Document 9J29rL8wBZdOqwakGKGK8m14p

[> Aiv`h. Oc*_up. Liv',ron. lf: .l:n -1 : 303 >(v H70) ** i*<on*i A^cr'<<>i o' ar-u Jfoot'Ui 5^ . nf^r V 'God 1^79 Kinetics of Tetrachloroethylene in Volunteers; | Influence of Exposure Concentration and Work Load ! A- C. Monster1, G. Boersrna1, and H. Steenweg2 1 Coronel Laboratory, Institute of Occupational and Environmental Health, Faculty of Medicine, University of Amsterdam, Eerste Constantijn Huygensstraat 20, Amsterdam, The Netherlands : TNO Research Institute for Environmental Hygiene, Indoor Air Pollution Division, Delft, The Netherlands Summary. Six male volunteers were exposed for 4 h to 72 ppm tetrachloroeth'' 'PERC' v r.-st, to 144 ppm PERC >>. rest, and to 142 ppm PERC at res! c- j,. with -n ork load (2 times 30 niir.. i: !0 W). Minute volume and conceni t. ..is in exhaled air were measured to estimate the uptake. Concentrations of PERC and trichloroacetic acid (TCA) were determined in blood. Exhaled air was : analysed for PERC; urine for TCA. The uptake/min decreased in the course of the exposure to 60 % of the initial uptake. The total uptake was influenced more by (lean) body mass than by respiratory minute volume or adipose tissue. During work load the uptake and 1 minute volume increased to 3 fold the value at rest. In the post exposure period i the quotient of the bloodconcentrations and exhaled air concentrations of PERC | remained nearly constant at 23. Following exposure about 80--100 % of the uptake was excreted unchanged by the lungs, whereas till 70 h after exposure the j amount of TCA excreted in urine represented about 1 % of the uptake. j Key words: Tetrachloroethylene -- Trichloroacetic acid - Toxicokinetics -- : Work load i \ i The kinetics of tetrachloroethylene (perchloroethylene, PERC) in humans has been I studied only to a limited extent. It has been established that PERC is mainly eliminated 1 through the respiratory tract. After exposure of volunteers to PERC, Hake et al. (1976), Fernandez et al. (1976) and Ogata et al. (1971) measured trace amounts of trichloro| acetic acid (TCA) in urine, whereas Ikeda et al. (1972 a, 1972 b) also detected tri| chloroethanol (TCE) in urine of workers exposed to PERC. | Considerably less is even known about uptake during exposure and the influence of j work load on uptake and metabolism. The purpose of our experiments is to explore 1 quantitatively the absorption, concentrations in blood, and excretion in volunteers 1 exposed to PERC. sJ Offprint requests to: A. C. Monster, M. D. (address see above) I 0304-0131/79/0042/0303/$ 1.40 j 304 \ < Fig. 1. Lung clearance (LC) during exposure to tetrachloroethylene (PERC) for 4 h. Eacli point represents the mean * s. d. of 6 subjects Table 1. Estimated uptake of 6 subjects exposed for 4 h to 72 and 144 ppm PERC at rest and to 142 ppm PERC at rest combined with 2 x 1/2 h 100 \V work load, the coefficient of variation in each condition (c. v i and anthropometric data of the subjects Subject uptake in mg 72 ppm 144 ppm 142 ppm at rest at rest at rest + work load body mass kg lean body mass kg minute volume at re.st I/min A 370 670 1060 70 62 7.6 B 490 940 1500 82 71 11.6 C 530 1000 1400 82 71 10.0 D 500 1210 1510 86 74 11.3 E 390 880 1320 67 61 12.3 F 450 970 1120 77 61 8.8 C. V. 14% 19% 14% Material and Methods Six healthy male volunteers (aged 27 -34 years) were exposed to 72 + 2 ppm PERC (488 ng/l) at rest, to 144 7 ppm at rest and to 142 t 6 ppm at rest combined with 2 x 1/2 h 100 W work load on a bicycle ergometer. Duration of exposure was 4 h. Between the exposure sessions of the same subject was an interval of two weeks. The design of these experiments was the same as in the methylchloroform exposure study. For detailed information see Monster ct al. (1978). Tetrachloroethylene was obtained from BDH Chemicals Ltd. product no. 30693. For analysis of blood and exhaled air the gaschromatographic technique described by Monster and Boersma (1973) for trichloroethylene, TCE and TCA was applied: in 2 ml blood PERC and TCA were determined simultaneously by means of head space technique; PERC in exhaled air was analysed under the same gaschromatographic conditions. TCA in urine was measured according to Ogata ct al, (1974) SL 037397 KR i & r ;nr i \ ti f Fi i, * \ l f t Kinetics ot 1 ci;.>diloroct'i; lene tn Volu:'.i..vi, iff* 3(0 pi M- Fig. 2. Tetrachloroethylene (PERC) in blood and exhaled air following exposure to ('I RC for 4 h. Each point represents the geometric mean s. d. of 6 subjects Fig. 3. Trichloroacetic acid (TCA) in blood following exposure to tetrachloroethylene (PERC) for 4 h. Each point represents the geometric mean + s. d, of 6 subjects Results Uptake The uptake/min and lung clearance were calculated as in the methylchloroform ex posure study (Monster ct a!., 1979). SL 037398 TCA in urine mg 7? ppm PERC JO ot rest !44 ppm PcRC flt Test 142 ppm PERC at rest and workload >\, ( Monitor ot ,il. i+i frh 0 22 46 70 I 0 22 46 70 1 0 22 46 70 h time after start exposure Fig, 4. Urinary excretion of trichloroacetic add following exposure to tetrachloroethvlene (PERC) for 4 h. Each point represents the mean + s. d. of 6 subjects time after exposure Fig. 5. Cumulative excretion of tetrachloroethylene (PERC) by the lung as percentage of the uptake following exposure to tetrachloroethylene for 4 h. Each point represents the mean s. d. of 6 subjects. Kincti.--. i4" f Mr.'.'N ' workload The u. higher chan ,u 72 ! PERC in Blood ai The mean PERC < are shown in Fig. 1 the concentratioi 30 min and 2 h a 5 nun after the e1 j In the post e j air concentratioi 1 The slope of | and 100 h after < I and about 55 h i Trichloroacetic. The concentrate exposure. From j with a half life t ` until 70 h after of the subjects 1 Recovery The amounts of j concentration c ` minute volume j until 2, 18,42 . (Fig. 5). At 16 j TCA excreted' J PERC and repi During exposure to PERC at rest lung clearance decreased slowly from 6.7 1/min initially to 5 1/min at 10 min, to 4.21/min at 1 h and to 3.8 1/min at 4 h. The mean minute volume of the subjects at rest was 10.3 1/min (range 7.6.-12.3). The minute volume seems to be rather high. This is caused by the dead space of the gasmask (0.15 1). With the usual frequency of respiratory ventilation of 14/min and a total dead space of 0.3 I (0.15 1 physiological dead space and 0.15 I of the gasmask) an alveolar retention can be calculated of about 60 % at the end of exposure. During work load (100 W) minute volume increased threefold to 29.81/min (range 25--35) and lung clearance also inclreased threefold (range 2.5--3.5) the values at rest. The mean lung clearance during rest and workload is presented in Fig. 1. During work load tire retention decreased. This resulted in decrease of lung clearance during work load. Durir.g the second work load tire mean retention was about 20 % (range 10--30) lower than during the First work load; this must be due to a higher saturation of tissues. For each subject the total uptake in each condition was estimated (Table 1). The individual total uptake was increased 40 % (range 15-60) by the extra 2 x 1/2 h 100 W Discussion Uptake The uptake/m During the fir the last expos The court of the concen (1976), assun Tire meai (Table 1). To subjects, the weight, lean 1 SL 037399 ^ laws Kir:i.'uv'. o*' i't'ir.uiii.'roctlrykne in Volunteer .'47 work load '1 ha individual uptake at 144 ppm at :e:>t was 2. I (range 1 .l|- 4 4) times higher titan at 11 ppm at rest. PERC in Blood and Exhaled Air Tire mean PERC concentrations in blood and exhaled air after eacli exposure condition are shown in Fig.2. The concentration in blood at 2 It after exposure was about 37 % of the concentration just before the end of exposure. The concentration in exhaled air at 30 min and 2 h after exposure was 60 % and 44 % respectively of the concentration 5 mtn after the end of exposure. In the post exposure period the quotient of the blood concentration and exhaled air concentration remained nearly constant at 23 4, The slope of the concentration curve of PERC in blood and exhaled air at 20, SO and 100 h after exposure corresponded with a half life of PERC of 12--16 h, 30^10 h and about 55 h respectively." Trichloroacetic Acid in Blood and Urine The concentration of TCA in blood continued to increase until 20 h after the end of exposure. From about 60 h after exposure the concentration decreased exponentially with a half life of 75-80 h (Fig. 3). Figure 4 shows the amounts of TCA excreted until 70 h after start of exposure. A base level of 0.6 mg TCA/day, measured in urine of the subjects before exposure, was subtracted from the mean. Recovery The amounts of PERC excreted in exhaled air after exposure were estimated from the concentration curves in exhaled air after exposure and multiplied by the mean individual minute volume as measured during exposure at rest. The amounts of PERC excreted until 2, 18,42 and 162 h after exposure were expressed as percentage of the uptake (Fig. 5). At 162 h the recovery represented 80--100 % of the uptake. The amounts of TCA excreted within 70 h after the start of exposure were recalculated to amounts PERC and represented about 1 % of the uptake. Discussion Uptake The uptake/min decreased in the course of the exposure due to a decrease in retention. During the first exposure hour at rest the uptake was about 25 % higher than during the last exposure hour. The course of the lung clearance at rest in our experiments agree with the course of the concentration in alveolar air during exposure, as obtained by Fernandez et al. (1976), assuming an alveolar minute volume of about 6 1/min. The mean coefficient of inter-individual variation in uptake at rest was 17 % (Tahie 1). To determine the relation between uptake and physical characteristics of subjects, the individual uptake was-divided by mean minute volume at rest, body weight, lean body mass and amounts adipose tissue. The mean coefficients of inter- tf SL 037400 f i t \i \ l i t lI 1 t | 3i\s A, C. Moribt-r cT ^1. individual variation were 17 7c. 10 G, 11 % and 19 %. From these figures we may conclude that the uptake of PERC ii> particularly influenced by the (lean) body mass PERC The concentrations in exhaled air after exposure in the present study agree with the results of comparable exposure studies by Stewart et al. (1961) and by Fernandez et al. (1976). The time course of the concentrations in blood and exhaled air show that a long period is necessary to complete elimination of PERC. As a result an accumulation of PERC in the body occurs in repeated exposures. This is confirmed by the study of Stewart et al. (1970) in single and repeated exposure of volunteers to 100 ppm PERC, 7 h/day. The concentrations in alveolar air after the 5th exposure, upto 100 h post exposure were about twice as high as after only one exposure. After exposure we found a 23 times higher concentration in blood than in exhaled air; the concentration in alveolar air, however, is about 1.4 times higher than in mixed exhaled air, so the partition coefficient for PERC between venous blood and alveolar air will be about 16 (23/1.4). Trichloroacetic Acid The quotient of the amount of TCA excreted per 24 h and the mean concentration of TCA in blood in the period 22--46 h and 46-70 h after start exposure was equal to the quotient found after exposure to trichloroethylene, Monster et al. (1976) and to 1,1,1-trichloroethane, Monster et al. (1979) (2.5-3.0). However in the period 0-22 h after start of exposure to PERC this quotient was much higher: about 10. This unex pected finding may be explicated by the following. The TCA in blood was measured with a specific gaschromatographic method and TCA in urine with a non-specific photometric method (Fujiwara reaction). The relatively high concentration in urine possibly was due to an unknown compound attributable to PERC exposure. This compound could not be identified as PERC or trichloroethanol. This compound must have a short half life because the excess excretion was only noticeable during the first 22 h after start of exposure. After single exposure experiments with PERC Ogata et al. (1971) and Fernandez et al. (1976), also using modifications of the Fujiwara method, also found the highest amounts of TCA in urine during the first 24 h after exposure. The concentration of TCA in blood continued to increase until 20 h after exposure and decreased with a half life of 75-80 h. Therefore, only a part of the total TCA was excreted in urine until 70 h after exposure. The remaining part will be about 1 % of the uptake. Therefore, in repeated exposure TCA will accumulate. Recovery Most of the PERC taken up was excreted after exposure unchanged by the lung (80--100 %). The excretion still continued after the 7th day; this accounts for at least 5 % of the uptake. The amount excreted by exhalation could only roughly be estimated because the degree of physical activity of subjects between measurements after exposure could not be taken into account; this probably will differ from that under the condition of the experiment. Only a small part of PERC taken up was excreted as TCA (2 %) in urine. The recovery of PERC in exhaled air in the various condition's decreased in the following order 72 ppm (95 %), 144 ppm (92 %), 142 ppm with work load (78 7c). '! i j *. j j j s : ! ! ; 1 i ; I KlTKi^s -Tr T'O I.CVli'V i Tins decu-se v. s:gii!.'it 1963). In the condition vof PERC and TCA were a as the uptake was 40 hi in recovers after work lor 1. overestunatiou of i 2. stimulation of an r 3. excretion of PERC We do not have reason to Acknowledgements. We vuOi F. Oudt. C 'an der Rliee am! Verberk, H. J. A. Salle and R the Organization for Health F References Fernandez. J.. Guberan. F,, C vapor and elimination in Hake, C. I,.. Stewart, R. D., V lene: I Absorption and i lanta. Georgia, 1976 To lkeda, M., Oiltsuji, H.: A eon in urine of humans and i ethylene. Br. J. Ind. Med lkeda. M., Ohtsuii, H., imami trichloroethanol ami trie tetrachloroethylene. Br. Monster, A. C., Boersma. G.: blood and exhaled air h\ 163 (1975) Monster, A. C., Boersma. G., Influence of work load a 87-102 (1976) Monster, A. C., Boersma, G., ence of exposure concei 301(1979) Ogata, M., Takatsuka, Y., To, persons exposed to vapr 28, 386-391 (1971) Ogata, M,, Tomokuni, K., As and trichloroacetic acid Page, E. B.: Ordered hypotlu Amer. statist. Ass. 58, 2 Stewart, R. D., Gay, II. H., F ehloroethvlene vapor. A Stewart, R. D.. Baretta, E. D tetrachloroethylene. An Received July 7. 1978 / Ace, SL 037401 1 h'-i lw .:ic.;se \v,i' si-ini!!'.' : .. ii 05,ni!uiiince tes! ! :nc.ir i.m- :,. I) in Llit condition`a ' ' '.oik load the moan conccu .' . uin: .inio.mis c\c rctcri of'PURC and TCA were uivji '0 higher than in the condition v.ith only icst, where as the uptake was 40 7c hk'Jtei. The following hypothetic possibilities for the decrease in recovery after work load may be considered: 1, overestimation of uptake during work load 2, stimulation of an unknown rnetahohe pathway during work load 3, excretion of PERO by another route during wnrk load We do not have reason to prefei one of these possibilities. Acknowledgements. We uish to thank the volunteers P. M. C. van den Berg, P. Heh. R Nolet, 1". Omit, C. van der Rhee ami M M Verberk for their cooperation m the experiment'. M. M. Verberk, H, J. A. Salta and R. 1 Zielhuis for their helpful discussions. fins study supported by the Organization for Health Research TNO, The Hague. References Fernandez. J., Cube- raper- ; .perimental human e\rr .t to tetrjchloroethylsne vaporandal. abs1.1 uir inhalation. Am. lnd f` . \-,,oc. J 37.143-150 (1976) Hake, C. L., Stew ', o,, Wn. /Graff. S A. Experimental he .'nan exposure to perdiloroethy- lene: I. Absorpuon and Excretion. Abstracts 15th Annual Meeting Society Toxicology. At lanta, Georgia, 1976. Toxicol. Appl. Pharmacol. 37, 175 (1976r lkeda, M., OliGuji, 11.: A comparative study of excretion of Fujiv.ara reaction-positive substances m urine of huntans and rodents given trichloro- or tetrachloro-derivatives of ethane and ethylene. Br. J. lnd. Med 29. `>9 -104 (1972) lkeda, M_, Ohtsuji, H., lmainura, I., Komtuke, Y.: Urinary excretion of total trichloro-compounds. triehloroethanol and trichloroacetic acid as measure of exposure to trichloroethylene and tetrachloroethyiene. Br. j. Ind. Med. 29, 32S--333 (1972) Monster. A, C., Boersma, G.: Simultaneous determination of trichloroethylene and metabolites in blood and exhaled air by gaschromatography. lnt. Arch. Occup. Environ. Health 35. 155- 163(1975) Monster. A. C., Boersma, G., Duba, \V. C.: Pharmacokinetics of trichloroethylene in volunteers. Influence of work load and exposure concentration. Int. Arch. Occup. Environ. Health 38, 87-102 (1976) Monster. A. C., Boersma, G., Stcenweg, H.: Kinetics-of 1,1,1-trichloroethane in volunteers; influ ence of exposure concentration and work load. Int. Arch. Occup. Environ. Health 42, 293- 301 (1979) Ogata, M., Takatsuka, Y., Tomokuni, K.: Excretion of organic chlorine compounds in the urine of persons exposed to vapours of trichloroethylene and tetrachloroethyiene. Br. J. Ind. Med. 28, 386-391 (1971) Ogata, M., Tomokuni, K., Asahara, H.: Simple microdetermination of triehloroethanol glucuronide and trichloroacetic acid in urine. Int. Arch. Arbeitsmed, 32, 203-215 (1974) Page, E. B.; Ordered hypotheses for multiple treatment: a significance test for linear ranks. J. Amer. statist. Ass. 58, 216-230 (1963) Stewart, R. D., Gay, H. IE, Erley, D. S,, Hake. C. L,, Schaffer, A. W,: Human exposure to tetra- chloroethylene vapor. Arch. Environ. Health 2, 516--522 (1961) Stewart, R. D., Baretta. E. D., Dodd, H. C., Torkelson, T. R.: Experimental human exposure to tetrachloroethyiene. Arch Environ. Health 20, 224--229 (1970) Received July 7, 1978 / Accepted August 9, 1978 SL 037^02