* Department of Environmental Health, University of Cincinnati College of Medicine, 3223 Eden Avenue, Cincinnati, Ohio 452670056;
Health Science Resource Integration, 2976 Wellington Circle West, Tallahassee, Florida 32308;
Exponent, 4940 Pearl East Circle, Suite 300, Boulder, Colorado 80301; and
§ Exponent, 149 Commonwealth Drive, Menlo Park, California 94025
Received July 17, 2000; accepted September 21, 2000
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ABSTRACT |
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Key Words: chromium(III); chromium(VI); physiologically based human kinetic model..
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INTRODUCTION |
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A physiologically based model of chromium kinetics in the rat has been published (O'Flaherty, 1996). A unique group of controlled human studies in which Cr(III) or Cr(VI) compounds were ingested by adult human volunteers and totalchromium concentrations were subsequently followed in blood plasma, red cells, and urine (Finley et al., 1997
; Kerger et al., 1996
; Paustenbach et al., 1996
) offers the opportunity to develop linked physiologically based models of human Cr(III) and Cr(VI) kinetics and to examine the implications of the form and success of these models for a broader understanding of chromium kinetic behavior in humans.
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MATERIALS AND METHODS |
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The model program (see Appendix) is written for oral chromium exposurefor soluble Cr(III) and Cr(VI) salts present in the diet and in drinking water.
A study in which 4 adult male human volunteers were immersed below the shoulders in water containing 22 mg Cr(VI) as potassium dichromate (K2Cr2O7)/l for a period of 3 h has demonstrated that systemic chromium uptake under these conditions, while quantifiable, is relatively small (Corbett et al., 1997). At concentrations of about 10 mg Cr(VI)/l and above, water is bright yellow, so that dermal exposures of this magnitude are very unlikely to occur. Consequently, the model does not consider uptake through the skin.
It also does not include a physiologic lung compartment. Unfortunately, insufficient data exist to support the design and calibration of a physiologically meaningful lung model component for human chromium exposure by inhalation. Instead, simple assumptions are made to allow estimation of an upper limit to absorption from the lung. Inhaled chromium is not speciated. A single fractional absorption value is applied to all respirable inhaled chromium, and all non-respirable chromium is considered to be transferred to the gastrointestinal tract, where it is treated as having been fully reduced to soluble Cr(III) species and absorbed as such from the gastrointestinal pool.
New model parameters, specific to chromium, are the rate constant for movement past the gastrointestinal absorption region, the gastrointestinal absorption rate constants for both Cr(III) and Cr(VI), clearance constants for passage into and out of tissues including the red cell, the fractional rates of deposition with forming bone, rate constants for the reduction of Cr(VI) to Cr(III) in the gastrointestinal tract and in tissues, and urinary clearance.
Appearance of both Cr(III) and Cr(VI) in the blood (see Results) is so rapid that it is apparent both must be absorbed from the stomach. Both are also absorbed from the intestine (Donaldson and Barreras, 1966). Accordingly, the first-order rate constant for passage beyond the gastrointestinal absorption region is set at 14/day (14 da1), corresponding to a transit time of 1.7 h.
No information is available to suggest the magnitude of the rate of deposition of Cr(III) or Cr(VI) in human bone. In the absence of such data, the fractional rates of deposition were assigned the values 5 (for Cr(III)) and 15 (for Cr(VI)), the same values used in the rat chromium kinetic model (O'Flaherty, 1996). (This is in contrast to the value of 15,000 used in the corresponding human lead model.) These numbers represent the relative clearance of chromium into mineralizing bone, or the volume of blood plasma cleared of chromium per unit volume of new bone formed. While they define an amount of chromium assigned to the bone volume, in this range they have no detectable impact on blood chromium kinetic profiles.
The gastrointestinal absorption rate constants, the clearance constants for passage into and out of tissues, the reduction rate constants, and urinary clearance were estimated based on data from 4 experimental studies of human chromium kinetics in which chromium was given in drinking water. Data from a fifth study were used to test the calibrated model. The model code, including the values of all parameters, is given in the Appendix.
Experimental studies and their application.
Selected data from 5 studies of chromium kinetics in adult humans provided the database for this work. The results of these studies have been published, but not in the form used to calibrate and test this model.2 Specifically, because participants had collected individual urine voids for which the excretion time and volume were recorded and total chromium concentrations were determined, rates of urinary chromium excretion were recalculated on a per-sample basis rather than on a daily basis for the purpose of model development, calibration, and testing. Only plasma and urine concentration measurements above the analytical detection limits (0.30.5 µg Cr/l for plasma and 0.5 µg Cr/l for urine) were employed in the calculations. Reference to the original publication is given with the description of each study. Studies 14 were used for calibration of model parameters as described in this section. Study 5 was used to test the resulting model.
Table 1 gives information on the subjects participating in each of the studies. Simulations were tailored to the subject`s gender and age (O'Flaherty, 1993
). Default values, determined by gender and age, were used for their body weights.
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Chromium was slightly but detectably elevated in both blood plasma and red cells within 15 to 20 min of ingestion in 3 of the 5 subjects, but had returned to background levels within the next one or two sampling times, 30 min to 1 h later. Consequently, blood chromium concentrations from this study were too limited to be usable as a basis for setting parameter values. However, the rate of chromium excretion in the urine was detectably increased for several days following chromium ingestion, in all 5 subjects. The time dependence of the urinary excretion rate curve is responsive to the values of the tissue uptake and loss constants for Cr(III) through the (unobserved) time dependence of the plasma chromium concentration curve. In addition, it is known that Cr(III) does not selectively partition either into or out of the red cell (see Discussion). In the absence of any other information and on the premise that this nonpolarity applies also to tissues other than the red cell, a single optimized uptake and loss clearance value for Cr(III) was assigned to all soft tissues including the red cell. This value, 3 liters/day (l/day) for all subjects, was set by visual optimization of the model to the time dependence of the urinary excretion rate for all 5 subjects from Study 1.
The value of the first-order rate constant for gastrointestinal absorption of Cr(III) was visually optimized for each subject individually, based on the magnitude of the urinary excretion rate curve.
Study 2 (Kerger et al., 1996).
Four adult volunteer subjects drank a single 0.5-liter volume containing chromium as potassium dichromate (K2Cr2O7) reduced completely to Cr(III) in orange juice and diluted with water to a chromium concentration of 10 mg/l, for a total Cr(III) dose of 5 mg. Total blood plasma and red cell chromium concentration and the rate of chromium excretion in the urine were followed for at least 7 days subsequent to chromium ingestion. As in Study 1, plasma and red cell chromium concentrations were elevated for so short a period of time that too few measurements were available to be usable as a basis for setting parameter values, but urinary excretion rates were used to estimate the value of the Cr(III) gastrointestinal absorption rate constant from the orange juice medium for each of the 4 subjects. The data from Study 2 did not contribute to the urinary clearance function used to simulate the data from the other 4 studies (see Discussion).
Study 3 (Kerger et al., 1996).
Four adult volunteer subjects drank, within a 2-min period, a single 0.5-l volume of water containing 10 mg Cr(VI) as potassium dichromate (K2Cr2O7)/l, for a total Cr(VI) dose of 5 mg. One additional volunteer, excluded from the original report due to missing data, was included here because the method of calculation of urinary excretion rates was not dependent on the completeness of the urine collection. This subject (H1) drank a single 0.5-l volume of water containing 5 mg chromium, as K2Cr2O7,/l, for a total Cr(VI) dose of 2.5 mg. Total blood plasma and red cell chromium concentrations and the rate of chromium excretion in the urine were followed for at least 15 days after chromium ingestion in the first 4 subjects, and for 9 days in Subject H1.
Values were assigned to the Cr(VI) to Cr(III) reduction rate constants and the Cr(VI) gastrointestinal absorption rate constant by visual optimization of the model to the time dependence of the plasma concentration and urinary excretion-rate measurements. In order to do this, the clearance constant for soft tissue uptake of Cr(VI) from plasma and for loss of Cr(VI) from soft tissues to plasma was assigned a single value of 30 l/day, 10 times the value of the corresponding Cr(III) constant. Although this assignment is arbitrary and probably understates the actual rapidity of Cr(VI) membrane transfer, this constant is not rate-determining at the value assigned, and the predictions of the model are insensitive to increases in its value. The relative values of the reduction rate constants are in the ratios of gastrointestinal tract:liver, kidney:red cell:blood plasma:other tissues of 1.0:5.0:0.07:0.002:0.05, consistent with the experimental ranges reported by De Flora et al. (1997). A single value of the reduction rate constant was assigned to each tissue for all subjects. The Cr(III) gastrointestinal absorption rate constant was assigned the value 0.25/day, a rough mean of the nine estimates obtained from Studies 1 and 2. (Within the range observed, this value has a detectable, but only slight, effect on the shapes of the simulated concentration and urinary excretion rate curves for Cr(VI) administration.) The Cr(VI) gastrointestinal absorption rate constant was estimated individually for each of the subjects. During the course of these optimization exercises, clearance of Cr(III) into and out of the red cell was assigned a larger value consistent with the observed time dependence of red cell concentrations.
Study 4 (Finley et al., 1997).
Five subjects ingested repeated drinks of deionized water containing Cr(VI) as potassium dichromate (K2Cr2O7), with chromium concentrations increasing from 0.1 to 0.5 and 1.0 mg/l. Three of these subjects also ingested repeated drinks of deionized water containing Cr(VI) as K2Cr2O7 with chromium concentrations of 5.0 or 10.0 mg/l. Each water concentration was taken as three 333-ml doses at approximately 5-h intervals, for total daily doses of Cr(VI) of from 0.1 to 10.0 mg. Each concentration was ingested for 3 consecutive days. Intervals of at least 1 day intervened between periods of consumption of water containing different concentrations. Total blood plasma and red cell chromium concentrations and the rate of chromium excretion in the urine were followed from Day 1 of the study through at least one day after the last day of chromium ingestion.
In two of the subjects, plasma and red cell chromium concentrations were not clearly increased above background measurements at any of the dose rates, while these concentrations were elevated in 2 of the subjects only at the highest dose and in the fifth subject, at the two highest doses. Only the urinary excretion rate data were used from this study, as part of the composite data set on which the urinary clearance curve is based.
Study 5 (Paustenbach et al., 1996).
A single adult male subject ingested daily 5 drinks of deionized water containing Cr(VI) as potassium dichromate (K2Cr2O7). Each 400-ml drink contained 0.8 mg of Cr(VI), for a total daily dose of 4.0 mg Cr(VI). The drinks were ingested between 7 and 9 A.M., 10 A.M. and 1 P.M., 2 and 4 P.M., 4 and 7 P.M., and 8 and 11 P.M. for 17 consecutive days. Total chromium concentration in blood plasma and urine was monitored for 4 days prior to dosing, during dosing, and for two weeks after termination of dosing.
These results were used for model testing. The conditions of Study 5 were simulated and the predicted plasma chromium concentrations and rates of urinary chromium excretion were compared with those observed. In order to simulate this exposure scenario, the repeated introduction of 0.8 mg Cr(VI) into the gastrointestinal tract of a 44-year-old male was modeled, generally at 8:00 A.M., 11:30 A.M., 3:00 P.M., 5:30 P.M., and 9:30 P.M., the midpoints of the prescribed ingestion time periods, for a period of 17 days. Inspection of the urine collection record showed a number of instances in which several brief collections signaled the actual time of ingestion, and in these instances, the time of ingestion was set at the time indicated by the record. The value of the Cr(VI) absorption rate constant was set by inspection of the data, so that this is a test of the qualitative correctness of the time-dependence of the predicted concentration and excretion curves, and is not a rigorous test of their quantitative accuracy.
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RESULTS |
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Figure 2 is an example of a urinary excretion plot and simulation from Study 1, in which Cr(III) was ingested in water. The simulation was calibrated to these data by visually optimizing the absorption rate constant for this subject after the values of the tissue entry and loss clearance constants for Cr(III) had been established based on the shapes of the excretion rate curves for all 5 subjects and the urinary clearance curve had been defined as described above. The optimized absorption rate constants for all 5 subjects are given in Table 1
. They correspond to fractional absorption of from 0.7% to 2%. Chromium was undetectable in the urine prior to its ingestion, and urinary chromium concentrations fell below the detection limit within 4 days of ingestion.
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The simulations and results from Study 5, in which a single subject repeatedly ingested a soluble Cr(VI) salt, 5 times a day for 17 consecutive days, are shown in Figures 7 and 8. While the data from this study, in particular the urinary excretion rates, were extremely variable, both simulations generate reasonable time profiles of the data.
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DISCUSSION |
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It should be noted that fractional absorption of Cr(III) salts from the gastrointestinal tract is dependent on the chemical nature of the salt. While both dietary chromium and dietary supplements of chromium(III) chloride were found to be absorbed by humans to the extent of 0.4% (Anderson et al., 1983), 2.8 ± 1.14% of a dose of chromium(III) picolinate was absorbed by 8 adult human volunteers (Gargas et al., 1994
). In the present studies with inorganic salts, even in a citric acid milieu, the fractional absorption of Cr(III) was fairly consistent across subjects while the fractional absorption of Cr(VI) varied widely, both across subjects in Study 3 and within the single subject who participated in all 5 studies. An alternative approach to modeling absorption of Cr(VI) salts would have been to hold the absorption rate constant at a single arbitrary value and allow the rate constant for gastrointestinal reduction to vary with the subject. It appears likely that much of the variability in absorption of Cr(VI) is in fact due to variable efficiency of gastrointestinal reduction. De Flora et al. (1997) have estimated that gastrointestinal reduction capacity may vary by a factor of as much as 3 or more in an individual, depending on the timing of meals. Neither the timing of meals nor the nature or amount of the food ingested was controlled in these studies, so that the bolus doses could have entered a fasting or a postabsorptive environment or could, to a greater or lesser degree, have become admixed with (and perhaps sequestered by) foodstuffs in the stomach. Given the potential complexities of interaction of a bolus dose with these variable gastrointestinal environmental surroundings, it would not be surprising if wide differences in both rapidity of reduction and bioavailability were to be observed. Paustenbach et al. (1999) were able to correlate certain of the observed differences in fractional uptake with dietary patterns in 2 of the subjects.
Chromium has been observed to be excreted in the bile and across the wall of the gastrointestinal tract after intravenous administration of either Cr(III) or Cr(VI) to rats in experimental studies (Manzo et al., 1983; Sayato et al., 1980
). However, there is no evidence to suggest that extra-urinary excretion is significant under more natural exposure conditions. A compilation of data from all acceptable published sources gives mean chromium levels in the serum of non-industrially-exposed humans of 13 nmol/l, or 0.050.15 µg/l; in the urine, 210 nmol/l, or 0.10.5 µg/l, or 0.21.0 µmol/mol of creatinine (Brune et al., 1993
). Urinary excretion of chromium is 0.10.2 µg/day (Anderson et al., 1988
). These values place urinary clearance in the vicinity of 1-2 l/day in control individuals (Anderson et al., 1988
; Brune et al., 1993
; Kumpulainen et al., 1983
; Randall and Gibson, 1987
), suggesting low ultrafilterability or high reabsorption in the kidney in persons with low-to-moderate body burdens. All chromium excreted in the urine of humans appears to be Cr(III) regardless of the nature of the exposure (Minoia and Cavalleri, 1988
; Nomiyama et al., 1980
). That the excretion data define the same curve in the present study, irrespective of whether inorganic salts of Cr(VI) or of Cr(III) were administered, is consistent with these observations. Although a pathway for urinary excretion of Cr(VI) is included in the present model, it is essentially inoperative due to the rapidity of reduction of Cr(VI) to Cr(III).
Mutti et al. (1979) noted increasing renal clearance of ultrafilterable chromium, to about 7.5 l/day, in 2 men during a month of continuous workplace exposure, and clearances greater than 15 l/day in 8 study subjects with 24.5 ± 12.5 µg urinary chromium/g creatinine and a mean time of nearly 9 years of workplace exposure to chromium. Although these observations were made at a time when chromium analytical techniques were less reliable than they are today and measured absolute concentrations tended to be high, the relative measurements may nonetheless be meaningful. An observation that clearance of ultrafilterable chromium increases with increasing body burden suggests the possible operation of a capacity-limited renal reabsorption process. The implicit function that defines urinary clearance in the present model, which expresses the observed relationship between plasma chromium concentration and the rate of chromium excretion in the urine in the 4 studies in which chromium was given as an inorganic salt in drinking water (Fig. 1), is consistent with the operation of a capacity-limited renal reabsorption process; clearance increases to a maximum of 10 l/day at very high plasma chromium concentrations. However, the expression yields clearances much lower than 1.0 l/day in the control plasma concentration range; in fact, at a plasma chromium concentration of 0.1 µg/l, the modeled clearance is 0.003 l/day.
That the clearance curve described by the data from these studies is not consistent with that suggested by plasma concentration and urinary excretion data from ambient sources may be attributable to the form in which the chromium salts were administered. The inset in Figure 1 shows that Study 2, in which chromium was administered in orange juice, generates clearance measurements more in keeping with expectation. The apparent time lag between the appearance of chromium in the plasma and its appearance in the urine, which is also a feature of animal studies (Bragt and van Dura, 1983
; Edel and Sabbioni, 1985
), suggests that chromium is cleared from a compartment other than plasma, and the distribution of chromium out of the plasma has been shown to be strongly influenced by the form in which the chromium salt is administered, whether intravenously (Visek et al., 1953
) or orally (Anderson et al., 1996
). Administered intravenously, Cr(III) citrate produced by the reduction of Cr(VI) in an acid citrate milieu behaves electrophoretically like a free anion (Cunningham et al., 1957
), and it may be that the Cr(III) citrate administered orally in Study 2 also behaves kinetically more like a free anion after absorption than do the inorganic salts of Cr(III) and Cr(VI). The urinary excretion rate data from Study 2 suggest that when the chromium has been administered as Cr(III) citrate rather than as the inorganic salts CrCl3 or K2Cr2O7, transfer of chromium from the blood to a compartment from which excretion occurs is favored relative to transfers into other tissues (note also the discussion in Kerger et al., 1996). As a result, when the Cr(III) chloride clearance curve is applied and the value of the absorption rate constant is optimized as well as it can be to fit urinary excretion rates (Fig. 3
) from a Study 2 subject, plasma concentrations in the same subject are greatly over-predicted (Fig. 9
). Had the simulation been optimized to plasma concentrations, urinary excretion rates would have been correspondingly underpredicted. Application of the revised clearance expression illustrated in Figure 1
improves the excretion rate fit and drops the plasma concentration simulation into a more reasonable range, although, as noted above, plasma data from Study 2 are not adequate to support an estimate of goodness of fit by any simulation (Figs. 3 and 9
).
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Once in the blood, Cr(VI), rapidly taken up into the red cell as the chromate anion by the non-specific anion carrier pathway, is rapidly reduced by glutathione (Aaseth et al., 1982; Wiegand et al., 1984
) as well as by hemoglobin (Ebaugh et al., 1961
). The reduction step maintains the concentration of Cr(VI) in the cell at a low level, favoring continuing passage of Cr(VI) from the extracellular milieu into the cell. The Cr(III) resulting from reduction in the red cell tends to be tightly bound, partly to hemoglobin and partly to low-molecular-weight ligands, probably largely glutathione (Aaseth et al., 1982
; Wiegand et al., 1984
). De Flora et al. (1997) have estimated the reduction capacity of human whole blood to be of the order of 50 µg/ml, for a total reduction capacity on the order of 200 mg. Nearly all of this activity resides in the red cell, since the reduction capacity of blood plasma alone is low (Corbett et al., 1998
; Korallus et al., 1984
; Minoia and Cavalleri, 1988
). After absorption, any Cr(VI) escaping reduction in the portal vein would reach the liver, whose total reduction capacity is estimated at several grams of Cr(VI) daily (De Flora et al., 1997
). The amounts of Cr(VI) ingested even at the highest doses in these studies would therefore have been well within the reduction capacities of key portal fluids and tissues. The indistinguishability of urinary excretion-rate curves and plasma concentration curves, independent of whether Cr(III) or Cr(VI) had been administered, shows that they were. Therefore, maximum reduction capacities are not incorporated into this model, which is designed for oral exposures up to single doses of about 10 mg of Cr(VI) or up to several tens of milligrams daily, a level far above ambient intakes. The model is not applicable to the intravenous, intraperitoneal, or intramuscular exposures characteristic of some experimental animal studies, nor to massive doses that could swamp local reduction mechanisms.
Once reduced in the red cell, chromium does not remain with the red cell for the survival time of the cell. The apparent half-life of chromium in the human red cell in vivo, taking into account the survival time of the cell, is close to 30 days (mean residence time of about 43 days) (Eadie and Brown, 1954; Read, 1954
). This is not greatly different from the 20-day apparent half-life of chromium in the red cell of the rat (Bishop and Surgenor, 1964
) and the dog (Gray and Sterling, 1950
), suggesting that the rate of loss of reduced Cr(VI) from the red cell is not strongly species-dependent. A half-life of 30 days implies a first-order rate constant for loss from the red cell of bound Cr(III), produced by intracellular reduction of Cr(VI), of .693/30 da1, or approximately .023/da, the value assigned to this rate constant in the model. Figure 6
demonstrates that the residence time of red cell-chromium in the subjects of these studies is essentially the same as that of plasma chromium and is of the order of a day rather than tens of days, leading to the conclusion that chromium did not enter the red cell as Cr(VI) but as Cr(III). (Although red cell chromium tracks plasma chromium closely and peaks very shortly after chromium administration, a brief drop in the ratio of red cell to plasma chromium occurs almost immediately after administration of Cr(VI) (data not shown), reflecting a slight lag in uptake of red cell chromium.)
The kinetics of Cr(III) have been puzzling, partly because even soluble Cr(III) salts are poorly absorbed from the gastrointestinal tract but principally because Cr(III) behaves differently depending on the form(s) in which it is present in the plasma. In studies in which an inorganic Cr(III) salt was added directly to plasma or blood in vitro or was given by intravenous injection (Gray and Sterling, 1950), Cr(III) entered the red cell poorly if at all. This apparent exclusion of Cr(III) from the cell is probably due to the design of the study, since kinetic observations made following intravenous injection of chromium salts, particularly Cr(III) salts, or addition of Cr(III) salts directly to incubation media in vitro are difficult to interpret. The distribution in rats of intravenously administered Cr(III) salts is strongly dependent on the chemical nature of the anion (Visek et al., 1953
). In fact, the relative elevations in kidney, liver, and spleen chromium often seen in animal studies (see, for example, Anderson et al., 1997) appear in some instances to be related to the nature of the exposure; they are not characteristic of ambient human exposure (Schroeder et al., 1962
). Cr(III) entering the plasma by a more natural route than direct introduction tends to be solubilized by coordination with low-molecular-weight ligands. It appears that Cr(III) in these forms moves readily both into and out of the cell. For example, when Cr(III) coordination complexes with organic ligands were administered orally to mice (Gonzalez-Vergara et al., 1980
), absorption was low but measurable, and the initial phase of urinary excretion of the administered chromium was complete within about a day, documenting the operation of rapid absorption and excretion processes for these forms of Cr(III) with the slight excretion delay being attributable to rapid tissue uptake and loss (compare with Figs. 2 and 3
of the present work). In an experiment with 2 volunteer control human subjects, Aitio et al. (1984) also observed that urinary excretion of chromium had returned nearly to background levels within 24 h after a dose of Cr(III) chloride was given in drinking water.
Cr(III) does not partition selectively into the red cell, implying that clearances into and out of the red cell are not only rapid but also equal, Minoia and Cavalleri (1988) observed that in control subjects or in persons exposed only to Cr(III) salts, the red cell: plasma chromium concentration ratio was about 1:1, while in workers exposed predominantly to airborne Cr(VI), the red cell:plasma concentration ratio was much greater than it was in workers exposed predominantly to airborne Cr(III). Consistent with these observations, Cr(III) was taken up rapidly by red cells in the subjects of the current studies, and was rapidly lost (see Fig. 6 from Study 3, in which the chromium was administered as Cr(VI) in water but is behaving as Cr(III) once absorbed). It is also possible that some of the chromium associated with red cells in these studies had not been internalized but was associated with the cell surface. In either case, the implication is that the only detectable form of chromium associated with the red cell was diffusible Cr(III) rather than bound Cr(III) produced by intracellular reduction of Cr(VI); that is, although some Cr(VI) escaped reduction before absorption from the gastrointestinal tract, by the time the chromium had reached the systemic circulation no Cr(VI) was detectable by red cell uptake.
Estimates of chromium half-lives have been made and descriptive models of human chromium kinetics have been proposed. Lindberg and Vesterberg (1983) noted that chrome-plating workers appeared to be at steady state with regard to chromium excretion by Tuesday afternoon of the workweek, suggesting a relatively short effective half-life, of the order of hours rather than days. Two half-lives, of the order of 440 h and on the order of tens of days, have been observed in workers exposed to Cr(VI) compounds (McAughey et al., 1988; Tossavainen et al., 1980
; Welinder et al., 1983
).
Lindberg and Vesterberg (1989) characterized the decline of urinary chromium in chrome-plating workers after cessation of exposure by a 2-compartment model with half-lives of 23 days and about one month. They noted differences in the terminal rates of decline in chrome platers and in welders, and speculated that the differences might be due to continuing extended absorption from the lung in the welders after exposure had ceased, a process unlikely to be operative in chrome platers, in whom the exposure is to chromic acid aerosols. The concept of slow extended absorption from the lung is supported by studies in chromium workers who, long after termination of exposure, are found to have elevated tissue concentrations of chromium (Kishi et al., 1987). Even at ambient concentrations of chromium in air, some accumulation of chromium occurs in the lung. This chromium is not in rapid equilibrium with chromium in other tissues (Schroeder et al., 1962
).
Lim et al. (1983) proposed a 3-compartment model for the kinetics of Cr(III). The fast, medium, and slow compartments were assigned half-lives of 0.512 h, 114 days, and 312 months based on studies in 6 human subjects injected intravenously with CrCl3. While this model has been applied to predict the result in humans of extended low-level chromium intake (Stearns et al., 1995), its appropriateness for this purpose is questionable, due to the artificial nature of the exposure on which the model was based and the consequent implications for chromium disposition.
The physiologically based model presented here also has distinct limitations. An obvious one is the absence of a physiologic lung compartment while formal incorporation of a lung compartment is included in the corresponding rat model (O'Flaherty, 1996). While this would not be difficult to accomplish, insufficient data exist to titrate the lung portion of a model meaningfully. Furthermore, pulmonary chromium kinetics will be both compound- and particle size-dependent, possibly even more strongly so than with oral exposure. The maximum systemic impact of inhalation exposure can be assessed by assuming 100% absorption of inhaled respirable chromium, in order to estimate an upper limit on the blood and urinary chromium concentrations associated with specific environmental exposures. Alternatively, the model in its present form could be used to assist with evaluation of the impact of different percentage absorptions and/or different fractions of inhaled chromium remaining in the lung and transferred to the gastrointestinal tract as a result of mucociliary action and subsequent swallowing. A second limitation of the model is its basis in observations made following the ingestion of inorganic chromium salts, a study design that generates a clearance curve distinctly different from that generated after ingestion of a chromium citrate complex and from measured clearances in the general population. To model chronic oral chromium exposure, as in the diet or in drinking water, at ambient or somewhat above ambient levels, the physiologically based model in its present form should be usable for the generation of rough estimates with urinary clearance set to a constant value of 12 l/day and the rate constants for gastrointestinal absorption set at 0.25/day for Cr(III) and 2.5/day, or 10 times the value for Cr(III) (Donaldson and Barreras, 1966; MacKenzie et al., 1958
; Polansky and Anderson, 1983
), for Cr(VI).
Despite the uncertainties, several conclusions can be drawn about the kinetics of oral chromium compounds. These conclusions are central to a global understanding of the behavior of chromium in the human body.
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APPENDIX |
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!Ellen J. O'Flaherty
!This version of the physiologically based human chromium kinetic model is
!written for ACSL (Advanced Continuous Simulation Language, The AEgis Technologies Group, 13062 Hwy. 290 West, Suite 107, Austin, TX 78737),Level 11
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NOTES |
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2 A copy of the data in the form in which they were used for this work is available by request from S. Hays, who can be contacted at shays{at}exponent.com.
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REFERENCES |
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