Blood partition coefficient

Other important determinants of the effects of compounds, especially solvents, are their partition coefficients, e.g., blood-tissue partition coefficients, which determine the distribution of the compound in the body. The air-blood partition coefficient is also important for the absorption of a compound because it determines how quickly the compound can be absorbed from the airspace of the lungs into the circulation. An example of a compound that has a high air-blood partition coefficient is trichloroethane (low blood solubility) whereas most organic solvents (e.g., benzene analogues) have low air-blood partition coefficients (high blood solubility). 

Physiologically Based Phamiacokinetic (PBPK) Model—Comprised of a series of compartments representing organs or tissue groups with realistic weights and blood flows. These models require a variety of physiological information tissue volumes, blood flow rates to tissues, cardiac output, alveolar ventilation rates and, possibly membrane permeabilities. The models also utilize biochemical information such as air/blood partition coefficients, and metabolic parameters. PBPK models are also called biologically based tissue dosimetry models. 

Estimation methods for tissue-to-blood partition coefficients (i.e., Rt) have been the most prolific, no doubt due to the need for this parameter in most organ models. Both in vitro and in vivo parameter estimation techniques are available. 

JH Lin, Y Sugiyama, S Awazu, M Hanano. In vitro and in vivo evaluation of the tissue-to-blood partition coefficients for physiological pharmacokinetic models. J Pharmacokin Biopharm 10 637-647, 1982. 

Partition coefficients have also been reported for human milk from a group of 8 volunteers (Fisher et al. 1997). The milk/air coefficient was 4.66 and the blood/air coefficient was 2.13. A milk/blood partition coefficient of 2.10 was calculated from this data. 

A model describing transfer of -hexane via lactation from a mother to a nursing infant is also available (Fisher et al. 1997). Human milk/blood partition coefficients for 19 volatile organic chemicals including u-hexane were experimentally determined using samples from volunteers. These parameters were used to estimate the amount of w-hcxanc an infant would ingest from milk if the mother was occupationally exposed to w-hcxanc at the Threshold Limit Value (TLV) throughout a workday. 

No information is available as to whether w-hexane or its metabolites cross the placenta in humans. Transfer across the placenta has been demonstrated in rats for -hexane and two resulting metabolites, 2-hexanone and 2,5-hexanedione (Bus et al. 1979) no preferential distribution to the fetus was observed for either -hexane or the metabolites. Due to its relatively rapid metabolism, storage of -hexane in body fat does not appear to occur at air concentrations to which humans are exposed thus, there is unlikely to be mobilization of maternally stored -hexane upon pregnancy or lactation. -Hcxanc has been detected in samples of human breast milk (Pellizzari et al. 1982) however, -hexane was not quantified, nor was any attempt made to assess the subjects exposure. A human milk/blood partition coefficient of 2.10 (Fisher et al. 1997) indicates there would be preferential distribution to this compartment if significant absorption occurred however no pharmacokinetic experiments have been... 

There is no experimental evidence available to assess whether the toxicokinetics of -hexane differ between children and adults. Experiments in the rat model comparing kinetic parameters in weanling and mature animals after exposure to -hexane would be useful. These experiments should be designed to determine the concentration-time dependence (area under the curve) for blood levels of the neurotoxic /7-hcxane metabolite 2,5-hexanedione. w-Hcxanc and its metabolites cross the placenta in the rat (Bus et al. 1979) however, no preferential distribution to the fetus was observed. -Hexane has been detected, but not quantified, in human breast milk (Pellizzari et al. 1982), and a milk/blood partition coefficient of 2.10 has been determined experimentally in humans (Fisher et al. 1997). However, no pharmacokinetic experiments are available to confirm that -hexane or its metabolites are actually transferred to breast milk. Based on studies in humans, it appears unlikely that significant amounts of -hexane would be stored in human tissues at likely levels of exposure, so it is unlikely that maternal stores would be released upon pregnancy or lactation. A PBPK model is available for the transfer of M-hcxanc from milk to a nursing infant (Fisher et al. 1997) the model predicted that -hcxane intake by a nursing infant whose mother was exposed to 50 ppm at work would be well below the EPA advisory level for a 10-kg infant. However, this model cannot be validated without data on -hexane content in milk under known exposure conditions. 

Tissue blood partition coefficients (R ) should be determined when steady-state has been achieved. Estimates based on samples obtained during the elimination phase following a single dose of the test substance may lead to underestimates of this ratio in both eliminating and noneliminating tissues unless its half-life is very long. Correction of these values for elimination has been described by several authors (Yacobi et al., 1989 Shargel and Yu, 1999 Renwick, 2000). 

Potential for bioaccumulation Due to their high Log values and high fat blood partition coefficient, the cyclic siloxanes are likely to be stored into the lipid tissue. However, bioaccumulation is not dependent just on the lipophilicity of the compound, but also in how fast it leaves the contaminated organism. Other indicators of bioaccumulation are the bioconcentration factor (BCF) and bioaccumulation factor (BAF). Values over 5,000 are usually characteristic for the bioaccumulative compounds. D4 has a BCF of 12,400 L/kg [293], D5 of 7,060 L/kg [279], and D6 of 1,160 L/kg [280], values calculated for fish. 

Internal burdens of epoxybutene in humans resulting from exposure to butadiene were predicted from models by Kohn and Melnick (1993), Johanson and Filser (1996) and Csanady et al. (1996) and were compared with simulations for rats and mice. In the model of Kohn and Melnick (1993), metabolic parameters were incorporated which had been obtained by Csanady et al. (1992) by measuring butadiene and epoxybutene oxidation and epoxybutene hydrolysis in human liver and lung microsomes in vitro, and conjugation of epoxybutene with glutathione in human liver and lung cytosol. Tissue blood partition coefficients were theoretically derived. The body burden of epoxy butene following exposure to 100 ppm butadiene for 6 h was predicted to be 0.056 pmol/kg in humans. 

In the model of Csanady et al. (1996), the biochemical parameters for butadiene in rats and mice were obtained by fitting model simulations to in-vivo data of Bolt et al. (1984) and Kreiling et al. (1986). The biochemical parameters for epoxybutene were identical to those of Johanson and Filser (1993, 1996). This model accurately predicted experimental data on epoxybutene. The most advanced models are those of Csanady etal. (1996) and Sweeney et al. (1997), since they can simulate both epoxybutene and diepoxybutane as metabolites of butadiene. The tissue blood partition coefficients for diepoxybutane were estimated by Csanady et al. (1996) to have a value of 1 for all tissues. Sweeney et al. (1997) obtained tissue blood partition coefficients from in-vitro measurements (Table 23). Both models yielded good predictions for mice and rats for both metabolites. For humans, no measured data have been reported against which the predictions could be validated. In addition, the model of Csanady et al. (1996) predicted accurately the measured haemoglobin adduct levels (Osterman-Golkar etal., 1993 Albrecht et al., 1993) of epoxybutene in rodents following exposure to butadiene. None of the models published has included the fonnation and elimination of epoxybutanediol. 

Black, K.A. Finch, L. (1995) Acrylic acid oxidation and tissue-to-blood partition coefficients in rat tissues. Toxicol. Lett., 78, 75-78... 

Two groups of three male volunteers were exposed by inhalation to chlorodifluoromethane at either 327 or 1833 mg/m for 4 h. The average maximal blood concentrations were 0.25 and 1.36 (.ig/mL, respectively, and were achieved within 1 h of the beginning of exposure. The average blood/air partition coefficients for chlorodifluoromethane towards the end of the exposure period were 0.82 and 0.76, respectively, and the fat/air partition coefficients were 7.7 and 8.1. Thus, the fat/blood partition coefficient was estimated to be... 

Tissue Blood Partition Coefficients Used in the Keys et al. (1999) Model 3-6. Physiological Parameter Values Used in the Keys et al. (1999) Model... 

Tissue blood partition coefficients for DEHP and nonionized MEHP were estimated from their n-octanol water partition coefficients (Kow), using the approach reported by Poulin and Krishnan (1993). 

Tissue blood partition coefficients for total MEHP (ionized and nonionized) were determined experimentally using a vial-equilibration method with correction for pH (Table 3-5). 

A model-based dependence of human tissue-blood partition coefficients of chemicals on lipophilidty and tissue composition was recently described [78], For 36 neutral chemicals, the partitioning between seven different tissues and blood in humans was modeled, considering accumulation in the membrane, protein binding, and dis-... 

Balaz, S. and Lukacova, V., A model-based dependence of the human tissue/blood partition coefficients of chemicals on lipophilicity and tissue composition, Quant. Struct.-Act. Relat., 18, 361-368, 1999. 

DeJongh, J., Verhaar, H.J.M., and Hermens, J.L.M., A quantitative property-property (QPPR) approach to estimate in vitro tissue-blood partition coefficients of organic chemicals in rats and humans, Arch. Toxicol., 72, 17-25, 1997. 

Poulin, P. and Krishnan, K., An algorithm for predicting tissue blood partition coefficients of organic chemicals from n-octanol water partition coefficient data, J. Toxicol. Environ. Health, 46, 117-129, 1995. 

Haddad S, Poulin P, Krishnan K. 2000a. Relative lipid content as the sole mechanistic determinant of the adipose tissue blood partition coefficients of highly lipophilic organic chemicals. Chemosphere 40 839-843. 

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