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M H Abraham

Publications and source records attributed to M H Abraham.

52 records · Page 3Linked to original sources
PubMed1996

Estimating the sensory irritating potency of airborne nonreactive volatile organic chemicals and their mixtures.

This article describes the possibility of estimating whether or not a mixture of nonreactive volatile organic chemicals (NRVOC) is likely to elicit complaints of sensory irritation in humans. For this estimation we rely on: a) the sensory irritating potency of individual NRVOC can be estimated from a variety of physicochemical properties of these chemicals, b) at low exposure concentrations, the additivity rule can be applied using the potency of each chemical in a mixture and c) a threshold concentration exists below which no sensory irritation will occur. We used this estimating approach and we compared the results obtained with those obtained experimentally in humans exposed to a well defined mixture. The approach presented can be used to arrive at a decision as to whether or not exposure to a mixture of NRVOC is likely to result in sensory irritation complaints by humans, either in the general indoor air situation or for industrial workers.

Air Pollution, Indoor↗
PubMed1995

Physicochemical properties of nonreactive volatile organic chemicals to estimate RD50: alternatives to animal studies.

This article presents the correlations obtained between the results on the potency of nonreactive airborne chemicals as sensory irritants and several of their physicochemical properties. The potency of airborne sensory irritants obtained from a reflexively induced decrease in respiratory frequency has been measured in the past using mice. Typically, their potency has been expressed as the exposure concentration necessary to decrease respiratory frequency by 50% (RD50). A large database of RD50 values is now available and such values are highly correlated with occupational exposure guidelines such as threshold limit values (TLVs). We used the nonreactive volatile organic chemicals from this database, for which relevant physicochemical variables are available or can be calculated. These variables were vapor pressure (P) or Ostwald gas-liquid partition coefficients (L). The liquids used for L values were n-hexadecane, octanol, N-formylmorpholine, tri-(2-ethylhexyl)phosphate, and olive oil. Excellent correlations were found between log RD50 and log P, as well as between log RD50 and log L16, log L(Oct), log L(NFM), log L(EHP), or log L(Oil). It follows that as an alternative to the bioassay, these physicochemical variables can be used to estimate RD50 of nonreactive volatile organic chemicals. Appropriate exceptions to general estimation of RD50 values from physicochemical variables are also presented, as well as the most appropriate estimates which can be obtained within homologous series.

Air Pollutants, Occupational↗
PubMed1995

Hydrogen-bonding. Part 36. Determination of blood brain distribution using octanol-water partition coefficients.

It is shown that the octanol-water partition coefficient (Poct) cannot be used to predict blood brain distribution (BB) rectilinearly, but can be combined with Abraham solute descriptors to yield a predictive regression equation, eq (15), in which the solute descriptors sigma alpha H2 and sigma beta H2 are the overall summation hydrogen-bond acidity and basicity respectively. It is also demonstrated that of the various predictive models now available, that of Abraham, Chadha and Mitchell, eq (14), still yields the best results on a new test set of drug molecules; where the other solute descriptors are: R2, an excess molar refraction; pi H2, the dipolarity/polarisability; and Vx the characteristic volume of McGowan. Thus, solute dipolarity/polarizability, hydrogen-bond acidity and hydrogen-bond basicity favour blood, and solute size favours brain. logBB = +0.055 + 0.203logPoct - 0.507 sigma alpha H2 - 0.500 sigma beta H2 n = 49 rho = 0.9491 sd = 0.201 F = 136.1 (15) logBB = -0.038 + 0.198R2 - 0.607 pi H2 - 0.715 alpha H2 - 0.698 beta H2 + 0.995Vx n = 57 rho = 0.9522 sd = 0.197 F = 99.2 (14)

Blood-Brain Barrier↗
PubMed1994

The Ferguson principle and an analysis of biological activity of gases and vapors.

The Ferguson principle, that Pnar/PO (Pnar is the partial pressure of a series of compounds giving rise to a particular effect on a given system by a physical mechanism, and PO is the saturated vapor pressure of the liquid narcotic) is constant for a series of nonreactive narcotics or toxicants in a given system, is examined and shown to have no thermodynamic basis, contrary to the position of Brink and Posternak. Conditions under which Pnar/PO might be expected to be roughly constant, as an empirical observation, are set out and it is shown that such an observation is consistent with a receptor area in which the liquid narcotic solubilities are roughly constant. An interpretation of relationships between agonist descriptors and biological effects is carried out with three simple biological models. It is shown that the biological potency of nonreactive gases and vapors can be controlled either by an equilibrium between the agonist in the gas phase and the agonist in a receptor or by an equilibrium between the agonist in the gas phase and the agonist in a receptor phase. It is further shown that with the solvation equation of Abraham, solvents can be chosen that mimic the chemical properties of the receptor or receptor phase. For the example of upper respiratory tract irritation of male Swiss OF1 mice, such solvents include N-formylmorpholine, a trialkylphosphate, and wet octanol, but not water itself.

Chemistry, Physical↗
PubMed1994

Hydrogen bonding. 32. An analysis of water-octanol and water-alkane partitioning and the delta log P parameter of seiler.

A general linear solvation energy equation has been used to analyze published partition coefficients in the systems water-octanol (613 solutes), water-hexadecane (370 solutes), water-alkane (200 solutes), and water-cyclohexane (170 solutes). The descriptors used in the equation are R2, an excess molar refraction; phi H2, the solute dipolarity/polarizability; sigma alpha H2 and sigma beta H2, the effective solute hydrogen-bond acidity and basicity; and Vx, the characteristic volume of McGowan. It is shown that the water-octanol partition coefficient is dominated by solute hydrogen-bond basicity, which favors water, and by solute size, which favors octanol, but solute excess molar refraction and dipolarity/polarizability are also significant. For the water-alkane partition coefficients, the same factors are at work, together with solute hydrogen-bond acidity as a major influence that favors water. An analysis of 288 delta log P values shows that solute hydrogen-bond acidity is the major factor but that solute hydrogen-bond basicity and, to a lesser extent, solute dipolarity/polarizability and size are also significant factors that influence the delta log P parameter.

Alkanes↗
PubMed1994

Hydrogen bonding. 33. Factors that influence the distribution of solutes between blood and brain.

It is shown that neither the set of directly determined blood-brain concentration ratios (BB) of Young and Mitchell nor the set of indirectly obtained values of Abraham and Weathersby are suitable for the construction of a general equation for the interpretation and prediction of log BB values. However, combination of both sets leads to the general equation log BB = -0.038 + 0.198R2 - 0.687 pi H2 - 0.715 alpha H2 - 0.698 beta H2 + 0.995Vx (n = 57, rho = 0.9522, sd = 0.197, F = 99.2), where the solute descriptors are R2, an excess molar refraction; pi H2, the dipolarity/polarizability, alpha H2 and beta H2, the effective or summation hydrogen-bond acidity and basicity; and Vx, the characteristic volume of McGowan. Thus solute dipolarity/polarizability, hydrogen-bond acidity, and hydrogen-bond basicity favor blood, and solute size, as Vx, favors brain. Methods are given for the estimation of solute descriptors through fragment schemes, so that log BB values themselves may be obtained simply from knowledge of solute molecular structure.

Blood-Brain Barrier↗
PubMed1994

Hydrogen bonding. 30. Solubility of gases and vapors in biological liquids and tissues.

The general solvation equation log L = c + rR2 + pi H2 + a alpha H2 + b beta H2 + l log L16 has been used to analyze the solubility of solute gases and vapors, as log L values, in water, blood, and a variety of other biological fluids and tissues. The explanatory variables are R2, the solute excess molar refraction; pi H2, the solute dipolarity/polarizability; alpha H2 and beta H2, the solut hydrogen-bond acidity and basicity; and log L16, where L16 is the solute Ostwald solubility coefficient of hexadecane. The obtained coefficients then serve to characterize the biological phase as follows: r + s is the phase dipolarity/polarizability, a is the phase hydrogen-bond basicity, b is the phase hydrogen-bond acidity, ald l is the phase lipophilicity. In addition to characterization of phases, the equation can be used to determine quantitatively solute/phase interactions and predict further log L values. A similar equation in which McGowan's characteristic volume, Vx, replaces the log L16 descriptor can be used to analyze partitions between phases. For example, water/phase and blood/phase partition coefficients are analyzed, and the analysis leads again to coefficients that characterize phases and to the prediction of partition coefficients.

Blood↗
PubMed1993

Molecular organization of liquid n-octanol: an X-ray diffraction analysis.

We recorded X-ray diffraction patterns from n-octane, n-octanol, and fully hydrated n-octanol. These patterns were analyzed using a modified version of the Percus-Yevick hard-sphere theory for liquids. A model is presented for the molecular organization of n-octanol that accurately predicts the observed diffraction patterns. The octanol molecules are associated in aggregates, with their hydroxyl groups forming roughly spherical clusters and their hydrocarbon chains pointing outwards, almost fully extended. When n-octanol is hydrated, the overall organization does not change greatly, but water molecules coordinate the hydroxyl groups in the clusters. Estimates are made for the maximum number of octanol molecules in the aggregates.

1-Octanol↗
PubMed1991

Role of hydrogen bonding in general anesthesia.

The importance of hydrogen bonding in determining the potency of a general anesthetic is controversial. In order to investigate the role of hydrogen bonding further, we have used a multiple linear regression approach to quantify the relative importance of various physical properties of an anesthetic molecule (i.e., its ability to donate or accept a hydrogen bond, its dipolarity and polarizability, and its size) in determining its anesthetic potency. For comparison, we have applied the same approach to partitioning between water and three simple, but contrasting solvents (n-octanol, n-hexadecane, and N,N-dimethylacetamide) and to inhibition of an enzyme (firefly luciferase) which mimics many of the properties of general anesthetic target sites in animals. We present equations which accurately predict potencies (over many orders of magnitude) for producing general anesthesia and inhibiting the firefly luciferase enzyme. We find that the aqueous potency (defined as the reciprocal of the aqueous EC50 concentration) of a molecule as a general anesthetic or an inhibitor of luciferase is determined overwhelmingly by its size (which increases potency) and its ability to accept a hydrogen bond (which decreases potency), but only marginally by its ability to donate a hydrogen bond or by its dipolarity and polarizability. We conclude that general anesthetic target sites in animals must have, in addition to their overall hydrophobicity, a polar component which is a relatively poor hydrogen bond donor, but which can accept a hydrogen bond about as well as water.

Adenosine Triphosphate↗
PubMed1987

Solubility properties in polymers and biological media. II. A new method for the characterisation of the adsorption of gases and vapours on solids.

Henry's constants at zero solute pressure have been determined by the gas chromatographic peak shape method for twenty-two solutes on four adsorbents (Rohm and Haas Ambersorb XE-348F carbonaceous adsorbent at 323 and 373 K, Sutcliffe Speakman 207A and 207C at 323 K, and Calgon Filtrasorb activated carbon at 323 K). The limiting values of log KH have been analysed in terms of solute dipolarity (pi 2*), solute hydrogen-bond acidity (alpha 2), and basicity (beta 2), and a new solute parameter (log L16), the solute Ostwald absorption coefficient on eta-hexadecane. The multiple linear regression equation, SP = SP0 + l.log L16 + s(pi 2* + d delta 2) + a alpha 2 + b beta 2 where in this instance SP = -log KH, can be used to identify the nature of the solute-adsorbent interactions, and to predict further values of log KH. For the solutes and solids we have studied, only the l.log L16 term is statistically significant, and hence--log KH is proportional to l.log L16. It is concluded that interactions between the gaseous solutes (that include alcohols and amines) and the four adsorbents involve just general dispersion forces.

Acetonitriles↗
PubMed1987

Solubility properties in biological media 9: prediction of solubility and partition of organic nonelectrolytes in blood and tissues from solvatochromic parameters.

Solubilities in and partition among human blood, brain, lung, kidney, muscle, and fat tissue are well correlated by linear solvation energy relationships of the form: XYZ = XYZo + mVI/100 + s pi + b beta m where XYZ is the logarithm of the solubility property, VI is the intrinsic (van der Waals') molar volume, pi and beta are the solvatochromic parameters that measure solute dipolarity/polarizability and hydrogen-bond acceptor basicity, respectively, and the subscript m indicates that for self-associating compounds, the parameter applies to the non-self-associated "monomer" solute. The equation for log K(brain--blood) indicates that increasing molar volume favors, whereas increasing dipolarity and hydrogen-bond acceptor basicity oppose, solute transfer from blood into brain.

Chemical Phenomena↗
PubMed1986

Linear solvation energy relationships: 36. Molecular properties governing solubilities of organic nonelectrolytes in water.

Molar solubilities of non-hydrogen bond donor and weak hydrogen bond donor liquid aliphatic solutes in water, or the nearly equivalent quantities, Sg/Kgw, where Kgw is the gas-water partition coefficient and Sg is the solute concentration in the solute saturated vapor (Sg = Patm/24.5) are well correlated by the equation: log Sw congruent to log (Sg/Kgw) = 0.54 - 3.32V/100 + 0.46 pi* + 5.17 (beta or beta m) (at 25 degrees C) n = 105, r = 0.9954, SD = 0.137 V is the solute molar volume (the molecular weight divided by the liquid density at 20 degrees C), and pi* and beta are the solvatochromic parameters that are measures of solute dipolarity-polarizability and hydrogen bond acceptor basicity. The equation, which applies to liquid monofunctional aliphatic solutes is used to calculate additional new beta and beta m values. The beta m values, which are intended to apply to self-associated compounds when acting as "monomer" solutes, are: methanol, 0.42; all primary alkanols, 0.45; all secondary alkanols, 0.51; and all tertiary alkanols, 0.57.

Alcohols↗
PubMed1986

Solubility properties in polymers and biological media: 6. An equation for correlation and prediction of solubilities of liquid organic nonelectrolytes in blood.

Gas/blood partition coefficients, Kgb, and molar solubilities in blood, Sb, of 27 liquid aliphatic nonelectrolyte solutes are described by the equation: log Sb congruent to log (Sg/Kgb) = 1.35-3.05V/100-0.28 pi* + 3.58 beta (at 37 degrees C) r = 0.9870 and SD = 0.144 where Sg is the solute concentration in its saturated vapor at 37 degrees C, given by Sg = Patm/25.4; V is the solute molar volume; and pi* and beta are parameters that are measures of solute dipolarity/polarizability and hydrogen bond acceptor basicity, respectively. The above equation applies to compounds with calculated log solubilities greater than -1.5. A nondipolar solubility reservoir provided by hydrophobic pockets in hemoglobin leads to greater than predicted solubilities for the less soluble alkanes, alkylbenzenes, and chlorobenzenes. It is suggested that equations similar to the one above can be constructed to describe and predict gas-lipid and gas-homogenized tissue, and hence blood-lipid, blood-tissue, tissue-lipid, and tissue-tissue partition coefficients of pharmacologically and toxicologically active solutes.

Hemoglobins↗
PubMed1985

Solubility properties in polymers and biological media 5: an analysis of the physicochemical properties which influence octanol-water partition coefficients of aliphatic and aromatic solutes.

Octanol-water partition coefficients of 102 aliphatic, polychloro aliphatic, and aromatic non-hydrogen-bond donor and hydrogen-bond donor solutes are well correlated (r = 0.989, SD = 0.175) by the equation: log Kow = 0.20 + 2.74 V/100 - 0.92 pi - 3.49 beta, where V is the molar volume (taken as the molecular weight divided by the liquid density) and pi and beta are the solvatochromic parameters that measure solute dipolarity/polarizability and hydrogen-bond acceptor basicity. A set of "ground rules" (modifications of the input parameters) are described which allow the inclusion of both aliphatic and aromatic solutes in the same correlation equation. Monomer beta values (betam) are used for alcohol solutes.

Chemical Phenomena↗
PubMed1985

Solubility properties in polymers and biological media. 2. The correlation and prediction of the solubilities of nonelectrolytes in biological tissues and fluids.

Solubilities of a range of nonelectrolyte solutes in biological systems, such as blood, plasma, brain, lung, liver, kidney, muscle tissue, and human fat, are correlated and predicted through an equation that takes the form log Ltissue = c + w log Lwater + o log Loil, where L is the Ostwald solubility coefficient (or gas/liquid partition coefficient). The ratio of the constants o and w gives a measure of the "oiliness" of a given biological tissue or fluid. The strong possibility exists that, for many types of nonelectrolyte solutes, simple measurements of solubilities in water and oil (gas/liquid partition coefficients) will allow accurate predictions of solubilities in the above biological solvents, as well as tissue/blood partition coefficients. The solubility of rare gases and the inorganic gases H2, N2, CO, and O2 may be correlated through the simpler equation log Ltissue = l'RG + d', where l' and d' are constants that characterize the phase, and RG is a known parameter, obtained by normalizing and averaging solubilities over a range of solvent systems, that characterizes the solute. Both of the above equations allow prediction of L in biological solvents to within about 20%, which compares well with the precision of the experimental measurements.

Adipose Tissue↗