3
BIOLOGIC MARKETS OF SUSCEPTIBILITY AND EXPOSURE

Biologic markers of susceptibility and exposure are intimately related in the evaluation of populations at risk for effects of xenobiotics. Although objective indicators of exposure, such as excreted metabolites or DNA adducts, are often convenient to identify a population at risk, the problem might be much more complex. For example, members of a population can vary widely in their susceptibility; a population defined as being at risk in the absence of knowledge of susceptibility might consist mostly of people who are not susceptible and therefore are not at risk or are susceptible to various degrees. This complication is particularly pertinent for diseases like cancer which have a long latency period and can involve a sequence of biologic changes. The situation can be less complex in the case of toxic responses that are related directly to a toxicant or its metabolites. Because of those fundamental principles, linking exposure to disease is difficult when large fractions of the population are not susceptible. For example, the tobacco industry maintains that smoking does not cause cancer, on the grounds that 95% of smokers never develop cancer. The power of biologic markers of exposure can be increased if they are linked to biologic markers of susceptibility and effect. Making that linkage provides a means to identify a real high-risk group among those exposed and can also provide an understanding of the mechanisms of disease.

POPULATIONS AT RISK

A major thrust of environmental-health research has been in the definition of acceptable magnitudes of exposure in the workplace and environment—usually without adequate data on effects on individuals or populations. Definition of risk with biologic markers can provide objective information concerning the effects of exposure on individuals and populations. This information can, in turn, be used to design cost-effective strategies of mitigation and is related directly to the ethical and practical issues discussed in Chapter 1.



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Biologic Markers in Urinary Toxicology 3 BIOLOGIC MARKETS OF SUSCEPTIBILITY AND EXPOSURE Biologic markers of susceptibility and exposure are intimately related in the evaluation of populations at risk for effects of xenobiotics. Although objective indicators of exposure, such as excreted metabolites or DNA adducts, are often convenient to identify a population at risk, the problem might be much more complex. For example, members of a population can vary widely in their susceptibility; a population defined as being at risk in the absence of knowledge of susceptibility might consist mostly of people who are not susceptible and therefore are not at risk or are susceptible to various degrees. This complication is particularly pertinent for diseases like cancer which have a long latency period and can involve a sequence of biologic changes. The situation can be less complex in the case of toxic responses that are related directly to a toxicant or its metabolites. Because of those fundamental principles, linking exposure to disease is difficult when large fractions of the population are not susceptible. For example, the tobacco industry maintains that smoking does not cause cancer, on the grounds that 95% of smokers never develop cancer. The power of biologic markers of exposure can be increased if they are linked to biologic markers of susceptibility and effect. Making that linkage provides a means to identify a real high-risk group among those exposed and can also provide an understanding of the mechanisms of disease. POPULATIONS AT RISK A major thrust of environmental-health research has been in the definition of acceptable magnitudes of exposure in the workplace and environment—usually without adequate data on effects on individuals or populations. Definition of risk with biologic markers can provide objective information concerning the effects of exposure on individuals and populations. This information can, in turn, be used to design cost-effective strategies of mitigation and is related directly to the ethical and practical issues discussed in Chapter 1.

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Biologic Markers in Urinary Toxicology The section following immediately discusses nephrotoxicity. Discussions of genitourinary cancer follow later in the chapter. Hereditary Susceptibility to Nephrotoxicity Hereditary renal conditions are a documented but infrequent cause of end-stage renal disease (ESRD). The most prevalent hereditary renal disease is cystic kidney disease, which accounts for 3.4% of the cases of ESRD. Other hereditary or congenital renal disease accounts for 0.9% of the cases of ESRD (NIH, 1993). An intriguing observation regarding the relationship between hereditary factors and ESRD comes from a case-control study of 325 men in which occupational exposure was sought as an etiologic explanation of their ESRD. Only patients whose diagnoses were compatible with toxicant-induced renal injury were included in the analysis; patients with other known causes of renal failure were excluded. That ESRD was most strongly associated with a family history of renal disease (odds ratio, 9.30:1) (Steenland et al., 1990), not with occupational exposure, suggested the presence of hereditary susceptibility. Substantial evidence supports a sex-related predilection for susceptibility to various nephrotoxicants. For example, male rats are more sensitive than female rats to the nephrotoxic effects of carbon tetrachloride and aminoglycoside antibiotics (Bennett et al., 1991). In contrast, Moore et al. (1984) demonstrated a higher susceptibility of women than of men to the nephrotoxic effects of aminoglycoside antibiotics. In any case, there seems to be a sex-related effect in both rats and humans; whether these differences are genetic in origin remains to be determined. Direct evidence of race as a risk factor in toxicant-induced renal injury is lacking, but blacks and some other minority groups are highly susceptible to other forms of renal disease, such as has been demonstrated for the renal disease due to hypertension and diabetes mellitus (see Chapter 2) (NIH, 1992). Inherited renal disorders might influence susceptibility to toxic injury. The potential impact of genetic factors on the renal response to environmental agents has not been widely appreciated or reviewed. One important and complicating aspect is the highly variable penetrance or expression of most of the genetic abnormalities that involve the kidney. Many people who carry genes for renal abnormalities might be only mildly affected or remain completely asymptomatic for many decades. Although it might be relatively easy to identify the first person in a genetic line with overt clinical manifestations of genetic kidney disease, a much larger pool of asymptomatic people might also be at higher risk than normal for damage from exposure to biohazards. A number of inherited disorders affect renal development or structure; these disorders have been extensively documented, and their clinical features

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Biologic Markers in Urinary Toxicology are well described, as are the various modes of inheritance (Brenner and Rector, 1986; Fisher and Brenner, 1989). The best-studied among those diseases are autosomal dominant (adult) polycystic kidney disease, autosomal recessive (infantile) polycystic kidney disease, hereditary nephritis (Alport's syndrome), and hereditary osteoonychodysplasia (nail-patella syndrome). Many inborn errors of metabolism can also have a major, if not primary, impact on the kidney. A variety of inherited disorders result in compromise of the secretory or reabsorptive functions of the renal tubule system (Brenner and Rector, 1986). Prominent among them are defects in phosphate transport, amino acid transport, and glucose-handling. The clinical characteristics of people affected by these genetic defects of metabolism are, for the most part, well reviewed in standard medical texts, and inheritance patterns have also been well studied. Affected persons with tubular impairment that does not reach clinical significance and those with late onset of disease might well be at increased risk for toxic injury. The issue deserves investigation. Heredity also plays an important part in a wide variety of systemic diseases that can damage the kidney and thereby increase the risk of renal injury from biohazards. Among the most important are diabetes, hereditary amyloidosis, and alpha-antitrypsin deficiency (Brenner and Rector, 1986; Fisher and Brenner, 1989). Autoimmune diseases, many kinds of vasculitis, and systemic lupus erythematosus can also be considered in this susceptibility category. Again, attention should be paid to family members of persons with diagnosed, clinically significant disease to identify the possible increased risk to apparently unaffected carriers of the defects. Finally, hereditary aspects of immune responsiveness appear to contribute to the susceptibility to a number of renal diseases (Ballardie, 1992; Oliveira, 1992). That finding is not surprising in light of the great importance of immune and inflammatory responses in mechanisms of glomerular and tubulointerstitial disease. Long-term effects of toxic injury might involve immunopathologic mechanisms (see Chapter 4), and genetic aspects of immune responsiveness could contribute substantially to susceptibility to kidney damage from exposure to biohazards. Susceptibility to develop Goodpasture's syndrome, with anti-glomerular-basement-membrane antibodies, appears to be strongly associated with a very small number of Class II major histocompatibility antigens; other Class II histocompatibility antigens have been implicated in susceptibility to membranous nephropathy (Oliveira, 1992). The link with immune response genes is of special importance in susceptibility to toxic injury, inasmuch as organic solvents, heavy metals, and drugs have also been suggested to play a role in the pathogenesis of those immune disorders of glomeruli (see Chapter 4). Class II major histocompatibility antigens have also been evaluated in the heredity of

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Biologic Markers in Urinary Toxicology IgA nephropathies, membranoproliferative glomerulonephritis, minimal change disease and tubulointerstitial nephritis (Oliveira, 1992). Although some claim to have established significant associations, the results remain controversial, requiring study of larger populations and more investigation. Evidence has suggested a role of genes of Class I major histocompatibility antigens in susceptibility to injury by immunological mechanisms. At present, however, it seems that linkage-disequilibrium phenomena can explain the link to Class I antigens, given the strong association with Class II antigens of the histocompatibility complex. Genetic deficiencies of the complement system, many of them also mapping in the major histocompatibility complex, have been shown to be predisposing factors in lupus nephritis and IgA nephropathy. Studies with animal models have identified highly significant genetic components of susceptibility to experimental tubulointerstitial nephropathies, but little or no similar evidence is available on humans (Ballardie, 1992). Nutrition The glomerular hyperfiltration that regularly follows the ingestion of a protein-rich diet can induce glomerulosclerosis and chronic renal failure in animals deprived of their renal reserve. Furthermore, variation in the body's mineral content has been linked with chronic renal injury, as in the case of severe hypokalemia induced by eating disorders, and shown to augment toxicant-caused injury, as in the association of calcium depletion with lead nephropathy or of salt depletion with analgesic nephropathy. Socioeconomic Factors The relationship between income and the incidence of ESRD has previously been described (see Chapter 2). It is not clear whether income is a true independent variable or is closely associated with race or other factors. Age Age is a well-recognized factor in determining the severity of acute renal failure—particularly that acquired in hospitalized patients (Porter, 1989). In older patients, not only is there an increased susceptibility to injury, but once injury has occurred the rate of recovery is decreased. For example, weanling rats, as opposed to adult rats, are relatively resistant to the nephrotoxic effects of aminoglycoside antibiotics and have a greater capacity for tubular epithelial-cell repair (Fernandez-Repollet et al., 1992). There is indirect support of the proposition that the elderly are at increased risk for the development of toxicant-induced chronic renal failure. In a study of patients who were 70 years old or older (Chester et al., 1979), 29% of the

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Biologic Markers in Urinary Toxicology patients were classified as having chronic interstitial nephritis, a diagnosis quite compatible with toxicant-induced renal failure. The proportion was much higher than the 10.4%, observed when patients 50 and older were included (Marcias-Nunez and Cameron, 1987). Because toxicant-induced chronic renal failure is theorized to occur after years of low-level exposure, it stands to reason that the incidence of chronic renal failure would be clustered in elderly patients. Coexisting Chronic Disease Pre-existing renal insufficiency is well documented as a risk factor in acute nephrotoxic renal failure. For chronic renal failure, the information is circumstantial. Patients with sickle-cell disease who have a high incidence of renal papillary necrosis as a result of their underlying disease process also have a predisposition to analgesic use because of the pain associated with "sickle crisis." In this situation, it is difficult to determine whether the analgesic use increases the severity of the papillary necrosis. Another example of the relationship between pre-existing renal insufficiency and acute nephrotoxic renal failure is the increased risk of nephropathy associated with contrast medium in patients with diabetes mellitus or multiple myeloma. It has been suggested (Mudge, 1980) that in up to 25% of diabetic patients with contrast-medium-induced renal injury, the serum creatinine concentration does not return to baseline, and further deterioration of renal function occurs. The role of hypertension was alluded to in the discussion of race. Presence or absence of coexisting chronic disease in other organs can modify the effects of some urinary tract toxicants. Addictive Behavior and Recreational Drug Use Drug abuse is increasingly common among young people, and it is not surprising that it has been linked to renal injury. Heroin use is associated with a severe form of nephropathy and is a recognized cause of focal sclerosing glomerulonephritis with associated nephrotic syndrome. The resulting glomerular injury often progresses to ESRD and might account for up to 10% of the cases of ESRD in cities with large addicted populations (Cunningham et al., 1983). Renal ischemia can be an acute effect of cocaine inhalations, although cardiac ischemia and cerebral ischemia are more common (Pogue and Nurse, 1989; Singhal et al., 1990). Rhabdomyolysis and acute renal failure can accompany free-basing inhalation of cocaine (Horst et al., 1991). Various acid-base and electrolyte abnormalities can result from solvent abuse, as occurs with exposure to toluene from gluesniffing (Carlisle et al., 1991; Gupta et al., 1991). When intravenous amphetamine (speed) was a popular street drug, a form of drug-induced polyarteritis no-

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Biologic Markers in Urinary Toxicology dosa with progressive renal failure and severe hypertension was a recognized outcome. Occupational or Environmental Exposure Drugs and environmental toxicants have in some instances induced acute renal failure but evidence of their causing the development or progression of chronic renal failure is circumstantial and thus less compelling. That is not surprising, given the insidious and progressive nature of chronic renal failure and the long latency between exposure and the onset of disease. Compounding this is the superimposition of other chronic conditions that are also associated with progressive renal failure and the lack of a uniform system of classifying renal disease. Finally, the presence of many potential nephrotoxicants in our environment suggests that the causes of many forms of renal failure are multifactorial (Sandler, 1987). It has been estimated that nearly 4 million workers were exposed to known or suspected nephrotoxicants in the workplace in 1971–1972 (Landrigan et al., 1984). It is of interest to note that the specific nephrotoxicants that were cited in preparing that estimate are those believed to be capable of producing chronic renal failure and eventually ESRD. They include heavy metals (e.g., lead, mercury, uranium, and cadmium), solvents (especially light hydrocarbons), silica, beryllium, pesticides, and arsenic. Solvents have been implicated as inducers of glomerulonephritis (Sandier and Smith, 1991), and the association between chronic interstitial nephritis and analgesic abuse is widely recognized (Gregg et al., 1989). The association between hypertensive renal disease (nephrosclerosis) and lead nephropathy continues to be explored (Staessen et al., 1990). In evaluating the occurrence of lead nephropathy in the general public, Staessen et al. (1992) concluded that although lead exposure could impair renal function, they were unable to demonstrate a cause-effect relationship. Examples of environmental contamination that have renal consequences are many. One that stands out is the poisoning by methyl mercury in industrial effluents that occurred in the Minamata Bay region of Japan and resulted in neurologic and renal impairment in several hundred adults who ate tainted fish (Iesato et al., 1977). Table 3-1 provides a breakdown of some common chemical agents that cause nephrotoxicity. MARKERS OF SUSCEPTIBILITY One of the most important factors in the development of a xenobiotic-induced disease process is susceptibility. It would be of great advantage to be able to predict an individual's susceptibility to the adverse effects of a xenobiotic. Given the broad definition of biologic markers in general as indicators of variations in cellular or physiologic components or processes that alter structure or function, it is reasonable to

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Biologic Markers in Urinary Toxicology TABLE 3-1 Common Chemical Agents That Cause Nephrotoxicity Industrial and Environmental Substances ■ Glycols ■ Heavy metals ■ Organic solvents ■ Insecticides, herbicides, fungicides Drugs ■ Prescription Antibiotics Antibacterial agents Antiviral agents Antifungal agents Immunosuppressive agents Antineoplastic agents ■ Nonprescription, including nonsteroidal anti-inflammatory drugs ■ Illicit (recreational), including heroin and cocaine extend the definition to include genotypic (reflecting genetic constitution of the individual) or phenotypic (reflecting the entire' physical, biochemical, and physiologic makeup of an individual as determined both genetically and environmentally) markers as indicators of susceptibility. Genetic changes can result from exogenous exposures to occupational or environmental toxicants. These changes or mutations in DNA are usually considered markers of effect but under some circumstances can serve as markers of susceptibility. The objective of this section is to provide a framework for identifying markers of susceptibility and determining their relative value for individual risk assessment. Ideally, the relationship between the presence of the marker and the incidence of disease has high degrees of sensitivity and specificity (see Chapter 1). If that is not the case, many people with a given marker of susceptibility might be monitored unnecessarily. It is reasonable to use the techniques of molecular biology to identify new or more precise markers of susceptibility. Care must be taken to distinguish between the effects of acute high-level exposure and chronic low-level exposure. For example, in two separate population studies of the relationship of exposure to aromatic amines and the development of bladder cancer, outcome could not be predicted on the basis of the industrial-hygiene guidelines for estimates of peak exposure, but outcome and duration of exposure were statistically correlated. Epidemiologic studies are useful for identifying xenobiotic substances with overt health effects and to set standards for exposure, but it might be difficult to determine the percentage of people who suffer adverse health effects of low-level exposure or of exposures to multiple agents in population studies. The interaction of multiple low-level toxicants might be difficult to elucidate even in a multivariate analysis. Modifying Factors of Susceptibility In assessing potential risk, it is important in any model to account for individual variability of drug-metabolizing

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Biologic Markers in Urinary Toxicology enzymes and health or environmental status. Differences in those factors will alter susceptibility to potential chemical-induced injury. Three main conditions can alter susceptibility: underlying disease or altered physiologic function, nutritional status, and renal workload. Whether each of those conditions affects susceptibility depends on the chemical in question and on the route of exposure. Pharmacokinetics can play an important role because metabolism in other organs might be required for the generation of the eventual nephrotoxic metabolite, For example, many nephrotoxicants are metabolized by hepatic enzymes (e.g., cytochrome P-450 or GSH S-transferase) to generate a substrate for a renal enzyme; this substrate is transported to the kidneys, where the eventual reactive and toxic metabolite is produced. Hence, any disease state that compromises liver function (e.g., cirrhosis) can alter delivery of protoxicant to the kidneys and thus modify susceptibility to nephrotoxicity. Xenobiotics that are ingested depend on proper intestinal function for delivery to the site of action; intestinal disease or another defect that diminishes absorption can modify susceptibility to injury. Similarly, xenobiotics that are inhaled depend on proper pulmonary function; any form of pulmonary disease that results in decreased absorption across the lung epithelium can modify susceptibility to injury. Other general disease states that can modify the response to a nephrotoxic chemical include diabetes and ischemia. Reduction of functional nephron number, such as occurs after removal of a diseased kidney or in renal failure, can markedly alter drug metabolism, energy metabolism, and susceptibility to injury (see Fine, 1986, and Wolf and Neilson, 1991, for recent reviews on the physiologic and biochemical effects of reduced nephron number). Unilateral nephrectomy and the compensatory growth that follows increased renal GSH concentrations, particularly in the proximal straight tubule, where GSH concentrations are increased by more than 50% after compensatory growth, compared with normal conditions (Lash and Zalups, 1992; Zalups and Lash, 1990; Zalups and Veltman, 1988). The mechanism by which this increase occurs appears to be an increase in GSH synthesis in renal proximal tubules (Lash and Zalups, 1994). Nutritional status can be an important determinant of responsiveness to toxicants. For example, essentially all the major drug-metabolism (both bioactivation and detoxification) pathways are directly or indirectly energy-dependent. Changes in nutritional status, such as starvation or vitamin deficiencies, can have profound effects on activities of numerous drug-metabolism pathways. Finally, renal workload is particularly relevant for renal function and susceptibility to nephrotoxicants because of the high energy requirements for maintaining basal renal function. Changes in transport work (e.g., altered sodium or potassium ion loads) can directly lead to changes in the supply of energy avail-

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Biologic Markers in Urinary Toxicology able for drug metabolism and detoxification. Hence, such changes in renal function can produce changes in susceptibility to chemical injury. A major question to be addressed is the scientific approach to be adopted for identifying markers of susceptibility. The methods involved can include in vitro studies, in vivo animal models, study of patients with clinical disease that might have been associated with a xenobiotic, and studies of populations at risk. Identifying a specific marker of susceptibility to a xenobiotic substance requires the identification of the active xenobiotic. Clues to the identification of an active xenobiotic might come from epidemiologic data or from the finding of the xenobiotic in a tissue. Parenchymal Renal Disease Although the liver has generally been the focus of most drug-metabolism studies and is one of the most important sites of metabolism, numerous studies over the last 2 decades have shown that the kidneys are capable of extensive oxidation, reduction, hydrolysis, and conjugation (Table 3-2) (Anders, 1980; Jones et al., 1980). Enzyme systems similar to those found in other tissues are involved in renal drug metabolism, including both Phase I enzymes (which catalyze oxidation, reduction, and hydrolysis) and Phase II enzymes (which generally catalyze conjugation). Moreover, the kidneys are critical sites of biotransformation of many classes of xenobiotics because some metabolic pathways that are present at low activities in other tissues are present at high activities in specific regions of the nephron. One of the best examples is the mercapturic acid pathway. Pharmacokinetics and interorgan metabolism are important to consider in studying the role of metabolism in chemically induced nephrotoxicity (Cohen, 1986). Interorgan pathways can depend on the specific chemical involved and on the route of administration. The simplest scheme involves a chemical, such as cyanide or carbon monoxide, that does not require enzymatic activation to elicit nephrotoxicity and is delivered, via the circulation, directly to the kidneys; but there are few such nephrotoxicants—most toxic (or carcinogenic) chemicals require bioactivation to elicit their effects (Anders, 1985). In an alternative scheme, a chemical is delivered directly to the kidneys and metabolized by renal enzymes to a toxic form. Other, more complex schemes of interorgan processing of nephrotoxicants, involving both renal-hepatic and enterohepatic pathways, can also occur. Species and strain differences in interorgan levels and distributions of enzyme activities are also important. An example of how species differences contribute to differences in interorgan patterns of metabolism is the processing of GSH and GSH S-conjugates, which undergo a series of metabolic transformations involving enzymes of the liver, biliary epithelium, small intestinal epithelium, and renal proximal tubular epithelium (Lash et al., 1988). In mam-

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Biologic Markers in Urinary Toxicology TABLE 3-2 Drug-Metabolism Enzymes in Kidneya Phase I Enzymes Phase II Enzymes Ancillary Enzymes Cytochrome P450 Esterase GSH peroxidase Microsomal FAD-containing mono-oxygenase N-Acetyltransferase GSSG reductase Alcohol and aldehyde dehydrogenases GSH S-transferase Superoxide dismutase Epoxide hydrolase Thiol S-methyltransferase Catalase Prostaglandin synthase UDP glucuronosyl transferase DT-diaphorase Monoamine oxidase Sulfotransferase NADPH-generating pathways a Phase I enzymes catalyze oxidation, reduction, or hydrolysis. Phase II enzymes generally catalyze conjugation. Ancillary enzymes function in a secondary or supporting manner to facilitate drug metabolism. mals, gamma-glutamyltransferase activity is at its highest in the kidneys; there is also a wide range of activities in the liver and biliary epithelium (Ballatori et al., 1988; Hinchman and Ballatori, 1990). The relative contributions of the various organs can differ substantially in different species. Both intrarenal and interorgan metabolic pathways are important in the determination of susceptibility and the development of markers of toxic exposure. Each cell population possesses a distinct complement of drug-metabolism pathways, so the bioactivation mechanism for a specific chemical might differ among regions of the nephron. For example, one mechanism might occur in proximal tubular cells and another in the medullary thick ascending limb cells. Such biochemical heterogeneity probably contributes to the targeting of nephrotoxic chemicals to particular nephron cell types, and a given chemical might be a potent toxicant in one cell population and relatively inert in another (Lash, 1990). Renal drug-metabolism pathways and their role in bioactivation have been the subject of several excellent reviews over the last decade (Anders, 1980, 1989; Anders et al., 1988; Commandeur and Verneulen, 1990; Dekant et al., 1988a; Gram et al., 1986; Jones et al., 1980; Kaloyanides, 1991; Lash et al., 1988; Rush et al., 1984; Walker and Duggin, 1988). The major renal bioactivation pathways are cytochrome P-450, prostaglandin synthase, GSH conjugation, and the cysteine conjugate beta-lyase.

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Biologic Markers in Urinary Toxicology Cytochrome P-450-Dependent Activation of Nephrotoxicants The basic biochemistry of the renal cytochrome P-450 system is essentially the same as that of the more-studied hepatic system, but there are important differences involving substrate specificity patterns and inducibility (Jones et al., 1980). The various cytochrome P-450 isozymes and the associated electron-transport systems composed of both NADPH- and NADH-dependent cytochrome P-450 reductases are not uniformly distributed in the kidney but are found predominantly in the proximal tubular region (Guder and Ross, 1984; Jones et al., 1980). The toxicologic implication of this observation is that the cellular localization of the bioactivating enzyme system determines the site specificity of the toxicity. The basic principle is that reactive metabolites are generated by this enzyme system and are responsible for toxicity near the site at which they are produced. Examples of nephrotoxicants that are bioactivated by renal cytochrome P-450 are chloroform (Smith, 1986), acetaminophen and p-aminophenol (Newton et al., 1982), and cephaloridine (Tune, 1986). Prostaglandin H Synthase-Dependent Activation of Nephrotoxicants The ability of renal medullary tissue to oxidize drugs even though it lacks the cytochrome P-450 mono-oxygenase system (Guder and Ross, 1984) suggested that another system brings about these reactions (Spry et al., 1986). Prostaglandin H synthase (PHS) is a hemecontaining protein found predominantly in the interstitial and collecting duct cells of the renal medulla and in smaller amounts in Henle's loop and medullary thick ascending limb, and it is associated with the endoplasmic reticulum and nuclear membranes. Two reactions are catalyzed: a fatty acid cyclo-oxygenase step and a prostaglandin hydroperoxidase step. The cyclo-oxygenase activity, which is specifically inhibited by aspirin and indomethacin, is responsible for the initial his-dioxygenation of unsaturated fatty acid substrates, such as arachidonic acid. The product, a hydroperoxy cyclic endoperoxide, is reduced by the hydroperoxidase activity to the hydroperoxy form. The heme moiety of the peroxidase loses two electrons or gains oxygen during the reduction of peroxides. Rereduction of the peroxidase heme is accomplished by enzymatic removal of two electrons or donation of oxygen to a suitable electron donor, which acts as a reducing cosubstrate and is thereby oxidized (Spry et al., 1986). Although the specific endogenous cosubstrate has not been identified, tryptophan, ascorbate, and uric acid might function in vivo. Of toxicologic importance is the ability of some xenobiotics to function as reducing cosubstrates (Spry et al., 1986; Zenser and Davis, 1984). The cooxidations include dehydrogenations, demethylations, epoxidations, sulfoxidations, N-oxidations, C-oxidations, and dioxygenations (Anders, 1989). Once oxidized to reactive metabolites, the co-

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Biologic Markers in Urinary Toxicology Anders, 1991; Harris et al., 1992; Hayden et al., 1992; Hill et al., 1978; Inskeep and Guengerich, 1984). Those adducts might be useful as markers of exposure because they are generally chemically stable. The chemical nature of the thioacylating intermediate is important in determining the nephrotoxic response in that S-conjugates of chloroalkenes are both acutely nephrotoxic and mutagenic, but S-conjugates of fluoroalkanes are acutely nephrotoxic and not mutagenic (Green and Odum, 1985; Vamvakas et al., 1989c). Other Enzymes Involved in Cysteine S-Conjugate Metabolism Although the cysteine conjugate beta-lyase is the best characterized of the enzymes known to be involved in cysteine S-conjugate bioactivation, recent work has shown that several other enzymes can metabolize cysteine S-conjugates, and some of them also produce nephrotoxicity (Anders et al., 1988; Dekant et al., 1988a). These alternative metabolic pathways include the L-2-amino (hydroxy) acid oxidase found in rat kidney cytosol and peroxisomes, pathway 3 (Lash et al., 1990b; Stevens et al., 1989; Tomisawa et al., 1986; Webster and Anders, 1989); the cysteine conjugate S-oxidase, pathway 6, which is a flavin-containing mixed-function oxygenase found in both renal and hepatic microsomes (Lash et al., 1994; Sausen and Elfarra, 1990); the thiol S-methyltransferase, pathway 8 (Jakoby and Stevens, 1984); and N-acetylation to form the mercapturic acid, pathways 1a and 1b. The latter two are detoxification pathways that generate stable, nontoxic, and readily excreted products. As the kinetics and regulation of those interacting pathways become better understood, they will increase the ability to define susceptibility. Moreover, many of the terminal metabolites or products of reactive metabolites and cellular macromolecules can be developed into early markers of exposure. Susceptibility Factors in Cancers of the Genitourinary Tract Susceptibility factors for cancer can be either hereditary or acquired. Hereditary factors can be divided into factors that result from inheritance of one inactive allele for a tumor-suppressor gene and factors that result from inheritance of a metabolic type that places the individual at higher risk by virtue of how carcinogens or procarcinogens are metabolized. Heritability of defective alleles follows the original hypothesis of Knudson (1971), who demonstrated that retinoblastoma followed such a heritable pattern. Recently, Wilms's tumor has been shown to follow this pattern of heritance with the WT1 gene. One important finding has been that although such inherited cancers as retinoblastoma and Wilms's tumor are rare, the genes involved are often involved in sporadic cancers that develop later in life. In these cases, somatic damage to both alleles occurs. The human genome comprises 23 pairs of chromosomes, including one pair of sex chromosomes. Females have a pair of X chromosomes;

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Biologic Markers in Urinary Toxicology males have one X chromosome and one Y chromosome. The total display of these 46 chromosomes is called the human karyotype. Conventional karyotyping and interphase karyotyping with fluorescence in situ hybridization (FISH) are being used to identify common chromosomal abnormalities, which might identify chromosomes that contain tumor-suppressor genes or oncogenes. An inherited genotype can be a marker of susceptibility, but additional somatic alterations can provide markers of effect or disease that have utility as markers of prognosis. Cancer of the Kidney Familial and Sporadic Nonpapillary Renal-Cell carcinoma Karyotypic analysis of the individual chromosomes at mitosis, in cases of familial renal-cell carcinoma, has revealed translocations involving chromosomes 3 and 12 and chromosomes 3 and 6. Those translocations involve the exchange of segments of two chromosomes without the loss of any material. As described in Chapter 2, karyotypic analysis of patients with the von Hippel-Lindau disease has also identified abnormalities at chromosome 3 (Latif et al., 1993). The studies strongly implicate the short arm of chromosome 3 in the pathogenesis of renal-cell cancer; that is, the short arm might harbor a suppressor oncogene. The nonfamilial form of adenocarcinoma of the kidney is also linked to the short arm of chromosome 3 but in a different fashion (Gnarra et al., 1994; Herman et al., 1994). In the sporadic form of nonpapillary renal-cell carcinoma, there are deletions in chromosome 3 (Gnarra et al., 1994; Herman et al., 1994). In addition to deletions in chromosome 3, 65% of the cases of renal-cell carcinoma involve another chromosome, most frequently chromosome 5. Papillary Renal-Cell Carcinoma Papillary renal-cell carcinoma is a second type of renal parenchymal tumor. In contrast with the nonpapillary type, papillary renal-cell carcinomas do not demonstrate abnormalities principally on chromosome 3. The tumors have some of the characteristic changes consistent with duplications in chromosomes 7 and 17 and a loss of the Y chromosome in men. Polysomy of chromosomes 7 and 17 has been reported in 70–75% of the cases studied (Kovacs et al., 1991). Other findings include trisomy of chromosomes 12, 16, and 20, and the p53 tumor-suppressor gene is on chromosome 17. Cancer of the Bladder Karyotypic Studies To date, no gene has been specifically linked to bladder cancer, but gene mutations have been identified on a number of chromosomes that are commonly involved. The most frequent anomalies in bladder cancer are associated with chro-

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Biologic Markers in Urinary Toxicology mosomes 1, 7, 9, 5 and 11 and the Y chromosome. The most frequently observed anomaly is loss of all or part of chromosome 9, which is believed to be the most important cytogenetic event; it has been hypothesized that this chromosome contains the tumor-suppressor gene in bladder cancer, particularly cancer that develops along the low-grade papillary-tumor pathway. It has been proposed that markers of chromosomal loss, such as the deletion of chromosome 9, can occur not only in the tumor, but in dysplastic areas in the bladder. Metabolic Pathways and Susceptibility to Bladder Cancer The factors that activate or inactivate xenobiotic toxicants might be primary in bladder carcinogenesis. For example, acetylation inactivates aromatic amines, which are important carcinogens. Consequently, slow acetylators exposed to those compounds have a higher incidence of bladder cancer than do fast acetylators. The N-acetyltranferase (NAT) gene occurs as a single copy, and the rate of acetylation seems to depend on both transcriptional and translational events. Phenotypic analysis has revealed marked differences among ethnic groups. For example, there is a 1:1 distribution of slow to fast acetylators among North American Caucasians but a 1:9 distribution in the Japanese population. The metabolic pathways for acetylation and the differences in mutagenicity of the products complicate the scheme of slow and fast acetylators. For example, acetylation of some compounds, such as arylamines, reduces their carcinogenicity because the N-acetylated arylamines are poor substrates for PHS—a key enzyme in the oxidation of 2-naphthylamine and the expression of its carcinogenicity. But benzidine, which requires oxidation for its activation as a carcinogen, is a poor substrate for PHS in its unacetylated form. Thus, to characterize the susceptibility of a population to bladder cancer as a consequence of its exposure to those compounds, one should design a strategy that includes characterization of the metabolic pathways and the particular compounds to which the population is exposed. The NAT gene, which controls acetylation, and the CYP2D6 gene, which is a member of the P-450 oxidative enzymes, have each been a focus of such studies. Epidemiologic studies (Lower et al., 1979) support the metabolic information noted above. DNA Adducts DNA adducts constitute a direct, measurable chemical change in DNA in susceptible cells and can result from carcinogen exposure (Hemminki, 1993). DNA adducts are a more specific indication of exposure than is the excretion of metabolites; because the presence of DNA adducts demonstrates that the target molecule has been affected by the exposure, they can also be considered as the first marker of effect. In the blad-

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Biologic Markers in Urinary Toxicology der, the urothelial cells normally sloughed into the urine are convenient for monitoring bladder carcinogen exposure (Talaska et al., 1993). Although the identification of adducts does demonstrate exposure, it does not demonstrate that particular critical genes have been damaged. Adducts are often found in superficial cells, which will eventually be sloughed, so only the presence of adducts in bladder stem cells is significant for long-term carcinogenesis. The adducts indicate sites where mutations might occur when the cell divides. If these mutations persist, they potentially can serve as markers of effect. DNA adducts can be identified with very high sensitivity in the range of one adduct per 107 base pairs by 32P-post-labeling or immunoassays, but the concentration of adducts does not necessarily correlate with disease, nor has a dose-response been documented. The lack of a dose-response relationship might reflect the efficiency of DNA repair processes or the absence of adduct formation in critical basal cells. Alternatively, in the bladder it might reflect the efficiency of the bladder's protective mechanisms that limit exposure of the critical basal layer (Bodenstab et al., 1983). The efficiency of these mechanisms suggests that carcinogens delivered through the blood can be more effective than those delivered through the urine unless there is some pre-existing damage to the protective layer or urinary retention. As with all markers of exposure, interpretation in terms of individual risk requires linkage to susceptibility and specific effects. Acquired Conditions Predisposing to Bladder Cancer Some congenital and acquired clinical conditions influence susceptibility to bladder cancer. The most common and important might be urinary stasis and infection, both of which can result from bladder-outlet obstruction secondary to benign prostatic hyperplasia or neurologic dysfunction. An increase in the incidence of transitional-cell carcinoma by a factor of 15 has been associated with diverticulum of the bladder, which can be congenital or acquired. Stone disease, which also can be congenital or acquired, can predispose the bladder and renal pelvis to the development of cancer, which often is manifested in squamous cell carcinoma (Catalona, 1992). Special cases associated with the increased risk of cancer include inflammatory conditions, such as cystitis cystica and cystitis glandulares (Catalona, 1992). Patients with ureterosigmoidostomy (anastomosis of the ureter to the colon) can develop cancer at the site of anastomosis (Ambrose, 1983; Bergerheim et al., 1991; Filmer and Spencer, 1990). A common feature of the increased risk of these conditions might be the formation of nitrosourea compounds (which can be mutagenic) as a consequence of urinary stasis and infection. These special cases might provide clues to the identification of biologic markers of susceptibility. The linkage between cellular differentiation, proliferation, and carcinogen exposure is complex. Cohen and Ellwein

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Biologic Markers in Urinary Toxicology (1991) point out that the target for carcinogens is the stem cells of any epithelial layer because differentiating cells are fated to die apoptotically. Alterations in the ratio of differentiating to stem cells will lead to clonal expansion of an initiated cell. The role of differentiation can be complex. With 2-acetylaminofluorene (2-AAF) carcinogenesis, initiated bladder cells dedifferentiate sufficiently so that they no longer produce the enzyme that metabolizes 2-AAF to the proximate carcinogen and are therefore resistant to additional carcinogenic ''hits.'' Carcinogenesis must then depend on endogenous processes. In the liver, that is not true, so the two organs show quite different dose-response curves. Loss of apoptosis in differentiating cells will result in retention of an altered genotype that can continue to progress to the malignant phenotype. In summary, the balance between differentiating cells fated for apoptotic death and initiated cells, the differential effects of xenobiotic exposure on foci of initiated cells and on normal cells, and any differential proliferative responses among stem and differentiating cells or among initiated cells can lead to carcinogenesis. Cancer of the Prostate Few data support a prominent role for occupational or environmental toxicants in the genesis of prostatic carcinoma, but the sharp differences in prevalence of prostatic cancers around the world and the convergence toward a prevalence in migrated ethnic groups similar to that in indigenous populations suggest prominent environmental factors. Whether these factors are protective or promotive is not known. Familial studies indicate the presence of predisposing genetic factors, and families can be useful for defining markers of susceptibility in the form of suppressor genes or other genetic markers. Karyotypic changes that occur in prostatic cancer suggest the presence of a tumor-suppressor gene, as discussed below. An additional important factor is the introduction of prostate-specific antigen (PSA) as a marker of prostatic cancer that serves as a useful model of the advantages and disadvantages of identifying an early marker to detect disease; this is discussed in Chapter 4. Population Studies A finding of increased risk of prostatic cancer in probands of family members with prostatic cancer indicates the importance of genetic factors in disease susceptibility. In a case-control study, Spitz et al. (1991) observed an increased risk of 2.41 if a first-degree relative (i.e., father or brother) had prostatic cancer. Carter et al. (1992) conducted a case-control study of 691 men with prostatic cancer and 640 spouse controls. Fifteen percent of the cases but only 8% of the controls (p<0.001) had a father or brother with prostatic cancer. A proband with two or three

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Biologic Markers in Urinary Toxicology first-degree relatives with the disease experienced a risk of developing prostatic cancer increased by a factor of 5-11. In the same study, 29 "cancer families" were identified; they had an earlier age of onset of malignancies of multiple organ sites. Other cancers, including multiple myeloma and head and neck tumors, have been associated with prostatic cancer; this suggests the potency of the underlying carcinogenic process. In another study, Umbas et al. (1992) interviewed 355 patients with histologically proven prostatic cancer and 339 controls. Of the cancer patients, 21 (4%) had a family member with prostatic cancer, but 9.5% of the controls. With a first-degree relative affected, the incidence is 2.8 times that of the general population; with both a first-and a second-degree relative, incidence is 6.1 times. In an earlier study, Woolf reported a statistically significantly increased incidence of prostatic cancer in a Mormon population compared with controls (Woolf, 1960). That was also true of the family members of those originally identified as having prostatic cancer. For deaths related to cancers other than prostatic cancer, there were no significant differences between the two groups. In another study reported by Ghadirian et al. (1991), 140 prostatic cancer patients' families and families of 101 controls were interviewed. Of the prostatic-cancer patients, 15% gave history of the same cancer among first-degree relatives, compared with 2% of the controls (OR=8.7; CI=95%). The major limitation and the most difficult factor to control in these studies was the influence of the environment. Karyotypic Analysis Bergerheim et al. (1991) found deletions in chromosomes 8, 10, 16, and 18. The most frequent deletions (in 65% of cases) occurred on 8p, and the long arm of chromosome 16 had deletions 56% of the time. The results suggest that tumor-suppressor genes are localized on chromosomes 8, 10, and 16. Research to identify the genes associated with susceptibility clearly should have a high priority. Histopathologic findings confirm the importance of genetic alterations in chromosome 16. Additional studies in animals and humans have focused on the E-cadherin gene, on chromosome 16, as an important site. E-cadherin is a member of the cell-adhesion gene family, which is important in formation of gap junctions between cells. Abnormalities in this gene could be responsible for the histologic appearance of prostatic cancer cells, as reflected by the Gleason scoring system, and could be important in determining the tumor aggressiveness. Taken together, the findings suggest the existence of a tumor-suppressor gene that could be altered by an environmental toxicant so as to permit the development of cancer, as proposed in the Knudson hypothesis (see Chapter 2).

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Biologic Markers in Urinary Toxicology MAKERS OF EXPOSURE A critical issue in assessment of human exposure to environmental pollutants or other toxic chemicals is development of a marker of exposure that is noninvasive and sensitive. The goal is to enable early detection and therapeutic intervention and thereby prevent progression to chemical-induced injury. Measurements are typically made in urine to indicate exposure that involves renal metabolism or later renal toxicity or correlates with tumorigenesis in the genitourinary tract. Table 3-5 lists of environmental agents associated with cancer of the urinary tract. A distinction must be made between markers of exposure and markers of effect (injury), which are discussed elsewhere (see Chapter 4). Three issues must be considered: (1) What properties constitute a useful marker of exposure? (2) What techniques are available to measure these markers? (3) How can a marker of exposure be correlated with the dose that reaches a target tissue? Because the goal in using a marker of exposure is to detect exposure as early as possible, the marker should be highly sensitive and should be a stable indicator. The criterion of sensitivity means that the entity being measured (e.g., presence of a metabolite) should be detectable at a concentration below that at which any overt injury occurs. If that is not the case and the marker is not detectable until the exposure causes toxicity, the marker is not useful in helping to prevent injury. Once again, establishing the relevant concentrations is difficult when the risk of disease is low. TABLE 3-5 Cancers of the Urinary Tract Associated with Environmental Agents Renal parenchyma Renal adenoma and adenocarcinoma Aromatic amines Nitroso compounds Hydrazines Alkylating agents Anticancer drugs Cadmium and lead Squamous-cell carcinoma Various chemical carcinogens Chronic infections Renal Pelvis or Ureter Transitional-cell carcinoma Papillary tumors Various industrial carcinogens Urothelial carcinoma Balkan nephropathy Analgesics Bladder Transitional-cell carcinoma Cigarette-smoking Coffee-drinking Aromatic amines (2-naphthylamine, xenylamine) Squamous-cell cancer Chronic irritation, such as presence of urinary calculi Chronic urinary tract infection Neurogenic bladder Parasitic infection Adenocarcinoma Bladder extrophy Persistent urachus The criterion of stability refers to the chemical properties of the marker or metabolite; markers of exposure are generally terminal metabolites that are chemically unreactive (or not very reac

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Biologic Markers in Urinary Toxicology tive) and thus do not spontaneously decompose to other substances. If the marker is stable, it is assumed that it is formed in amounts that are proportional to exposure dose. That assumption depends on the kinetic properties of the enzymatic pathway responsible for generation of the metabolite. For example, if the enzyme that generates the terminal metabolite saturates at a relatively low substrate concentration, the amount of metabolite formed will not be proportional to exposure at normal doses. The Km of the critical enzyme therefore must be higher than substrate concentrations that are typically encountered. Most terminal metabolites are highly polar molecules that are readily excreted from the body. That provides a marker source (e.g., urine or feces) that makes the detection procedure noninvasive. The terminal metabolites that can often be used as markers and that are relevant to chemicals that can produce renal injury include N-acetylcysteine S-conjugates, sulfoxides, sulfones, thioethers, glucuronide conjugates, and sulfate conjugates. For most parent chemicals of interest, the metabolites are recovered in urine. It must be kept in mind that some xenobiotics, such as pesticides, can be retained within the body in fat; if they can mimic or alter hormonal factors, the tiny amounts that leach into circulation can have profound effects and be difficult to detect in the form of excreted metabolites. Many analytic techniques for detection and quantitation of terminal metabolites of drugs are available. The choice of method depends on the sensitivity required and on whether the analysis is being performed in laboratory animals or in humans. Radiolabeled drugs can be used and recovery of labeled metabolite can be determined as a sensitive marker of exposure, but this method is generally suitable only for laboratory animals. A variety of chromatographic methods can be used to identify metabolites of xenobiotics. They include high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS) and can provide unambiguous identification and measurement of metabolites by comparison with standards. The recent development of nuclear magnetic resonance (NMR) spectrometry techniques has expanded the ability to detect stable, terminal metabolites noninvasively, but NMR techniques are generally not very sensitive. HPLC analysis of urinary metabolites obtained after exposure of rats to the hepatotoxic and nephrotoxic halogenated hydrocarbon trichloroethylene showed only the oxidation products generated by cytochrome P-450 (Dekant et al., 1986a). It has been demonstrated, however, that a small portion of the administered trichloroethylene is metabolized by the GSH conjugation pathway and that this minor pathway is associated with nephrotoxicity (Dekant et al., 1987a). Therefore, even though more than 90% of metabolites is recovered by HPLC and it might be sensitive enough to indicate exposure, it might not be sensitive enough to detect the metabolites that are critical indicators of potential nephrotoxicity. For some of the halogenated hydro-

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Biologic Markers in Urinary Toxicology carbons, many of which are potent and specific nephrotoxic agents, 19 F NMR spectroscopy has been used to detect terminal metabolites in urine and in experimental situations. An example of the latter was the detection of stoichiometric amounts of chlorofluoroacetate as a stable metabolite of the nephrotoxicant chlorofluoroethene (Dekant et al., 1987b). Although the studies were performed for analytic purposes in in vitro preparations, the basic method is easily applied to metabolites of halogenated hydrocarbons in rat and human urine. A recent study by Harris and Anders (1991a,b) demonstrated formation of aldehydes and glucuronides as terminal metabolites. The relevance for human exposure analysis and risk assessment is that these and many similar chlorofluorocarbons are being investigated as substitutes for the ozone-depleting chlorofluorocarbons now in use. Because of the potential commercial importance of the substitutes, there is notable potential human exposure to them. As mentioned previously, HPLC or NMR might not be sensitive enough to detect metabolites of interest, GC-MS was used to detect and measure urinary metabolites of S-carboxymethyl-L-cysteine (CMC) in human urine (Hofmann et al., 1991). CMC is a model compound for characterizing the relative roles of the pertinent biotransformation pathways in humans. Many analogues of CMC, including several cysteine S-conjugates of halogenated hydrocarbons, are nephrotoxic and thus pose a health risk to humans. Study of human metabolism of CMC can suggest how the other nephrotoxic chemicals are handled. A different approach to the use of biologic markers for nephrotoxicant exposure was developed by Woods and colleagues (Bowers et al., 1992). They determined that urinary porphyrin excretion patterns are altered in response to methyl mercury exposure and that the changes can correlate with both the magnitude of exposure and whether irreversible renal injury has occurred. That is, a molecule other than a terminal metabolite of the chemical under study is being used as a marker of exposure. The HPLC, GC-MS, and NMR studies illustrate how the methods can be used for noninvasive measurement of stable terminal metabolites. They can provide two types of information: metabolite data can show which enzymatic pathways are involved in biotransformation of a xenobiotic, and a detected metabolite can be used as a marker of exposure to the xenobiotic. Interpretation of the first type of information can generally be straightforward because many terminal metabolites can be formed by only one pathway. In the latter case, however, it is not always simple to correlate urinary concentrations of a terminal metabolite with exposure; with the appropriate choice of metabolite, this can be achieved, and the metabolite can function as an early marker of exposure. SUMMARY For diseases of the urinary tract, the

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Biologic Markers in Urinary Toxicology most efficient program for determining the importance of occupational and environmental toxicants and carcinogens requires the identification of susceptible populations and the correlation of disease processes with the magnitudes and durations of exposure to the agents. Various factors modify human susceptibility to the effects of occupational and environmental nephrotoxicants and carcinogens. Although much of the information on nephrotoxic chronic renal failure is circumstantial and comes from epidemiologic surveys that started with ESRD patients, for some agents the evidence is substantial. The most obvious group at risk consists of persons exposed to known or suspected nephrotoxicants in the workplace. Also at risk are people who live in regions of documented contamination. The possible link between a family history of renal disease and the development of renal failure might be an inherited susceptibility or a common geographic exposure. Altered nutrition and some coexisting diseases, including addictive behavior, are additional characteristics that indicate increased risk associated with nephrotoxicants. Gender, race, and socioeconomic status provide tantalizing clues, but much more information needs to be collected than is currently available. Targeting populations at risk for future evaluation and followup is the most efficient strategy for the identification of patients early in the course of their toxic injury. This strategy might make it possible to introduce protective measures to reduce the progression of renal disease and to decrease the rate of entry of patients into ESRD programs. Susceptibility factors for cancer can be either hereditary or acquired. For example, various hereditary conditions are associated with the development of progressive renal disease. Moreover, specific genes that predispose people to develop disease, such as tumor-suppressor genes, have been identified. These people inherit one defective copy and are at much greater risk for cancer than people who have two intact copies. Likewise, individual variations in the metabolic pathways play a large role in susceptibility to both urogenital cancer and nephrotoxicity. The identification of specific markers of susceptibility and exposure is a daunting task. A susceptible person might be characterized by specific genotypic or phenotypic markers. Identifying these markers is likely to require a more complete understanding of the biochemical and physiologic properties of the kidney and lower urinary tract, as well as better insight into factors that control links between cellular growth, differentiation, proliferation, and malignant transformation. Consequently, these issues are addressed in detail in this report. The goal of identifying the markers is not to separate one population from another, but rather to identify exposures that can be tolerated by all.

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