Ivan D. Dobrev

Evaluation of potential toxicity from co-exposure to three CNS depressants (toluene, ethylbenzene, and xylene) under resting and working conditions using PBPK modeling.

Under OSHA and American Conference of Governmental Industrial Hygienists (ACGIH®) guidelines, the mixture formula (unity calculation) provides a method for evaluating exposures to mixtures of chemicals that cause similar toxicities. According to the formula, if exposures are reduced in proportion to the number of chemicals and their respective exposure limits, the overall exposure is acceptable. This approach assumes that responses are additive, which is not the case when pharmacokinetic interactions occur. To determine the validity of the additivity assumption, we performed unity calculations for a variety of exposures to toluene, ethylbenzene, and/or xylene using the concentration of each chemical in blood in the calculation instead of the inhaled concentration. The blood concentrations were predicted using a validated physiologically based pharmacokinetic (PBPK) model to allow exploration of a variety of exposure scenarios. In addition, the Occupational Safety and Health Administration and ACGIH® occupational exposure limits were largely based on studies of humans or animals that were resting during exposure. The PBPK model was also used to determine the increased concentration of chemicals in the blood when employees were exercising or performing manual work. At rest, a modest overexposure occurs due to pharmacokinetic interactions when exposure is equal to levels where a unity calculation is 1.0 based on threshold limit values (TLVs®). Under work load, however, internal exposure was 87% higher than provided by the TLVs. When exposures were controlled by a unity calculation based on permissible exposure limits (PELs), internal exposure was 2.9 and 4.6 times the exposures at the TLVs at rest and workload, respectively. If exposure was equal to PELs outright, internal exposure was 12.5 and 16 times the exposure at the TLVs at rest and workload, respectively. These analyses indicate the importance of (1) selecting appropriate exposure limits, (2) performing unity calculations, and (3) considering the effect of work load on internal doses, and they illustrate the utility of PBPK modeling in occupational health risk assessment.

Inhalation Dosimetry Modeling with Decamethylcyclopentasiloxane in Rats and Humans

Decamethylcyclopentasiloxane (D(5)), a volatile cyclic methyl siloxane (VCMS), is used in industrial and consumer products. Inhalation pharmacokinetics of another VCMS, octamethylcyclotetrasiloxane (D(4)), have been extensively investigated and successfully modeled with a multispecies physiologically based pharmacokinetic (PBPK) model. Here, we develop an inhalation PBPK description for D(5), using the D(4) model structure as a starting point, with the objective of understanding factors that regulate free blood and tissue concentrations of this highly lipophilic vapor after inhalation in rats and humans. Compared with D(4), the more lipophilic D(5) required deep compartments in lung, liver, and plasma to account for slow release from tissues after cessation of exposures. Simulations of the kinetics of a stable D(5) metabolite, HO-D(5), required diffusion-limited uptake in fat, a deep tissue store in lung, and its elimination by fecal excretion and metabolism to linear silanols. The combined D(5)/HO-D(5) model described blood and tissue concentrations of parent D(5) and elimination of total radioactivity in single and repeat exposures in male and female rats at 7 and 160 ppm. In humans, D(5) kinetic data are more sparse and the model structure though much simplified, still required free and bound blood D(5) to simulate exhaled air and blood time courses from 1 h inhalation exposures at 10 ppm in five human volunteers. This multispecies PBPK model for D(5) highlights complications in interpreting kinetic studies where chemical in blood and tissues represents various pools with only a portion free. The ability to simulate free concentrations is essential for dosimetry based risk assessments for these VCMS.

PBPK modeling of complex hydrocarbon mixtures: gasoline.

Petroleum hydrocarbon mixtures such as gasoline, diesel fuel, aviation fuel, and asphalt liquids typically contain hundreds of compounds. These compounds include aliphatic and aromatic hydrocarbons within a specific molecular weight range and sometimes lesser amounts of additives, and often exhibit qualitatively similar pharmacokinetic (PK) and pharmacodynamic properties. However, there are some components that exhibit specific biological effects, such as methyl t-butyl ether and benzene in gasoline. One of the potential pharmacokinetic interactions of many components in such mixtures is inhibition of the metabolism of other components. Due to the complexity of the mixtures, a quantitative description of the pharmacokinetics of each component, particularly in the context of differing blends of these mixtures, has not been available. We describe here a physiologically-based pharmacokinetic (PBPK) modeling approach to describe the PKs of whole gasoline. The approach simplifies the problem by isolating specific components for which a description is desired and treating the remaining components as a single lumped chemical. In this manner, the effect of the non-isolated components (i.e. inhibition) can be taken into account. The gasoline model was based on PK data for the single chemicals, for simple mixtures of the isolated chemicals, and for the isolated and lumped chemicals during gas uptake PK experiments in rats exposed to whole gasoline. While some sacrifice in model accuracy must be made when a chemical lumping approach is used, our lumped PK model still permitted a good representation of the PKs of five isolated chemicals (n-hexane, benzene, toluene, ethylbenzene, and o-xylene) during exposure to various levels of two different blends of gasoline. The approach may be applicable to other hydrocarbon mixtures when appropriate PK data are available for model development.

Closed-Chamber Inhalation Pharmacokinetic Studies with Hexamethyldisiloxane in the Rat

Gas uptake methods together with physiologically based pharmacokinetic (PBPK) modeling have been used to assess metabolic parameters and oral absorption rates for a wide variety of volatile organic compounds. We applied these techniques to study the in vivo metabolism of hexamethyldisiloxane (HMDS), a volatile siloxane with low blood/air (partition coefficient PB ≈ 1.00) and high fat/blood partitioning (partition coefficient PF ≈ 300). In contrast to other classes of metabolized volatiles, metabolic parameters could only be estimated from closed-chamber results with confidence by evaluating both closed-chamber disappearance curves and constant concentration inhalation studies. The constant-concentration inhalation results refine the estimate of the blood/air partition coefficient and constrain model structure for storage of the lipophilic compound in blood and tissues. The gas uptake results, from Fischer 344 rats (male, 8-9 wk old) exposed to initial HMDS air concentrations from 500 to 5000 ppm, were modeled with a 5-tissue PBPK model. Excellent fits were obtained with diffusion-limited uptake of HMDS in fat and a lipid storage pool in the blood. Metabolism, restricted to the liver, was described as a single saturable process (V max = 113.6 µmol/h/kg; K m = 42.6 µmol/L) and was affected by inhibitors (diethyldithiocarbamate) or inducers (phenobarbital) of cytochrome P-450s. Exhalation kinetics of HMDS after oral/intraperitoneal administration showed low bioavailability and significant lag times, also quite different from results of other classes of volatile hydrocarbons. In general, estimates of metabolic clearance by gas uptake studies were improved by simultaneous examination of time-course results from constant concentration inhalation studies. This conclusion is likely to hold for any volatile lipophilic compound with low blood/air partitioning.

Assessing Kinetic Determinants for Metabolism and Oral Uptake of Octamethylcyclotetrasiloxane (D4) from Inhalation Chamber Studies

The pharmacokinetics of octamethylcyclotetrasiloxane (D4), a highly lipophilic and well-metabolized volatile cyclic siloxane, are more complex than those of other volatile hydrocarbons. The purpose of the present study was to evaluate rate constants for saturable metabolism in the body, to estimate possible presystemic D4 clearance by respiratory-tract tissues, and to assess rate constants for uptake of D4 after oral dosing. These experiments provided the opportunity to refine current physiologically based pharmacokinetic (PBPK) models for D4 and to independently estimate key model parameters by sensitive inhalation methods. The PBPK model could only be fitted to gas uptake results when metabolic capacity was included in the respiratory-tract epithelium. The model simulations were highly sensitive to the parameter for total percent of whole-body metabolism allocated to the respiratory tract, with optimal fits observed with this value equal to 5%. Oral uptake of D4 was evaluated using both closed and open chamber concentration time-course studies after intubation of D4 in corn oil. Conclusions from the oral uptake studies were also verified by comparison with independent data sets for blood concentrations of D4 after oral dosing. The pharmacokinetic (PK) analysis of uptake from the gut and release from blood into chamber air results for oral doses from 10 to 300 mg D4/kg body weight were consistent with a combination of prolonged and slow uptake of D4 from the gastrointestinal tract and of reduced absorption at higher doses, as well as the extrahepatic clearance of D4 in pulmonary tissues. These closed chamber gas uptake studies provide a valuable confirmation of the conclusions reached in other pharmacokinetic studies and have uncovered a situation where closed chamber loss is highly sensitive to respiratory-tract clearance. This sensitivity largely arises from the unusual characteristics of D4: high-affinity metabolic clearance and low blood:air partitioning.