Document ymMO2Gx5wbVGJLGXgDo58rxR6

vera Fiserova-Betgerova, PhD' ~ FISEROVA-BERGEROVAV. Toxicokinetics of organic solvents. Scund J Work Environ Health 11 ,1965): suppl 1, 7-21. Organic solvents, because of their small molecules and large solubility in fat, -,,a[er, or both, are expected to be readily absorbed through the skin or by inhalation. Toxicokinetic (empirical, pharmacokinetic, and simulation)are used to describethe time course of their absorp:!cn dnd elimination. Special attention is given in this review to simulation models in which rate constants derived from physiological parameters of the exposed subject (alveolar ventilation, tissue perfusion, b,~) build) and from physicochemical properties of the inhaled chemical (partition coefficient, meta~ . O I I cSlearance). Such a simulation model is used to gain insight into the uptake, distribution, and eliminarion of inhaled vapors of organic solvents. Large differencesbetween kinetic patterns of hydrophobic 3nd hydrophilic solvents are indicated by the effects of biosolubility, metabolic clearance, changes in ph! siological parameters, exposure duration, and concentration fluctuation on the uptake, distribution, and elimination of solvents. Because kinetics is the basis for interindividual and intraindividual differences in pulmonary uptake and bioavailability and in the development of toxic effects, simulation models have practical application in the biological exposure monitoring and medical surveillance of <\posed workers. /+.Iierms: biological monitoring, elimination, hydrophilic,hydrophobic, inhalation, pulmonary uptake, .Imulation model. To"cokinetics is the study of the time course of the constants used in the functions are derived by statis- H r p r j o n , distribution, and elimination of toxic tical, pharmacokinetic, or physiological means. The m i c a 1 5 in man and animals. Modern toxicokinet- following three types of mathematical models 7' \ is a powerful tool for the design of experiments, describe kinetic data: (i) empirical models, (ii) phar- interpretation of data, extrapolation from macokinetic models, and (iii) simulation models. rnlmals to man, extrapolation from one exposure Empirical models describe experimental data but -1men :o another, and the evaluation of the effect lack flexibility for application t o altered conditions. d a variety of physiological and pathological changes The function and the values of the constants are the dwelling of toxic chemicals in the body. Since found by optimum fit t o the experimental data. The .mputer technology has made the practical applica- most common application is in determining the 'm of toxicokinetic models accessible to profes- amount of chemicals eliminated in urine or in ponals lacking expertise in mathematics, toxicokinet- exhaled air. Some investigators (65, 70. 86, 87) have can provide health personnel with valuable infor- suggested applying empirical models t o biological ex- rmtion on the dwelling of industrial chemicals in the hi?F.or example, biological monitoring of envimrnenral and occupational exposure to toxic vapors rod gases and the health surveillance of exposed subc.?c can be improved if toxicokinetic techniques are posure monitoring. Such an application is restricted to precisely specified conditions however. Lowe suggested an empirical model for main- taining safe clinical anesthesia (58). The anesthetic concentration of any inhalation anesthetic in the rmplo! ed in setting exposure standards compatible *::h particular exposure conditions (13, 14, 23, 29, a.36, 40, 41, 45, 6 3 , 65, 72, 76, 80). brain is rapidly reached and safely maintained if the inspired concentration (CJ is proportional to the reciprocal square root of the time ( t ) . Kinetic data are commonly described by mathe-xical functions in which time and concentration +C, = 1.3 MAC (1 Xbl,gast L': the ~ariablesT. he functions are usually exponen- (describing first-order processes) or rectangular where MAC denotes the desired anesthetic concentra- '\wbolas (describing saturable processes). The tion in alveolar air, is the blood-gas partition coefficient of the anesthetic agents at body tempera- ? q m i m e n r of Anesthesiology, University of Miami ture, and t denotes minutes after the start of anesthe- khool of Medicine, Miami, Florida, United States. sia administration. k n m requests to: Prof V Fiserova-Bergerova (V Tho%.'. DrFarrment of Anesthesiology. University of Miami 0: \ledicine, PO Box 016370, Miami, Florida 33101, '\ Pharmacokinetic models utilize sophisticated mathematical techniques to describe the bioavailability of drugs (38, 5 7 , 6 6 ) . Such models were developed as a tool for designing the optimum therapeutic 7 effect of drugs; they were applied to problems of industrial toxicology by Piotrowski (72). Compart- ments and their parameters - such as volume of dis- tribution, elimination constants, area under curves, and systemic clearance - were introduced to facili- tate the mathematical treatment of the model. Deep and shallow compartments were introduced to explain biphasic elimination. The compartments and their parameters are mathematical entities which, with few exceptions, have no immediate association with in vivo processes. Up until the last decade, pharmacokineticists failed to recognize that experimental data are the result of the interaction of physiological and bio- chemical processes in organisms. In consequence, pharmacokinetic models lack the capability of interpreting data or extrapolating for changed physiological (or pathological) conditions of xenobiotic recipients. Recognition of the role of blood flow in drug distribution resulted in the introduction of the concept of flow-independent "intrinsic clearance of the organ" to deal with differences between bloodflow-limiting and organ-clearing processes (6, 89). Simulorion models utilize sophisticated mathematical techniques similar to those used in pharmacoki- netic models. The mathematical expressions, how- ever, utilize real physiological and physicochemical parameters to describe the biological processes which affect the dwelling of a xenobiotic in the body. The fitting of curves to experimental data is not used in the preparation of the simulation model, but is used to verify the model (30,40). This procedure contrasts with the procedure used for the preparation of empirical and pharmacokinetic models. Simulation models have the capability to interpret the data, to extrapolate for altered physiological conditions of exposed subjects and altered exposure regimens, and to predict behavior of new chemicals in the body. The most significant contributions t o the development of a simulation model were made in studies of the uptake, distribution, and elimination of gases and vapors of industrial solvents and inhalation anesthetics. Organic solvents are small-molecule compounds which are liquid at room temperature. The vapor pressure of organic solvents at room temperature is usually high enough to produce intoxication by inhalation. Organic solvents are soluble in water or in lipids or in both. Water and lipids being the main constituents of the body, organic solvents are soluble in blood and soft tissues. Their small molecules and good biosolubility allow them to cross biomembranes readily and be absorbed if ingested, inhaled, or placed in contact with the skin. Kinetic studies of inhalation exposure have provided a sufficient data base for the development of a simulation model. But skin exposure and skin absorption are so complex, and the kinetic data so scattered, that no simulation model has yet been proposed. Skin penetration is related to the structural features of the skin at the site of exposure and to the physical properties of the chemical (82, 83). Studies of percutaneous absorption are subject t o divergencies caused by regional variation of skin permeabilit! and by the varying effects of the form in which the chemical is applied to the skin (60). Because the stratum corneum has affinity for both water-soluble and lipid-soluble compounds, organic solvents appear as likely candidates for skin absorption (92). Also, the small molecules of organic solvents facilitate rapid penetration through the stratum corneum. Skin absorption of organic solvents was studied in man through exposing the skin of volunteers to vapors (15) or liquids of solvents while the volunteers breathed clean air ( 5 , 16, 17, 18, 77, 8 5 ) . The rapid skin penetration o f liquid solvents seems to be related to the weakened barrier function of the skin caused by impairment of the horny layer by the solvent (77, 83). Riihimaki (74) showed that skin absorption of a solvent can be different if the solvent is applied in a mixture with another solvent. Dutkiewicz and coworkers were the first to collect kinetic data on the skin absorption of solvents. They showed that pene- tration through the skin is a temperature-dependent process ( 5 ) which can be explained on the principle of Fick's law (16). They also determined the rate of skin penetration of several solvents (17, 18), showed thar skin uptake of methanol is a biphasic process (16), and reported differences in metabolic clearance following cutaneous and inhalation exposure to ethyl- benzene (17). Sat0 & Nakajima (77) suggested that the difference in metabolic clearance can be explained by migration of the chemical in the body. Blood concentration of a volatile chemical absorbed through the skin is reduced prior t o entering the hepatoportal vein by the first pass through the lune. Thus, after skin absorption, the availability of \ olatile solvents to biotransformation is diminished b! pulmonary clearance. The basis for the theory of pulmonary uprake and elimination of volatile chemicals was established a[ the end of the last century by studies of pulrncnar! uptake and the elimination of inert gases during and foilowing hyperbaric conditions (96, 104) and b! studies of the elimination of ethanol and acefonc (100, 101, 102) from man. The transfer of vapory and gases from air to blood and from blood to tissurc \$a` explained on the principle of Henry's law. B l 0 a d - 9 ~ and tissue-blood partition coefficients were u 4 to describe the equilibrium. The equilibration of 3Por pressures in the body and in the environment a. rei- ognized as a driving force in the pulmonary and elimination of vapors and gases. I t was condajcd that pulmonary uptake is predetermined by tissue U P take. It was explained that the equilibration ra:` I` dictated by pulmonary ventilation, or by cardiac <'ut. put, or by a combination of both, dependins of.Ihz solubility of the inhaled chemical in the blood- Thc 8 tion of pulmonary fur lubility was further el he search for a safe t ation anesthesia lic (19, 47, 61) ere suggested a! ogists. Such a teack r the Apple coml: considered diffus as another rate-1 ange between air, blood, of nonionized chemicals is fect of metabolism of styrene, was t o o con nal mathematics. Van experiments wjth vol and her co-WOI ct of exercise on tl solvents in volur nted the slow uptake i , by providing a tool for ations of chemicals in e rams for solving simult; describing nonlinear m inetic data accessible to hematical expertise to per nd I first atten intrinsic clearance of the inhaled chemical. Physiological parameters for the model can be determined by measurement, or they can be found in biological tables or in references 2, 35,o r 23. A review of interspecies extrapolation can be found in references 10 and 32. Biosolubility is defined by blood-gas and tissue-gas partition coefficients at body temperature. The partition coefficients of some solvents have been determined and can be found in reference 26. The methods used for determining partition coefficients have been reviewed in the same reference. Partition Val" (J/min) VRG 38 2 95w coefficients can be predicted from chemical structure (34) or if tissue composition and the solubility of chemicals in water and oil are known (58). No standard method exists for determining intrinstc clearance. It has been suggested that metabolic clearance can be calculated from the metabolic rate . determined from pulmonary uptake (4, 24, 25, 28, 31, 36, 88), from the distribution of chemicals or their metabolites in tissues at steady state (28, 33), from the elimination of metabolites at steady state (46), or from the slope of the elimination phase of the desaturation curve (44, 80). Metabolic clearance obtained by these indirect methods can embrace the effects of flow restriction and tissue redistribution and therefore can be unsuitable for use in the sirnulation model. Interspecies extrapolation of metabolic clearance by a scale-up power equation has also been suggested (4, IO). Such extrapolation must be done very cautiously because of unpredictable species differences in metabolic pathways (68). The five basic compartments comprise a single central compartment connected to four tissue compartments (figure 1). The central compartment in- cludes alveolar air, lung tissue, and arterial blood The amount of chemical supplied to the central compartment during exposure consists of the amount inhaled and the amount returned by venous blood The chemical is removed from the lung by arterial blood. Because the partial pressures of vapors and gases in alveolar air and arterial blood readily eqwlibrate, the amount removed is determined by cardiac output, alveolar concentration, and the blood-gas partition coefficient. When exposure terminates, the chemical continues to be brought into the lune b! mixed venous blood and continues to be remobed b\ arterial blood, but the role of breath reverses, ar shown in the following scheme: R = resting *V=FRC+ "tid' king CI 'art Abl,/gas+VlungA lung/gas chemical flow into the lung 'During exposure: V.I,~,,~+ Qc,. C," E"," After exposure: <E," E"*" QCwn chemical flow Out of the lung Qc,,X, Qc,iAi p + ' d a c e Figure 1. Simulation model: Tissues are assigned to the lung compartment. which includes functional residual capacity (FRC), one-third of the tidal volume (V,,,), lung tissue, and arterial blood; the VRG (vessel-rich group) Compartment, which includes brain, gastrointestinal tract, glands, heart, kidneys, and spleen; the MG (muscle group) compartment, which includes muscles and skin; the FG (fat group) cornpart. ment, which includes adipose tissue and white marrow: and the liver compartment. The volume (V) of each compartment (in liters) IS indicated in the lower left-hand corner of the com- partments. Perfusion (F) rates (in liters per minute) are indi- cated at the right of the compartments, the top numbers indi- cating the indicating rates for a the rates resting (R) man and the for a working (W) man l(o5w0eWr n).uvm, beriss alveolar ventilation (in liters per minute) The parameters given for a standard man (70 kg. 170 cm) are taken from reference 2. The arrow at the bottom of the liver compartment indicates intrinsic metabolic clearance (CI) (in liters per minute). where Q is cardiac output, Val" is alveolar \ ? n t l i 3 tion, and c is the concentration in blood or in 3lr indicated by the subscripts. The large concen[rdri"r gradient across the lung is characteristic of \ datil' compounds and is the driving force behind dmL' nary uptake and elimination. Arterial blood carries the chemical to the [It\"'' The larger the perfusion, the faster the equilibrJ1'"' rate. Brain and viscera are the organs with the Idrep' perfusion These organs account for 9 mo 01 mass and under resting conditions are per!ukedP 75 To of the cardiac output The perfusion rde' I" brain, spinal cord, glands, and the hepdt~lPL"" 10 I 1 predicted from chemical st alculated from the oulmonary uptake be unsuitable for use # p e c kextrapolation e-up power equation =use of unpredictable s )lit pathways (68). compartments comprise a :nt connected t o four tissu 1). The central compartm , lung tissue, and arterial :mica1supplied t o t :xposure consists nount returned by ,oncentration, and the d and continues t o be t the role of breath wing scheme: oncentration in blood or in the driving force behind imination. wries the chemical to the usion, the faster the equili era are the organs with the I areb,trrm similar, average 0.75 ml g-I . min-I, Jnd .hrmlia~ little affected by exercise or exposure These organs can thus be treated as a to the single . 4 P ar:ment, which (VRG).If will be referred t o as the vessel the inhaled chemical undergoes mcraboilsm,it is convenient t o treat the liver as a earare compartment. The perfusion of muscle, skin, ,,d 3j.pose tissue is significantly less than the perfu,:on 0f the vessel rich group and depends on the th,slcal activity of the exposed subjects. The perfu- varies from 0.027 ml . g-I . min-I in a ,ntrng man t o 0.8 ml . g-l . rnin-l in a man per- ,,rming strenuous exercise. Muscle, skin, and ,jlpO,c ussue, because of the similarity of their per!usion. can be treated as a single compartment, ,,,less special stress is imposed o n particular muscles. 4jlpo,e tissue should, nevertheless, be treated as a ,parate compartment because of the large differen- .is the solubility o f most chemicals in lean and fatty tlSSUe. &fore steady state or equilibrium is reached in an ,,, . ( p u r e , the partial pressure of an inhaled chemical arterial blood is larger than the partial pressure in tissue. Partial pressures in tissues equilibrate ,,]th partial pressures in regional venous blood how- ever. At steady state, the partial pressures in arterial blood, venous blood, and tissues are equilibrated, except for those in the excretory organ, in the blood perfusing the excretory organ, and in mixed venous blood (in which the partial pressure is always smaller). This concentration gradient across the excretory organ is the driving force behind pulmonary uptake at steady state. At steady state, the pulmonary uptake rate equals the elimination rate. When exposure is interrupted, the chemical is removed from tissues by venous blood, part being eliminated from the body and part being redistributed in the body and tending toward equilibration. Metabolism, the main excretory pathway of solvents, is described in the model by the intrinsic clearance of liver. At a small exposure concentration, the hepatic metabolism of many solvents is restricted by hepatic flow so that the metabolic rate is u = Fhepcm.Intrinsic metabolic clearance can, however, be larger than the flow of the inhaled chemical into the liver. Metabolic intrinsic clearance is a constant unless exposure is so large that the capacity of the microsomal enzyme system is exceeded. If the metabolic capacity is exceeded or if metabolism is inhibited or 7~13 A tis/bl 1oc 5c tIlC I 41 c1 dl 1 Methyl chloroform 2 n-Octane 3 Methylene chloride 4 Benzene 4 5 Chloroform 67 TErtihcehrloroethylene 8 Toluene 9 Methyl ethyl ketone 10 lsobut anol 11 Acetone 12 n- Propanol 13 Isopropanol 14 Ethanol 15 Methanol I 1 vl,.., 1 5 F 7 -4I ~ 1 I' 'I I I , I' I 300 11 400 500 600 7 0 0 800 '900 1000 1100 fa1 g a s 0 liver 5 muscle 0 fat FIOure 2. Comparison of partition coefficients of 15 selected solvents The points correspond to values of fat-gas (abscissa) and hsue-blood (ordinate) partition coefficients at body temperature, as obtained from an earlier report (26) or as recently lelermlned in our laboratory. Lean tissues are represented by human liver ( 0 )and muscles ( O ) , fat is represented by human subc~:aneousadipose tissue (0)T. he numbers at the top of each vertical line identify the solvents, which are shown ordered Ana numbered in sequence according to increasing blood-gas partition coefficients. With the exceptions of methyl ethyl 'elone and isobutanol, the solubility of solvents in fat is significantly different from their solubility in lean tissues. 11 t ht bl 10 5 1 - 1 Methyl chloroform 2 n-Octant 3 Methylene Chloride 4 Benzene 5 Chloroform 6 Trich oroethylene 7 Ether 8 Toluene 1, 0.5 * o,, , 0.05' 11 Acetone 12 n-Propanol 13 Isopropanol 14 Ethanol 15 Methanol @ 10 Icobutanol ,-?, 9 Methylethyl ketone w * 5 10 50 100 log is-* ,,=1.89-0867 log b L , ,.I "I DI 'gas .'500 'Oo0 "gas Figure 3. Correlation between fat-blood anc blood-gas partition coefficients. The numberec circles identify the solvents and indicate the (voarlduiensatoef) tphaertbitliooond-cgoaesff(icaibesnctiss.saT)haendcofrarte-bialotioocr between the logarithms of the fat-blood anc blood-gas partition coefficients is described b) the regression equation shown below the graph Additional information on Dartitio.n c-o-e-ffic-ie-nt.<- can be found in figure 2. ' Rising of aIv conc of selected solvents Pulmonary uptake rate 7 CI =o elation between 1 'ion coefficients. T the solvents and ood-gas (abscissa) ion coefficients. Ti agarlthms of the fat-blood 'ion coefficients is descrlt equation shown bel ,mation on partitioi ) figure 2. . i 81 orm Ioride kne e tone ....._... ~ "(39,215 3 4h mulation conditi ) kg, 170 cm) to r to avoid the iin ions: (i) the solv :ompietely met; concentration c n a comparison Figure 5. Effect of solubility and me- tabolism on rate of pulmonary u p I take. The simulation conditions are the same as in figure 4, but the expo- sure concentration is 1 pmoill. The striking difference between the up- take of hydrophobic and hydrophilic 3 4hn solvents and the increase in pulmonary uptake by metabolismis clearly noticeable. mduced during or following exposure, then the metabolic clearance is no longer a constant but changes .Ith the concentration of the chemical in the liver. Capacity-limited metabolism can be accommodated m the model if metabolic clearance is made dependent on the rise or decline of the concentration in !per as follows: v,,CIl = 2U = CI Km+c, (eq 2) *here 0 ,is the metabolic clearance at time t when :he metabolic rate u, depends on the actual concen- 'ration in hepatic venous blood, c,; V,, and K,,,are constants (Vmax is defined as the maximal rate by nhrch the chemical can be metabolized if no flow 'ntrictions are imposed, and K,,, denotes hepatic mous blood concentration at which u, = !h V,,. 25. 28, 37). if a chemical has more than one metabolic Slhuaj, each pathway is described by a pair of m t a n t s (Vma and K,). If the constants for the XthNays are different, then the ratio of produced mabolites depends on the exposure concentration !31 Such a concentration-dependent ratio of meta- bolites was observed, for example, in experimental studies of styrene (39) and trichloroethylene (52). My colleague J Vlach and I recently prepared a program for the solution of such a nonlinear model. Toxicokinetics of organic solvents in view of the simulation model Organic solvents are not similar to one another in chemical structure or in hydrophobic characteristics. To obtain insight into the effects of the solubility and metabolism of organic solvents on their uptake, distribution, and elimination, we simulated exposures t o 15 organic solvents for which the bloodgas and tissue-gas partition coefficients are known. These 15 solvents are listed in the sequence of increasing blood-gas partition coefficients in figure 2. Statistical analysis shows no correlation between fatgas and blood-gas partition coefficients or between fat-gas and fat-blood partition coefficients. Figure 2 shows that, with few exceptions, tissue-blood partition coefficients for lean tissues are between 0.5 and 2. This range indicates that the solubility of organic solvents in blood and in lean tissues is similar. Fat- 13 h 200 160 120 80 40 E f f e c t of metabohsm and exerctse at steady state 100) r2 - 80 s 60 .- w f 40 4- (P 20 on saturatlon level in tlssuer wtth no metabohsm 1 Methyl Chloroloim 2 n-Octane 3 M c l h y l c n e ChlOr8de 4 Benzene 5 Chloroform 6 Tr~ChlorOeihytenc B TOl"."e 9 Melhylelhyt ketone (0 Irobulanol 11 Acetone 12 "-Plopa"ol 13 Isopropanol 14 Elhanol min 150 120 Q .=E 90 =I 60 r 30 I Methyl ~ h l D r ~ l o r r n 2 n-oc,anc 3 Mclhylenr ChlOnbe 4 Benzene 5 Chlorororm 6 TrIChloroelh~lene 7 Ether 8 loluene 9 Melhylelhyl kelone u) I~Obul."01 11 Acelon~ 12 n-Prop.noi 13 Isop'opln01 I4 Ethanol 0 20) -.g- 16 12 u E8 14 I on Concentrallon in arterial blood min 10 8 6 4 2 D sleeping standard man(CI:O) .effect of activity (50W. CIzO) e f f e c t of m e t a b o l i s m (CI:FhepAbligas ) 1 2 3 4 5 6 7 8 91011 12131415 nvolunteer i 5 0 W cexp-l; CIsFhep hbl,gas *loox i s level i f metabolism is inhibited Figure 7. Effect of activity and metabolism on saturatlw levels and blood concentrations at steady state. The simul* tion conditions are as in figure 4. The bars represent fM aSYmPtOtiC values for a resting (plain bars) and :%,Orklnc (striped bars) man. The solvents are identified by the numbel 'on the abscissa. Metabolism reduces the saturation levels all the solvents (upper graph), the reduction being largerfn resting man than in a working man. Although hydroPhilti solvents reach the lowest saturation levels, their blood to^ centrations are larger than the blood concentrations d hydrophobic solvents (lower graph). This difference can explained by the restriction of solvent supply by alveo!arve tilation and by the large capacity of blood hydrophilic solvents. Figure 6. Effect of activity and metabolism on the half-times of the three decays apparent on desaturation curves. The half-times were obtained for the 15 selected solvents with the use of the simulation model in figure 1 , The solvents are iden- tified by the numbers on the abscissa. To show the most common range of diurnal fluctuation. the half-times were cal- culated for a standard man (70 kg. 170 cm) either sleeping (plain bars, parameters taken from reference 2) or working (solid bars, parameters shown in figure 1). Activity largely reduced all the half-times of all the solvents. To show the effect of metabolism, the simulations for a sleeping man were repeated, this time on the assumption that solvents are extensively metabolized in liver (clearance = FX,, It is clearly noticeable that metabolism reducedall the hAf-times of all the solvents, that for hydrophilic solvents the half-time of the elimination phase (upper graph) was reduced the most, and that the half-time of the other two decays was reduced the least (middle and lower graphs). 'lean tissues. Figure 3 shows two distinct groups solvents, the hydrophobic solvents (numbered I-" and the hydrophilic solvents (numbered 11-1-'1 Hydrophobic solvents have relatively small b1od-g" Partition coefficients and have fat-blood coefficients much larger than 1. Hydrophilic .d\Snir have blood-gas partition coefficients larger [ha" P and have fat-blood partition coefficient. mu'' smaller than 1. Figures 4 through 10 show tha: !he L' netic patterns of hydrophobic and hydrophiii; -' vents are very different and shah that the hiI1"'**''' two solvents with large solubility that IS apprL>\imJ:: ly equal in all tissues (methyl ethyl ketone. n m k ' , blood partition coefficients are, with two exceptions, much smaller or much larger than I . Therefore some solvents are significantly more soluble and some significantly less soluble in fat than in blood and in other hydrophilic solbents. Figure 4 she\\' yiferences in the rise of alveolar concen[ra[!"n'. figure 5 shows the differences in the pulniL1rlJf' take rate of the selected solvents. B e ~ a " ~ Simulation IS done on the assumption !ha' !' 14 -n and eaercise at steady 711 k v e l in ttssues with 110 metJbolism 5 Chlot&rm 6 Trichlatoclhwi. ation in -, Ccxp''; cIsFhep*bI/s mtabolism is inhibited ,oitents do not undergo metabolism, differences in uptake and distribution must be attributed to Jlilsrences In their solubilities (graphs on the left- band side). TO vbtain insight into the effect of metabolism on .he kinetics of Solvents, we repeated the simulation inthe assumption that the metabolic rate of each ',Iten[ equals the flow of the solvent into the liver ,CI = FhepXbVigea, re;xtraction ratio equals 1). IF the I, ? r3phs on the right and left sides of figures 4 and 5 rre it is obvious that metabolism reduces !, ..he alveolar concentration and enhances the pulmonary I ,pral;c of all solvents. To obtain insight into the ef- 1i of alveolar ventilation and tissue perfusion on /he iinetics of solvents, we simulated the same expo- ;"re> twice by using the physiological parameters of a man. One exposure was under sleeping or ~ I [Bring conditions (volunteers in many laboratory (Iudies), and one exposure was under working condi1 :ions (workers with energy expenditure of 50 W). ! Figure 6 shows that exercise, as well as metabolism, ,horlenS the half-times of all compartments and that half-times of the elimination phase of hydrophilic *]vents by metabolism is shortened the most. (The 1 fialf-timesof two additional decays that were shorter :ban 4 min are not shown in figure 6 . )Figure 7 shows :ha[ metabolism reduces the saturation levels of all I *]vents in all tissues, that the reduction is larger in a resting man than in a working man, and that, &Wsivpeitnersthaerefasmctatlhleart tshaatnursaatitounratleiovnelsleovfelhs yodfrohpyhdirloic- reduces the satuktlon , the reduction beinQ phobic solvents, the Concentrations of hydrophilic iolvents in blood are larger than the concentrations of hydrophobic solvents. Figure 8 shows that the pulmonary uptake of working individuals is much larger graph). This different f solvent supply by ah capacity of blood t4- ws two distinct than the pulmonary uptake of resting individuals, rhat metabolism enhances the pulmonary uptake of dl solvents, and that the pulmonary uptake of hydrophilic solvents is much larger than that of hydrophobic solvents. To obtain insight into the rffect of body fat on pulmonary uptake, we simubred 8-h exposures to each solvent, using physiological parameters for men 150 cm or 185 cm tall and a n 1. Hydrophilic xfficients larger th i tition coefficients drough 10 show that I , ' weighing 70 kg (35). The pulmonary uptake and the iiarting conditions of the elimination phase of the fesaturation curves of hydrophobic solvents in.Teased with body fat ( 3 9 , but pulmonary uptake and the desaturation of hydrophilic solvents were lit- '!e affected by body fat. Figure 9 shows the difference .J the patterns of the desaturation curves of hydro- 1 show that the k ?hobic and hydrophilic solvents, trichloroethylene md acetone being the examples. Figure 9 also shows , 'he differences in the effects of exposure duration on Figure 4 shows t 'k Pulmonary elimination of hydrophobic and ?drophilic solvents. Similar differences were docu- ,alar concentrati by data 12). Figure 10 'hoW how the fluctuation of exposure concentration ':'fects and blood of hydro- :hobic and hydrophilic solvents. Figure 10 shows that the concentration variation of solvents in alveolar air and blood is small compared to the concentration variation of gases (represented in figure 10 by CF, . CH,CI), that the larger the solubility of the solvent, the smaller the concentration variation in biological material, and that concentrations of hydrophilic solvents (represented by acetone) in alveolar air and blood maintain a rising trend during the entire exposure. 8 { 2 0, f 2f ,o e f 56 Volunteer 1 Methyl chlorolorm 2 n-Octane 3 Methylene chlorde 4 Benzene 5 Chloroform 6 Trlchlorocthylenr 7 Ether 8 Toluene 9 MelWethyl ketone l o 1wbut M o l 11 1l c i ~~ l o n c ~ 12 n-Propenol 13 Isopropanol 14 Elhmol 15 Methanol Worker - innaiw - - - -." - .- - ..- -- - .- Ouptake nometabollsm CI = 0 Ixte - -., . . .C e x p = l r ~ s / 1 . 8 h lu.re_e. triec~r .o i m~ e.ra~wi.t.sm ana acr.i.vi.r.y on r.Lne puimonacy u1prtgallkew01 eIresolsviemnutsladteudrinfokana&hreestxionogsu(urep.pTehr egeraxopohs) uarensd t o a working (lower graph) Standard man with the simulation con- ditions in figure 4. The sol've-n.ta a_r.e- identified h_v t,he n..ii_m_h.a.r_a_._ on the abscissa. The distance between the two horizontal lines W -.solvents ead space") i which do not nrldeiaccanm[.n' ethea'lvaemoloi.uni ntse Of. (nhaled plain oars ..represent body burden at I.he end of an 8-h exeosure. on the assumption that the solvent is not ~~ metabolized (clearance =~ 0,plain bars to the left of the striped bars) or is extensively metabolized (clearance = ,Fhe&,l,pU, plain bars above striped bars). The striped bars reipresent the amount metabolized --damuroinugntthmee8t-ahbeoxlipzoesdurreep.rTehseenstusmpuolfmthollB-la-bl-yo..d.uyp^bt.^auInr.^dc:eUAn,U.a-:In-~^dI VtYhaell 8-h exposure. It is apparent that the hydrophilic solvents were extensively absorbed in alveoli and that metabolism in- creased their pulmonary uptake littie but greatly reduced their body burden. im I ~ I I TRICHLOROETHYLENE ACETONE 100 --c =100pprn--': exp / . -._-c IOOL*-- c i l o o p p r n - - exp ._.. :;IJ-L 10. a 1xI 10. "@ 1' 1. -.1' - - - - - - - '- - '\ - \- .-.----.-.---_-_. L 24682468 hours i .1 - - - - - - - '! - - 24682 hours --- 46 - 8 Figure 9. Effect of exposure duration and solubility on desaturation curves. Simulation was made of a 2-, 4-, and 8-h exposure (exp) of a working man to 100 ppm of trichloroethylene and acetone. The simulation conditions were as shown in figure 4, but real clearance (CI) for trichloroethylene (CI = 41 Ilrnin) and acetone (CI = 18 Ilmin) were used. The difference in the decline of the concentrations (c) of hydrophobic (trichloroethylene) and hydrophilic (acetone) solvents in mixed exhaled air (C,,") 1s clearly noticeable. n CF,-Cn,Cl cnlcil 7 r renous blood In ACE TOUE I-------. 11315678h EXPOSURE DURATION ''Flgure 10. Effect of solubility on alveolar and venous blood concentrations during exposure to a fluctuating concentration Eight-hour exposures to the gas 2,2,2-trifluoro-l-chloroethane (CF, . CH,CI) and the solvents methylene chloride ( c H z c ' ~ ~ '.'toluene, and acetone were simulated for a standard working man exposed to a time-weighted average cOnCentra"On 100 ppm. The exposure (exp) concentration (c) fluctuated (the shaded areas) in the range restricted by the excursion It is clearly noticeable that alveolar (alv) and blood (ven = venous) concentrations of solvents fluctuate less than COnce"" tions of the gas and that the smaller the solubility the larger the fluctuation 16 .CETONE 1- I I 82 hours 4 as made of a 2-, 4- itlons were as sho b used. The differe 6 8 'P, LCETM cimulation model and experimental data ,;-...I.. rhe I-.-,-*:. a A f L ? L l J C C l I V L U1 th- 11IC J L I I I U I'Ci t i o n s shown in figures 4 h r o l ~ g h IO was to obtain general insight into the , p 1 3 ~ e ,distribution, and elimination of organic .,llcnts under differeilt ex]posure conditions. If the ~t,,,lii,~tiomnodel is to be applied to a specific ex- ?,<ure situation such as bilological exposure moni- sring, thorough testing of 1the model by comparison ,i<,perimental and simulation data must precede its ,ppllcation. A good examplie of the testing of a simu- J[lon model was publishec by Chberan (40)' who cmpioyed the model which was developed by Droz ,121 for trichloroethylene to simulate experimental .,Docures by other investigaitors (21, 54, 86). Experi- -r nental data used in the testing were mean values ,,btained from a group of healthy volunteers exposed ,rider well-controlled conditions. The experimental jata and the simulation data matched well. In fact, differencesin physiology 3nd life-style result in large differences in uptake and <bmination among exposed persons' For .1ur simulations have shown that the variability of :.hau!ssieolothgeicacloncpenartraamtieotnesrsofcIflipeoxpphoilsiecdsolvents can in ex- 9aled air collected 16 h after an 8-h exposure to differ ----J~ to 15 times, depending on !\ 16 of the subjects (29). h after exposure an oAvseia"l\thI.We.' II C..->"w:-p-'cqo-irfkicer aenxdample, who per- *Ormsmoderate work (50 -'' 0 toluene and who rests W )U U I I I arla' ' 'Ieeps I ~d 8-h exposure after his work- ..hift N I "11 e x* m e a 1.2--t'imes larger concentration of ...:oluene th-n LIIUL. an 911 au.nIAlu,=c.-l.wnc&ltnjrhl+l ..,--Car KGl hwIIu Y-..F-Cl---- dentary work during the same exposure but who twrcises after his workshift. Furthermore, in actual f nnnu+, -IuatcoiLa-ul:u, uc w-lac..a--i-a--ii&c raries among individuals and varies intermittently in as ..:he same individual a result of circumstantial "-+It m.C.".F* .n,r .e-,r--a..m.r.-n,le r*.I" hrnnir Ya.bC.nVIh.Vn. l ian..st=anlcn , ,c=*In.IbaI.,..c.nc.aJ. :he metabolism of solvents (79), but acute alcohol in- :ake (75, 81, 97, 0-0-,1071."d, anA U.." r."nc, =Avy-Vf iaeu. .'v* - tn LV c,,cI,,,- _ . -:ais (24, 49, 50, 51, 69, 78, 91998) reduce the lneta- rolic clearance of inhaled solvents. The reduction is ex- micro soma^h,,.i.,ne~ VI..." " J u r."r,,3\pm.LlnLI"nC t:t:.,a lLl lhl l:lhV:l+l l:U--l l 9I f xyed-function 0)ci'd'ase ('5-6-). It has been shown ex;.srimentally (24, 99). as well as by simulation (24, 2!), that reduced metab.ol.i.c clearance is manifested -.i)t onlv- b<v smaller *ut also by reduced .ancentrations of in paum.l.mo- u-on.n.t-as_r_oy_f urinary a_U_p_ .t_aIK_ _t: metabolites, nd increased haled chemicals in blood, tissues, Ind ex-hale-d air. . Other factors, such as enzyme induc- i;:.3n:1i1et-fuiV.dr-e,,f.4acI_8rht,a.n_nSrIgc.)e",(,t-9h-p%,eo,luypE,.-AmPtYaot*crI,epJZ-haAl,insdmL".JCe,b.l,i.inm&Uma.iltnlrealtta(iob6no4l,oi7sfm9c)h,(ea2mn2i)d-, .ais bk altering physiological parameters or metabol- :clearance. The kinetics also change if inhalation Vosure is accompanied by skin absorption. .r,,,,,,,,,. oawecnACC -_--L---- . -- - v I I J I ~ L c I I t UIIIGICIICCS simui1ati. on ana ex- xrimental data can, however, signal a particular behavior of the inhaled chemical. An example is the simulation of inhalation exposure to hydrophilic solvents. Our simulation of experiments by Astrand and her co-workers (1) was successful for hydrophobic solvents, but was only partly successful for hydrophilic solvents. In simulation, the rising and declining of acetone in blood followed a pattern similar to the pattern of experimental data, but blood concentrations, pulmonary uptake, and the pattern of the concentrations in alveolar air were different from experimental data. These differences prompted us to investigate the retention of vapors of solvents in respiratory airways (27). Using a rabbit trachea, we showed that concentrations of vapors of hydrophilic solvents, such as acetone and alcohols, are reduced by 20 t o 70 Vo during passage through the trachea and that the lost amount can be recovered if the trachea is washed with clean air. No significant retention of inert gases or vapors of hydrophobic solvents in the trachea was observed (table 1). Obviously, retention and desorption on the walls of the respiratory airways means that the concentration of hydrophilic solvents in end-exhaled air does not represent the concentration in alveolar air. These factors explain the differences between experimental and simulation data. Before the simulation model is applied to specific hydrophilic solvents, the following two problems must be solved: (i) a method for evaluating retention in respiratory airways in man must be developed; (ii) the respiratory airways must be treated in the simula- tion model as a separate compartment. Table 1. Retention of vapors in rabbit trachea in vitro: S-UD.S,dance 2,2,2-Trifluoro-lchloroethane 1.1-Difluoro-2chloroethv' lene -Methylene chloride Halothane (CF3 CHCIBr) Freon-12 (cci,F,) Trichloroethykne Toliinne Ethyie& oxide SFtyrzeneoztate n-Amyl alcohol Acetyl acetone 1-Eiitan-ol 1-Propanol Ethanol 1,4-Dioxane Methanol Percentaae of inflow concentraiion retained Nb Mean Standard error 6 -0.1 0 9 5 0.0 1 0 5 25 30 5 6.7 0 5 5 69 03 5 8.3 1.6 10 10.6 1.2 4 139 14 6 17.6 1 7 9 17.7 2.4 9 21.9 1.0 5 41.1 1.3 6 45.8 1.4 7 48.2 3.0 5 54.0 1 5 11 5 8 2 2 4 3 595 1 7 5 68.6 0 7 a Retention was calculated from the difference between inflow and outflow concentrations as follows: R = 1m- Oh. Cbn D N indicates the number of experiments performed 17 i l If III i fi i li I i Toxicokinetics and toxic effect Acute toxicity of organic solvents is frequently manifested by depression of the function of the central nervous system. Some lipophilic solvents, such as trichloroethylene, ethyl ether, and chloroform, have been used for clinical anesthesia. Berman et al (7), by exposing control rats and rats pretreated with phenobarbital t o an anesthetic concentration of methoxyflurane, documented that the anesthetic effect is related to blood concentration rather than to exposure concentration. [Methoxyflurane (CH,-0CF2-CHCI,) is an anesthetic agent with solubility resembling that of toluene.] The unpretreated control rats were anesthetized within 10 min of exposure, but the pretreated rats, which had their blood concentration reduced by 25 To, showed no symptoms of anesthesia. The reduced blood concentration was the result of increased metabolic clearance caused by induction. The pretreated rats became anesthetized when their blood concentration was raised by 25 To. It is beyond the scope of this article to review the literature documenting that anesthetic effect is related to brain concentration of the agent, that the rates of submerging in and emerging from anesthesia are related to the blood solubility of the agent, that anesthetic concentration can be derived from the lipid solubility of the agent, and that anesthetic concentration can be predicted from physical constants and the chemical structure of the agent. The reviews can be found in references 19, 58, 67, and 90. Hydrophilic solvents also exhibit analgesic effects, yet they have not been used for clinical anesthesia or analgesia (with the exception of ethanol). In my opinion, their fat-blood partition coefficient, being smaller than 1, prevents the damping in cerebral lipids and lipoproteins. Thus hydrophilic solvents act upon other receptors, and cardiac or respiratory arrest precedes the development of the anesthetic effect. The hepatotoxic effect of chemicals is usually related t o their hepatic metabolism (84). In many instances, hepatotoxicity is related t o the alteration of the metabolic pathway of the chemical after the capacity of one step in the metabolic pathway is saturated o r when a particular enzyme is inhibited. Both capacity-limited metabolism and competitive inhibition during inhalation exposure to organic solvents have been documented. It remains to be seen whether hepatotoxic effect can be predicted from toxicokinetic parameters such as V,,, and K, in a simila- manner as anesthetic effect can be predicted from solubility. Acknowledgments This study was supported by NIH grant ES 01029-08. References 1. Astrand 1 Uptake of solvents in the blood and tissue. ' of man Scand J Work Environ Health 1 (1975)199- 218. 2. Astrand I. Effect of physical exercise on uptake distribution and elimination of vapors in man In 1 Fiserova-Bergerova V,ed. 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