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6 Dose-Route Extrapolations: Using Inhalation Toxicity Data to Set Drinking Water Limits This chapter presents a pharmacokinetic model for the disposition of volatile organic compounds (VOCs) and their metabolites in biological systems. It is intended to allow extrapolation from the inhalation dose route in animals to the ingestion route in humans and may play a useful role in the overall risk assessment for such compounds. VOCs are present in many drinking water supplies throughout the United States (Brass et al., 1977; Symons et al., 19751. Chloroform and certain other trihalomethanes are believed to form during chlorination processes, in which chlorine reacts with humic acids and other organic materials in water supplies. Other VOCs are emitted into drinking water during man- ufacturing and other activities involving the use of chemicals. Waterborne VOC concentrations typically vary from several micrograms per liter (ppb) to a few milligrams per liter (ppm). Higher concentrations are found in river water downstream from chemical spills and in well water near pol- lutant point sources such as hazardous-waste disposal sites. 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. The best toxicity data base from animal studies for predicting risk to humans would be experiments in which VOCs were provided to laboratory animals in their drinking water. Two constraints make this difficult, however. First, achievable concentrations are small because the water solubility of most VOCs is 16~3

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Dose-Route extrapolations 169 TABLE 6-1 Physiological Constantsa Used in Kinetic Modeling of Rats and Humans Parameter Rat Human (bw) Body weight (kg) 0.3 70 (Qp) Alveolar ventilation (liters/hr)b 5.74 325 (Qc) Cardiac output (liters/hr)b 5.74 325 (ka) Absorption rate constants 5.0 5.0 (Vw) Water intake (liters/day) 0.030 2.0 Blood flow rates (portion of total) (Q') Liver 0.25 0.25 (Of) Fat 0.09 0.09 (Qm) Muscle 0.19 0.19 (Qr) Richly perfused tissue (viscera) 0.47 0.47 Tissue group volumes (portion of body weight) (Vl) Liver 0.041 0.025 (Vf) Fat 0~090 0.200 (Vm) Muscle 0.720 0.610 (Vr) Richly perfused tissue (viscera) 0.059 0.075 aValues similar to those used by Ramsey and Andersen (1984), with minor changes in alveolar ventilation (increased from 4.5 to 5.7 liters/hr) and percentage of cardiac output that perfuses the liver (decreased from 37% to 25%). bCalculated from an allometric relationship: y = 14(bw)074. CAbsorption rate was assumed to be invariant with body weight. 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), and second, rats consume only about 30 ml of water daily. In industry and commerce, humans are exposed to VOCs usually by inhalation and to a lesser extent by skin contact. Over the years, the toxicity of many VOCs has been examined through subchronic or chronic inhalation studies in laboratory animals. These are often conducted at high vapor concentrations and can generally be designed to ensure overt toxicity in animals exposed at the highest concentration. In addition to high air- borne vapor concentrations, the inhalation dose rate is much higher than that achieved in a drinking water study, because the daily alveolar ven- tilation (approximately 140,000 ml; see Table 6-1) is much greater than daily water consumption. For many VOCs, inhalation studies provide the only data from which drinking water standards can be derived. Using such results to predict the risks associated with human consumption of contam-

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~ 70 DRINKING WATER AND HEALTH inated drinking water therefore requires both a dose-route and interspecies extrapolation of toxicity data. Even in a prospective sense, inhalation may be a very good surrogate route, and perhaps the only one available for estimating expected toxicity of contaminants in drinking water. 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. The differences between these two exposure routes are not insignificant, however, as discussed in this chapter and further developed in the two appendixes to this chapter. BACKGROU ND There has been no consensus on how or even whether inhalation studies could be used to establish drinking water standards. Various groups re- sponsible for assessing chemical hazards in drinking water have handled the problem differently. Some have declined to use inhalation data, rea- soning that the target organ, disposition, and ensuing toxic effects of inhaled chemicals may differ markedly from that which occurs when the agents are ingested. Others have argued that whereas results of inhalation studies may be of value from a qualitative standpoint, inhalation data are likely to be of limited utility quantitatively in predicting consequences of the ingestion of chemicals. Stokinger and Woodward (1958) advocated use of threshold limit values (TLVs) to set water standards. They proposed a direct conversion from uptake at the TLV concentration to an acceptable waterborne concentra- tion, assuming that humans ingest 2 liters of drinking water per day. Their approach also attempted to take into account the proportion of chemical absorbed by either route of administration. The general calculation for a water standard based on a TLV would be: TEV (in mg/m3) x 10 m3/day x proportion absorbed in inhalation _ proportion absorbed orally x 2 liters/day x safety factor - (1) where 10 m3/day represents an estimate of a moderately active employee's total ventilation during an 8-hour work shift. Since TLVs apply to human occupational exposure, no additional safety factor was proposed for gen- eral use. Stokinger and Woodward (1958) did provide estimates for both inhalation and ingestion absorption factors. A variation of this general approach has been used in most attempts to establish drinking water standards for humans from inhalation data based

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Dose-Route extrapolations 171 on animals. When toxicity data from animal studies are used, the TLV is replaced by the highest no-adverse-effect concentration in the inhalation experiments in animals. The safety factor, varying from 10 to 1,000, depends on the nature of the inhalation study, the seventy of the response, and the presence or absence of a history of human exposure to the test chemical. This approach has recently been used to derive adjusted ac- ceptable daily intake (AADI) values for trichloroethylene, perchloroeth- ylene, and methylchloroform (EPA, 19841. These calculations represent an attempt to conduct a direct route-to-route extrapolation based on de- livered dose, given the most fundamental assumption that the relationship between delivered dose (milligrams absorbed per day) and the dose re- ceived by target organs is independent of the route of exposure and the species. There is no obvious toxicological or pharmacokinetic basis for such an assumption. Routes of Exposure The route of exposure significantly influences the quantity of a chemical that reaches a particular target tissue, the length of time it takes to get there, and the degree and duration of effect. Volatile organic compounds are readily absorbed by the lung because of its large surface area, intimate alveolar-capillary interfaces, and high rate of blood perfusion. 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. The uptake in the first few breaths is related to blood solubility and ventilation:perfusion ratios. The proportion retained was derived by Haggard (1924a,b,c) and, in the terminology used in this chapter (see Appendix B), is: Fraction retained = Qc b ~ QcPb + Qp I (2) This relationship also applies throughout exposures to soluble chemicals (i.e., Pb of about 5 or larger) that are well metabolized at the exposure concentrations used. Compounds absorbed into the pulmonary circulation are transported via the arterial blood directly to potential target organs. The gastrointestinal (GI) tract is also well suited for the absorption of volatile organic compounds, although its total surface area is less than that of the lung and it receives only about 4% of the cardiac output that perfuses the lung. The presence of food in the GI tract delays absorption and reduces the availability of orally administered halocarbons (Counts et

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|72 DRINKING WATER AND H"LTH al., 1982; D'Souza et al., 19851. Compounds absorbed from the GI tract into the bloodstream are also subject to first-pass elimination by the liver and lungs (i.e., reduction of blood concentrations before the chemical reaches the systemic circulation). Although Andersen (1981a) and his coworkers (Andersen et al., 1980) evaluated hepatic metabolism of inhaled halocarbons and estimated the metabolism of inhaled styrene during a single pass through the systemic circulation (Andersen et al., 1984), no one has yet directly measured first-pass hepatic elimination of orally ad- ministered 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). For most VOCs encountered in the environment, a substan- tial proportion of a low oral dose will be removed by the liver before it reaches the arterial circulation. Andersen (1981a) compiled a list of VOCs that would be expected to demonstrate substantial first-pass extraction by the liver when present in portal blood at concentrations below saturating levels for enzymes. For organics that do undergo extensive first-pass hepatic extraction, the liver will receive a higher dose and may therefore be injured more by an oral dose than it would by a comparable inhalation exposure. This process is expected with well-metabolized halocarbons that are metabolically activated to cytotoxicants. Ingested VOCs will also be subject to a first-pass pulmonary exhalation. The extent of this effect is determined by the blood:gas partition coefficient of the volatile chemical. It is relatively easy to use an analysis similar to that of Haggard (1924 a,b,c) or Andersen (1981a) to derive a relationship for the proportion of circulating volatile compound that will be eliminated in a single pass through the lung when inhaled air contains none of the test chemical: Fraction exhaled = Q A+ Q. (3) which is about 1/~1 + Pb), since cardiac output (QC) and alveolar venti- lation Espy are approximately equal. Acting sequentially, presystemic elimination by the liver and lungs could significantly diminish the amount of VOC that reaches the bloodstream after low-dose oral ingestion. Dose-Response Curves For all routes of administration, VOCs are absorbed by complex pro- cesses involving passage from an exterior compartment through a series of cells, tissues, and organs until some portion of the original dose reaches

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Dose-Route Extrapolations 173 the systemic arterial circulation. The toxic chemical can then be distributed to various organs remote from the site of entry. Frequently, toxicologists Know what organs are affected but lack detailed knowledge of the mo- lecular mechanisms of toxicity. Despite the inadequacy of the data base on such mechanisms, toxicologists and regulators must make prudent, well-documented decisions about expected risks to humans based on data derived largely from studies in animals. The linchpin of any risk assessment is determination of a dose- (or concentration-) response curve under specified experimental conditions. The dose-response curve can either assess a virtual no-effect or minimal- effect level (for nongenotoxic or noncarcinogenic effects) or support ex- trapolation to expected low-level incidence (for genotoxic or carcinogenic effects). These curves should, of course, be based on an estimate of target- tissue dose, which, however, may not be related in any simple manner to applied dose (Andersen, 1981b; Gehring et al., 19781. Applied dose for inhalation or drinking water studies is normally expressed as ppm or mg/m3 (in air) or as mg/liter (in drinking water). On the other hand, target- tissue dose, also called internal dose (O'Flaherty, 1985), 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 me- tabolite concentration curve, or some other appropriate measure of target- tissue exposure. The proper measure of target-tissue dose must be selected carefully. Consideration must be given to whether the toxic chemical is presumed to be the parent compound or a metabolite (i.e., whether the dose-response curve is consistent with parent chemical toxicity or more complex), and to the relative reactivity of the toxic metabolites (i.e., whether they are stable or very short-lived). The pharmacokinetic models developed for risk assessment extrapolations must have sufficient biological and bio- chemical detail to describe these various measures of target-tissue dose. In addition, the toxicologist and regulator should be aware of the critical distinction between target-tissue dose and applied dose and should un- derstand how a proper measure of the former can influence risk assessment computations. Measurement of Tissue Dose Selection of the appropriate measure of target-tissue dose depends on the nature of the chemical component that is associated with the toxic effects. Toxic chemicals can interfere with normal physiological and cel- lular function through a variety of biochemical mechanisms. For the VOCs of interest, toxic effects are most frequently associated with stable me- tabolites or with reactive metabolites that bind covalently and essentially

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~ 74 OR ~ N K! NG WATER AN D H "LTH irreversibly with important cellular macromolecules. Their toxicity is not usually simply associated with concentrations of a parent chemical but, rather, with amounts or concentrations of the toxic metabolites. Some toxicants, such as curare, reversibly bind to endogenous receptors. Their toxicity depends on their tissue concentration, receptor binding affinity, and receptor concentration. This is more of a classical pharmacological interaction. Among environmentally important chemicals, the prime ex- ample of a pharmacologically acting toxicant that has very marked inter- species differences in toxic potency is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Murphy, 1980, p. 3891. For chemicals with pharmacological activity, the proper measure of target-tissue dose would be the tissue concentration divided by some mea- sure of the receptor binding constant for the toxic chemical. High receptor binding affinity arises from strong noncovalent interactions between spe- cific portions of the protein binding surface and the chemical structure of the toxicant. Interspecies differences arise when portions of the binding site are not conserved from species to species, in which case both affinity and toxicity can become markedly species-dependent. Fortunately, a pharmacological mechanism of action, with its potential for significant species differences, is not frequently observed with the chemicals usually found in drinking water. Much more commonly, toxicity is caused by the intrinsic chemical reactivity of foreign compounds or their metabolites. In these cases, there is a direct reaction between critical cellular constituents and reactive chem- icals, and the reactions leading to toxicity are expected to proceed ac- cording to second-order rate equations. Extreme differences in toxicity among species are not expected under these conditions, since tissues and organs are very similar in content and function among species, and the reactivity of their cellular constituents should be similar when exposed to any particularly reactive toxic chemical. The second-order rate equation for loss of a critical cellular component, CCri'' as it reacts with a toxic chemical, T. is: dlCcrit = _ kccritT. (4) In a simplistic way, the rate equation can be rewritten to express the dependence of the reduction in cellular components on the time integral of the toxic chemical, i.e., the area under the tissue-concentration curve (AUTC): t4Ccrit = kiTdt = k(AUTC); thus, J ccrit Ash

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Dose-Route Extrapolations 175 in (ccrit~t = _k(AUTC). ~ crit)O (6) In this case, with a directly reactive species, the loss of critical sites is related to integrated tissue dose. Frequently, metabolites are responsible for toxicity. Metabolite for- mation `'nay occur through first-order processes or capacity-limited, enzyme-catalyzed ones; the latter are more usual. 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). For an enzyme-mediated formation of reactive metabolite, TM*, d(TM*) (Vm X T) 1 dt \~Km + T} Vr (7) By analogy with Equation 5, the burden of metabolite per unit volume of tissue becomes: id(TM*) = V J 1 r Vm X T ~ AURMC --m V' AMEFF. (8) where the AURMC (area under the rate-of-metabolism curve) could also have been developed for first-order production of metabolites. This equa- tion does not describe a true concentration; it describes an effective con- centration (AMEFF; see Appendix B of this chapter) that would have been achieved by the production of a specified amount of reactive metabolite, TM*, in a particular volume, Vr. The concept of correlating toxicity with the area under the rate-of-metabolism curve was previously developed by Andersen (1981a). Further elaboration of the concept to include the ef- fective volume of reaction is necessary to extend its use to interspecies comparisons (see the section entitled Interspecies Extrapolation later in this chapter). The toxicity of reactive intermediates is related to the portion of the intermediate that ultimately reacts with the critical cellular targets for both carcinogenic and noncarcinogenic end points. In chemical terms, this is illustrated by a scheme in which there are several pathways for con- sumption of the reactive metabolite. Each pathway has a first-order rate constant, the sum of which is iki. There is also a pathway that leads to reaction with critical cellular components; its rate constant is he. Therefore, the relative concentration of the reactive intermediate, TM*, involved in . . . tox~c ~nteract~ons is: CTM* = :$k (AMEFF) (9)

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~ 76 DRINKING WATER AND H EALTH This relationship is more important for interspecies extrapolation, i.e., when krl5,ki might vary between species, than for a dose-route extrapo- lation in a given species, where it is assumed that the ratio does not change very much with concentration of the parent VOC. In addition to situations in which the parent chemical or short-lived metabolites are the reactive toxic chemical, other, more complex patterns may exist when stable metabolites are the reactive chemicals associated with toxicity. An example-is the neurotoxicity associated with inhalation of n-hexane or methyl n-butyl ketone, which is due ultimately to circulating concentrations of the metabolite 2,5-hexanedione (DiVincenzo et al., 19781. Although the relationship between concentration of precursor and for- mation of metabolite may be complicated (Clewell et al., 1984), the appropriate target-tissue dose on which risk assessment would be based would be similar to that expressed in Equation 7, except that AUTC would be replaced by area under the target-tissue metabolite-concentration curve (i.e., AUTMC). In a simple system involving a stable toxic metabolite TM formed from a precursor T at a concentration CT, in which a constant fraction of the metabolic pathway is converted to the metabolite of interest, the metabolite is retained in a specified volume of distribution VTM and eliminated by a first-order process with rate constant kTM. The mass-balance equation for the metabolite in its volume of distribution is: VTM4CTM kr (Vm X CT) k V C (10) The AUTMC then is related to the metabolism rate of the parent chemical, but the dependence cannot be expressed as a simple analytical expression. The expected steady-state concentration of the metabolite can be written in a simple form: k /sk (Vm X CT) (CTM)S S kTM X VTM (1 1) The denominator in Equation 11 is identical to the compartmental clearance CITM of the stable metabolite. PHARMACOKINETIC MODELS An attractive and potentially economical approach to risk-assessment extrapolations is the development of predictive physiologically based phar- macokinetic (PB-PK) models for the disposition of volatile organic com- pounds and their metabolites in biological systems. These models are based

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Dose-Route Extrapolations ~ 77 INTERSPECIES EXTRAPOLATION RAT No-Effect I nhaled (1 ) Concentration (rat ) No-Effect Drinking Water Concentration (rat ) H UMAN ~ 1 No-Effect I No-Effect (3 No-Effect ~ . ) Drinking Water Target Tissue ~ I Target Tissue - ~ Dose (rat) | Dose (human) Concentration (human) Dose Equivalence FIGURE 6-1 Physiologically based pharmacokinetic extrapolations involved when results of inhalation studies in laboratory animals are used to establish drinking water standards for humans. / on the known physiology of the experimental animals and on known or easily measurable physical, chemical, and biochemical properties of the VOCs. PB-PK models predict general behavior of toxicants, and models successful with one chemical are usually easily adapted to describe the kinetic behavior of many others. This chapter demonstrates a possible PB-PK approach for conducting dose-route and interspecies extrapolation. The underlying premise in a pharmacokinetic risk assessment is that there is a coherent dose-effect curve relating the incidence or severity of response to an appropriate measure of target-tissue dose. Pharmacokinetic risk-assessment extrapo- lations are conducted by assuming that a particular target-tissue dose achieved by one route of exposure in a particular species will have the same biological effect as an equivalent target-tissue dose achieved by another route of exposure or in some other species. The dose-route ex- trapolation between inhalation and oral ingestion is based on an under- standing of the physiological differences in the processes of chemical absorption by these two exposure routes (see Appendix A of this chapter). 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) or minimal-effect concentration in

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]78 DRINKING WATER AND HEALTH the inhalation studies in animals. In Step 1 of Figure 6-1, the target-tissue dose is estimated in a test species based on the no-effect inhalation ex- posure concentration. Step 2 determines the drinking water concentration associated with an equivalent target-tissue dose in the test species. Step 3 determines the drinking water concentration that produces a target-tissue dose in humans equal to the no-effect target-tissue dose from the inhalation study in the test species. In this chapter, the two extrapolation processes are handled separately, but in practice they would be combined and the dose-route extrapolation for test animals would not be conducted as an independent step. To be useful in risk-assessment extrapolations, the pharmacokinetic models used to estimate tissue doses must have sufficient biological detail to describe the differences in absorption by the two exposure routes and to account for structural and physiological differences between various mammalian species. Some PB-PK models do contain the anatomical and biochemical detail for such extrapolations (see, for example, Andersen, 1981a; Fiserova-Bergerova, 1976; Gerlowski and Jain, 1983; Himmelstein and Lutz, 1979; Ramsey and Andersen, 19841. These models, which are particularly easy to develop for a variety of VOCs, are nothing more than a series of mass-balance differential equations describing the movement of a chemical through a number of tissue compartments within the body. In the past, solving such equations was difficult and time-consuming, and there was substantial reluctance to use these descriptions unless the system of equations had a formal, analytical solution (Gibaldi and Perrier, 1975; Teorell, 1937a,b). With modern digital computers and improved techniques for numerical integration, however, the solution of even rel- atively large sets of differential equations is easy. Furthermore, many physiologically based models that are useful for risk assessment with VOCs require only 4 to 10 ordinary differential equations and can be solved rapidly with microcomputer-based procedures. Data-Based Inhalation Models A typical data-based compartmental model attempts to relate the blood or tissue concentration profile of a parent chemical or metabolite to the administered dose of parent chemical using a set of mathematical equa- tions. The parameters for these equations are determined from experiments that follow the time course of the chemical in body fluids, usually blood, and occasionally in specific tissues. A simple data-based inhalation model (Figure 6-2) was developed to examine the pharmacokinetics of inhaled styrene (Ramsey and Young, 19781. This model was used by Young et al. (1979) to describe kinetic behavior in rats and by Ramsey et al. (1980) to describe kinetic behavior in humans. It consisted of a central com-

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Dose-Route Extrapolations 215 METABOLISM IN THE LIVER The liver constitutes approximately 2% of the body weight of the adult human and about 4% of the adult rodent. It is an unusual organ in that it receives both an arterial (hepatic artery) and venous (portal vein) blood supply. Of the total blood flow (approximately 1 ml/min/g liver), an estimated 70% to 80% arrives via the portal vein. It is particularly noteworthy that the portal vein drains more than 90% of the length of the GI tract, including the bulk of the absorbing surface of the intestine. Anatomically, most orally ingested VOCs must pass through the liver to reach the systemic arterial circulation. Within the liver, blood from both arterial and venous supplies traverses the sinusoids (incompletely lined channels between the parenchymal cells of the liver) before exiting via the hepatic vein. This arrangement ensures that toxicants sufficiently lipophilic to have gained entry across the mu- cosal membrane will rapidly equilibrate into the parenchymal cells and become available to the xenobiotic chemical-metabolizing enzymes there. Metabolism of a toxicant during this first passage through the liver is a major component of the presystemic elimination of toxicants. The metabolic capability of the liver for the elimination of toxicants is well known and has been described extensively elsewhere (for a general review, see Goldstein et al., 1974; Testa and Jenner, 19761. Briefly, two groups of reactions are recognized. The first, termed Phase I metabolism, is usually oxidative in nature and acts to insert or reveal a polar function in the toxicant. The second, or Phase II metabolism, acts to conjugate such polar groups with endogenous, highly water-soluble compounds, such as glucuronic acid and inorganic sulfate. In only two steps, Phase I and II metabolism usually converts highly lipophilic toxicants that cannot be excreted in the kidneys to highly hydrophilic derivatives that cannot be retained in the body. Phase I reactions oxidize toxicants and are usually catalyzed by enzymes dependent on cytochrome P450. Phase II reactions include a wide range of activities. In addition to glucuronide and sulfate conjugation, activities in this category involve addition of the sulfur in glutathione and the oxygen in water to arene oxides, glutathione substitution reactions, conjugation of carboxylic groups with the nitrogen of glycine, and the acetylation of basic groups. Of particular importance, all these reactions require endog- enous 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) may be expressed in terms of the fraction extracted by the liver during the first pass (E). Thus,

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2 ~ 6 DRINKING WATER AND H"LTH F= 1 E. Furthermore, since liver clearance (elk) is the effective volume of blood from which the toxicant is completely removed per unit time, hepatic clearance (Cli) is given by the product of the blood flow to the liver per unit time (I) and the fraction extracted (E). Thus, Clot= ME. The fraction extracted (known as the extraction ratio) depends on several factors, including the ratio of unbound to bound (to plasma proteins) toxicant, mass transfer and permeability terms, and the intrinsic clearance of the toxicant in the liver (CIi,:~. During the latter, clearance occurs under conditions that do not limit the rate at which the toxicant is delivered to the surface of the metabolizing enzymes, i.e., when the tissue substrate concentration is much below the apparent binding constant (see the second equation in this appendix). From a biochemical viewpoint, the free intrinsic clearance under first-order conditions may be estimated by dividing the maximal velocity of the enzyme reaction (V,~) by the apparent Michaelis- Menten-Henri binding constant (Km) Thus, the intrinsic clearance is equiv- alent to the first-order rate constant for the enzymic reaction (see the second equation in this appendix) as Cli approaches zero. Rearrangement and substitution of these and associated mathematical expressions lead to the following relationship: Q V F = Q + Cl ; Clint = K Since intrinsic clearance can be related to the enzyme parameters V,~ and Km' this expression indicates that under first-order conditions, the fraction of the dose reaching the systemic arterial circulation depends on flow of blood to the liver and the metabolic capability of the liver to remove that drug. Several important consequences follow from this relationship. First, the coadministration of an inhibitor or a competitive substrate for a major metabolic elimination pathway of a potentially toxic substance would lead to a decrease in the pathway's intrinsic clearance and a major increase in systemic availability. Thus, a dose of substance normally considered safe could, under appropriate circumstances, become highly toxic. Conversely, induction of the xenobiotic chemical-metabolizing enzyme (that is, an increase in V,na,`) would act to decrease systemic availability. Because both the constituent level and inductive capacity of hepatic metabolism are under genetic control in humans, there may be a great variation in intrinsi clearance, and the activity of specific pathways for specific toxicants in some subsets of the population may be very low. Thus, some persons

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Dose-Route Extrapolations 217 may have very low intrinsic clearance rates for specific xenobiotic com- pounds and may exhibit atypical systemic availability and toxic response. When intrinsic clearance is very high relative to liver blood flow, the relationship reduces to: F = QICIin~. Since the intrinsic clearance for a given toxicant and person may be regarded as constant, the systemic availability will depend largely on liver blood flow. Thus, drugs that alter blood flow may influence availability, whereas induction or even partial inhibition may have little effect. Con- versely, for toxicants with intrinsic clearances that are low relative to blood flow, availability may be very sensitive to induction or inhibition effects and resistant to blood-flow alteration. In recent years, it has become increasingly apparent that most VOCs are well metabolized by hepatic oxidation at appropriate concentration ranges. The term well metabolized refers to the condition where Clint is much greater than liver blood flow. Andersen (1981a) has provided a list of VOCs that show this behavior. Although these compounds are well metabolized at low concentrations, the enzymes have only moderate max- imum velocities and are readily saturated. The earlier idea that VOCs were poorly metabolized came from experiments in which high oral doses were administered and large amounts of VOC were eliminated unchanged. As noted earlier, this does not indicate lack of metabolism but, rather, saturation of metabolism and an increased relative clearance by exhalation (see Equation 3~. Even many anesthetics are now known to be well me- tabolized. The V,na,` for the oxidative metabolism of halothane in a 250- g rat is approximately 2.5 mg/hr. At low inhaled concentrations, its in- trinsic 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. Not surprisingly, when humans or animals were exposed to anesthetic concentrations, about 1,500 ppm, most absorbed halothane was eliminated in exhaled breath as the parent chemical. More recent, as-yet-unpublished studies by Gargas and asso- ciates show clearly that diethyl ether is also well metabolized by micro- somal oxidation at inhaled concentrations below 200 ppm (M. E. Andersen, Air Force Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Ohio, personal communication, 19851. In fact, most VOCs have large intrinsic clearances and will be subject to very significant f~rst- pass elimination upon oral ingestion.

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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

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Dose-Route Extrapolations 219 Symbol or Abbreviation Units p Definition Proportion of flow cleared by perfusion to organs of elimination Pb liter/liter Blood: air partition coefficient Qc liter/hr Cardiac output Is liter/hr Dead-space ventilation Of liter/hr Blood flow in fat A liter/hr Liver blood flow Up liter/hr Alveolar ventilation Qr liter/hr Blood flow in highly vascularized organs Qs liter/hr Blood flow in muscle and skin Q. liter/hr Total pulmonary ventilation T concentration Toxic substance TLV concentration Threshold limit value TM concentration Toxic metabolite Vat liter Volume of distribution Am percent body weight Muscle volume V,~ mg/hr Maximum rate of enzymatic reaction Vw liter Water consumption in a given time period y ml/day Intake REFERENCES Adolph, E. F. 1949. Quantitative relations in the physiological constitutions of mammals. Science 109:579-585. Andersen, M. E. 1981 a. A physiologically based toxicokinetic description of the metabolism of inhaled gases and vapors: Analysis at steady state. Toxicol. Appl. Pharmacol. 60:509- 526.

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