Hon-Wing Leung

Development and utilization of physiologically based pharmacokinetic models for toxicological applications.

Recent advances in physiologically based pharmacokinetic (PB-PK) modeling have introduced novel approaches for evaluating toxicological problems. Because PB-PK models are amenable to extrapolation of tissue dosimetry, they are increasingly being applied to chemical risk assessment. This paper reviews the development of PB-PK modeling for toxicological applications. It briefly compares and contrasts the fundamental differences between conventional compartmental analysis and PB-PK modeling. The theory and principles, data requirements and the methodologies to obtain them, and the steps to construct PB-PK models are described. A comprehensive listing of PB-PK models for environmental chemicals developed to date is referenced. Salient applications of PB-PK modeling to toxicological problems are illustrated with examples. Finally, the uncertainties and limitations in PB-PK modeling are also discussed.

A physiological pharmacokinetic description of the tissue distribution and enzyme-inducing properties of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat

A five-compartment physiologically based pharmacokinetic (PB-PK) model was developed to describe the tissue disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the Sprague-Dawley rat. This description included blood, liver, fat, muscle/skin, and visceral tissue groups. On the basis of other literature, the liver compartment was modeled to include two TCDD-binding sites, corresponding to a cytosolic receptor and a microsomal binding protein. A pharmacodynamic description was developed in which microsomal enzyme induction, both of arylhydrocarbon hydroxylase activity and of the amount of the microsomal TCDD-binding protein, was linked to fractional occupancy of the cytosolic receptor. This description was then used to analyze previously published data on TCDD disposition. The dissociation constant of the cytosolic Ah receptor (KB1) in vivo was estimated to be 15 pM by fitting enzyme induction data from McConnell et al. (1984). The ratio of liver to fat concentration of TCDD (about 4:1) was found to be primarily determined by the dissociation constant of the microsomal binding protein (7 nM) and the basal and induced concentration of this protein in the liver (25 and 200 nmol/liver, respectively). With these parameter values, the tissue distribution of TCDD in fat and liver, the two primary sites of accumulation, was accurately described following either single or repeated dosing with TCDD in the rat. The pharmacokinetic behavior described by the model was extremely sensitive to binding affinities, and only moderately sensitive to binding capacities in the dose range studied. Induction of microsomal TCDD-binding proteins was necessary in order to account for the differences in disposition at low (0.01 microgram/kg) and high (1.0 microgram/kg) daily doses of TCDD. Since the tumorigenicity of TCDD in rats is believed to be correlated with the biological responses of the Ah-TCDD complex, the present physiological pharmacokinetic description, which contains information on receptor occupancy at various dose levels, provides a plausible mechanistic connection for devising pharmacodynamic models which predict the cancer risk of TCDD in the rat.

Application of Pharmacokinetics to Derive Biological Exposure Indexes from Threshold Limit Values

The importance of incorporating the fundamental concepts of pharmacokinetics into biological monitoring program that involve the collection of various body fluid and tissue specimens is discussed. The application of these principles to establish biological exposures indexes bioequivalent to airborne exposure limits is described. Specific illustrative examples involving acetone, aniline, benzene, carbon tetrachloride, dieldrin, ethylbenzene, hexane, lead, methylene chloride, pentachlorophenol, phenol, styrene, toluene and xylene are presented.

Use of physiologically based pharmacokinetic models to establish biological exposure indexes

This paper presents a simulation modeling approach to establish biological exposure indexes (BEIs) from ambient occupational exposure limits (OELs). A physiologically based pharmacokinetic (PB-PK) model was used to describe the disposition of volatile organic chemicals in the human. The model was used to simulate an exposure regimen similar to a typical work schedule. Exposure concentrations were set to equal the ambient OELs of the corresponding chemicals. Chemical concentrations in the expired air and blood and concentrations of metabolites in the urine were estimated with the PB-PK model for this exposure condition. Because the OELs establish the criteria for ambient exposure to chemicals, the concentrations of chemicals or their metabolites in biological media resulting from exposure to the OELs would likewise define acceptable exposure standards. On the basis of this rationale and method, BEIs were developed for 13 common industrial organic chemicals.

Techniques for Estimating the Percutaneous Absorption of Chemicals Due to Occupational and Environmental Exposure

Abstract This article reviews the scientific principles involved in determining the percutaneous absorption of chemicals. To assist industrial hygienists in assessing the risks of dermal uptake of chemicals in workplaces, lists of absorption rates and example calculations including the use of wipe sampling to estimate skin exposure are presented. Recent advances in the use of mathematical models to examine the various factors influencing the percutaneous absorption of chemicals from matrices are discussed. Results from various models suggest that the skin uptake of nonvolatile, highly lipophilic chemicals in soil will range from about 30 percent to 50 percent, while the uptake of volatile chemicals will usually be less than 5 percent. The available published information suggests the following rules of thumb: (1) the bioavailability of chemicals in media vary widely; consequently, it is important to account for matrix effects; (2) proper wipe sampling should be conducted to estimate the degree of skin cont...

Elimination half-lives of selected polychlorinated dibenzodioxins and dibenzofurans in breast-fed human infants.

Elimination half-life estimates for several polychlorinated dibenzodioxins/furans (PCDD/F) were calculated by modeling the blood and breast milk concentrations in two breast-fed human infants as reported by Abraham et al. (1996, 1998). Our analysis differs from that of other investigators in that we analyzed individual dioxin and furan congeners while the other studies considered TCDD only and we determined the half-lives in infants, rather than simply predicting body burdens in infants and older children. The average half-life values for each consistently measurable congener were determined to be less than about 6 mo and did not vary substantially between the two infants studied. The average elimination half-life values for 2,3,7,8-tetraCDD, 1,2,3,7,8-pentaCDD, 1,2,3,6,7,8-hexaCDD, 1,2,3,4,6,7,8-heptaCDD, and octaCDD were 0.40, 0.32, 0.39, 0.32, and 0.46 yr, respectively, and 0.27 yr for 2,3,4,7,8-pentaCDF. These values are in stark contrast with the 7 to 15+ yr values reported for these congeners in human adults (Michalek et al., 1996). These much shorter half-life values, likely attributable to rapid growth of the adipose tissue volume and enhanced fecal excretion of dioxins for breast-fed infants, explain why the much higher daily dioxin intake during breastfeeding does not translate to proportionately higher tissue concentrations. Thus, the shorter half-life of dioxins during breastfeeding needs to be considered when evaluating the dioxin hazard to children. Funding to conduct the research and compensation for the time needed to write a portion of this article were provided by Dow Chemical Company. It has supported research to better understand the toxicology of the dioxins and furans for more than three decades and has been involved in litigation associated with these chemicals for a number of years.

Physiologically based pharmacokinetic and pharmacodynamic modeling in health risk assessment and characterization of hazardous substances

Recent advances in physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) modeling have introduced novel approaches for evaluating toxicological problems. Because PBPK models are amenable to extrapolation of tissue dosimetry, they are increasingly being applied to chemical risk assessment. A comprehensive listing of PBPK/PD models for environmental chemicals developed to date is referenced. Salient applications of PBPK/PD modeling to health risk assessments and characterization of hazardous substances are illustrated with examples.

Concentration and age-dependent elimination kinetics of polychlorinated dibenzofurans in Yucheng and Yusho patients:

Half-life estimates of three polychlorodibenzofurans (PCDFs) were calculated using serial blood samples collected over a 15 to 19-year period. Blood fat PCDFs were modeled in eight individuals who were exposed to contaminated rice oil in Japan (Yusho, n = 5) and in Taiwan (Yucheng, n = 3). The elimination kinetics of PCDFs were concentration-dependent, with faster rates observed at higher concentrations and the apparent transition to slower rates occurring at about 1–3 ppb. Average half-lives of 1.1, 2.3, and 1.5 years above the transition concentration and 7.2, 5.7, and 3.5 years below it were estimated for 2,3,4,7,8-pentaCDF, 1,2,3,4,7,8-hexaCDF, and 1,2,3,4,6,7,8-heptaCDF, respectively. A positive linear correlation of half-life with age was observed for the combined group, with a rate of increase of 0.19, 0.12, and 0.05-year half-life per year of increase in age for penta-, hexa-, and hepta-CDF, respectively. The distinctly younger Yucheng patients exhibited far lower variability in half-lives and age-related trends that were quite consistent with the corresponding data on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for younger persons exposed in the Seveso incident. These age- and concentration-dependent half-lives for PCDFs may have important risk assessment implications for estimating body burdens. The current study provides limited additional evidence that PCDFs, like TCDD, are more rapidly eliminated in younger individuals.

A Proposed Occupational Exposure Limit for 2,3,7,8-Tetrachlorodibenzo-p-dioxin

One contaminant produced unintentionally during the manufacture of chlorophenols and phenoxy herbicides is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The resulting TCDD-containing wastes have been detected at many hazardous waste sites which in recent years have been in the process of remediation. Concerns about worker exposure to TCDD-contaminated soil (dust) during remediation of hazardous waste sites have produced a need for an occupational exposure limit (OEL) for TCDD. The animal toxicology data and human experience with TCDD are reviewed, and an occupational exposure limit for TCDD is proposed. The animal data support risk estimations which are based on TCDD as a nongenotoxic carcinogen. Studies on human populations have failed to demonstrate clearly any significant long-term health effects at levels to which humans have been exposed. The data indicate that an 8-hr time-weighted average limit of 2 ng/m3 is appropriate, and the associated risk would be consistent with other carcinogens at their corresponding OELs. A preliminary OEL of 0.2 ng/m3 (200 pg/m3) is recommended, however, in light of other sources of exposure because of TCDDs ubiquitousness in the environment, its unclear mechanism of action, and its rather long biological half-life in humans. This limit provides an ample margin of safety to prevent chloracne following repeated, acute exposure, and it addresses those chronic effects of TCDD observed in animal studies as well as those observed after accidental human exposure. The resulting body burden caused by chronic exposure to TCDD at the proposed OEL is examined. Its toxicological significance is compared with human tissue data and with other similarly persistent chemicals.(ABSTRACT TRUNCATED AT 250 WORDS)

An Adaptable Internal Dose Model for Risk Assessment of Dietary and Soil Dioxin Exposures in Young Children

An adaptable model is presented for assessing the blood lipid concentrations of polychlorodibenzodioxins and polychlorodibenzofurans (PCDD/Fs) from dietary (breast milk, formula, milk, and other foods) and soil pathway exposures (soil ingestion and dermal contact) utilizing age-specific exposure and intake estimates for young children. The approach includes a simple one-compartment (adipose volume) toxicokinetic model that incorporates empirical data on age-dependent half-lives and bioavailability of PCDD/F congeners, child body size and intake rates, and recent data on breast milk and food dioxin levels. Users can enter site-specific soil concentration data on 2,3,7,8-chlorinated PCDD/F congeners for specific assessment of body burden changes from soil pathways in combination with background dietary exposures from birth through age 7 years. The model produces a profile of the estimated PCDD/F concentration in blood lipid (in World Health Organization 1998 dioxin toxic equivalents) versus time for a child from birth through age 7 years. The peak and time-weighted average (TWA) internal dose (defined as blood lipid dioxin toxic equivalents) for a variety of specific child exposure assumptions can then be compared to safe internal dose benchmarks for risk assessment purposes, similar to an approach taken by United States Environmental Protection Agency for assessing child lead exposures. We conclude that this adaptable toxicokinetic model can provide a more comprehensive assessment of potential health risks of PCDD/Fs to children because it integrates recent empirical findings on PCDD/F kinetics in humans and allows users to assess contributions from varied dietary and site-specific environmental exposure assumptions.