Gregory J. Lien

Physiologically based toxicokinetic modeling of three waterborne chloroethanes in rainbow trout (Oncorhynchus mykiss)

A physiologically based toxicokinetic model for fish was used to simulate the uptake and disposition of three waterborne chloroethanes in rainbow trout (Oncorhynchus mykiss). Trout were exposed to 1,1,2,2-tetrachloroethane, pentachloroethane, and hexachloroethane in fish respirometer-metabolism chambers to assess the kinetics of chemical accumulation in arterial blood and chemical extraction efficiency from inspired water. Chemical residues in tissues were measured at the end of each experiment. Trout exposed to tetrachloroethane were close to steady-state in 48 hr. Fish exposed to pentachloroethane were near steady-state in 264 hr. Extraction efficiency data showed that systemic (extrabranchial) elimination of both chemicals was small. Hexachloroethane continued to accumulate in fish exposed for 600 hr. Parameterized with chemical partitioning data obtained in vitro, the model accurately simulated the uptake of all three chloroethanes in blood and tissues and their extraction from inspired water. These results provide support for the basic model structure and the accuracy of physiological input parameters.

Uptake and elimination of ionizable organic chemicals at fish gills: II. Observed and predicted effects of pH, alkalinity, and chemical properties

Effects of exposure-water pH on chemical uptake at rainbow trout (Oncorhynchus mykiss) gills were investigated for nine weakly acidic, chlorinated phenols with different ionization constants and hydrophobicities and for a moderately hydrophobic, nonionizable reference chemical (1,2,4-trichlorobenzene). Uptake rates for all chemicals varied little from pH 6.3 to 8.4, despite ionization of the chlorinated phenols ranging from less than 1 to greater than 99.9% among these pH values and chemicals. At pH 9.2, uptake rates were reduced substantially for the chlorinated phenols but not for the reference chemical. These results indicate greater bioavailability of neutral chemical forms but also considerable bioavailability of ionized forms that varies with pH. Three mechanisms were evaluated regarding such ionized chemical bioavailability. First, reduced pH at the gill surface causes net conversion of ionized molecules to more readily absorbed neutral molecules. This mechanism was tested by increasing exposure-water alkalinity, which increased gill surface pH and reduced uptake of the chlorinated phenols but not of the reference chemical. Magnitudes of these effects were close to predictions from a mathematical model for chemical exchange at fish gills that incorporated this mechanism. Second, ionized molecules contribute to uptake by maintaining high gradients of neutral molecules across epithelial membrane barriers, even if the barriers are impermeable to these ions. This mechanism was demonstrated to explain the similarity of uptake among pH values and chemicals at pH less than 8.4 and the degree to which uptake declined at pH 9.2. Third, membrane barriers can have some permeability to the ionized forms, but this was not important for the chemicals and conditions of the present study. Increased exposure-water pH also was demonstrated to increase elimination rates of these chemicals, which also was in accord with model expectations.

Uptake and elimination of ionizable organic chemicals at fish gills I. Model formulation, parameterization, and behavior

A mechanistic model for the uptake and elimination of ionizable organic chemicals at fish gills is presented. This model is a modification of a previous model for nonionizable organic chemicals that addressed the transport of chemical to and from gill surfaces in water and blood, diffusion of chemical across epithelial cells, and binding of chemical to components in water and blood. For ionizable chemicals, three additional processes are included. First, excretory products alter the pH at gill surfaces, affecting the relative amounts of neutral and ionized molecules compared with that in the bulk exposure water. Second, ionized molecules support chemical flux to and from epithelial cell membranes and help maintain high diffusion gradients of neutral molecules across these membranes, thereby contributing to uptake and elimination even if the membranes are impermeable to ionized molecules. Third, membrane barriers are not completely impermeable to ionized molecules, and even limited permeability can have appreciable effects on chemical flux. Approaches for model parameterization are discussed. Model-predicted relationships of uptake and elimination rates to exposure water pH, alkalinity, and chemical properties are presented and discussed in terms of model processes. The model is shown to predict important features of reported effects of pH on uptake rates of weak organic acids.

Predicting branchial and cutaneous uptake of 2,2′,5,5′-tetrachlorobiphenyl in fathead minnows (Pimephales promelas) and Japanese medaka (Oryzias latipes): Rate limiting factors

A physiologically based model was used to predict the bioconcentration of a waterborne, neutral, nonmetabolized xenobiotic compound in fathead minnows (Pimephales promelas) and Japanese medaka (Oryzias latipes). This study included a quantitative assessment of the primary mechanistic variables regulating uptake across branchial and cutaneous surfaces in these small fish. Model simulations suggest that branchial and cutaneous surfaces have approx. equal capacity to support exchange of 2,2′,5,5′-tetrachlorobiphenyl (TCB). A large cutaneous surface-area-to-volume ratio and a relatively small diffusion distance across the skin in these fish both contribute to the relatively greater contribution of cutaneous absorption as compared to larger fish. The accuracy of model simulations was evaluated by comparison of predicted and observed bioconcentration of TCB in fathead minnows and Japanese medaka. The complete model, incorporating simultaneous branchial and cutaneous flux, predicts absorption of TCB that is in basic agreement with bioconcentration observed in this study. This suggests that the absorption of neutral waterborne xenobiotics by small fish (< 4 g) can be accurately described in terms of a few fundamental physiological, morphological and physico-chemical parameters and that a physiologically based modeling approach can be used effectively to predict the bioconcentration of xenobiotics in small fish.

Physiologically-based toxicokinetic modeling of three waterborne chloroethanes in channel catfish, Ictalurus punctatus

A physiologically-based toxicokinetic model for fish was used to describe the uptake and disposition of three chlorinated ethanes in channel catfish (Ictalurus punctatus). Catfish were simultaneously exposed to 1,1,2,2-tetrachloroethane (TCE), pentachloroethane (PCE), and hexachloroethane (HCE) in fish respirometer-metabolism chambers to assess the kinetics of chemical accumulation in arterial blood and chemical extraction efficiency from inspired water. Chemical residues in tissues were measured at the end of each experiment. These data were used to evaluate the accuracy of model simulations and to form a basis for comparison with information collected previously from rainbow trout. TCE was at or near steady-state in catfish after 48 h. For PCE and HCE the time to steady-state appeared to be considerably longer than 48 h. Parameterized with in vitro chemical partitioning information, the model accurately simulated the accumulation of TCE in arterial blood and its uptake from inspired water, but consistently underestimated the uptake and accumulation of both PCE and HCE. The cause of these discrepancies was not conclusively determined; however, several possible sources of error were evaluated, including physiological and chemical partitioning inputs, and underlying modeling assumptions. A comparison of data sets and modeling efforts for rainbow trout and channel catfish suggests that gross similarities between the two species can be attributed to the comparability of relevant physiological and chemical partitioning parameters.

A Physiologically Based Toxicokinetic Model for Dermal Absorption of Organic Chemicals by Fish

A physiologically based toxicokinetic model was developed to describe dermal absorption of waterborne organic chemicals by fish. The skin was modeled as a discrete compartment into which compounds diffuse as a function of chemical permeability and the concentration gradient. The model includes a countercurrent description of chemical flux at fish gills and was used to simulate dermal-only exposures, during which the gills act as a route of elimination. The model was evaluated by exposing adult rainbow trout and channel catfish to hexachloroethane (HCE), pentachloroethane (PCE), and 1,1,2,2-tetrachloroethane (TCE). Skin permeability coefficients were obtained by fitting model simulations to measured arterial blood data. Permeability coefficients increased with the number of chlorine substituent groups, but not in the manner expected from a directly proportional relationship between dermal permeability and skin:water chemical partitioning. An evaluation of rate limitations on dermal flux in both trout and catfish suggested that chemical absorption was limited more by diffusion across the skin than by blood flow to the skin. Modeling results from a hypothetical combined dermal and branchial exposure indicate that dermal uptake could contribute from 1.6% (TCE) to 3.5% (HCE) of initial uptake in trout. Dermal uptake rates in catfish are even higher than those in trout and could contribute from 7.1% (TCE) to 8.3% (PCE) of initial uptake in a combined exposure.

A physiologically based toxicokinetic model for lake trout (Salvelinus namaycush).

A physiologically based toxicokinetic (PB-TK) model for fish, incorporating chemical exchange at the gill and accumulation in five tissue compartments, was parameterized and evaluated for lake trout (Salvelinus namaycush). Individual-based model parameterization was used to examine the effect of natural variability in physiological, morphological, and physico-chemical parameters on model predictions. The PB-TK model was used to predict uptake of organic chemicals across the gill and accumulation in blood and tissues in lake trout. To evaluate the accuracy of the model, a total of 13 adult lake trout were exposed to waterborne 1,1,2,2-tetrachloroethane (TCE), pentachloroethane (PCE), and hexachloroethane (HCE), concurrently, for periods of 6, 12, 24 or 48 h. The measured and predicted concentrations of TCE, PCE and HCE in expired water, dorsal aortic blood and tissues were generally within a factor of two, and in most instances much closer. Variability noted in model predictions, based on the individual-based model parameterization used in this study, reproduced variability observed in measured concentrations. The inference is made that parameters influencing variability in measured blood and tissue concentrations of xenobiotics are included and accurately represented in the model. This model contributes to a better understanding of the fundamental processes that regulate the uptake and disposition of xenobiotic chemicals in the lake trout. This information is crucial to developing a better understanding of the dynamic relationships between contaminant exposure and hazard to the lake trout.

Effects of Diet on Growth and Survival of Larval Walleyes

Abstract The effects of diet quality on larval walleye (Stizostedion vitreum vitreum) growth and survival are described. The cyclopoid copepod Diacyclops thomasi consumed larval walleyes within 10 min at dense copepod concentrations and within 1 d at lower densities (500 organisms/L). At initial feeding, larval walleyes consumed both copepods and cladocerans 500-1,100 μm total length. Postlarva-II walleyes fed four different diets (minnow larvae, brine shrimp, and two size grades of zooplankton) for 6 d averaged 4.00 mg, 3.48 mg, 2.23 mg, and 1.92 mg (dry weight), respectively. No appreciable differences in survival (70-85%) were observed on these diets. During the first 3 weeks of life, the survival of walleye larvae at optimal conditions of diet, temperature, light, space, and density was 71% (range, 52-87%). The combined influence of higher water temperatures and smaller food organisms stimulated initial feeding 3 d sooner than previously reported for larval walleyes. Sufficient food and higher tempera...

Dermal Absorption of Three Waterborne Chloroethanes in Rainbow Trout (Oncorhynchus mykiss) and Channel Catfish (Ictalurus punctatus)

In vivo estimates of xenobiotic chemical flux across the dermal surface of intact fish were obtained by measuring chemical loss from venous blood to expired water. An experimental system was developed to separate the dermal route of exposure from all other routes. The system was then used to measure dermal absorption of tetrachloroethane (TCE), pentachloroethane (PCE), and hexachloroethane (HCE) in channel catfish (Ictalurus punctatus) and rainbow trout (Oncorhynchus mykiss), two fish with very different skin anatomies. The kinetics of accumulation varied among chemicals, but for each compound were similar among species. TCE accumulated rapidly, reaching steady state in blood within 48 hr. Steady state was not reached in 48 hr with PCE or HCE, although blood levels of PCE were probably close to steady-state values. Dermal flux estimates (based on branchial efflux) for TCE, PCE, and HCE were two to four times greater in catfish than in trout. Arterial blood concentrations of each compound were three to six times greater in catfish. These observations are indicative of greater flux across catfish skin, augmented by higher blood:water chemical partitioning. Trout skin is covered with scales and has no taste buds, while catfish skin does not possess scales and has numerous taste bud papillae. Both scales and taste bud papillae originate in the dermis and extend to the skin surface through the epidermis. In catfish these taste buds may offer channels through which chemicals diffuse across the epidermis to the more vascularized dermis. A comparison of dermal and branchial uptake was made by estimating zero-time dermal and branchial fluxes for all three chloroethanes. The mean dermal fluxes for TCE, PCE, and HCE ranged from 1.4 to 2.8, 1.8 to 3.6, and 1.4 to 3.2% of the total flux (branchial plus dermal) in rainbow trout and channel catfish, respectively. This research demonstrates that dermal absorption of waterborne chemicals occurs in large adult fish and results in distribution kinetics similar to those observed in inhalation exposures. Compared to branchial uptake, the dermal route of exposure appears to be relatively unimportant in large fish. It may, however, be very important in smaller fish and for juveniles of larger species.

Individual tissue weight to total body weight relationships and total, polar, and nonpolar lipids in tissues of hatchery Lake trout

Abstract Individual tissue or organ weight to total body weight relationships, total lipid, and major lipid subclasses were measured in 3- and 4-year-old hatchery-reared Lake Superior Isle Royale strain “lean” lake trout Salvelinus namaycush to obtain a more in-depth understanding of the major lipid compartments of lake trout for use in predicting the distribution and disposition of xenobiotics in these fish. No significant (P > 0.05) differences between males and females were observed in individual tissue or organ weight to total body weight relationships. The weight of internal organs and tissues made up approximately 11% of body weight, while the remaining carcass accounted for 85%. Muscle accounted for slightly more than half of the carcass weight. Dorsal and ventral muscle were approximately equal in proportions. Mean (±SD) calculated whole-body total lipid for the lake trout was 15.2% (±2.2%). No significant (P > 0.05) differences between males and females were observed in total lipid content or in ...