Drinking Water and Health, Volume 6 (1986) / Chapter Skim
Currently Skimming:
6. Dose-Route Extrapolations: Using Inhalation Toxicity Data to Set Drinking Water Limits
6. Dose-Route Extrapolations: Using Inhalation Toxicity Data to Set Drinking Water Limits
Pages 168-225
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 168... ...
Drinking water standards have been established to protect people from potentially adverse health effects associated with ingestion of contaminated waters. Such effects must often be determined by conducting toxicity studies in laboratory animals and in some way extrapolating these results to predict toxic effects in exposed humans.
|
From page 169... ...
Uptake can be modeled as arising from a blood perfusion rate into a given tissue volume, in which case the human rate constant would be: k ka (bw2) limited (i.e., their wafer: air partition coefficients are small)
|
From page 170... ...
Inhalation studies, in which a chemical is absorbed at a fairly uniform rate over a specified exposure period, are not very different from drinking water studies, in which a chemical is absorbed at a variable, moderate rate throughout a day. Well-designed, properly conducted inhalation toxicity studies may, in fact, provide an excellent experimental model for deriving drinking water standards for a variety of volatile chemicals.
|
From page 171... ...
VOCs are small, uncharged, lipophilic molecules that are quickly absorbed from the alveolus into the systemic circulation (Astrand, 19751. Although the uptake of inhaled volatile organics varies with the exposure concentration and the chemical, in humans it typically ranges from 25% to 75% (Astrand, 19751.
|
From page 172... ...
, no one has yet directly measured first-pass hepatic elimination of orally administered volatile organics. Nevertheless, there is no reason why the liver should not metabolize ingested VOCs as efficiently as it does those that are inhaled (i.e., the liver removes virtually all the VOC presented to it by the blood when inhaled concentrations are not high enough to saturate metabolism)
|
From page 173... ...
, might be the area under the blood or tissue concentration-time curve, the peak tissue concentration, the total amount metabolized, the area under a tissue metabolite concentration curve, or some other appropriate measure of targettissue exposure. The proper measure of target-tissue dose must be selected carefully.
|
From page 174... ...
3891. For chemicals with pharmacological activity, the proper measure of target-tissue dose would be the tissue concentration divided by some measure of the receptor binding constant for the toxic chemical.
|
From page 175... ...
When the reactive toxic chemical is short-lived, the appropriate measure of tissue dose is the ratio of the amount of toxicant produced divided by the volume of tissue in which the reaction takes place (Vr)
|
From page 176... ...
PHARMACOKINETIC MODELS An attractive and potentially economical approach to risk-assessment extrapolations is the development of predictive physiologically based pharmacokinetic (PB-PK) models for the disposition of volatile organic compounds and their metabolites in biological systems.
|
From page 177... ...
. Interspecies extrapolations are conducted by deterring the drinking water concentration that would lead to the same target-tissue dose in humans achieved at the no-effect (Figure 6-1)
|
From page 178... ...
In Step 1 of Figure 6-1, the target-tissue dose is estimated in a test species based on the no-effect inhalation exposure concentration. Step 2 determines the drinking water concentration associated with an equivalent target-tissue dose in the test species.
|
From page 179... ...
dAmt2 = V24C2 = k~2v~c~ —k2~V2C2 (13) In these mass-balance equations, kit and kin are intercompartmental transfer rate constants, Vat and V2 are volumes of the two compartments, ko is a zero-order input rate, and k~c is a first-order elimination rate constant.
|
From page 180... ...
Because an accurate anatomical description is used along with measured tissue solubilities, the intercompartmental rate constants are now defined by blood flows, tissue partition coefficients, and tissue volumes. A model derived from this approach can predict the qualitative behavior of the experimental time course without being based directly on the time-course data themselves.
|
From page 181... ...
. FIGURE 6-3 Schematic diagram of a physiologically based pharmacokinetic model for VOC inhalation, used to describe styrene kinetics.
|
From page 182... ...
or on gas uptake experiments (Andersen et al., 1980; Filser and Bolt, 1979; Gargas et al., 19861. These experimentally accessible constants for tissue solubility and VOC metabolism, together with the general physiological parameters, provide a model of parent chemical behavior and rate of metabolism that can predict parent chemical kinetic behavior at various concentrations, for various dose routes, in a variety of species, and with any number of exposure scenarios.
|
From page 183... ...
For example, in the physiological models for pulmonary uptake, end alveolar air and arterial blood are assumed to be in equilibrium and arterial blood concentrations are equal to the end alveolar air concentrations times the blood:air partition coefficient (Pb)
|
From page 184... ...
When the published curves for the first four chemicals were analyzed with the styrene model, the best-fit uptake rate constant was found to be about 7/fur (Gargas and Andersen, Air Force Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Ohio, personal communication, 19851. To describe drinking water exposures accurately, the temporal patterns of water ingestion in the test species must be approximated by the input equations.
|
From page 185... ...
= 76 |
From page 186... ...
In the model developed here for drinking water consumption, a small dose of chemical appears in the stomach at equally spaced intervals. The chemical is completely absorbed into the liver compartment with a first-order absorption rate constant of S/hr.
|
From page 187... ...
Regardless of whether the effect investigated is chronic toxicity or carcinogenicity, risk assessment should still be based on the amount of toxic chemical at the appropriate target tissue. The development of PB-PK models for trichloroethylene and benzene requires knowledge of their partition coefficients.
|
From page 188... ...
1 ,000 FIGURE 6-6 Dose-route extrapolation for inhalation and drinking water exposures of rats to trichloroethylene. AMEFF is the effective concentration of reactive metabolite formed in a compartment of specified volume.
|
From page 189... ...
. The model was applied at a variety of drinking water concentrations to estimate targettissue dose for the reactive trichloroethylene metabolite.
|
From page 190... ...
. The benzene drinking water model predicted equivalent no-effect target-tissue doses for drinking water concentrations of 109, 111, 118, and 183 mg/liter for the sipping, 1-hour, and 2-hour episodic scenarios and for the bolus dosing regimen of water consumption, respectively (Figure 6-7B)
|
From page 191... ...
AUTMC is area under the target-tissue metabolite-concentration curve. The numbers at the ends of the drinking water curves indicate the number of equal doses given to the test animals.
|
From page 192... ...
= 2.87 500 1 / 311 ~ mg/liter ~ ~C=~-—~ 1 1 1 1 1 0 ~ 500 1,000 DRINKING WATER CONCENTRATION (mg/liter) FIGURE 6-8 Dose-route extrapolation for inhalation and drinking water exposures of rats to benzene, based on area under the blood benzene concentration curve.
|
From page 193... ...
The cornerstone of a scientific approach to interspecies extrapolation of physiological pharmacokinetic behavior is the predictable relationship observed between the values of various physiological parameters and species body weight. The allometric relationship for water intake from Adolph (1949)
|
From page 194... ...
Tissue Dose Scale-Up The basis for choosing an appropriate tissue dose scale-up strategy is the kinetic behavior of the particular chemical and its mechanisms of toxicity. In this first example, the chemical has a well-defined volume of distribution; it is eliminated by processes dependent on organ perfusion in the liver, kidney, or lung, and its toxicity is related to the area under its blood or tissue concentration curves.
|
From page 195... ...
Rate constants for the approach to a steady state will decrease with increasing body weight, but the area under the blood concentration-time curve during inhalation of an equivalent VOC concentration will be nearly independent of the body weight of the species. An examination of drinking water ingestion can also be based on the water concentration required to give a particular integrated tissue dose of parent chemical.
|
From page 196... ...
Whether toxicity is correlated with integrated tissue dose of a parent or a stable metabolite, equivalent water or inhaled concentrations are expected to produce similar tissue doses regardless of body weight. Even with a conservative approach to standard setting, therefore, no-effect concentrations in test animals should provide a good estimate for the expected no-effect concentrations in humans.
|
From page 197... ...
Even with the most successful descriptions of pharmacokinetic behavior in a test species, there is still some element of uncertainty and art involved in restructuring the model to describe kinetics in humans. Part of this uncertainty would quickly evaporate with conscientious efforts to validate some of the assumptions, such as the scaling of V,,~ and the body weight independence of Km, presently made when scaling up animal kinetic models to predict human kinetic behavior.
|
From page 198... ...
The no-effect or minimal-effect drinking water concentrations are determined as follows: the no-effect target-tissue dose from Figure 6-6A or Figure 6-8A is located on the y-axis, and a line parallel to the x-axis is drawn through this point. To estimate the human no-effect drinking water concentration associated with each pattern of water consumption, lines are dropped down perpendicular to the x-axis from the intersection points on the curves.
|
From page 199... ...
1 / 6 ,/ // 0 100 200 300 400 500 DRINKING WATER CONCENTRATION (mg/liter) FIGURE 6-9 Interspecies extrapolations for trichloroethylene and benzene, based on PB-PK estimates of equivalent target-tissue doses.
|
From page 200... ...
Given the extensive heterogeneity in the human population, it is vital to either evaluate or simulate the effect of altered metabolism or altered physiological states on kinetic behavior. Physiological models can be readily used for this, since metabolic constants and physiological parameters are explicitly defined for organs of elimination and for target tissues.
|
From page 201... ...
Implementation of this general approach could improve the scientific basis of risk assessment extrapolation procedures and could usefully focus toxicologists' attention on acquiring experimental data more relevant for quantitative physiological models that describe the kinetic behavior of important toxicants and their metabolites. PB-PK MODELS IN RISK ASSESSM ENT A commonly voiced concern about introducing pharmacokinetic considerations in general risk-assessment decision making is that it is too difficult to determine the time-course cubes necessary to model parent chemicals and to undertake the analytical studies needed to quantify and identify the metabolites of the test chemical.
|
From page 202... ...
To assess relative risks from an integrated tissue dose of this metabolite, the kinetic model would have to include TCA production and its elimination and predict liver concentrations of TCA at different times. A model then would be articulated to include major pathways for this metabolite (Figure 6-101.
|
From page 203... ...
This coordinated approach to data acquisition would facilitate ultimate interspecies extrapolation with the kinetic model, a process that should be a primary goal of any pharmacokinetic model intended for risk-assessment extrapolations. Similarly, a more extensive kinetic model for benzene might include biochemical constants for metabolism in marrow, identification of the stable toxic metabolite, and determination of its clearance mechanisms.
|
From page 204... ...
The toxicity of a reactive metabolite is partially determined by the ratio of the amount reacting with target sites divided by the total amount reacting by all pathways, i.e., the krliki term in Equation 9. The interspecies extrapolations assume that this distribution of reactive intermediate would be the same in humans as in rats.
|
From page 205... ...
Ciliated cells, basal cells, epithelial serous cells, and many other cells in the upper airways have little capacity for xenobiotic metabolism. Clara cells have considerable cytochrome P450 activity, because they have large amounts of smooth endoplasmic reticulum.
|
From page 206... ...
Thus, in addition to its function in gas exchange, the lung has varying regional capacities for the metabolism of xenobiotic compounds. Metabolic Properties of Lung Cells CLARA CELLS Clara cells are conciliated bronchiolar cells that increase in number as distance from the bronchioles increases.
|
From page 207... ...
The vascular endothelium is exposed to large quantities of xenobiotic compounds in the bloodstream, but there have been no reports that reactive intermediates have been formed at this site as the result of the metabolic processes. Ciliated bronchiolar cells bind 4ipomeanol to a much lower extent than do Clara cells, suggesting that their metabolic activity is rather low (Boyd, 19801.
|
From page 208... ...
, and at the concentrations generally used in humans, their elimination rate is controlled by the same factors that are important to uptake: pulmonary ventilation, blood flow, and solubility in blood and tissues (Cowles et al., 19681. The respiratory loss of xenobiotic compounds may be an important means of lowering toxicant concentrations in the blood.
|
From page 209... ...
This is not at all unexpected, however, and is nothing more than an expression of the differences in kinetic character of metabolic clearance and clearance by exhalation. The former is capacity-limited and displays zero-order kinetics at high blood concentrations, whereas the latter displays first-order kinetics at all concentrations.
|
From page 210... ...
, and the blood:air partition coefficients (Pb) of the test substances.
|
From page 211... ...
One important feature of this site, however, is that the venous blood supply drains from this top portion of the GI tract directly into the systemic venous system. That is, it does not enter the portal vein and hence does not first pass through the liver before reaching the general circulation.
|
From page 212... ...
Presystemic Elimination The amount of an orally ingested VOC that eventually reaches systemic target tissues depends largely on the physiochemical characteristics of the compound, which determine its rate of absorption across the membranes of stomach and small intestine, and on the extent to which it is degraded within the GI tract, the liver, and the lung on its way to the systemic arterial circulation. Elimination before reaching the systemic arterial circulation is referred to as presystemic elimination.
|
From page 213... ...
and probably contribute to metabolism of xenobiotic compounds in the lumen. Little attention has been paid to this source of lumen activity, however, and its quantitative importance is largely unknown.
|
From page 214... ...
At low doses or concentrations, first-pass clearance by the mucosal cells may be a major component of body clearance, comparatively small amounts of toxicant penetrating to the systemic arterial circulation. At higher doses or concentrations, however, nonlinear behavior is to be expected, and much greater proportions of the toxicant could reach the general circulation and, hence, target tissues.
|
From page 215... ...
Of particular importance, all these reactions require endogenous cosubstrates that, with the exception of water required for epoxide hydrolase activity, are capable of being depleted during the metabolism of xenobiotic compounds. The fraction of a dose of VOC that penetrates to the systemic arterial circulation (F)
|
From page 216... ...
by the apparent MichaelisMenten-Henri binding constant (Km) Thus, the intrinsic clearance is equivalent to the first-order rate constant for the enzymic reaction (see the second equation in this appendix)
|
From page 217... ...
At low inhaled concentrations, its intrinsic clearance is greater than hepatic blood flow (Andersen, 1981a; Gargas and Andersen, 19821. However, its metabolism becomes saturated at an inhaled concentration of 100 ppm, which corresponds to an arterial blood concentration of only 2 mg/liter.
|
From page 218... ...
2 l~ DRINKING WATER AND H"LTH APPENDIX B: DEFINITIONS OF SYMBOLS AND ABBREVIATIONS Symbol or Abbreviation Units Definition AUBC mg/liter x hours Area under the blood concentration-time curve AMEFF mg/liter The effective concentration of reactive metabolite formed in a compartment of specified volume AURMC mg Area under the rate of metabolism curve AUTC mg/liter x hours Area under the tissue concentration curve AUTMC mg/liter x hours Area under the tissue metabolite time curve bw kg Body weight C mg/liter or ppm Concentration Cl liter/hr Clearance Clint liter/hr Intrinsic metabolic clearance Cw mg/liter Water concentration of contaminant E Extraction ratio for an organ of elimination F Fraction of substance passing through an organ of elimination Km mg/liter Apparent Michaelis constant for substrate binding to metabolizing enzyme kr hr- ~ Rate constant for pathway leading to reaction with critical cellular components
|
From page 219... ...
1981 a. A physiologically based toxicokinetic description of the metabolism of inhaled gases and vapors: Analysis at steady state.
|
From page 220... ...
1984. Inhalation pharmacokinetics: Evaluating systemic extraction, total in vivo metabolism, and the time course of enzyme induction for inhaled styrene in rats based on arterial blood:inhaled air concentration ratios.
|
From page 221... ...
1985. Physiologically based simulation analysis of gas uptake data.
|
From page 222... ...
1983. Physiologically based pharmacokinetic modeling: Principles and applications.
|
From page 223... ...
1978. Complications in the estimation of hepatic blood flow in vivo by pharmacokinetic parameters.
|
From page 224... ...
1979b. Partition coefficients of some aromatic hydrocarbons and ketones in water, blood and oil.
|
From page 225... ...
1983. Effect of vehicle on the pharmacokinetics and uptake of four halogenated hydrocarbons from the gastrointestinal tract of the rat.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.