Relative lipid content as the sole mechanistic determinant of the adipose tissue:blood partition coefficients of highly lipophilic organic chemicals
Introduction
The biopersistence of chemicals is determined by the rates of elimination and accumulation. In mammals, for example, the greater the storage of chemicals in adipose tissues, the greater is the possibility for continued internal exposure even after the cessation of external exposure. The degree of accumulation in adipose tissues is determined by the adipose tissue:blood partition coefficient (PCat:b). By definition, adipose tissue:blood partition coefficient is the numerical value representing the ratio of concentration in adipose tissues and blood at equilibrium.
Even though the general perception is a proportional increase in adipose tissue:blood partition coefficient as a function of lipophilicity or n-octanol:water partition coefficient (PCo:w) of chemicals, this may not be entirely true above a certain PCo:w value. This has actually been demonstrated in aquatic toxicology studies with respect to the bioconcentration of lipophilic organics. Here, the bioconcentration factor (BCF) of organic chemicals has been shown to be dependent on PCo:w, for upto log PCo:w value of four. However for chemicals with log PCo:w > 6 the BCF in fish appears to be fairly constant, suggestive of a plausible upper limit of bioconcentration (Bruggeman et al., 1984). In the case of aquatic biota it is not so much the adipose tissue per se that accounts for chemical storage, but it is the neutral lipid portion of the various tissues. These observations suggest that there may as well be an apparent upper limit of chemical partitioning into tissues other than the adipose tissue. The occurrence of such a phenomenon would imply that there is a theoretical upper limit of tissue:blood partition coefficients (PCt:b). There has not been any attempt (i) to identify the theoretical upper limit of PCt:b in mammals, or the PCo:w value after which there would no longer exist a demonstrable linear relationship between PCo:w and PCt:b, and (ii) to elucidate the mechanistic basis for such a lack of linear relationship between PCo:w and PCt:b. The present study focussed to evaluate these characteristics for the adipose tissue:blood partition coefficients (PCat:b) of organic chemicals.
Section snippets
Approach
The quantitative relationship between PCo:w and PCat:b can be evaluated with the use of a recently validated tissue and blood compositions-based algorithm (Poulin and Krishnan 1995). Accordingly, the PCat:b of chemicals that do not bind significantly to biological macromolecules can be predicted as follows:where Fnat is the Fraction of neutral lipids in adipose tissue; Fnb the Fraction of neutral lipids in blood; Fpat
Volatile HLOCs
Even though a positive relationship may be anticipated to exist between PCo:w and PCat:b, after a certain PCo:w value the PCat:b may not increase and will likely attain a maximal value. This maximal value of PCat:b should be equal to Rnl,at:b per Eq. (4). Table 2 shows that, regardless of the PCo:w value (2738–67,200), the average value of human PCat:b for several volatile HLOCs () is close to the Rnl,at:b (i.e., 199.65) listed in Table 1.
Non-volatile HLOCs
A compilation of human adipose tissue:serum
Application to other species
The observations presented in the preceding paragraphs imply that the PCat:b of HLOCs in other species can also be anticipated to be equal to Rnl,at:b. In the case of the rat, the PCat:b of HLOCs, regardless of their PCo:w values, should then be equal to Rnl,at:b (=449.26) (Table 1). This value of lipid ratio is fairly close to most of the PCat:b values used in previous efforts of physiologically-based pharmacokinetic modeling of HLOCs: 2,2′,4,4′,5,5′-hexachlorobiphenyl (400), hexachlorobenzene
Conclusion
The PCt:b represents the relative distribution of chemicals between tissues and blood at equilibrium. The distribution in each of these matrices is determined by chemical solubility in certain components such as lipids and water. The present study investigated the relationship between PCat:bs of HLOCs and their PCo:w. The results show that PCat:bs of HLOCs do not increase proportionally with their PCo:w; instead the PCat:b reaches a plateau after a certain `cut-off' value of PCo:w. This is
References (30)
- et al.
Breast milk monitoring to measure Michigan’s contamination with polybrominated
Lancet
(1978) - et al.
A mechanistic model of effects of dioxin on thyroid hormones in the rat
Toxicol. Appl. Pharmacol.
(1996) Partitioning and levels of neutral organochlorine compounds in human serum, blood cells, and adipose and liver tissue
Sci. Total Environ.
(1991)- et al.
A mechanistic algorithm for predicting blood: air partition coefficients of organic chemicals with the consideration of reversible binding in hemoglobin
Toxicol. Appl. Pharmacol.
(1996) - et al.
Disposition of polychlorinated biphenyl congeners in occupationally exposed persons
Toxicol. Appl. Pharmacol.
(1982) - et al.
Modeling receptor-mediated processes with dioxin: implications for pharmacokinetics and risk assessment
Risk Anal.
(1993) Concentrations of chlorinated hydrocarbon pesticides in human blood and their relation to the concentration in depot fat
Toxicol. Appl. Pharmacol.
(1972)- et al.
Comparative study of DDT and its derivative in human blood samples in Norfolk Country and Holland Marsh, Ontario
Bull. Environ. Contam. Toxicol.
(1975) - et al.
Polychlorinated biphenyl (PCB) partitioning between tissue and serum
Bull. Environ. Contam. Toxicol.
(1984) - et al.
Bioaccumulation of super-lipophilic chemicals in fish
Toxicol. Environ. Chem.
(1984)
Pharmacokinetics of halogenated hydrocarbons
Ann. NY Acad. Sci.
The organochlorine insecticide content of human tissues
Arch. Environ. Health
Partitioning of polybrominated biphenyls (PBBs) in serum, adipose tissue, brest milk, placenta, cord blood, biliary fluid and feces
Arch. Environ. Health
Cohort study of Michigan residents exposed to polybrominated biphenyls: epidemiologic and immunologic findings
Ann. N.Y. Acad. Sci.
Cited by (107)
A New Version of the Tissue Composition-Based Model for Improving the Mechanism-Based Prediction of Volume of Distribution at Steady-State for Neutral Drugs
2024, Journal of Pharmaceutical SciencesLevels, tissue distribution and isomer stereoselectivity of Dechlorane Plus in humans: A critical review
2023, Science of the Total EnvironmentAn overview of the literature on emerging pollutants: Chlorinated derivatives of Bisphenol A (Cl<inf>x</inf>BPA)
2021, Environment InternationalCitation Excerpt :As mentioned above, ClxBPA have been found in several human biological matrices such as urine (Liao et al., 2012), adipose tissue (Fernandez et al., 2007), breast milk (Cariot et al., 2012), colostrum (Migeot et al., 2013), plasma (Cambien et al., 2020; Del Olmo et al., 2005; Li et al., 2020) and placental tissue (Jimenez-Diaz et al., 2010; Vela-Soria et al., 2011). Log P values suggest that these substances could accumulate in adipose tissue (Haddad et al., 2000). Different ClxBPA are more lipophilic than BPA (Migeot et al., 2013), so it is plausible that ClxBPA compounds accumulate more in lipid-containing matrices, such as breast milk and adipose tissue, rather than in urine or blood (Andra, Charisiadis, et al., 2015).
Bioaccumulation and transfer characteristics of dechlorane plus in human adipose tissue and blood stream and the underlying mechanisms
2020, Science of the Total EnvironmentThe challenging use and interpretation of blood biomarkers of exposure related to lipophilic endocrine disrupting chemicals in environmental health studies
2020, Molecular and Cellular EndocrinologyCitation Excerpt :In a steady-state, partitioning of highly lipophilic compounds between tissue and blood is agreed to be roughly equal to the tissue:blood lipid concentration ratio (Brown and Lawton, 1984). Accordingly, Haddad et al. (2000) explored the (theoretical) determinants of the adipose tissue:blood partition ratios (PCat:b) of organic chemicals, concluding that independently of the Kow, the PCat:b can be predicted from the lipid composition of tissue and blood (Haddad et al., 2000). Specifically, for organic chemicals with log Kow ≥ 4, the PCat:b equals the ratio between the fraction of neutral lipid equivalents in adipose and blood.