SATO, TAM1E NAKAJIMA, YUKIKO FUJIWARA, AND NINZO MURAYAMA Department of Hygiene, Shinshtt University Faculty of Medicine, Matsunioto, Japan abstract For a better understanding of absorption, distribution, excretion, and metabolism of trichloroethylene the time-course of blood concentration of the vapour and urinary excretion of its metabolites was examined using a pharmacokinetic model. After a single experimental exposure in w hich four men inhaled 100 parts per million (ppm) of trichloroethylene for four hours an elimin ation curve showed three exponential components, that is, x = 1005e~I6,7u + 0'449e_,,7l0t -f 0'255c'(1,20-7t. where x is the blood concentration in mg/1 and t the time in hours from 0 to 10. The overall rate constant for the disappearance of trichloroethylene was found to agree with the theo retical one. estimated by means of a mathematical model foi the blood concentration data. A - X/> plot, developed from a mathematical model for urinary excretion, could also give a good estimate of rate constants for the transfer of trichloroethylene in the body. The rate constant thus estimated from urinary excretion was consistent with data on the blood concentration. As industrial exposure to trichloroethylene vapour is liable to vary, air analysis does not necessarily give a real indication of the true exposure. A quanti tative index of a worker's exposure can be estimated according to the amount of trichloroethylene being absorbed in his body (Roach, 1966; Elkins, 1967). Monitoring trichloroethylene levels in blood or ex pired air and measuring urinary metabolites of tri chloroethylene are currently the most common techniques for determining the body burden of the vapour (Ahlmark and Forssman, 1951; Stewart et ah, 1962,1970,1974; Morgan et ah, 1970;Nomiyama, 1971; Ogata et al,, \91\ \ Ertle et ah, 1972; Ikeda et ah, 1972; Muller et ah, 1972, 1974; PfalTli and Backman, 1972; Kimmerle and Eben, 1973; Lowry et ah, 1974). Estimation and prediction of the body burden of trichloroethylene, however, require precise information on the absorption, distribution, excretion,and metabolism oftlie vapour in the human body. Such information, obtained from a single experimental exposure, would lead to knowledge of the transfer of trichloroethylene in the body in Receded for publication 2 February 1976 Accepted for publication IS June 1976 chronic exposure, which is a common situation in a work place (Sato and Nakajima, 1977). In the current study a mathematical model was developed to simulate the processes of absorption, distribution, excretion, and metabolism of tri chloroethylene, the rate constants for each pro cess being estimated from the time-course data of the vapour concentration in blood and the urinary excretion of its metabolites. Experiments SOLUBILITY OF TRICHLOROF.THYLENE IN TISSUES OF RATS The blood/air and tissue/blood partition coefficients were determined according to the method of Sato et ah (1974) with minor modifications. Tissue ex cised from a freshly killed rat was stripped of capsular and vascular connective tissues anil weighed. The tissue was then homogenised with a known volume of 0-9"' saline. Five vials of equal size, each 16-5 ml on average and containing I ml of the tissue homogenates, were used as test vessels. 01 ml of a trichloroethylene solution in saline containing 10 ftl/l was put into the vials on which rubber and aluminium-foil stoppers were placed as quickly as SL 032819 - 'iyyn.im*uri A pharmacokinetic modeI to study the excretion of trichloroethylene and its metabolites 57 possible. Five other vials were treated in a similar chamber ceiling recirculated the air thus providing manner to act as controls except that in these, there were no tissue samples. Both the test and control vessels were kept at a temperature of .77 C in a thermoregulated water bath with a shaker for about the homogenous exposure mixture. The atmospheric concentration was monitored by gas chromato graphy every 20 minutes during exposure. two to six hours. After equilibration of trichloro DETERMINATION OF TRICHLOROETHYLENE ethylene vapour between the lest material and over IN It LOO D AND EXHALED AIR lying air was achieved, I ml of the gas phase was The examiner entered the chamber towards the end extracted by an air-tight syringe through the stopper of the four hours' exposure and collected blood and was introduced into a gas chromatograph. The samples from cubital veins of each subject when his tissue/air partition coefficient, which equals (con exposure had ceased. Immediately after leaving the centration in tissucl/tconcentration in air) by defini chamber the subjects exhaled the end-tidal air into a tion. was calculated from peak heights on the chro 100 ml glass syringe through an air tube attached to matogram in the same way as reported by Sato et the end of the syringe. They held their breath for 10 al. (1974). The tissuc/blood partition coefficient was seconds at a normal expiration, and then exhaled expressed as the ratio of the tissue/air partition co the residue into the syringe. Thereafter, blood and efficient to the blood/air partition coefficient. end-tidal air were collected at predetermined in tervals for 10 hours. The concentration of tri EXPERIMENTAL HUMAN EXPOSURE TO chloroethylene in blood was determined by a gas TRICHLOROETHYLENE chromatographic equilibration method (Sato et al., Four male Japanese medical students, 20 to 21- 1975a). The concentration in exhaled air was years-old, and weighing on average 61-6 kg, served measured by injecting a portion of the sampled air as volunteers for the experiment in which they in directly into a gas chromatograph with an air-tight haled 100 ppm of trichloroethylene for four hours. syringe (Sato, 1968). After cessation of exposure the concentration of trichloroethylene in blood and exhaled air and the amount of its urinary metabolites, that is, trichloro DETERMINATION OF URINARY METABOLITES OF TRICHLOROETHYLENE acetic acid (TCA), trichloroethanol (TCE), ana total The subjects had to collect all urine excreted at tricftForocompbund (TTC), was measured and the preselected intervals after exposure. TCA, TCE, and time-course of these data was obtained. TTC were determined according to the method of Tanaka and Ikeda (1968). EXPOSURE CHAMBER Air for inhalation containing 100 ppm of trichloro Results ethylene was prepared by passing it through liquid trichloroethylene in a gas-washing bottle at a known SOLUBILITY OF TRICHLOROETHYLENE IN rate and diluting this saturated air with fresh air, BODY TISSUES OF RATS flowing in with a metered volume of ventilation. The partition coefficients of trichloroethylene for Several preliminary tests showed that this simple various body tissues arc shown in Table 1, as well as method of atmosphere generation was satisfactory. those for triolein, cholesterol, lecithin, human blood, The experimental exposure was as follows; The and human fat. The solubility coefficient of the volunteers entered the exposure chamber of 12-5 m3 vapour for fat is much higher than for other tissues: capacity in which there was no trichloroethylene. the tissuc/hlood partition coefficient was about 70 To achieve a rapid build-up to the required con for fat, and 1-3 for most other tissues. The high centration, a predetermined amount of liquid tri solubility of trichloroethylene in fat compared with chloroethylene was injected through a rubber stopper blood was also confirmed with human fat and blood. attached to the monitoring window of the chamber The fact that triolein has an extremely high affinity at a sheet of gauze hung behind the window. The in- for trichloroethylene compared with lecithin and ? jeeted trichloroethylene was vaporised and mixed cholesterol suggests that fat content in the form of ' thoroughly by an electric fan. Several minutes after neutral fat in any tissue is a primary determinant injection when the concentration had reached the for the level of solubility in that tissue. Fat tissue required level, the air stream saturated with tri chloroethylene (2 1/min) was introduced into the chamber, accompanied by a constant rate of ventila tion which had been adjusted beforehand so as to can he said therefore to play a very important role in the processes of absorption, distribution, and elimi nation of trichloroethylene. As in the case of other fat-soluble vapours such as benzene (Fiserova- maintain the desired concentration, 100 ppm, of Bctgerova et al., 1974; Sato et al., 1974), toluene trichloroethylene. An electric fan mounted on the (Sato et al., 1974), and tetrachloroethylcne (Guberan T SL 032820 58 Akto Sato, Tumic Nokajima, Yukiko Fujiwara, ami Ninzo Mttroyama Table 1 Partition coefficients of trichloroethylene for various body tissues of rats Mean Standard deviation Five rats Blood 'air Lung/blood Heart/blood Kidney/blood Liver/blood Musclc/blood Bram/blood Testis/blood Splccn/blood Fat/blood 25-82 I 03 ! * 10 1 55 1 69 0 63 1-29 0 7! 1 IS 25-59 1 70 0 17 0 31 0 48 0 37 009 028 0 12 0 20 1 08 Fjw* determinations Blood/air (human)1 Fm/atr (human)1 Lecilhm/air Cholesicrol/air Cholesterol olealc/air Tnolein/air 992 674-40 387-90 52 15 261 93 84,3 24 063 3408 27 97 9 59 35-20 31-33 'Prcverved blood from blood bank was used ! Die human fat tissue was obtained from a 23*>ear-o1d woman who died of acute mvcloid leukaemia. and Fernandez, 1974). a thrce-compartmcnt model can be applied to the transfer of trichloroethylene in the body, which is composed of (1) the tissue of the vessel-rich group (VRG) for example, brain, liver, kidney, etc,; (2) low perfused tissue of the muscle group (MG) for example, muscle and skin: and (3) poorly perfused tissue of tl\c fat group (FG) for example, fat tissue and yellow bone marrow (Eger, 1963). EXPERIMENTAL HUMAN EXPOSURE TO TRICHLOROETHYLENE Elimination kinetics of trichloroethylene in blood The decrease of trichloroethylene concentration in blood and exhaled air with time is shown in Fig. I. Each decay curve was resolved into three exponen tial components, using the general expression as follows: x = Aie_a,t 4- Aze-*-1 + A3e-at, (1) where x is the concentration in mg/1, t the time in hours, and the values for Ai and eti (i = 1,2, and 3) arc shown in the figure. Sato et al. (1974) reported that when a solvent reaches an apparent equilibrium throughout the entire body after a sufficient time has elapsed, the transfer of the vapour in the body can be simulated by the model in Fig. 2, where the whole body is treate'd as a single body mass. When this model is applied to trichloroethylene, its intake and output to and from the entire body can be expressed in the following differential equation: v= - + b>*. (2) where V is the distribution volume of trichloro ethylene and r equals the time elapsed after the trichloroethylene has reached apparent equilibrium period: In the equilibrium: V = AiVi 4- AaVa + A3V3. (3) Solving (2) for x, Axa + b x = Xoe V f, (4) yvhere x(> is the concentration of trichloroethylene in blood just when it has reached the equilibrium, that is, t -- 0. From equation 3, the rate constant for disappearance of trichloroethylene, (AAa + b)/V, becomes (A ya 4- b)/(AiVi + A>Vz + A3V3). Assuming that the eventual rate constant, a3 in (1), is equal to this rate constant, we have AAa + b 03 A1V1 + AaVa 4- A3V3 * ^ Since A3V3 > AiVi, A2V2 for equation 5 can be reduced to AAa + b as = ~vT trichloroethylene, (6) The metabolic clearance for trichloroethylene was unknovMi. Substituting the value in j able 2 for a& a", Aa, A3 and V3 in (6) resulted in b = 104. SL 032821 -t- TTP W A pharmacokinetic model to study the excretion of trichloroethylene ctnd its metabolites 59 Vgi bx shown in Fig. 4 (Williams, 1959; Daniel, 1963; Byington and Leibman, 1965), where all the rate constants arc assumed to be first-order rate con stants Let Xa, Xn, Xp.and Xi> be the amounts of A, B, C, and D, respectively, at time t which equals the time that has elapsed after the cessation of the exposure. We then have for the model in Fig. 4, dXA ,, = -- (ki 4- k)Xx, (7) dXn = kiXx -- (k2 + ki 4- kj)Xp, (8) dXc = kiXn -- k3Xc , (9) Fig. 2 A model for transfer of trichloroethylene in the body, a : Alveolar ventilation, 1/hour. b : Metabolic clearance, 1/hour. rC,J : Compartment composed of VRG. [Cj] : Compartment composed of MG. [C,] : Compartment composed of FG. x, ; Concentration in [CJ, mg/1. X; : Concentration in [C3], nig/I. x, : Concentration in |CS], mg/I. Av : Air/blood partition cocfTicicnt. A, ; V RG'blood pnitition coefficient. Aj : MG, blood partition cocfTicicnt. A, ; FG/blood partition coefficient. V, : Volume of VRG, 1, Vj : Volume of MG, 1. Vj . Volume of FG, 1. Broken lines w ith arrows show blood flow through each compartment. Table 2 Values used in the present model v,. I V,, I v,, I a, I /hour b, 1/hour A, Ai A. hour*1 8` 3P 1Q 336* 104* or* 15* 1-0* 68 0* 0-2027* 'died from Sato <*/ (tL (1974). 'Results obtained in (he current investigation. Excretion kinetics of urinary metabolites The time-courses of urinary excretion of TCA, TCE, and TTG arc shown in Table 3. The cumulative amount of each metabolite was plotted against time as shown in Fig. 3. The major metabolic pathway of trichloroethylene in a living body is generally considered to be as dXo and -jjj- = k3Xc . (10) Solving (7) for Xa, XA = A0c-ICAt. (ID where A,, is the amount of A at t = 0, and k* => ki + k i. (kx is the werall rate constant for loss of A from the body, and it has already been mentioned that kx will be equal to (AAa + b)/V, when tri chloroethylene will have reached an apparent equilibrium.) Front (8), (9), and f 11) we obtain Xc - Qne k'> - Qac-k' + Qie~k*' , (12) where kn = k3 + kt + kj (kn is the overall rate constant for loss of B from the body.). Bo and Co the amount of B and C at t = 0, respectively, and where kika Ql = (k'A - kn) (kA - k3)Ao ' ks ki Qs kn -- (Bo k$ 4- jk;x -- knp- Ao) k2 and Q3 = Co + ka -- k3 Bo 4- ktkz (kn - k3)(kA - k3)Ao- Substituting Xc in (12) into (10), dXn j~ = k3Q3e'k)t -- k3Q2e*kBt 4- k3Qre kAt (13) Solving (13) for Xp, k2 kika Xd ~ Do 4- Co 4- r-Bo 4- r--t~~ Ao kn kxkn ]^f| - - Q.)e-k>< + --Q;e-kB* - jCAQie_'tAt. (14) where D,, is the amount of D at t = 0. Let Doo be the total amount of D, that is, the total Tr rr 7 SL 032822 60 Akio Sato, Tatnic Nakajima, Yukiko Fnjiwara, and ffineo Murayanta amount of any one of TCA, 1CE, or TTC excreted in urine, we have Ddo -- ^3 (* Xcdt = Do 4- Co 4* f" Bo 4- ,--j-- Ao J ,, kn k.\kn The equation (14) can therefore be reduced to D -- Xd = Qse-,t,t -- j^Q2e~kl!t + Qie_k*1. _05) Since k3 <S kA or ki-,, we can see that when D -- Xr> is plotted on a logarithmic scale against time, the slope of the line drawn through the second half of the points will be -k3. When this line extra polated to t = 0 and |Qae_fc=< - (D - Xn)| is replotted, the slope of the line drawn through the points at the tail end of this plot will give an estimate of the smaller one of the two rate constants, kA and kn, and the slope determined from the residual points an estimate of the larger one (Fig. 5). The D - Xn plots for TCA, TCE. and TTC resulted in the expressions as follows: D - Xd(TCA) = 113'56e--177t - 59-30e-o-'is` 4- 16'89e-0-21!w D - Xn(TCE) = 216-23e- nS83t + 75-23e- i` D - Xd(TTC) = 303-24C-0-0-4' - 39 44c' + 79'34e_IMfis(H The estimates of kx thus obtained from TCA- and TTC-plots agree generally with the eventual rate constant, an in (1), which was more directly deter mined from the time-course of blood or exhaled air concentration of trichloroethylene. The reason why the TCE-plot alone did not result in a three-exponen tial expression has not yet been fully elucidated, but may be due to the fact that the plotted values for TCA and TTC are directly measured but the value for TCE is indirectly estimated, being expressed as the difference between these values for TCA and TTC. Discussion The quantitative study of the time-course of absorp tion, distribution, excretion, and metabolism of toxic substances is a useful tool in studying the characteristics of toxic elTccts induced by them (Levy and Gibaldi, 1972; Sato etaL, 1975b). The processes of uptake and washout of organic solvent vapours in a human body have recently been studied using an analogue or mathematical model, which simulates the processes and gives an adequate prediction (Fiserova-Bergerova et al., 1974; Cuberan and Fernandez, 1974), With few exceptions, most pharmacokinetic models have been built on the assumption that blood perfusion alone is an effective medium of transport for all tissues in a living body (Kety, 1951), The mathematical model based on this perfusionlimited assumption, failed to simulate the time-course of elimination of inhaled benzene and toluene in men (Sato et al1974). For the transfer of fat-soluble compounds direct diffusion between neighbouring tissues, each having different perfusion/partition properties and hence being tilled and emptied at a different rate, was found to be a significant pathway in addition to perfusion (Perl et al., 1965). Taking account of this intertissue diffusion, we have assumed that it takes no longer than three hours after exposure has ceased for trichloroethylene to reach an apparent equilibrium and then to be distri buted throughout the body according to its partitioning characteristics between blood and Tabic 3 Urinary excretion of TCA, TCE, and TTC Interval of measurements (hours) 0-1 1-2 2-4 4*8 8-12 12-16 16-24 24-36 36-48 48-60 60-72 72-84 84*96 96-1 OS 108*120 120-132 132-144 144-156 156*168 168-1 $0 Miditme (hour) 0-5 1-5 30 60 too 14 0 20 0 300 42 0 54 0 66 0 78 0 900 102 0 114 0 1260 138 0 1500 1620 174 0 Amount measured (mg) mean i SD TCA TCE 0 21 * o 18 0 25 0 08 0 57 0 27 2-37 1 57 1 32 0 61 0 93 *- 0 26 2 15 J_ 0 74 4 32 -b 1-31 8 17 _b 3 OS 7 79 1-84 7 83 148 6 95 -t 2-64 4 J4 0 91 4-56 t 22 3 32 0-93 3 23 J- 1 18 4 00 2 30 2 44 i 0-32 . I 44 * 0 53 2 55 0 32 13 03 3-25 11 00 4 66 21-46 10 34 36-28 5-55 31-45 7-15 26 70 7-64 33-58 5 75 39-70 10-99 22 57 7-76 17 03 J- 3 76 11-50 4-95 6 52 t 4-62 3-88 1 58 6 00 1-39 3-14 + 1 85 217 -b 1-29 1-65 0 54 0-88 -1- 0-70 108 0-80 1 17 0-53 TTC 13-24 h 3 12 11 24 4-73 22 03 10 44 38 65 6 35 32-77 7 30 27 63 4 53 35-73 5-56 44 02 11-01 30-74 8-76 24 82 2-28 19 33 6 28 13 47 4 10 8-22 2-36 10 56 2-44 6 45 261 541 1-88 5 66 2 83 3-32 069 2-52 099 3-71 0-76 SL 032823  i nma |il as and sorpm of - the Levy esses is in it* an 'ialcs etion and inctic that a of ion'Mrse i men iuble "'ing uion at a nvay king lied re an triits and A pharmacokinetic model to study the excretion of trichloroethylene and its metabolites 61 amount metabolised bx P - total amount absorbed ~ (-Ua"^- b)x TTb <16) Substitution of b = 104 for b in (16) resulted in p = 0-75, which is not very ditferent from the one measured more directly by other investigators. Therefore, the assumptions that trichloroethylene j ! ( Fig. 3 Cumulative amount of metabolites excreted in urine. tissues. The value of 104 1/hour for metabolic clearance was estimated by treating the whole body in the equilibrium as a single body mass. So far there is no proof for these assumptions, but they would be supported indirectly if the quantities predicted agreed with the quantities measured by other methods. About 70-80% of the absorbed trichloro ethylene was reported to be excreted in urine as metabolites and the remaining 20-30% to be eliminated unchanged in expired air (Bartonicek, 1962; Nomiyama and Nomiyama, 1971; Ogata et al., 1971). Assuming that the loss of trichloro ethylene absorbed in man through other pathways is negligible, the ratio, i>, of the amount metabolised to the total amount absorbed is given as follows: Fig. 4 Metabolic pathways of trichloroethylene. A : Trichloroethylene in the body. B : A metabolite of trichloroethylene in the body, possibly chloral hydrate.--TC C : A metabolite" of trichloroethylene in the body, which is to be excreted and applies to any one of TCA, TCE, and TTC. D : C excreted in urine (TCA, TCE, or TTC). k,, : Rate constant for the step A-i-B, which is another quantity from the metabolic clearance b in Fig. 1. kj : Rate constant for the step B->C. k, : Rate constant for the step C-i-D. k4 : Rate constant for the loss of A through other pathways than A-*B. (k, corresponds approxi mately to the elimination through the lungs, but is not identical to a in Fig, 1.) kj,kj : Rate constant for the pathways for disposal of B other than the B-+-C step. Table 3 Urinary excretion of TCA, TCE, and TTC JXn!4tt mgjhour 7CA TCE TTC 0 21 13 03 13-54 o :s II 00 1124 0 29 10 74 11 02 0 60 907 9-67 033 7 87 819 0-23 6 68 6 91 0 27 4 20 4-47 0 36 3 31 3 67 0 68 1-83 2 56 0 65 1 42 207 0 65 0 96 1-61 0 58 0 54 1-12 0 36 0 32 068 0 38 0 50 0 88 0-28 0-26 0-54 o v 018 0 45 0-33 0 14 047 0 20 0 07 0 28 012 009 0 21 0 2! 0-10 0-31 ^fhe value is equal to D. A'd, me TCA 021 0 45 102 3 39 4*71 5 64 7-79 1211 20-28 28 06 35-89 42-84 4718 51-74 55 05 58 29 62*29 61 73 66 16 68*711 TCE 13 03 24 02 45-48 81*76 113 20 139 91 173 49 213 18 235-76 252 79 264 29 27081 274 68 280 68 283 82 285-99 287 64 288*53 289*61 290 77' TTC 13 24 24 48 46-53 8518 1(7 90 145 53 181 27 225-29 256 03 280 85 300 17 313 64 321 86 332*42 338 87 344 28 349 93 353*25 355*77 359 48l - Xu. ":g TCA TCE 68 51 68*25 67*69 65 33 64-00 63 08 60 93 56 61 48*44 40*65 32 83 25 88 21*54 16 98 13 66 10 43 6 43 3 99 2 35 0 277-74 266 75 245*29 209 01 177-56 150*87 117-29 77 59 55 02 37-99 2649 1997 1609 1009 6*95 4 78 3 13 2-25 1*17 0 TTC 346-25 33501 312-98 274 33 241*57 213 94 178-21 134-19 103-45 78 64 59*31 45 84 3762 2707 20-61 15*21 9-55 6 23 3 71 0 TCA 43*06 41 36 38-12 33-25 27 85 22*50 13 36 - (D. - a-u)!, mt TCE TTC 67*59 62-50 52-35 36 84 23-93 13 78 8-13 49 73 45 06 35*74 2086 983 2 07 Ml SL 032824 TT- 62 Akio Sato, Tantie Ndkajitnti, Yukiko Fnjiwara, and Ninzo Mttrctyama parison of the D - Xi> plot (Fig. 5) and AXu/At plot (Fig. 6), shows that the former is clearly more linear. TCA accounts for about 20% of TTC, and TCE for about 80% in the present single exposure as is shown in Table 3. The fact that k,i for TCA is smaller than that for TCE, however, suggests that TCA has a longer biological half-life than TCE. which will lead to (|ip prediction that the prnnortion of urinary metabolites excreted as TCA increases in a chronic exposure (Sato and pJaicanma. iill). References Fig. 5 Semilogarithmic plots ofD^ -- Xd. Fig. 6 Semilogarithmic plots of AXd/Ai against midpoint time. will have reached an apparent equilibrium through out the body in three hours after exposure has ceased and that the whole body can then be treated as a single body mass, should not be unreasonable. The rate constants for thedisappearanceoftrichloroethylene estimated from the time-courses of urinary excretion of TCA and TTC based on these assump tions agreed with those determined from the timecourse of blood concentration of trichloroethylene. "" The method of estimating rate constants for absorption, metabolism, and elimination of drugs from urinary excretion data was reported by Wagner (1967), The method described above applies Wagner's method for trichloroethylene with several modifications. As is clear in (13). the plot of dXn/dt on a semilogarithmic scale against time is also ex pected to give an estimate of ka, kit. and k.y. The value of AXnlAt in Table 3, an estimate of dXn/dt, was plotted on a semilogarithmic paper (Fig. 6). Com Ahlmark, A-, and Forssman. $ (1951). Evaluating trichloro- eihylenc exposures by urinalyses for trichloroacetic acid. Archives of Industrial Hygiene and Occupational Medicine, X 386-398. Bartonicek. V'. (1962). Metabolism and excretion of tri chloroethylene after inhalation by human subjects. British Journal of Industrial Medicine, 19, 134-141. Byington, K. H.. and Letbman, K, C. (1965), Metabolism of trichloroethylene in liver microsomes. It. Identification of the reaction products as chloral hydrate. Molecular Phaimacology, 1, 247-254. Daniel. J W. (1963). The metabolism of "Cl-labelled tri chloroethylene and letrachloroethylcne in the rat. Bioihcmhtd Pharmacology, 12, 795-802. Eger, t`. I. II (1963). A mathematical model of uptake and distribution. In Uptake and Distribution of Anesthetic Agents, pp. 72-87. Edited by E. M. Papper and R. J. Kite. McGraw-Hill: New York. Elkins, H. B (1967). Excretory and biologic threshold limits. American Industrial Uegiene Association Journal, 28, 305308. Ertlo, T. Hcnschlcr, G.. Midler. G.. and Spassovski, M. (1972), Metabolism of trichloroethylene in man. I. The significance of trichloroethanol in long-term exposure conditions. Archie fur To.xikologie, 29, 171-188. Fiscrova-Bergcrova, V., Vlach, and Singhal, X. (1974). Simulation and prediction of uptake, distribution, and exhalation of organic solvents, British Journal of Industrial Medicine, 31, 45-52. Giiberttn. E^., and Fernandez, 5. (1974). Control of industrial exposure to tctrachlorocthyiene by measuring alveolar concentrations: theoretical approach using a mathematical model. British Journal of Industrial Medicine. 31, 159-167. Ikcda, M , Ohtsuji, H., Imamura, T., and Komoike, Y. (1972). Urinary excretion of total Irichloro-compounds, trichloroethanol, and trichloroacetic acid as a measure of exposure to trichloroethylene and tetrachloroethylcne. British Journal of Industrial Medicine, 29, 328-333. Kctv, s. S. (1951). The theory and applications of the ex change of inert gas at the lungs and tissues. Pharmaco logical Reviews, 3, 1-41. Kiinmcrlc, G., and Ehcn, A. (1973). Metabolism, excretion and toxicology of trichloroethylene after inhalation. 2. rxpcrunental human exposure. Archie fiir To.xikologie, 30, 127-138. Levy. G., and Gibaldi, M. (1972). Pharmacokinetics of drug action. Annual AVrtrir of Pharmacology, 12, 85-98. Lowry. E. K., Vandcrvort. R,, and Polakoff, P. L. (1974). 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