Document dY56vwjn44BVp8Q5G3eDbNOzG

1 d -4 British Journal of Industrial Medicine, 1980; 37: 42-49 Predictable "individual differences" in uptake and excretion of gases and lipid soluble vapours simulation study VERA FISEROVA-BERGEROVA,' JIRI VLACH,' A N D JANET C CASSADY3 From the Department of Anesthesiology,` and Department of Epidemiology and Public Health,3 University of Miami School of Medicine, Miami, Florida, USA, and Department of Electrical Engineering,2 University of Waterloo, Waterloo, Ontario, Canada ventilation, and lipid content in blood on uptake, distribution, and clearance of low and lipid soluble vapours during and after exposure. The model shows the extent ccntrations of lipid soluble vapours. The fluctuation is reduced by metabolism of inhaled These conclusions are recommended for consideration whenever evaluating the effect of above the threshold limit values used in the control of industrial exposures (by excursio The main problem in establishing threshold limit values of airborne contaminants (TLV) and biological threshold limits (BTL) is the number of factorsthat affect their concentrationsin the the most important being: Type of exposureduration of exposure, concentration variations in the air, repetition of exposure, duration of resting period, work load, etc. Time-time intervals between the onset and termination of exposure and sampling. Individual differencesamong exposed subjects. In our previous papers we presented a math- e x p ~ s u r e .T~he model is a flow-limited which the rate constants are determined nantly by tissue perfusion and by maxim of distribution of inhaled ~ubstance.~-~ factors such as body build, changes in vent caused by work load, or changes in lipid conte blood caused by food uptake, affect inhaled substances. In this study the mo to investigate the effect of variation in distribution, and clearance (exhalation an and solubility on uptake, distribution,and exhalation of organic solvents in man;3-7 to define the role of sampling time for data interpretation;3 and to show the effect of metabolism and vapour solubility in Methods MATHEMATICAL MODEL This study was supported by AFOSR 762970 and NIH appendix) linear to the first approximation. grant ES01029-02. Received 6 June 1978 Accepted 18 May 1979 metabolise the inhaled substance, and solub 42 I predictabk "individual difserences" in uptake and excretion of gases and lipid soluble vapours 43 the substance in the tissue. Lung tissue, functional fusion of viscera (ml/min/g), but increases perfusion air, and arterial blood form the central of MG and FG (appendix, equations A-16 to A-17). 1 compartment "LG", in which pulmonary uptake and clearance take place. The partial pressure of Ventilation inhaled vapour equilibrates with four peripheral The following were assumed: inhaled (exhaled) air Vessel-rich tissues form two flows in the direction of respiratory airways in which 1 peripheral compartments :BRcompartment includes brain, which lacks capability to metabolise most no mixing or uptake occurs. Tidal volume, perfusionventilation ratio, and ventilation ratio of dead space xenobioticS,and is treated as a separatecompartment to alveoli remain constant, dead space taking one- m a u s of its biological importance and the toxic third of tidal volume. Under these assumptions, effect of many vapours and gases on the central only two-thirds of tidal volume of room air enter the nervous system. VRG-compartment includes tissues alveoli with each breath: (one-third of tidal volume with sites of vapour metabolism such as liver, is alveolar air returning in the lung from respiratory kidney, glands, heart, and tissues of the gaStr0- airways). To account for dead space, the alveolar intestinal tract. Muscles and skin form compartment ventilation Val", comprising two-thlrds of minute .-MG", and adipose tissue and white marrow form ventilation V, is used in our model. compartment "FG". The FG-compartment is treated separately, since the dumping of lipid Solubility solublevapours in this compartment has a smoothing effect on concentration variation in other tissues, caused by changes in exposure concentrations, minute ventilation, and exposure duration. The one-compartment model used for evaluating body Lipid content in blood is higher postprandially than during fasting. The effect of a meal on blood-air partition coefficients of seven lipid-soluble vapours was investigated in 10 human volunteers. Blood-air partition coefficients were determined in blood burden did not describe this smoothing Bodv build Body build affects the volume of distribution. TO study the effect of body build on uptake, distribution, and clearance of inhaled vapours and gases, the volumes of pharmacokinetic compartments and their perfusion were estimated for three Somatotypes of body weight 70 kg: slim person (body height 185 samples collected 1-2 hours and 10-15 hours after a meal. The equilibration method was used for determination of blood-air partition coefficients at 37OC.5 To show the effect of a meal on uptake, distribution, and clearance of vapour, the extreme values of blood-air partition coefficient (hbljap = 7-5 or 13) were used for modelling of hypothetical lipid soluble vapour (mean X b l p r = 10). cm),person with normal build (170 cm), and slightly obese person (150 cm). The volumes of pharmaco- kinetic compartments were related to the ratio of body fat and lean body mass, estimated from specific density (appendix, equations A-1 to A-8). The percentages of body fat (adipose tissue) calculated for the three somatotypes Were 1 9 % , 8.6:/,, and 18.8%, respectively. Minute ventilation of 10 I/min and alveolar ventilation of 6.7 I/min Metabolic clearance Clearance by metabolism is defined in the model by the constant Gx. To determine Gx, the rate of overall metabolism is measured at the apparent steady state, when retention of inhaled substance in tissues is negligible and the rate of metabolism urnis almost equal to the uptake rate u.3 The uptake rate is calculated from the difference of exposure concentration (Cexp) and vapour concentration in were assumed for a person with normal build unless mixed exhaled air (Cexh) and minute ventilation V. otherwise specified. Alveolar ventilations and cardiac outputs for other somatotypes were adjusted Urn = u = (Cexp - Cexh) V (1) in proportion to body surface area (appendix, equations A-11 to A-17). Bloodflow Cardiac output and its distribution were adiusted to Constant Gx (expressed in the same units as pulmonary ventilation) can be calculated using equation 2. 1 related to surface areas of somatotypes according to oncardiac index (3 I/m2/min).ll Cardiac output under working conditions is related to given alveolar ventilation with the perfusion-ventilation ratio 1.25. The increase of cardiac output does not affect per- where Valv is alveolar ventilation, hbijair is blood-air partition coefficient at 37"C, and FVRGis blood flow to VRG-compartment. Modelling was done for two hypothetical substances of different solubility (low solubility gas and I 44 Tissue-air partition coefficients(at 37C)user!for mathematical modeling conpovnd Blood Brain VRG M G FG GZ Low solubility gas 0.5 0.8 0.8 0.8 0.8 7.7 Lipid soluble vapour 10 40 20 20 500 9 2 Fiserova-Bergerova, Vlach, and Ca metabolised low solubility gas, inert lipid vapour, and metabolised lipid soluble during and after one-hour, five-hour, and exposure are presented in figs 1-4. Body bu most profoundly concentrations and pul clearance of lipid soluble vapours-namely, lipid soluble vapour), each being modelled as nonmetabolised (inert substances, Gx = 0) and as extensively metabolised (Gx = 7.7 for gas and 9.2 for vapour). Partition coefficients and metabolic clearance Gx used in the modelling (presented in the table) were selected arbitrarily as being representative for industrial gases and vapours of organic solvents. To evaluate the significance of different factors on bodyexposurethefollowing variableswerecompared: (1) total uptake, (2) saturation (partial pressures equilibration) of brain, MG, and FG at the end of exposure and 24 hours after the start of exposure, (3) amount metabolised during the exposure day, (4) fraction of uptake metabolised during exposure, and ( 5 ) fractions of uptake exhaled or metabolised on the exposure day. Results 12345678 12345678 Expslrr hxrs Expowe hours 12345678 12345678 EXp5"re haKs -sure h r r Fig 2 Efecr of body b pressures of inhaled low l?re eflect of body build and exposure duration on gas (lower graphs). Par uptake, distribution, and clearance of four hypothetical substances (inert low solubility gas, 6 r Gas I coincide the broad lin unw ion fi\\uc cor Expowre harrs 12345678 Exwsure hours 1 2345670 Exposure h w r s Fig 1 Effect of body build on uptake and metabolism of low solubility gases (uppergraphs)and lipid soluble vapours (lower graphs) during an eight-hour exposure to concentration 100 pgll. Cumulative uptakes and amounts metabolised (mg) are calculated for a person with normal build (solid lines, Valv = 6 7 llmin), a slightly obese person (dashed lines), and a slim person (dotted lines).If lines coincide the broad solid line is used. Fig 3 Effect of body build on equilibration pressures of inhaled lipid soluble vapours in partial pressure of exposure concentration. Simula for non-metabolised vapour (upper graphs) and metabolised vapour (lowergraphs). Partial pressur ratios are calculatedfor brain, MG,and FG of a person with normal build (solid lines, Valv = 6 7 a slightly obese person (dashed lines),and a slim (dotted lines). predictable "individualdiferences" in uptake and excretion of gases and lipid soluble vapours Gas Gx= 0 Vawur 45 "n L 158 Hours 158 158 158 t l g 4 Effect of body build on clearance of low ,olubility gases and lipid soluble vapours afer one-hour, five-hour,and eight-hour exposures. Bars represent fructionsof uptake exhaled on exposure day (open areas), narabolised during exposure (diagonally striped areas), and metabolised afer exposure on exposure day (dottedareas). pars are calculated for a person with normal build ( Valu = 6-7 Ilmin). Effect of body build is ,hewn by lines drawn between values calculatedfor a ,lightly obese person (0)and a slim person (H).If elfect is smaller than halfper cent of valuefor a normal perron, effect of body build is not shown. . .Y . . L . , . _ . , _ _ _ . . . . . - . / 5 IO 15 20 Xbl,.,, after meal Fig 5 Postprandial and fasting effects on blood-air coefficientsof lipid soluble vapours. Intersections of crossed lines represent means of respective blood-air partition coefficientsat 37C (n = 5 ) for enflurane (E), halothane ( H ) , methylene chloride ( M ) ,benzerte (B), trichloroethylene(TRI),toluene (T),and methoxyfluorane (MOF).Crossed lines define standard deviations and +diamonds rhe standnrd errors of means. Line ( y = 0 . 6 1 ~ 0.246) is a regression defined by optimumfit to means, calculated by method of least squares. which are not metabolised. When exposed to the Same concentration, obese people have smaller tissue concentrations of these vapours than thin persons (fig 3), and thin people have faster pulmonary clearance than obese people (fig 4). The effect of' changes of blood-air partition coefficient on uptake was studied by modelling eight-hour exposures to hypothetical lipid soluble bapours. The blood-air partition coefficients measured in samples collected after a meal are greater than in those collected after fasting (fig 5). As shown in fig 5, the blood air partition coefficient of hypothetical lipid soluble vapour can vary from 7.5 to 13 (mean Xt+ir = 10).Variation of blood-air partition coefficient in this range affects uptake of such vapour by less than 10%and slightly affects iapour distribution in tissues (fig 6). The effect of alveolar ventilation and cardiac output on uptake, distribution, and clearance of gases and vapours was studied for alveolar ventilations 5.2, 6.7, and 10 I/rnin (for a person with normal build). A positive relation exists between alveolar ventilation and equilibration rate. Apparent steady state (defined as 95% of the steady-state partial pressure in the FG-compartment) is reached End of exposure 1' 16 hours after end d exposure G,=O q.9.2 Fig 6 Effect of blood-gas partition coefficienton equilibration of partial pressures of inhaled lipid soluble vapour in iissues with partial pressure of exposure concentration. Bars represent partial pressures ratios calculated for a person with normal build (Vatu = 6-7 Ilmin) at end of an eight-hour exposure and at end of exposure day for vapour with blood-air partition coefficients7.5 (openbars) and 13 (dotted bars). Tissues-airpartition coefficientsare in table. Effect of body build is shown by lines drawn between values calculated for a slightly obese person (0)and a slim person (H). i:uw i I I 1 I - r,, 46 ( :O Gxs42 1 5.2 6.' 10 5.2 6.7 lo Alveolar ventilation(1 Irnin) Fig 7 Effect of alveolar ventilation on uptake of lipid soluble vapour. Bars represent uptakes (mg)by a person with normal build during an eight-hour exposure to concentration 100 pgll. Dotted areas represent amounts (mg)of unchanged vapour remaining in body at end of exposure day. Effect of body build is shown by lines, (m).drawn between values calculated for a slightly obese person (0)and a slim person constant concentration represent examples of (dashedlines), 1.5 (dark Brain and M G G,= 0 08 $=9.2 FG G,= O G.9.2 0.7 06 05 st L?'0.4 0 '* 3 a'0.2 01 526710 B mTT I 5267 10 526710 5267 10 A W a r ventilation ( Ilmin) for the studied low solubility gas within fo one. For the studied metabolised pressure ratios at steady state are 0.88 respectively, for each alveolar Fig 8 Effect of alveolar ventilation on equilibration of partial pressures of inhaled lipid soluble vapour in tissues with partial pressure of exposure concentration. Bars represent the partial pressure ratios calculatedfor a person with normal build at end of an eight-hour exposure and at end of exposure day (dotted areas). Effect of body build is shown by lines drawn between values calculatedfor a slightly obese person (0)and a slim person (H). industrial exposure on uptake ance was studied for hypoth Fiserova-Bergerova, Vlach, and Ca increased transportation rate and retention rate of avpours in MG and FG compartments (fig 8). The work load has no effect on uptake or body burden, once the steady state is reached. Total body volume: effecton the fate of inhaled substance. According to the simulation, uptake during postprandial exposure BV = TBV (1 - 0.01 Of is greater than during fasting, deposition in fat VVRG= 0.081 BV (. being enhanced but deposition in lean tissues (and with it related availability for biotransformation) being lowered, due to changes in tissueblood partition coefficients (fig 6). Simulation by our model shows that the exposure VBR = 0.025 BV VMG = 0.58 BV K )+VFG = BV - 0-055 (. (&3 (1 duration has a strikingeffect on the ratio of fractions where the subscripts are related to PharmacokiL of uptake exhaled and metabolised (fig 4). This compartments as d-it.p.l in the t-vt agrees with experimental data. For example, Teisinger et recovered one-third of Uptake in exhaled air after a two-hour benzene exposure, while Teisinger et a125 recovered only 16% of uptake in exhaled air after a five-hour benzene exposure. Our simulation showed exhaled fractions of 30% and 16%respectively. The maximum volul .._ peripheral compartments are determined by volu of compartments and tiss~~e-nninr ttitinn cmffirir ci = V i Ai where "i" represents the various subscripts o f ' (A-5)-(A-8) and the appropriate tissue-air parti Equilibration of partial pressures of low solubility coefficient at 37C. gases is much faster than of lipid soluble vapours, The maxhum VO~Ume of distribution Of and is prevented by metabolism. Accordingly, the central compartment CLGis determined bY VOlu concentration variation in room air during exposure of lung tissue Vlune and arterial blood v b k 1 to gases causes a greater concentration variation in function residual capacity of the lung a~ tissues than does exposure to lipid soluble vapours. appropriate Partition Coefficients: t: (Note that when excursion factor 3 is used for two cLG= vlUnx, ~ ~ ~cp~r , ~v., . .1%. hours (figs 9 and 10) the partial pressures of inert lipid soluble vapour in tissues did not equilibrate with mean exposure concentration, but the partial Surface area or ` ' B pressures of inert gas in tissues temporarily exceeded c three times the partial pressure of corresponding cardiac output: 1 mean exposure concentration-TLV.) The variation is always diminished if the substance is metabolised. Q=3SA I Since toxic effect is related to concentration in tissue, the feasibility of considering solubility (or other storage mechanisms) in establishing excursion factors should be explored. Cardiac output under normal Fonditions related to alveolar ventilation Valv in li minute : Qn = 1.25 V s ~ v Appendix Blood flows in peripheral compartmen determined by Volumes and perfusions of pharmacokinetic compartments were calculated by the following equations:l113 26 Specific gravity SG is obtained from body weight BW in kilograms and body height BH in centimetres: +loglo SG = 0.848 L0.242 loglo BH 0.1 (3 loglo BW) - 0.0172] (A-1) The percentage of body fat: FVRG= 0.75 VVRG FBR = 0*53vBR +0 . 0 3 3 V ~ ~ (Q,,- Q)O.nqqv-.- FMG = 0-033Vuc + 0.022\ +0.022VFG (On - 0)os( FFG= and the transportation r !I 4 predictable "individual differences" in uptake and excivetion of gases and lipid soluble vapours 49 Gi = Fi hblpir (A-18) The uptake and clearance are described by the following system of differential equations: + + ++ +Vsjslv GVRG GBR GMG GFG -G\-nc EVRG -GBREBR -GMGEMG -GFG EFG = Cr- Val" (A-19) GVRG+ Gx + CVXG = b (A-20) where Es are instantaneous partial pressures of inhaled vapour in compartments (or vapour concentration divided by appropriate tissue-air partition coefficients),Gx is determined by equations 1 and 2 in text, and Crmm equals exposure concentration Cexp during exposure and equals zero after cessation of exposure. The mathematical solution was described pre\ i o ~ s l y .C~alculation was done by Univac 1100/20 computer. We thank Ross Schwelm and Dolores Fernandez, MS, for their excellent technical help. References Stokinger HE. Rationale for the use of biologic th:eshold limits in the control of worker exposure. Proceedings of the 3rd Annual Conference on Environmental Toxicology. Ohio : Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, 1972526. (AMRL- TR-72-130.) * Astrand J, Gamberale F. Effects on humans of solvents in inspiratory air: method for estimation of uptake. Environ Res 1978;15 :1-4. 'Fiserova-Bergerova V,Vlach J, Singhal K. Simulation and prediction of uptake, distribution, and exhalation of ' organic solvents. Br J Fiserova-Bergerova V. Ind Med 1974;31:45-62. Modeling of chronic toxicity. Proceedings of the 6th Annual Conference on Environ- mental ~oxicology.Ohio: Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, 1975: ' 175-91. (AMRL-TR-75-125.) Fiserova-Bergerova V .Biological-mathematical modeling of chronic toxicify. Ohio: Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, 1975: 1-124. (Toxic Hazards Research Unit Annual Technical Report AMRL-TR-75-5.) * Fiserova-Bergerova V. Simulation of uptake, distribution, metabolism, and excretion of lipid soluble solvents in man. Proceedings of the 3rd Conference on Environmental Toxicology. Ohio: Aerospace Medical Research Lab- oratory Wright-Patterson Air Force Base, 197253-69. (AMRL-TR-72-130.) ' Fiserova-Bergerova V. Mathematical modelling of in- halation exposure. J Combustion Toxic01 1976;3:201-10. Droz PO, Fernandez JG. Effect of physical workload on retention and metabolism of inhaled organic solvents. A comparative theoretical approach and its application with regards to exposure monitoring. Inf Arch Occup Environ Health 197738~231-46. * Roach SA. A most rational basis for air sampling programmes. Ann Occup Hyg 1977;20:65-84. lo Hickey JLS, Reist PC. Application of occupational exposure limits to unusual work schedules. Am Ind Hyg ASSOCJ 1977;38:613-21. l1 Burton AC. Physiology and Biophysics of the Circulation. Chicago: Year Book Medical Publisher, 1965:164. I* Threshold Limit Values of Airborne Contaminants. American Conference of Governmental Industrial Hygienists, 1976. la Eger EI. Mathematical model of uptake and distribution. In: Papper EM, Kitz RJ, eds. Uptakeand Distributionof Anesthetic Agents. New York: McGraw-Hill, 1963: 72-103. I4 Mapleson WW. Quantitative prediction of anesthetic concentrations. In: Papper EM, Kitz RJ,eds. Uptake and Distribution of Anesthetic Agents. New York: McGraw- Hill, 1963:104-19. Severinghaus JW. Role of lung factors. In: Papper EM, Kitz RJ, eds. Uptake and Distribution of Anesthetic Agents. New York: McGraw-HiH, 1963:9-71. Fiserova-Bergerova V, Cettl L. Electric model for the absorption, metabolism and excretion of benzene in man. Pracovni Lekarstvi 19722456-61. "Fernandez JG, Droz PO, Humbert BE, Caperos JR. Trichloroethylene exposure-simulation of uptake, excretion, and metabolism using a mathematical model. Br J Ind Med 1977;34:43-55. I' Piotrowski J. The Application of Metabolic and Excretion Kinetics to Problems of Industrial Toxicology. US Government Printing Office, 1971:276-382. lS Sato A, Nakajima T, Fujiwara Y,Hirosawa K.Pharmaco- kinetics of benzene and toluene. Inr Arch Arbeitsmed 1974;33: 169-82. Mason J, Dershin H.Limits to occupational exposure in chemical environments under novel work schedules. J Occup Med 1976;18:603-6. 'I Teisinger J, Soucek B. Significance of metabolism of toxic gases for their absorption and elimination by man. *' Cas Lek Cesk 1952;91:1372-5. Zenz C, Berg BA. The influence of submaximal work on solvent uptake. J Occup Med 1970;12:367-9. DiVincenzo GD, Yanno FJ, Astill BD. Human and canine exposures to methylene chloride vapour. Am Ind Hyg ASSOCJ 1972:125-35. l4 Teisinger J, Srbova J, Skramovsky S.Uptake and excretion of benzene in man. Pracovini Lekarstvi 1949;l:l-8. Is Teisinger J, Fiserova-Bergerova V, Kudrna J. Metabolism of benzene in man. Pracovni Lekarstvi 1952;4:175-88. I o Consolazio CF, Johnson RE, Pecosa U.Physiological measurements of metabolic functions in man. New York : McGraw-Hill, 1969:258-308.