Document 6ErndZB7M1eE7gaJmDY9xqDm

- -. Toxicology Letters 79 (1995) 77-86 I __. 1 parameters for physiologx Vera Fiserova-Bergerova Department of Anesthesiology, University of Miami School of Medicine, PO Box 016370, Mumi, FL 33101, USA .1 1 Accepted 5 April 1995 I Abstract M'Lsses of organs and fluids, pulmonary ventilation and cardiac output and its distribution are the basic input data used in physiologically based pharmacokinetic models. Since these parameters are rarely measured in pharmacokinetic studies, the values found in reference books or extrapolated to meet the specific exposure conditions are used in the models. In this review of the extrapolation of pertinent physiological parameters, power equations for scaling across mammals, adjustments to body build (lean body mass) and physical activity of humans and their significance for risk assessment of human exposure to solvents using animal data are assessed. Keywords: Inhaled dose; Pharmacokinetic compartments; Physiologically based pharmacokinetic models; Risk asst- ;merit 1. Introduction Physiological parameters, such as mass of organs and fluids, pulmonary ventilation and cardiac output and its distribution (perfusion rates of o i y ~ s ) a, re the basic input data for physiologically based pharmacokinetic models (PBPK) [I 51. These parameters are rarely measured in experimental pharmacokinetic studies and the choice of their values relies either on the values suggested for a ' reference man [6] and animals [7,8], or on extrapolation across species based on * Corresponding author, Vera Thomas, Ph.D., Department c " .-\nesthesiology. University of Miami School of Medicine, p(; Box 016370, Miami, FL 33101, USA. body weight [9-151. In this review of extrapolation schemes, the adjustments to body build and physical activity are stressed. 2. Tissue mass 2.1. Scaling across young adult mammals Weights of organs were measured in adult hu- mans [6],experimental animals [14], domestic animals (cattle) [lo] and African ungulates [9]. It was found that,!,across the species, the weights of vital organs (such -as liver, kidney, heart, glands and brain) correlate with body weight. The data were analyzed by numerous investigators and power equations were derived for extrapolations of weights of organs of young adult mammals. ' 0378-4274/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved S S D l 0378 -42 74(95)03 3 59-S 78 V. Fiserora-Bergeroaa 1 Toxicology Letters 79 (199s) 77-86 6ble 1 Constants for extrapolation of organ weights across adult species (using Eq. ( I ) ) Organ BW (kg) a b Mouse 0.022 Rat 0.20 Man \ ------ IO 4 Adrenals [I I] 0.001 1 0.92 0.019 0.14 31.5 (14) -I Brain [I I] Heart [I31 0.08I 0.002 0.70 1.043 0.70 (0.60) 0.050 3.3 (2.0) 0.50 200 (1400) 226 (330) Kidneys [I31 0.02 18 0.843 0.30 (0.34) 1.9 (1.9) Liver [I31 Lungs I131 SpGn [ I $1 Muscle [I31 0.0859 0.00316 0.00452 0.463 0.885 1.104 0.901 1.009 1.32 (1.3) n n96- 0.073 10.5 (IO) 9.3 (8.3) 11 1.1 0.54 97.1 (100) Constants a and b are taken from Mordenti [13] or Adolph [ I l l . Body weights of species chn-1rn 7iuAul lAAA\ {WU) 105 (180) 35 833 (28 000) L- I.-.,- *- I., -. I grams before substitution in Eq. (I). The calculated weights of organs are given in grams. The bAp.lrlllclllarlr ucLsIIIIIIIcu "dlUeS lor the reference man [a] and rodents (14,161 are shown in parentheses. Table 1 shows constants a and b which should be substituted in Eq. (1) in order to calculate weights of vital organs (Xin g) from body weight (BW in g) [11,131. X = a x BWb (l) To exemplify the accuracy of the prediction, values measured for a 22 g mouse [14,16] a 200 g rat [14,16] and a 70 kg man [6] are shown in Table 1 in parentheses. There is a striking difference between the predicted and measured mass of the human brain. The difference is in agreement with the observation that the mass of human brain per kilo of body weight is about ten times larger than that of non-primate mammals [16]. Two different equations were designed for calculation of the brain mass of young adult mammals 1161: For non-human primates: Brain mass (g) = 26.9 x BW6' . .< ( . , (2) F-ao.r mammals other than primate: .:*Brain mass (g) = '' 1 ~ .. ,_, / ' I , . where BW is given in kg. Thus'the brain masses of. a'70 kg human, a nonrhuman, priqate and a non-primate mammal are,lA kg,0.48- kg and 0.14 kg,, respectively. , L *.i Il Scalinrz of skin based on b- odv~ s--- - - - ---- ----- thickness is biased by regional, and interspecie:. differences of skin thickness [6,17]. Body build should be considered in thc muscles and fat. -r ---- I 2.2. Scaling for bodv build in humans The vaiiation in the amount of body fat (adipose tissues) [18] is the main source of inaccu- -racy in the estimation of the weights of organs Y ~- and compartments. Therefore, relating masses of organs and compartments to lean body mass (LBM) seerns to be appropriate [5,19]. Estimates of LBM and fat can be based on girth measure- ment [20], skinfold thickness measurement 1211, total body water [6,19,22,23], specific gravity [5,24], or creatinine excretion 241. No girth or skinfold measurements (which provide the most accurate information) were found in pharmacoki- netic studies. The LBM of hurnans can be estimated from total body water ( T I3W in kg), the calculation of which takes intn -Q-a~ uC nt the body build, defined by body we cm) 1 I I 1 I ' + +.TBW = '"- 12.86 0.1757 x BH 0.3331 x BW # ' . ..' I .,f " 81 I (5) a/ T$&dogy Letters 79 (1995) 77-86 79 i Normal values of BMI are between 17 a bf ' * women account for,a sm for men (see TFble 2). Similar equations for LBM calculation were tested by Hume [23]. The body mass index [25]is suggested for identifying the extremes in body build for which the BMI = BW/(O.Ol x BH)' p (7) The mass of organs can be calculate fraction of the LBM by using the fractional co- efficients shown in Table 2. The weight of adipose ,is calculated as the difference betwee t and lean body mass: I> r.Jr/. BF=BW-LBM (8) Body height cannoi be used for evaluati body build of animals.. It remains to be whether specific gravity or creatinine excretion, both easily measurable in animals, can be used for adjustments to body build. The LBMs of humans extrapolated from these parameters are not, al, ways in agreement with values based on TBW. Table 2 2.3. Scaling of mass of compartments Comparison of calculated weights of organs with values recommtnded for a reference man and woman I The mass of the vessel rich compartment, VRG, was calculated as a sum of the weights of the Referencea Calculated Fraction major and small organs listed in Table 2 (the liver and lungs are excluded). Weights of the muscles, Male Female Male Female skin and connective tissues (which account for BW/BH (kg/cm) 70/170 58/160 70/170 58/160 TBW 0%) 42 30 40.2 29.3 LBM (kg) 57Sb 4Ib 54.9 40.0 Adipose tissues 12.5 17 15.1 18.0 (k. - 1 Muhdes (kg) 28 17 24.7 18.0 0.4508 Skin (kg) 2.6 1.8 2.4 1.8 0.0446 7.3% of body weight [6]) are included in the muscle compartment, MG. The masses of the compartments represent the following fractions of LBM: liver, 0.0327; VRG, 0.126; MG, 0.52. The fat compartment, FG, equals the difference between BW and LBM. Sizes of compartments calculated for a reference man are compared in Major organs (kg) Brain 1.4 Bone marrow 3.0 Heart 0.33 1.2 2.6 0.24 1.5 1.07 3.2 2.31 0.32 0.23 0.0268 0.0578 0.0058 Table 3 with the default values recommended by the EPA [26] and with the values used by some investigators who pioneered the PBPK models. Intestine 1.0 0.95 1.1 0.81 0.0203 Kidneys I iber L U.1gs Spleen Stomach 0.31 0.27 1.8 1.4 0.44 0.36 0.18 0.15 1.5 1.4 0.33 0.24 1.80 1.31 0.45 0.33 0.19 0.14 1.65 1.20 0.0060 0.0327 0.0082 0.0034 00301 2.4. Scaling for growth It has been shown by Brody [lo] that there is a correlation between organ and body weights of young growing animals. Special power equations Total 9.96 8.57 10.54 7.54 0.1910 were derived to describe the growth of organs of Small organs (kg) TotalC 0.415 0.704 0.67 0.49 0.0122 some mammals at various stages of development. These equations may differ considerably from "ICRP [6]. "Since adipose tissues in ICRP are better defined than LBM, LLXI was calculated as the difference between body weight and ,tJipose tissues weight. equations used for extrapolation for young adults. For example, Eq. (9), suggested for the calculation of TBW for children in the prepubertal age [6],differs notably from Eqs. (4) and (5): 'The difference in weights of small organs is mainly the result of differences in reproductive organs. '-1TBW = 0.135 x BWO.- x BH0.535 (9) 80 V. Fisrrora- Bergerora 1 Toxicology Leriers 79 ( I 995) 77-56 Table 3 Weights or volumes of compartments used for a reference man Calculated @e) EPA [26] 0%) Eger P I (kg) Mapleson [2] (1) Lowe [3]" (1) -. Liver VRG MG FG 1.8 6.9 28.6 15.1 I .8 -C 3.9b 3.5 6.0' 2.32 43.4 33.0 37.4 13.3 14.5 12.8 4.0b 2.2d 29.8 10.5 'Lowe gives the volumes for a 100 kg man. The volumes for a 70 kg man were extrapolated using a multiplying factor of 0.7 bAll splanchnic tissues. 'Liver is a part of the V R G compartment. dInclude only heart, brain and kidney. 3. Pulmonary ventilation Val"(l/min) = 0.41 14 x BW0.78- 0.1477 x BWO 'O Minute ventilation and alveolar ventilation depend on the size and physical activity of the subject. Both ventilations correlate with oxygen consumption, which, at rest, is mainly related to heat dissipation @e. to the body surface) [lo] and is increased by physical activity of the subject [27]. 3.1. Scaling across young adult maiiiriials Minute ventilation and alveolar ventilation are determined by three parameters: tidal volume (Tv), anatomic dead space (Ds), and respiratory rate (Rr). Minute ventilation: V = Tv x Rr (10) Alveolar ventilation: VdV= (Tv - Ds) x Rr (11) Stahl [12] measured pulmonary parameters in resting adults (unanesthetized humans and experi- ' mental animals) and described the scaling across the species by the following equations: . .. olume: Tv (ml) = 7.69 'Dead space: Ds (ml) =2.76 x BW0.96 (12) i (13) ., (16) Eq. (15) is similar to Eqs. (17) and (18), which were obtained in two studies by optimum 'it of the direct measurements of minute ventilation [12,28]. V (l/min) = 0.379 x BW0.'O (17) V (I/min) = 0.3735 x BWO." (18) Table 4 compares the values of minute ventilation and alveolar ventilation, predicted by Eqs. (15) through (18) for adult humans and mme Table 4 Minute ventilation and alveolar ventilation for resting adults Mouse Kat Monkey Dog Human Minute ventilation (I/min) .EPA [26] ..EQ;(15) , Eq. (17) ..(IS) 0.037 0.174 0.023 0.140 1.44 0.02 ' 0.125 1 0.023' 0.132-' veolar ventilation (Ilmin) I .I, EPA [26] " 0.025 0.117 I- -- Eq. (16)-- 0.012 0.084 - 1 7.5 2.48 11.3 v'(l/min) = 0.4114 x BW-78 .*. . j' Values in parentheses indicate fractions of minutd;ventilati,qn calculated by using Eq. (15). The EPA document [26] 'assumes that the. alveolar ventilation of. all animal s k i e s (15) accounts for 67% of the minute ventilation: mi' 1 -- V. Fisbro$AJB, GI g. erov-a Toxicology Letters i -, 79 (1995) 77-86 81 ,xperimental animals with the ommended by the EPA [26] b experimental -data. I The value EPA document [26] are lower for h higher for laboratory animals' than derived by -using the equations based-onStahl's [12] and Guyton's, [28] data. The different'values are the result of 'the unconformity of the EPA database which includes data for an anesthetized man and non-anesthetized animals. This in* tu) rn ' affectsthe slope of the regression. 3.2. Scaling for humans Basal conditions. The data for basal conditions were obtained in anesthetized humans. Basal alve- olar ventilation (V:,") can be calculated using the (e*)perfusion ventilation ratio (which at basal condi- tions equals 1.25) and cardiac output [l]: V,*,,= Q*/1.25 (19) Cardiac output of a resting -human (Q* in ljmin) is related to body surface (SA in m2) [24] and can be estimated as follows: Q*(l/min)= 3.3 x SA (20) SA (m2)k0.0072 x (BW0.425x) (BHO 725) (21) where BW is body weight in kg and BH is body he$. in cm. Basal alveolar ventilation can be calculated after substituting in Eq. (19): V,*lv(ljmin) = 0.019 x (BW0.425x) (BH0.725) (22) Basal cardiac output and alveolar ventilation calculated for a reference man using Eqs. (20) and (22) are 5.95 l/min and 4.78 l/min, respectively. These values are smaller than values obtained by usi:-g Eq. (16) which is based on measurements in non-aesthetized mammals. Working conditions. It can be estimated from studies by Astrand [27] that physical activity in- creases alveolar ventilation of an adult by about 0.28 l/min per watt of energy expenditure. Thus alveolar ventilations for an active man (Va,,)can be scaled by using Eq. (23): v:,:("I/min) = Vzlv+ 0.28 x W (23) where W denotes energy expenditure in watts. According to Eq. (23), a reference man perform- g moderate work (50 watts) has an ntilation of 18.8 l/min, which is'the Val red in laboratory exercise studies [27]. r191 estimated a somewhat smaller increment'in alveolar ventilation (0.22 l/min per watt) which corresponds, at moderate activity, to an a ;ventilation of 15.8 l/min. 4. Tissue perfusion Cardiac output, like pulmonary ventilation, depends on the size and physical activity of the subject. Measurements and extrapolations of distribution of cardiac output are confounded by the dependence of cardiac output on the activity and posture of the subject [271, the environmental temperature [29], the altitude [30] and the measuring technique. In a resting man, the perfusion rates of organs included in the VRG compartment are closely related to oxygen consumption by basal metabolism [101. Therefore, their perfusion rates are closely related to basal cardiac output and are affected very little by physical activity. On the other hand, the oxygen consumption and perfusion rates of muscles, skin and adipose tissues are profoundly affected by physical activity and are therefore closely related to the increase of cardiac output during the activity. 4.1. Scaling perfusion of organs across young adult mammals Since oxygen consumption is related to heat dissipation, it is expected that, at rest, cardiac output and perfusion rates are related to the body surface. The following power equations were derived for scaling of cardiac output [12,15]: Cardiac output (l/min): = 0.187 x B\V.*' (24) (l/min): =0.211 x BW".75 (25) Plasma perfusion rates were measured in livers, kidneys, spleens and muscles of five experimental animal species [13,14]. Below are power equations derived from these data by Mordenti [13] and re-calculated for blood flow using a hematocrit of 0.45 and BW in kg: Hepatic flow (l/min): = 0.0408 x B\V"792 i (26) 82 V . Fiseroca-'Bergeroca 1 Toxicology Leilers 79 (1995) 77-S6 Table 5 Distribution of cardiac output among the compartments (physical activity is not included) Species Reference Cardiac output (I/min) Fraction of cardiac output Liver VRG MG Anesthetized reference man Resting reference man Mouse Eger [I] Mapleson [2] Bogen [31] EPA [26] Eq. (20) Bogen [31] EPA [26] 6.0 6.48 6.2 6.2 5.98 0.021 0.017 Eqs. (24) and (26) 0.0094 Rat Bogen [31] 0.085 EPA [26] 0.083 Eqs. (24) and (26) 0.061 0.7Sa 0.24 0.46 0.26 0.44 0.26 0.44 0.24 0.25 (0.21) (0.25) 0.23 0.24 0.25 (0.17) (0.20) 0.22 0.53 0.51 (0.48) (0.54) 0.53 0.51 (0.48) (0.48) 0.18 0.18 0.23 0.25 0.21 0.15 0.18 0.15 . \ FG -- -----.- 0.054 0.05 0.05 0.05 0.02 0.09 0.05 0.09 'Eger [I] includes liver in the VRG compartment. Values in parentheses are cited in the EPA document [26] and are based on measurements by different authors. The nhysical activity is not specified. r Renal flow (l/min): = 0.0391 x BWo.802 (27) Muscle flow (llmin): = 0.040 x BWo.81 (28) Spleen flow (mllmin): = 3.949 x BW'.028 (29) There are indications that brain perfusion of all mammals (including humans) is about 0.50 ml/ min per g of brain tissue [16]. Combining this information with Eqs. (2) and (3) results in the following equations for scaling of brain perfusion of mammals: I, Non-human primates (ml/min): = 13.45 x BW".68 Non-primate mammals (ml/min): = 3.36 x BW0.72 if (31) perjiiion rates ,bf compartment; -? < * > . P l , i ,a 1.were published in anesthesi icai ejramples of fractions fusjng the major compartments of !(1.. SA or resting man are shown in Table 5. A more complete summary of the distribution of cardiac output among compartments used by various investigators can be found in the EPA document [26]. There seems to be good agreement among authors on the distribution of cardiac output. The validity of estimates is strongly supported t y the agreement between simulation and experimental data on pulmonary uptake and elimination of a number of solvents and anesthetic agents. However, the simulation of pulmonary desaturation of anesthetized men suggests that the, fit to experimental data improves if inner adipose tissue, which is three times more perfused than subcutaneous adipose tissue [32], is treated as FG compartment [33]. . . (In the absence of a suitable database, scaling Ifo' r. festing mammals 'can be based on the 'assbmp- .t.i,oIn that the distribution of cardiac output'among compartments (i.e. "the fraction of 'c perfusing individual compartments) d6pendent. Simulation of controlled-: exposure V. Fiserova-Bergersa'/ Toxicology Letters 79 (1995) 77-86 83 suggest thai the assumption is plausi perfusion rates of compartments based on experimental data obtained for mice and humans 'exposed to tetrachloroethylene do not supp suggestion [34]. Scaling.for physical activity. During physical activity, the excess of oxygen consumption*:coI*)rrelates with the increased energy expenditure.;Ph$sical activity has a negligible effect on perfu$on /of the viscera (VRG) [27], so that the increa$ in cardiac output is distributed according to :the increased oxygen demand by tissues included in the hiG and FG compartments. Based on these assumptions, Droz et al. [19] recommend the following increments for perfusion rates (in l/min) of compartments due to physical activity: defining'their transportation rates from' the"enk ronment to the'' alveoli. Thus, the relati (expressed per 'kg of body weight) avail pulmonarjl Bbsoiption of a hydrophobic, &&reactive compound is calculated by multiplying:the body 'weight ratio by':the concentration and exposure durat The exceptions are reactive and hydrophilic 'c6mpounds, in which retention in the respiratory 'air- Fig. 1 shows the relative dose calculated for a reference man (70 kg, 170 cm) and a reference woman (58 kg, 160 cm)with energy expenditures shown on the abscissa in watts. The relative dose available for a man performing light or strenuous Liver: perfusion rate is reduced by a small fraction of the basal perfusion rate. The decrease = - 0.000182 x W x F* VRC- perfusion rate is unchanged MG: perfusion rate increases by 0.0745 x W FG: perfusion rate increases by 0.0095 x W where F* is the perfusion rate of livers at rest (F* = 0.25 x Q*) and W is the energy expenditure in watts. The energy expenditure for the same task increases with body weight [24]. I 5. Csnsiderations in risk assessment Species differences in physiological and biochemical parameters are of concern in the extrapolation of human toxicity from animal data. The physiological parameters determine the availability of the inhaled compound for pulmonary absorption and the capacity of the body and organs to store the compound. However, the actual absorkd dose and the biological levels of the inhaled compound are further affected by the biochemical parameters which define the interactions between the compound and tissues (metabolism and binding) and the excretion (pulmonary, ciliary and renal clearances). 5. I . Availability for pulmonary absorption The availability of compounds for pulmonary absorption is predetermined by the parameters 3Jtg MONKEY 7Okg MAN .I LI o uGm I1 II 50 MODERATE io0 HWvr m w PrtrstcAL LOAD Fig. 1. Effect of workload on inspired dose. Using Eqs. (22) and (23). inspired doses (expressed as the inspired dose per kilo of body weight assuming the inspired concentration equals 1) were calculated for a reference man (70 kg, 170 cm) and reference woman (58 kg, 160 cm)performing physical activity with energy expenditure shown in watts on the abscissa. The dashed lines indicate the inspired dose for a reference man and laboratory animals calculated by using Eq. (I@, which is based on scaling for body weight but not for physical activity. The ratio of alveolar ventilation to body weight indicates that the doses available for a mouse,a rat and a dog are comparable with the doses available for a human performing strenuous, light to moderate and little activity, respectively. 84 V. Fiserocu-Bergeroau Toxicology Lctters 79 (1995) 77-86 physical activity increases three or eight times, respectively, above the dose at rest. Fig. 1 shows that the doses available for a human performing activities classified as strenuous, light to moderate and very light are comparable with the doses available for a mouse, rat and dog, respectively. 5.2. Storage capacity of solrents Based on Fick's law, the amount of vapor in tissues is determined by the mass of the tissues and by the solubility of the vapor in the tissues. At equilibrium, the tissue-air concentration ratios equal the tissue-gas partition coefficients at body temperature. However, if the compound is metabolized or excreted, steady state is established before equilibrium can be reached and before the capacity to store the compound is filled. Therefore, tissue-air concentration ratios remain smaller than partition coefficients regardless of the duration of exposure. Blood-gas and lean tissue-gas partition coefficients are similar. However, the fat-gas partition coefficients of lipophilic compounds and hydrophilic compounds are, respectively, much larger and much smaller, than the partition coefficient for lean tissues [38,39]. Therefore, the capacity of the body to retain the compound depends on the body build. Fig. 2 shows how body height affects the fat and lean body mass of a 70 kg man. Lean body mass (determined by using Eqs. (4)and (6)) and body fat (determined by using Eq. (8)) were calculated for 70 kg men of different body build. The lean/fatty tissue ratio increases from 2.14 in an obese man (150 cm tall) to 3.6 in the reference man and 8.7 in a slim man (200 cm tall). ` The storage capacity, SC, available per kilogram of body weight can be calculated by using Eq. (32): LBM in which the compound is distributed. LEAN DODY MASS AND.DODY PAT OF A 70 KO MAN fusion rates of n rease, but the cl $`&;;sceraol rgans are Eata for adjustmen1 physical activities Fie Scarce for anim< Since relative pul of body weight) fger than in rest pors and gases il c ................................ \..* .................................. FA i' e also larger in mans. The value: :rfusion adjusted 1 nge of values obt 1lo ;ry animals (Fig. 130 140 150 160 170 180 190 200 )&es differences BODY HlG1IT In CM umans and experi Fig. 2. Effect of body build on lean body mass and body fat of man. Lean body mass (LBM) and body fat of 70 kg men of body height shown on the abscissa were calculated using Eqs. (4), (5), ( 6 ) and (8). The shown numbers are values calculated for a reference man (170 cm tall). LBM/fat ratio is also shown. ient appear neglig ve and quantitatij iteractions of the ents. These differe The dotted lines show values derived for a 70 kg man :sed on the assumption that the LBM of any mammal acciu;ts for 78% of body weight (no adjustment for body build). 6. Conclusions r Simple power equations using body weight were used for scaling of basic physiological parameters across animal species. The estimates, which apply only to resting young adults, do not tah:- into account the effect of body build on the mass of individual tissues, nor the profound effect of physical activity on pulmonary ventilation and tissue perfusion. Organ mass estimates based on lean body mass ark more realistic than those based on body weight. In humans, the effect of body build on lean body mass can be estimated from body weight and body height. est, heat dissipation (and thus the body area) is the most decisive factor in determining pulmonary ventilation and cardiac output ts distribution. Physical stress (work, exerincreases the demand for oxygen and the increases in pulmonary ventilation and cardiac output .correlate with the energy expended in per- <f.o*.k. i n g the task. During physical activity, the .This study was nent Developmel Standard DeveloF Eof the National I md Health. References them. Br. J. Ani I pp. 11-37. [4] Fiserova-Bergerc pulmonary admi and gases. In: \ k! Inhalation Expo Elimination. VC 73-100. ............. LBM/fat ratio is also sh :nt for body build). stimated from b (and thus the bo 2isive factor in detern and cardiac output 11 stress (work, exerfor oxygen and the tilation and cardiac rgy expended in per)hysical activity, the V. Fiserova-BergerovaJ Toxicology Letters 79 (1995) 77-86 perfusioI n rates of muscles and skin progressively increase, but the changes in perfusion rates of visceral organs' are barely 'apparent. Er data for adjustment of physiological pa : [SI Fiserova-Bergerova, V., VIxh, J. (1980) Predictable `individual differen excretion of gases and lipid soluble v study. Br. J. Ind. Med. 37, 42-49. [6] International Commission on Radi to physical activities a , Report of the task group on reference man. (1984),JCRP are scarce for .animals. Since relative pulmo , No. 23, Pergamon Press, New York. I , 1 [7] Hamilton, W.F and Dow. P. (Eds.) (1 lation. Handbook of Physiology, Sect. 2, American Physip\ogical Society, Washington, DC. Altman, P.L. (1959) Handboo In: vapors and gases inh Dittmer, D.S. and Grebe, R.M. ders, are also larger in small animals than in resting Philadelphia, PA. huma'ls. The values of pulmonary ventilation and [9l Quiring, D.P. (1938) A comparison of certain gland, perfujion adjusted to activity of humans are in the organ and body weights in some African ungulates and the African elephant. Growth 2, 335-346. `range of values obtained by scaling across labora- tory animals (Fig. ~ 1 ) .The consequences of inter- [lo] Brody, S. (1945) Basal energy and protein metabolism in relation to body weight in mature animals of different species differences in ph'ysiological parameters of species. In: Bioenergetics and Growth. Reinhold Publ. humans and experimental animals for risk assess- Corp., New York, NY,pp. 352-649. ment negligible with the qualita- tive and quantitative differences in the biochemical [Ill Adolph, E.F. (1949) Quantitative relations in the physio- logical constitutions of mammals, Science 109, 579-585. [121 Stahl, W.R, (1967) scaling of respiratory variables in interactions of the compound with tissue compo- mammals. J. Appl. Physiol. 22, 453-460. nent! 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