Steady-state Tissue Research Articles

The significance of excursions above the ADI: duration in relation to pivotal studies.

The significance of excursions of intake above the ADI, TDI, or PTWI can only be assessed by reference to the database which led to the derivation of these, most particularly the duration of the pivotal study (chronic, subchronic, acute), the pharmacokinetic parameters, and the nature of toxicity and mechanism of action. Although this implies a case by case assessment, a number of typical situations may be recognized: (1) The substance (usually a contaminant, not an additive) has a very long half-life leading to accumulation in target organs/tissues, e.g., Cd or dioxin. The chronic toxicity is manifested when critical concentrations are achieved in these tissues and there is a large difference between the acutely toxic dose and the chronic NOAEL. In such a case, the effect of excursions above the PTWI on tissue levels is readily calculated; peak excursions of several times the PTWI for short periods (days, weeks, or even months) or lower peak intakes for even longer periods (months to years) may be inconsequential provided that the integrated exposure over longer periods does not lead to critical steady-state tissue concentrations being achieved. (In such cases, it is clearly inappropriate to divide the PTWI by 7 and treat this as an ADI.) (2) A more common situation for food additives is where the ADI is based on a chronic study, but the t1/2 is short, i.e., the situation is one of chronic stress rather than cumulative toxicity. In such cases, e.g., BHA or BHT, the effects on the target organ (hyperplasia, foci of altered cells, etc.) can usually be identified in subchronic studies, although progressive changes may occur in chronic studies. Two subsituations then arise. First, when the effects seen at the LOAEL in subacute/subchronic studies are truly reversible (e.g., methemoglobinemia), short-term studies with a reversibility component may become pivotal in assessing the consequences of short-term excursions above the ADI. Second, when the short-term effects are not fully reversible, or are even progressive, the consequences of short-term peaks of intake above the ADI would require careful evaluation against the NOAEL or LOAEL in subacute or subchronic studies. (3) A rare situation might arise where the ADI is based on a chronic toxicity study but the margins between the chronic NOAEL and some aspects of acute toxicity may be small. For example, for a compound which behaved like retinol, the ADI might be based on chronic effects on the liver but at maternally nontoxic doses the substance may be teratogenic following acute exposure during early pregnancy. Clearly in such a situation, the acute NOAEL for teratogenicity would be used appropriately to evaluate the risks associated with short-term peaks of exposure, i.e., a different study may be pivotal in determining the effects of large excursions above the ADI than that which was used to calculate it. Clearly, these cases are not comprehensive but do provide a framework against which to discuss the potential effects of excursions above the ADI and to reach rational conclusions which are not based on the misapprehension that the ADI (or worse, the PTWI x 7) is a lower bound of toxicity.

Effect of continuous melatonin infusions on steady-state plasma melatonin levels, metabolic fate and tissue retention in rats under near physiological conditions.

The fate and disposition of melatonin released into the circulation is still poorly understood, and almost all current knowledge is derived from measurements made after one single, often very large dose of labeled melatonin. In continuous infusion experiments in freely moving rats, 500 ng melatonin/mL hr had to be infused in order to elevate the circulating hormone from low daytime levels to the 10-fold higher nocturnal steady state concentrations. To study the fate and tissue accumulation of the infused melatonin, tritiated melatonin was added to the infusion solution, and the retention of [3H]-melatonin and chloroform-insoluble [3H]-melatonin-metabolites were measured in almost all body tissues and their subcellular compartments immediately at the end of the infusion period and six hours later. A considerable amount of the infused melatonin was found in the gut and in all tissues, some melatonin was covalently attached to proteins.

Altered tissue distribution and elimination of amikacin encapsulated in unilamellar, low-clearance liposomes (MiKasome).

Amikacin in small unilamellar liposomes (MiKasome) has prolonged plasma residence (half-life > 24hr) and sustained efficacy in Gram-negative infection models. Since low-clearance liposomes may be subject to a lower rate of phagocytic uptake, we hypothesized this formulation may enhance amikacin distribution to tissues outside the mononuclear phagocyte system. Rats received one intravenous dose (50 mg/kg) of conventional or liposomal amikacin. Amikacin was measured for ten days in plasma, twelve tissues, urine and bile. Liposomal amikacin increased and prolonged drug exposure in all tissues. Tissue half-lives (63-465 hr) exceeded the plasma half-life (24.5 hr). Peak levels occurred within 4 hours in some tissues, but were delayed 1-3 days in spleen, liver, lungs and duodenum, demonstrating the importance of characterizing the entire tissue concentration vs. time profile for liposomal drugs. Predicted steady-state tissue concentrations for twice weekly dosing were >100 microg/g. Less than half the liposomal amikacin was recovered in tissues and excreta, suggesting metabolism occurred. Amikacin was not detected in plasma ultrafiltrates. Tissue-plasma partition coefficients (0.2-0.8 in most tissues) estimated from tissue-plasma ratios at Tmax were similar to those estimated from tissue AUCs. Low-clearance liposomal amikacin increased and prolonged drug residence in all tissues compared to conventional amikacin. The long tissue half-lives suggest liposomal amikacin is sequestered within tissues, and that an extended dosing interval is appropriate for chronic or prophylactic therapy with this formulation.

Reduced striatal tyrosine hydroxylase activity is not accompanied by change in responsiveness of dopaminergic receptors following chronic treatment with deprenyl

Deprenyl is the only selective monoamine oxidase B (MAO-B) inhibitor that is in clinical use for the treatment of Parkinson's disease. Our previous studies showed that chronic treatment of rats with low (MAO-B selective) doses of deprenyl inhibited dopamine (DA) re-uptake and enhanced DA release in the striatum. These changes could affect DA synthesis rate by activation of negative feedback loops. Chronic deprenyl treatment has also been suggested to cause down-regulation of release-modulating DA receptors. The effects of chronic and acute treatment with deprenyl on ex vivo striatal tyrosine hydroxylase activity were therefore studied, by determination of steady-state tissue level of DOPA following administration of NSD-1015 (100 mg/kg i.p.). In addition, we assessed changes in the in vivo sensitivity of dopaminergic receptors from the reduction in DOPA extracellular level after systemic apomorphine administration (2.5 mg/kg s.c.), following elevation of microdialysate DOPA by systemic or local aromatic amino acid decarboxylase inhibition with NSD-1015. Chronic treatment with deprenyl (0.25 mg/kg s.c. daily for 21 days) caused a significant reduction in tyrosine hydroxylase activity to 60% of control, with no change in the apomorphine-induced reduction of microdialysate DOPA and DOP AC. The reduction in tyrosine hydroxylase activity is compatible with our previous results showing an increase in striatal DA extracellular level following chronic treatment with deprenyl. The increased extracellular striatal DA level could reduce tyrosine hydroxylase activity through activation of a negative feedback loop, by activation of either presynaptic or postsynaptic DA receptors.

Effects of season, protein and nutritional state on glucose tolerance during an annual cycle of growth in young red deer stags.

Two hypotheses were tested in gonad-intact, young (aged 6-18 months), growing red deer stags during an annual growth cycle. First, that glucose clearance rate is faster during summer than during winter. Secondly, that increased dietary protein availability will enhance winter growth. Stags were randomly assigned into one of two groups: group 1 (n = 5) had 16% while group 2 (n = 6) had 48% of dietary protein naturally protected against fermentative degradation in the rumen. Total crude protein and energy remained similar for each diet (12 and 14% respectively for protein and 11 MJ metabolisable energy/kg dry matter). Stags were kept indoors in individual pens for 12 months and given monthly intravenous glucose tolerance tests (IVGTT), at a dose of 200 mg/kg, in the fed and fasted (48 h) states to determine both growth and steady-state tissue requirements. Protein level had no effect on food intake, weight gain, insulin kinetics, or glucose clearance rate. In the fed state, insulin peak (highest level' after IVGTT) increased (P < 0.01) from October (139 pmol/l) to December (247 pmol/l) (S.E.D. = 42) and remained elevated during the summer, before declining (P < 0.01) from February (223 pmol/l) to April (130 pmol/l) (S.E.D. = 25). Glucose clearance rate was faster (P < 0.05) in December (1.69 litres/min) than June (0.61 litres/min) in the fed state (S.E.D. = 0.30), and decreased (P < 0.05) from February (1.75 litres/min) to April (0.92 litres/min) (S.E.D. = 0.39). During fasting, the pattern of glucose clearance was similar to that observed in the fed state, but the amplitude was lower, while the pattern for insulin peak was similar to that of the fed state. We concluded first, that additional protected protein does not benefit growth during winter. Secondly, we concluded from the fasted, steady-state data that stags are insulin resistant during summer. Thirdly, despite insulin resistance, data on the fed state demonstrated that stags have higher tissue energy requirements during summer growth.

Comparative toxicokinetics of tributyltin in five marine species and its utility in predicting bioaccumulation and acute toxicity

The acute toxic response (LC50), bioconcentration factor (BCF), lethal tissue residue (LR50), uptake clearance constant (k 1), and elimination rate constant (k 2) for tributyltin (TBT) were examined and compared in four marine invertebrate and one marine fish species. The toxic response and BCFs were vastly different among the species when exposed to the dissolved compound, which was reflected in their unequal uptake clearance and elimination rate constants. Based on the dual-rate constant approach for a one compartment, first-order kinetic model (1CFOK), predicted values for both the acute toxic response and BCF based on these toxicokinetic constants were matched closely by observed values. Additionally, a strong correlation between the LC50 and BCF was found, which was expected based on their relationship to the balance between uptake and elimination and a consistent LR50 (lethal residue causing 50% mortality) among species. Predictions were made about the time to steady-state tissue concentrations with k 2 values and how this would affect the results of the standard 10 day toxicity bioassay. Because acute TBT toxicity occurs at tissue concentrations 100 times lower than compounds exhibiting a narcosis mode of action, tributyltin is very toxic at low environmental concentrations, especially to organisms that have high uptake clearance and low elimination rate constants. Making predictions about toxicity based on uptake clearance and elimination rate constants in conjunction with the critical body residue will be helpful when choosing sensitive organisms for determining water and sediment quality criteria.

PHYSIOLOGICALLY BASED ALGEBRAIC FOR PREDICTING STEADY-STATE TOXICOKINETICS OF INHALED VAPORS

Algebraic expressions are developed for predicting steady-state toxicokinetics of volatile organic chemicals (VOCs) by sim plifying the mathematical descriptions used in physiologically based toxicokinetic (PBTK) models. The equations use 5 or less input parameters (instead of the 17 used in conventional PBTK models) to predict steady-state tissue or blood concentrations of VOCs at low exposure concentrations. The adequacy of the steady-state equations was assessed by comparing blood and tissue concentrations obtained using these equations with those generated by validated rat and hum an PBTK models for toluene and m -xylene. The results show that for 1-ppm exposures of rats and humans to toluene or m -xylene, the difference in the steady-state blood and tissue concentrations calculated using the algebraic expressions and full-fledged PBTK m odels is less than 1%. The algebraic expressions developed in the present study represent a simpler and faster method of describing the steady-state toxicokinetics of...

Serotonin-induced changes in L-leucine transport across rabbit jejunum

The aim of the present study has been to determine the effect of serotonin (5-HT) on the absorption of L-leucine across the rabbit jejunum. The results show that serotonin significantly diminishes the uptake and steady-state tissue accumulation and the mucosal to serosal flux of L-leucine. This effect does not change with previous intestinal exposure of the mucosa to the 5-HT. Serotonin does not seem to modify amino acid simple diffusion across the intestinal epithelium. The effect on the amino acid uptake is due to an inhibition of the Na +-dependent system of transport, mainly through a reduction of the apparent Vmax. Moreover, this hormone, added to the incubation solution, does not affect the L-leucine uptake across brush border membrane vesicles. In presence of trifluoroperazine, TMB-8 and staurosporine, the serotonin effect disappears. These results suggest an effect mediated by intracellular processes related to protein kinase C which inhibit the intestinal absorption of L-leucine.

Theoretical analysis of transurethral laser-induced thermo-therapy for treatment of benign prostatic hyperplasia. Evaluation of a water-cooled applicator

A mathematical model for predicting the temperature rise in transurethral laser-induced thermo-therapy for benign prostatic hyperplasia was developed. In the model an optical line source emitting light from an Nd:YAG laser isotropically was placed in the urethra. Water cooling of the urethral epithelium was modelled using a two-tube system. The relationship between the difference in outlet and inlet water temperatures and the highest tissue temperature level reached was theoretically investigated. It was found that the water temperature difference was linearly dependent on the steady-state maximum tissue temperature. The theoretical calculations suggest that the water-cooled applicator can be used to measure the maximum tissue temperature. With temperature control, the prostatic tissue temperature can be prevented from exceeding the boiling point of water, excluding tissue carbonization. The model was also used to evaluate the influence of a number of different parameters on the damaged tissue volume. Increasing the urethral lumen radius by a factor of two by means of inserting different sized tubes was found to augment the tissue volume raised to therapeutic temperatures by up to 50%. The calculations showed that cooling of the urethral epithelium can result in an increase in the damaged volume by 80% as compared to not applying any cooling. The temperature of the cooling water was found to influence the tissue temperature only to a small extent.

Disposition and toxicokinetics of diquat in channel catfish

The disposition of the aquatic herbicide diquat was studied in channel catfish ( Ictalurus punctatus) after water exposure to 14C-diquat dibromide concentrations of 5 and 20 μg/ml for up to 6 days. An apparent steady-state plasma concentration of 0.6% of the exposure water concentration was achieved after 24 h, and steady-state tissue levels were reached by 72 h. The highest steady-state concentration of diquat occurred in the trunk kidney, which was about 100 times that observed in plasma. Diquat concentrations in white muscle were low and similar to plasma levels of diquat. Autoradiographs of sagittal sections of a catfish exposed to 14C-diquat dibromide also indicated that the highest concentration of residue present in the animal was located in the trunk kidney and that lower concentrations were associated with the liver and gills. The majority of liver residue, and especially that in the bile, was unidentified metabolites. After intravascular administration of 1 mg/kg, toxicokinetic analysis of the plasma concentration-time profile of diquat using a two-compartment model provided the following values: steady-state volume of distribution (V ss) = 2920 ± 740 ml kg −1; total body clearance (Cl b) = 87.8 ± 27 ml h −1 kg −1 and elimination halflife (t 1 2 ,β ) = 35.8 ± 8.9 h .

Analysis of tissue distribution of valproate in guinea-pigs: evidence for its capacity-limited tissue distribution.

The tissue distribution of valproic acid (VPA) was investigated over a wide range of steady-state plasma levels (Css) in guinea-pigs. The VPA concentrations in various tissues, except the kidney, were all lower than in plasma. Tissue-to-unbound plasma concentration ratios (Kpu) of VPA for adipose, heart, kidney, liver, lung, muscle, pancreas and skin all decreased significantly with increasing unbound plasma concentration (Cuss). The Kpu for brain (0.5-0.9), intestine, spleen and stomach failed to show significant change with Cuss. The disposition of VPA in tissues is adequately described by a model in which VPA was distributed in interstitial and intracellular fluid and bound to interstitial albumin, with limited tissue binding. Tissue binding was extensive only in the kidney. Most of the measured apparent Kpu values agreed well with simulated Kpu values. Steady-state tissue concentration of VPA can be predicted from Css and Cuss when reference data for interstitial albumin and tissue total water are available.

Regulation of Ca(2+)-dependent ATPase activity in detergent-skinned vascular smooth muscle

We measured force, actin-activated myosin adenosinetriphosphatase (ATPase) activity, and myosin light-chain (MLC) phosphorylation levels in Triton X-100 detergent-skinned media of swine carotid arteries. Pseudo-ATPase activity composed of MLC kinase and phosphatase activities contributed maximally 12% to steady-state tissue ATPase activity. An increase in the Ca2+ concentration ([Ca2+]) induced an increase in force, MLC phosphorylation, and actin-activated myosin ATPase activity; this protocol was defined as the force development phase of contraction. Force maintenance was defined as the state induced by decreasing the [Ca2+] after a maximal contraction. Lowering the [Ca2+] decreased MLC phosphorylation to levels similar to those measured during force development at each [Ca2+]. In contrast, force remained at elevated levels while actin-activated myosin ATPase activity fell to significantly lower levels than those measured during the development phase for each [Ca2+]. We suggest that the significantly lower actin-activated myosin ATPase activity observed during a state of elevated force, compared with the development phase of a contraction, is evidence of slowly cycling latch bridges.

Dopamine release in the rat cerebellum and hippocampus: a tissue 3-methoxytyramine study

Multiple lines of evidence indicate dopamine is a neurotransmitter or neuromodulator in the cerebellum and hippocampus. In this study, we explored the utility of 3-methoxytyramine as an index of dopamine release in these regions. We found that: (1) cerebellar and hippocampal 3-methoxytyramine levels can be measured by combined gas chromatography-mass fragmentography with negative chemical ionization; (2) basal 3-methoxytyramine accumulation rates following monoamine oxidase inhibition, but not the steady-state tissue levels, are several times lower in these regions than in the frontal cortex; (3) accumulation of 3-methoxytyramine in the hippocampus and cerebellum can be enhanced following electroconvulsive shock, but not acute haloperidol (0.4 mg/kg) treatment. We conclude that 3-methoxytyramine accumulation may be a useful index of dopamine release in the cerebellum and hippocampus, but dopamine release is regulated differently in these regions than in the frontal cortex and striatum.

Effects of substrate and inhibition of oxidative metabolism on contraction and myosin phosphorylation in ASM.

Steady-state active stress in smooth muscle is maintained by cross bridges which undergo continuous cycling and myosin phosphorylation, and the two processes both consume ATP. In this study, we investigated whether energy utilization by cross-bridge cycling and myosin phosphorylation is compartmentalized and examined their relative affinities for ATP in airway smooth muscle. We measured active stress, myosin phosphorylation, O2 consumption, and tissue ATP content in bovine tracheal smooth muscle activated by K+ depolarization when glucose was replaced by pyruvate and when oxidative metabolism was inhibited by hypoxia or uncoupled by 2,4-dinitrophenol. The results indicate that ATP produced from both glycolysis and oxidative metabolism is available to both cross-bridge cycling and myosin phosphorylation. However, steady-state myosin phosphorylation was insensitive to the inhibition of oxidative metabolism by hypoxia and mitochondrial uncoupling when steady-state isometric stress and tissue ATP content were significantly reduced. These results suggest that, relative to actomyosin adenosine 5'-triphosphatase, myosin light chain kinase has a higher affinity for ATP in intact airway smooth muscle. However, peak myosin phosphorylation associated with the initial rapid stress development was sensitive to inhibition of oxidative metabolism, probably reflecting a lower content of intracellular calcium store as a result of metabolic inhibition.

Disposition of toxic metals in the agricultural food chain. 2. Steady-state bovine tissue biotransfer factors

Disposition of toxic metals in the agricultural food chain. 2. Steady-state bovine tissue biotransfer factors

Reduction of Remnant Nephron Hypermetabolism by Protein Restriction

To study the metabolic mechanisms involved in the protective effect of dietary protein restriction on the progression of chronic renal failure, experiments were performed in Sprague-Dawley rats subjected to five-sixths nephrectomy and pair-fed on isocaloric low (4%) protein (LP) or high (50%) protein (HP) diets. Protein restriction reduced the severity of uremia, with lower blood urea nitrogen (BUN) concentrations (8.9 +/- 1.1 v 30.0 +/- 2.9 mmol/L [25 +/- 3 v 84 +/- 8 mg/dL] both n = 12, P less than 0.01), and resulted in lower mortality at 2 weeks (0% v 33%, P less than 0.05), 4 weeks (16% v 58%, P less than 0.05), and 10 weeks (16 v 83%, P less than 0.01). Isolated perfusion of the remnant kidney at 3 weeks demonstrated reduced O2 consumption (QO2) (0.77 +/- 0.2 v 2.56 +/- 0.5 mumol/min/g, both n = 7, P less than 0.05) in the absence of significant differences in inulin clearance (239 +/- 53 v 341 +/- 39 microL/min/g, NS) and net sodium reabsorption (34 +/- 8 v 49 +/- 6 mumol/min/g, NS) in rats fed the LP diet. A lower renal QO2 in protein-restricted animals was also demonstrated in vivo (4.1 +/- 0.9 v 13.8 +/- 2.7 mumol/min/g, P less than 0.01). In vivo P-31 nuclear magnetic resonance (NMR) studies of remnant kidneys did not demonstrate any difference in the steady-state tissue concentrations of adenosine triphosphate (ATP) or inorganic phosphate between rats fed LP and HP diets. Dietary protein restriction decreases the severity of uremia and diminishes renal QO2 in the remnant kidney model.(ABSTRACT TRUNCATED AT 250 WORDS)

Length-dependent myosin phosphorylation and contraction of arterial smooth muscle

Ca2+, calmodulin-dependent myosin light chain phosphorylation is generally considered to be an important regulatory mechanism of smooth muscle contraction. We investigated the length dependence of myosin phosphorylation and active stress induced by K+ depolarization in arterial smooth muscle by measuring the two variables in the swine carotid media held at three steady-state tissue lengths-optimal length for contraction (Lo), 1.5 Lo, and slack length. We found that the length dependence of peak and steady-state myosin phosphorylation with respect to tissue length was different. Peak myosin phosphorylation was highest at Lo but lower at both slack length and 1.5 Lo, whereas steady-state myosin phosphorylation was similar at both Lo and 1.5 Lo, but lower at slack length. Stretching tissues to 1.5 Lo did not significantly change the steady-state myosin phosphorylation induced by K+ depolarization, but releasing tissues to slack length was associated with a 42% decrease in the steady-state myosin phosphorylation induced by K+ depolarization. These data indicated that one or more steps coupling membrane depolarization and Ca(2+)-dependent myosin phosphorylation were length sensitive. Additional data from skinned tissue experiments indicated that the length-sensitive step was not the coupling between Ca2+ and myosin phosphorylation. Therefore, these data together suggest that one or more steps coupling membrane depolarization and the increase in cytosolic Ca2+ concentration are length sensitive.

Predicting chemical accumulation in shoots of aquatic plants

Chemical exchange dynamics expected for diffusive transfer of a chemical between aqueous solution and plant shoots, and expected bioconcentration based on partitioning properties of the chemical, are explored by using a three—compartment model. The model utilizes three dynamic compartments-leaves, stems, and aqueous exposure medium. Chemical mass flux is dependent on the morphometry of the plant species, on exposure concentration, and on partitioning character of the chemical. The steady-state bioconcentration factor (KSH) is dependent on composition of the plant species and partitioning character of the chemical. The model was parameterized for three species of aquatic plants (Myriophyllum spicatum, Bacopa caroliniana, and Hydrilla verticillata) and two chlorinated benzenes (1,2,3,4-tetrachlorobenzene [TCB] and 1,2-dichlorobenzene [DCB]). Predictions of uptake and bioconcentration are compared to results of static laboratory studies conducted with whole shoots of the three species over exposure periods ranging from 1 h to 21 d. Predicted tissue burdens and Ksh values are generally within one standard deviation of measured values. Shoots approach steady-state tissue burdens between 1 and 3 d after initial exposure. Ksh values for TCB (360-750), the more hydrophobic chemical, are at least an order of magnitude greater than those measured for DCB (11-28).

Experimental Basis for Use of Fluconazole for Preventive or Early Treatment of Disseminated Candidiasis in Granulocytopenic Hosts

To determine the potential for the use of fluconazole for prevention and treatment of disseminated candidiasis in granulocytopenic patients, we investigated its activity and pharmacokinetics in models of acute, subacute, and chronic forms of disseminated candidiasis in persistently granulocytopenic rabbits. Fluconazole was administered for systemic prophylaxis, early treatment, and delayed treatment. Single-dose and steady-state plasma pharmacokinetics, tissue penetration, and dose-response studies of the investigational compound were studied in subacutely infected granulocytopenic rabbits. Fluconazole was more effective when used for systemic prophylaxis or early treatment of disseminated candidiasis than for delayed treatment. Fluconazole was as effective as amphotericin B plus flucytosine in preventive and early treatment of disseminated candidiasis but was significantly less effective than amphotericin plus flucytosine in the treatment of chronic candidiasis. Dose-response studies demonstrated that the antifungal effect of fluconazole was dose- and time-dependent. Studies of the pharmacokinetics of fluconazole in rabbits demonstrated a long half-life in plasma and a large volume of distribution, properties that correspond to the attainment of high levels of penetration into tissues at multiple organ sites. We conclude that fluconazole is effective for prevention and early treatment of disseminated candidiasis in persistently granulocytopenic rabbits and that the evaluation of its use in preventive or early treatment of disseminated candidiasis in carefully designed clinical trials is warranted.

Assessment of human exposure to gaseous pollutants.

A mathematical model to aid in assessment of human environmental exposure to volatile organic substances is presented. The model simulates the convective and diffusive transport of gas from the ambient environment into the human body by way of the respiratory and circulatory systems. Data required include easily obtained physical and chemical properties of substances as well as several estimated or measured physiological parameters. Transient and steady-state tissue concentrations resulting from an input atmospheric partial pressure are predicted. From these concentrations, an effective dose may be calculated, allowing for the determination of an exposure-response relationship based upon independently obtained dose-response data. The model's results compare favorably to experimental data on oxygen and halothane. Steady-state conditions are reached very rapidly. These results suggest that uptake of these substances is limited by both ventilation and perfusion. rates are demonstrated to be essentially linear within the current neighborhoods. Conditions in which the primary processes of ventilation, diffusion, perfusion, and elimination limit uptake of gases are considered. Expressions describing the conditions necessary for a single process to limit gas uptake are derived. Accompanying equations for estimating tissue concentrations under these limiting conditions are presented.