Biologic Markers in Urinary Toxicology (1995) / Chapter Skim
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5 BIOLOGIC MARKERS IN EXTRAPOLATION
5 BIOLOGIC MARKERS IN EXTRAPOLATION
Pages 153-190
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From page 153... ...
Extrapolation is required to support prediction and the design of a suitable treatment. Extrapolation from epidemiologic studies is commonly used to predict risks to other cohorts.
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From page 154... ...
Indeed, it is the desire to be predictive that drives the need to develop and apply good experimental systems. Such systems have at least four advantages: they allow predictions of human health effects and the magnitude of those effects before human exposure occurs or before adverse effects are manifested in exposed populations; they can be altered to clarify 154 aspects of the process leading from exposure to adverse health effects when similar experimentation in humans would be unethical; they can be designed to eliminate many factors that confound the determination of causeeffect relationships in epidemiologic studies; and they can suggest directions for epidemiologic investigation by providing the hypotheses that epidemiologic studies might be able to test.
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From page 155... ...
at doses far greater than the human exposures of interest. The conclusion that the occurrence of bladder cancers in dogs exposed to MOCA implies a bladder-cancer risk for humans assumes that the qualitative relationship between MOCA exposure and bladder cancer can be extrapolated from dogs to humans.
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From page 156... ...
Biologic mariners of renal transport, concentrating, and metabolic functions of the lcidney are reproduced in many species, including humans, although quantitative differences have been demonstrated. Therefore, it is reasonable to use animal models for extrapolation to humans unless specific information on specific chemicals dictates otherwise.
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From page 157... ...
This is in contrast with human studies, in which only noninvasive studies of renal function are possible. Markers identified through in vitro studies of systems that use animal and human cells or tissues in culture can often give insight into potential toxicity.
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From page 158... ...
The need, therefore, is for standard diagnostic criteria that are sensitive enough to serve as mariners of renal damage in the presence of renal functional reserve. Much of the nephrotoxicity that follows the administration of inert, relatively nontoxic chemicals is related to the formation of reactive electrophiles during their metabolism (Ford and Hook, 1984~.
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From page 159... ...
Some researchers have suggested that the anesthetic agents by themselves can alter renal function. Tubular Function Tubular dysfunction in experimental animals can be assessed through relatively simple and inexpensive tests, such as those for the measurement of glucosuria, enzymuria, and osmolality.
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From page 160... ...
talcen up by proximal tubular cells. Indeed, the reabsorption of proteins that pass the glomerular membranes is very efficient; even slight decreases in tubular fractional reabsorption due to tissue damage increases the excretion of relatively low-molecular-weight proteins.
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From page 161... ...
Because renal enzymes are not distributed uniformly along the nephron, it might be possible to localize renal damage within the nephron on the basis of the pattern of enzymuria. The site selectivity of single enzymes is questionable.
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From page 162... ...
, readily induced bladder cancer in dogs but did not induce bladder tumors in rats until massive closes were given chronically by oral gavage (Hiclcs et al., 1982~. In fact, it has been stated that the failure of the rat bladder to respond to the aromatic amines was one factor that led to the use of the maximum tol
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From page 163... ...
Attempts to demonstrate a broader base for this mechanism with other treatments known to induce bladder tumors have not been successful (Anderson, 1991~. There are few data to support the notion that tissue concentration of zinc is related to the development of bladder cancer.
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From page 164... ...
Studies with NaSacc and several other monovalent-cation salts that have been shown to induce bladder tumors in male rats have led to the hypothesis that increased urinary pH and monovalent-cation concentration can cause bladder epithelial hyperplasia and even induce bladder tumors (Cohen et al., 199 lb; Ito and Fukushima, 1989~. iG4 Although potassium salts have the same response, divalent-cation salts do not induce the effects, at least in short-term experiments (Anderson et al., 1988; Cohen et al., 1991b; Hasegawa and Cohen, 1986; Ito and Fuicushima, 1989~.
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From page 165... ...
Growth Factors Urine is an important component in bladder tumorigenesis, at least in experimental animals.
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From page 166... ...
is more than 107 times the mean human exposure from drinking water in Canada after many years of use of NTA in laundry detergents. TECHNIQUES USED IN RISK ASSESSMENT Animal Studies Renal function and nephrotoxicity in experimental animals can be studied at various levels of tissue structure and organization (Table 5-1)
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From page 169... ...
an ~ .
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From page 170... ...
Substantial advances in development of perfusion buffers that closely simulate renal arterial plasma have been made in recent years (Maack, l986~; these advances have enabled investigators to maintain tissue viability for longer periods. Examples of measurements that are possible with the isolated perfused Icidney are those of renal clearance and metabolism.
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From page 171... ...
In Vitro Studies In vitro models for studies of renal function generally use physical means or digestive enzymes to separate cellular material from specific regions of the lcidney. To obtain detailed information on biochemical mechanisms of action of toxic chemicals or on pathologic states, it is necessary to use living material from specific nephron regions.
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From page 172... ...
One limitation of separation methods based on cell density is that enrichment, rath er than absolute purification, is ob tained because cell density is not a dis crete property; rather, a given cell popu lation generally contains cells with a range of densities. Either tubule fragments or isolated cells can be used as starting material from which to obtain enriched cell pop ulations.
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From page 173... ...
With suspensions of isolated cells, in contrast, single cells are the starting material for any further purification steps. Isolated proximal tubule fragments have been used extensively to characterize the basic transport and energetic properties of this nephron segment (GulIans et al., 1984a,b; Brazy et al., 1984~.
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From page 174... ...
Uses and Limitations of Freshly Isolated Renal Cells Freshly isolated renal cells, prepared by collagenase perfusion and then separated into discrete cell populations by Percoll density-gradient centrifugation, have proved to constitute an extremely useful in vitro system for biochemical toxicology studies (Lash, 1990, 1992, 1993; Lash and Toicarz, 1989, 1990; Lash and Woods, 1991; Lash ant!
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From page 175... ...
However, for many toxicologic studies, the critical issue is not the physical separation of the membrane surfaces but the retention of enzymatic and transport activities on these membranes when the individual epithelial cells are placed into suspension. Ample evidence from studies with isolated proximal tubular cells *
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From page 176... ...
system. Renal-Cell Cultures as Models of Chronic Injury and Carcinogenesis Limitation of maintenance of viability of isolated tubules and isolated renal cells to, at most, 4 hours restricts investigations to processes that occur on a scale of minutes to hours and necessitates the development of other types of model systems to study processes that 176 occur on a scale of hours to days.
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From page 177... ...
The three principal challenges to successful primary culture of renal epithelial cells are to obtain starting material of a highenough purity derived from a specific nephron-cel1 population, to maintain differentiated function during the period of culture, and to prevent fibroblast overgrowth. To validate a primary epithelial cellculture procedure, several criteria must be satisfied.
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From page 178... ...
or a more complete acIdition of hormonal supplements to growth media to improve cellular energetics (Lash 1994; Toicarz and Lash, 1993~. Although most of the studies with primary renal-cell culture have used animal tissue as starting material, recent advances have been made in the use of human renal tissue as starting material for primary culture of proximal tubular cells (Chen et al., 1990b; Detrisac et al., 1984; Trifillis et al., 1985~.
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From page 179... ...
Acute cytotoxicity of bladder carcinogens such as biphenyls, nitrofurans, and 3-methy~cholanthrene- has been examined in cultured normal human uroepithelial cells (Reznilcoff et al., 1986~. Recluction in cell number (luring culture was used as the index of toxicity.
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From page 180... ...
The issue of markers of exposure and susceptibility, which is a major focus of this report, has not been addressed directly in the in vitro systems. Tissue samples, such as those used as starting material for human uroepithelial-cell cultures (Jacob et al., 1991; Meisner et al., 1 988; Messing et al., 1 988; Pratt et al., 1992; Reznilcoff et al., 1983, 1986, 1988; Wu et al., 1991)
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From page 181... ...
The balance between competing pathways is often the primary determinant of the ultimate biologic response. Knowledge of the biochemical regulation of the pathways and of the interorgan and intrarenal distribution of the various enzymes involved is necessary for correlation of in vitro data with the in vivo situation and of data from experimental animals with human risk assessment and development of marl |
From page 182... ...
The lcidneys are sometimes overlool |
From page 183... ...
Whether the GSH S-conjugate is metabolized to the cysteine S-conjugate or to the N-acety~cysteine S-conjugate determines how actively the protoxicant is transported into renal cells for further metabolism to a reactive intermediate. Because most biochemical studies on the metabolism and transport of GSH, GSH S-conjugates, and related metabolites have used rats, the view that has evolved from numerous investigations is based on the extremely high y-glutamyltransferase activity of rat renal proximal-tubular brush-border membranes ant!
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From page 184... ...
human risk associated with exposure to different chemicals. Progress in the elucidation of underlying mechanisms of toxicity indicates possible highdose phenomena)
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From page 185... ...
Dashed lines indicate that individual susceptibility influences the rates of progression, as do other variables. Biologic markers represent a continuum of changes, and the classification of change might not always be distinct.
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From page 186... ...
The utility of an approach that considers biologic markers of effective dose, ~6 early biologic effect, and altered structure or function is related to our ability to model the relationships among those markers. The fundamental assumption of extrapolation i.e., that relationships observed and modeled in one setting hold in another setting-can be applied at the more specific level of those marker-to-maricer relationships.
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From page 187... ...
Differences in those factors will alter susceptibility to potential chemical-induced injury. SUMMARY Extrapolation from animal models is a common and necessary component of risk assessment for humans.
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From page 188... ...
systems are available for study of renal metabolism, renal function, and nephrotoxicity. They range from whole-animal studies to those in the isolated perfused kidney, lcidney slices, isolated nephron segments, isolated tubule fragments, and isolated renal cells.
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From page 189... ...
The importance of enzymatic activation of toxic chemicals is central to an understanding of chemically induced renal injury. Species and strain differences in amounts and tissue distribution of various enzymes can be critical in determining the ultimate toxic response.
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