Biomedical subjects

M Béliveau

Publications and source records attributed to M Béliveau.

6 recordsLinked to original sources

PubMed2001

Quantitative structure-pharmacokinetic relationship modelling.

This article presents the current methods in quantitative structure-pharmacokinetic relationship (QSPkR) modelling along with examples using chemicals of toxicological significance. The common method involves: (i) collecting pharmacokinetic data or determining pharmacokinetic parameters (e.g. elimination half-life, volume of distribution) by fitting to experimental data; and (ii) associating them with the structural features of chemicals using a Free-Wilson model. Such QSPkRs have been developed for a few series of chemicals but their usefulness is limited to the exposure scenario and conditions under which the experimental data were originally collected. The alternative approach involves the development of quantitative structure-property relationship (QSPR) models for parameters, blood:air partition coefficient, tissue:blood partition coefficient, maximal velocity for metabolism and Michaelis affinity constant, of physiologically-based pharmacokinetic (PBPK) models which are useful for conducting species, route, dose and scenario extrapolations of the tissue dose of chemicals. Mechanistic QSPRs are available for predicting tissue:blood and blood:air partition coefficients from molecular structure information of chemicals, whereas such approaches are not currently available for hepatic metabolism parameters. However, at the present time, the pharmacokinetics of inhaled volatile organic chemicals can be simulated adequately by considering the physiological limits of the hepatic extraction ratio (0-1) and molecular structure-based estimates of partition coefficients in the PBPK model. This current state-of-the-art of structure-based modelling of pharmacokinetics will advance with the development of QSPRs for other chemical-specific parameters of PBPK models. Integrated QSPR-PBPK modelling should facilitate the identification of chemicals of a family that possess desired properties of bioaccumulation and blood concentration profile in both test animals and humans.

Animals↗

PubMed2001

Blood:air partition coefficients of individual and mixtures of trihalomethanes.

The objective of the present study was to determine the rat blood:air partition coefficients (P(b:a)) of chloroform, bromodichloromethane, dibromochloromethane and bromoform present in vitro individually or as mixtures. The experimentally determined P(b:a) of chloroform, bromodichloromethane, dibromochloromethane and bromoform present individually corresponded to (mean +/- SD, n = 8) 21.3 +/- 1.8, 41.8 +/- 6.2, 97.5 +/- 4.1, and 187 +/- 7.4, respectively. The P(b:a) of these trihalomethanes (THMs) showed a decreasing trend during mixed in vitro exposures to 0.138 +/- 0.002 or 0.273 +/- 0.002 micromol of each of the four THMs. In general, the P(b:a) determined during mixed exposures differed by < or = 15% of the average P(b:a) determined for THMs present individually. The results of this study suggest that an alteration of P(b:a) of the individual THMs is unlikely to occur at the blood concentrations of THMs observed during mixed exposures in rats.

Animals↗

PubMed2001

A PBPK modeling-based approach to account for interactions in the health risk assessment of chemical mixtures.

The objectives of the present study were: (1) to develop a risk assessment methodology for chemical mixtures that accounts for pharmacokinetic interactions among components, and (2) to apply this methodology to assess the health risk associated with occupational inhalation exposure to airborne mixtures of dichloromethane, benzene, toluene, ethylbenzene, and m-xylene. The basis of the proposed risk assessment methodology relates to the characterization of the change in tissue dose metrics (e.g., area under the concentration-time curve for parent chemical in tissues [AUCtissue], maximal concentration of parent chemical or metabolite [Cmax], quantity metabolized over a period of time) in humans, during mixed exposures using PBPK models. For systemic toxicants, an interaction-based hazard index was calculated using data on tissue dose of mixture constituents. Initially, the AUCtarget tissue (AUCtt) corresponding to guideline values (e.g., threshold limit value [TLV]) of individual chemicals were obtained. Then, the AUCtt for each chemical during mixed exposure was obtained using a mixture PBPK model that accounted for the binary and higher order interactions occurring within the mixture. An interaction-based hazard index was then calculated for each toxic effect by summing the ratio of AUCtt obtained during mixed exposure (predefined mixture) and single exposure (TLV). For the carcinogenic constituents of the mixture, an interaction-based response additivity approach was applied. This method consisted of adding the cancer risk for each constituent, calculated as the product of q*tissue dose and AUCtt. The AUCtt during mixture exposures was obtained using an interaction-based PBPK model. The approaches developed in the present study permit, for the first time, the consideration of the impact of multichemical pharmacokinetic interactions at a quantitative level in mixture risk assessments.

Air Pollutants, Occupational↗

PubMed2000

Estimation of rat blood:air partition coefficients of volatile organic chemicals using reconstituted mixtures of blood components.

The objective of the present study was to estimate the rat blood:air partition coefficients (PC) of some volatile organic chemicals (VOCs) using reconstituted mixtures of blood components. Based on previous observations, three blood components (water, lipid, hemoglobin) should be necessary in the case of lipophilic VOCs (e.g. bromoform (BF), chlorobenzene (CB) chloroform (CF), and ethylbenzene (EB)) whereas a mixture of oil (lipid surrogate) and water should be adequate to estimate the blood:air PC (P(b:a)) of other VOCs (e.g. butyl methyl ether (BME), t-butyl methyl ether (tBME), diethyl ether (ETH), isooctane (ISO), methyl ethyl ketone (MEK), and alpha-pinene (PIN)). Vial equilibration studies showed that the matrix:air PCs for the oil+water samples were similar or greater than those of rat blood (mean+/-S.E., n=7-8) for BME (11.1+/-2.0 vs. 6.64+/-1.4), tBME (15.0+/-4 vs. 15.0+/-2), ETH (9.50 +/-1.16 vs. 9.24+/-0.75), ISO (2. 88+/-0.5 vs. 1.92+/-0.4), MEK (159.3+/-8 vs. 139+/-6), and PIN (20. 5+/-2.7 vs. 16.9+/-1.8), whereas they were significantly lower for BF (19.0+/-3.4 vs. 161+/-5), CF (3.4+/-0.75 vs. 16.9+/-1.1), CB (8. 3+/-2.35 vs. 61.8+/-2.8), and EB (7.13+/-1.6 vs. 50.8+/-1.3). These results suggest that additional consideration of solubility/binding in blood proteins is essential in order to adequately determine rat P(b:a) of BF, CB, CF, and EB. The PCs determined using whole blood were comparable to those obtained using a reconstituted mixture of n-octanol (lipid surrogate), water and hemoglobin (mean+/-S.E., n=3-4) for BF (154+/-1.5), CB (55+/-6), CF (15+/-0.87), and EB (30+/-1.5). The results of the present study suggest that VOC partitioning into three blood components, namely, water, lipids and hemoglobin determines to a large extent the magnitude of their blood:air PCs.

Air↗

PubMed2000

Concentration dependency of rat blood: air partition coefficients of some volatile organic chemicals.

The rat blood:air partition coefficient (PC) of lipophilic volatile organic chemicals (VOCs) cannot be predicted with the sole consideration of their solubility in blood water and lipids, suggesting an important role of blood proteins. The possible concentration dependency and the quantitative nature of VOC binding to blood proteins [i.e., association constant (Ka), number of binding sites (n)] have not been investigated previously. The objectives of this study were therefore (1) to determine the concentration dependency of the blood:air PC (P(b:a)) of four VOCs, bromoform (BF), chloroform (CF), chlorobenzene (CB), and ethylbenzene (EB), hypothesized to display binding to rat blood proteins; and (2) to derive Ka and n values for these chemicals in rat blood. In vitro studies were conducted using 0.1-0.5 ml whole blood, or an equivalent mixture of water and n-octanol exposed to varying amounts of VOCs (BF, 0.11-11.4 micromol; CB, 0.11-24.6 micromol; CF, 0.11-186.6 micromol; and EB, 0.11-20.2 micromol) in sealed glass vials. The P(b:a) of CB, CF, and EB decreased significantly at higher amounts added, with no significant change in their n-octanol + water mixture:air PC. For each in vitro exposure situation, the concentration of free chemical (Cfree) in rat blood was calculated with the PC for the n-octanol + water mixture, whereas the concentration of bound plus free chemical (Ctot) was calculated from knowledge of the PC determined experimentally with whole blood. The respective values of Ka and n for hemoglobin binding estimated by linear regression of a plot of the reciprocal of the molar ratio of bound chemical versus 1/Cfree were: BF, 0.8, 4; CB, 2.8, 1.4; CF, 1.8, 1.2; and EB, 2, 1.4. The results of this study suggest that the concentration-dependent nature of P(b:a) need not be considered for modeling rat inhalation exposures to these VOCs for up to several thousand parts per million.

1-Octanol↗

PubMedDate not supplied

A spreadsheet program for modeling quantitative structure-pharmacokinetic relationships for inhaled volatile organics in humans.

The extent and profile of target tissue exposure to toxicants depend upon the pharmacokinetic processes, namely, absorption, distribution, metabolism and excretion. The present study developed a spreadsheet program to simulate the pharmacokinetics of inhaled volatile organic chemicals (VOCs) in humans based on information from molecular structure. The approach involved the construction of a human physiologically-based pharmacokinetic (PBPK) model, and the estimation of its parameters based on quantitative structure-property relationships (QSPRs) in an Excel spreadsheet. The compartments of the PBPK model consisted of liver, adipose tissue, poorly perfused tissues and richly perfused tissues connected by circulating blood. The parameters required were: human physiological parameters such as cardiac output, breathing rate, tissue volumes and tissue blood flow rates (obtained from the biomedical literature), tissue/air partition coefficients (obtained using QSPRs developed with rat data), blood/air partition coefficients (Pb) and hepatic clearance (CL). Using literature data on human Pb and CL for several VOCs (alkanes, alkenes, haloalkanes and aromatic hydrocarbons), multi-linear additive QSPR models were developed. The numerical contributions to human Pb and CL were obtained for eleven structural fragments (CH3, CH2, CH, C, C [double bond] C, H, Cl, Br, F, benzene ring, and H in the benzene ring structure). Using these data as input, the PBPK model written in an Excel spreadsheet simulated the inhalation pharmacokinetics of ethylbenzene (33 ppm, 7 h) and dichloromethane (100 ppm, 6 h) in humans exposed to these chemicals. The QSPRs developed in this study should be useful for predicting the inhalation pharmacokinetics of VOCs in humans, prior to testing and experimentation.

Animals↗