7
CONCLUSIONS AND RECOMMENDATIONS

The recommendations of the Subcommittee on Biologic Markers in Urinary Toxicology follow in sequence the main sections of the report. This report brings into focus the limitations of current epidemiologic methods and laboratory tests for clearly defining the adverse effects of xenobiotics on the genitourinary tract. Current advances in epidemiology, biochemistry, molecular biology, and biologic-marker research have laid the groundwork for the development of programs of individual risk assessments and disease prevention. These programs will be most effective if implemented before the onset of irreversible nephrotoxicity or symptomatic cancer. To advance biologic-marker research, a multidisciplinary approach coupled with integration into a policy aimed at disease prevention could substantially reduce the adverse health effects associated with toxic exposures and the accompanying costs. The ability to assess an individual's risk, as opposed to a group risk, offers an additional approach to protecting the health of workers and the general public. In the conclusions and recommendations that follow, parallels have been drawn, when possible, between the effects of nephrotoxicants and those of other xenobiotics that are involved in carcinogenesis or have other adverse effects on the kidney, bladder, or prostate.

TOXIC EXPOSURE OF THE URINARY TRACT

The Kidney

Conclusion

In a substantial number of persons who have ESRD, the precise cause of kidney failure is unknown. Despite the data that have been collected on the nature of the patient population with ESRD, a definitive statement about the impact of occupational and environmental nephrotoxicants cannot be made. Specifically, the subcommittee noted the disproportionate incidences of ESRD among minority populations in the United States, and it has become known that several factors—including



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Biologic Markers in Urinary Toxicology 7 CONCLUSIONS AND RECOMMENDATIONS The recommendations of the Subcommittee on Biologic Markers in Urinary Toxicology follow in sequence the main sections of the report. This report brings into focus the limitations of current epidemiologic methods and laboratory tests for clearly defining the adverse effects of xenobiotics on the genitourinary tract. Current advances in epidemiology, biochemistry, molecular biology, and biologic-marker research have laid the groundwork for the development of programs of individual risk assessments and disease prevention. These programs will be most effective if implemented before the onset of irreversible nephrotoxicity or symptomatic cancer. To advance biologic-marker research, a multidisciplinary approach coupled with integration into a policy aimed at disease prevention could substantially reduce the adverse health effects associated with toxic exposures and the accompanying costs. The ability to assess an individual's risk, as opposed to a group risk, offers an additional approach to protecting the health of workers and the general public. In the conclusions and recommendations that follow, parallels have been drawn, when possible, between the effects of nephrotoxicants and those of other xenobiotics that are involved in carcinogenesis or have other adverse effects on the kidney, bladder, or prostate. TOXIC EXPOSURE OF THE URINARY TRACT The Kidney Conclusion In a substantial number of persons who have ESRD, the precise cause of kidney failure is unknown. Despite the data that have been collected on the nature of the patient population with ESRD, a definitive statement about the impact of occupational and environmental nephrotoxicants cannot be made. Specifically, the subcommittee noted the disproportionate incidences of ESRD among minority populations in the United States, and it has become known that several factors—including

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Biologic Markers in Urinary Toxicology race and economic status—can be important predicters of ESRD. The lack of specific and comprehensive information on the impact of occupational and environmental nephrotoxicants on diseases of the kidney and urinary tract is troublesome. The possible correlations between the development of clinically significant renal disease and race, economic status, and exposure to occupational and environmental nephrotoxicants suggest the need for epidemiologic studies. Recommendation For patients entering programs for treatment of ESRD, details of occupational history or other factors that would show the impact of patients' environments on their condition should be obtained. As a first step, available information in relevant databases should be examined. Studies should be undertaken to determine whether the higher incidences of ESRD among minority groups and the economically disadvantaged are related to occupational or environmental exposure to nephrotoxicants. Epidemiologic studies need to focus on the various populations at risk; this focus should include not only the identification of the populations but their continued monitoring. Conclusion Some susceptible populations in the United States have anatomic or physiologic differences in the kidneys at birth that might help to explain their propensity for renal damage. As a result, they are less tolerant of various stresses, including exposure to environmental or occupational nephrotoxicants. Although emphasis has been placed on the toxicity of environmental and occupational nephrotoxicants, as well as diagnostic and therapeutic agents, a less well-defined problem is the frequency and severity of renal injury that results from recreational-drug use. Understanding the spectrum of urologic and renal diseases that might be produced by occupational or environmental agents requires integration of studies of the anatomy, biochemistry, and physiology of the kidney in conjunction with knowledge of the mechanisms of injury and disease. Recommendation Studies should be performed to determine whether an association between anatomic or physiologic differences of the kidney at birth and the later response to environmental or occupational nephrotoxicants leads to susceptibility to disease or to progression once disease occurs. Data should be collected on the incidence of renal abnormalities among recreational-drug users to determine the influence of those substances on the rate of progression of renal disease due to other causes. Basic studies are needed to deter-

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Biologic Markers in Urinary Toxicology mine the effects of occupational and environmental toxicants on specific segments of the kidney. These effects should be correlated with biochemical and anatomic changes. The Bladder Conclusion Bladder cancer has been strongly associated with xenobiotic exposure. The bladder is an accessible site and is therefore an excellent model system for investigations of xenobiotic carcinogenesis. Recommendation Human bladder cancer induced by xenobiotic exposure in worker cohorts should be investigated to develop strategies of individual risk assessment, to formulate programs for prevention, and to evaluate new forms of therapy. Strategies of individual risk assessment need to be developed as the cornerstone of prevention. Once cohorts of at-risk persons are identified, they should be enrolled in long-term monitoring studies to assess the efficacy of prevention and treatment strategies. Conclusion Xenobiotics are potentially of importance in diseases of the bladder other than cancer. Recommendation Further research on the direct effect of xenobiotics on the bladder and the interactions of xenobiotics with the protective mechanisms of the bladder is very likely to uncover additional evidence that the bladder is a target organ. Markers associated with susceptibility should be identified to define the higher relative risk of disease in an exposed subset of the population. The Prostate Conclusion In the United States, widespread screening for prostatic cancer has become accepted for white men over the age of 50 and black men over the age of 40. This screening has been associated with a high false-positive rate. In addition, quiescent disease is not sufficiently differentiated from biologically active disease. Recommendation Options for improving the efficacy of screening procedures should be studied. Tests with lower false-positive rates should be developed, as should tests able to detect premalignant changes and to separate quiescent from biologically active disease.

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Biologic Markers in Urinary Toxicology BIOLOGIC MARKERS OF EXPOSURE AND SUSCEPTIBILITY The most efficient program for determining the importance of occupational and environmental toxicants and carcinogens in diseases of the urinary tract would include the identification of various susceptible populations and the correlation of disease processes with exposure to the agents. Linking markers of susceptibility and effect with markers of exposure is potentially a very powerful strategy for individual risk assessment. Biologic markers substantially increase the ability to evaluate the importance of low-level exposures, whether single or multiple. Conclusion To use markers to their greatest advantage, high-risk populations must be targeted. Recommendation Populations at risk of renal insults and carcinogenesis should be defined. Markers of human exposure and susceptibility should be sensitive (i.e., detectable before injury occurs), noninvasive, and chemically stable. Conclusion Susceptibility of particular populations is important in determining the onset of many diseases. Various factors modify human susceptibility to the effects of occupational and environmental nephrotoxicants. For example, specific genes that determine whether people are predisposed to develop disease have been identified. Some people inherit one defective copy of a tumor-suppressor gene and are at much greater risk for cancer than people who have two intact copies. Likewise, individual variations in metabolic pathways play a large role in susceptibility to cancer and toxicity. The goal of identifying markers of susceptibility and exposure is not to separate one population from another but rather to limit exposure to magnitudes that are tolerated by all. Recommendation Genetic and nongenetic factors that modify susceptibility to occupational and environmental genitourinary toxicants and carcinogens should be considered in the evaluation of individual susceptibility. These include sex, race, nutrition, socioeconomic factors, age, coexisting chronic disease, and drug abuse. Conclusion Some forms of renal disease are closely associated with chronic exposure tonephrotoxic agents, such as the renalinjury that accompanies heavy use of analgesic agents, including nonsteroidalanti-inflammatory drugs. In others, the

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Biologic Markers in Urinary Toxicology data relating exposure to disease are circumstantial but highly suggestive, such as the renal injury that has been associated with exposure to various hydrocarbons. Recommendation Markers of exposure and susceptibility should be identified to determine the relationship between coincident exposure to nephrotoxicants and the development or progression of chronic renal disease. Particular attention should be given to the role of widespread and sometimes excessive use of analgesics, including non-steroidal anti-inflammatory drugs, in diseases of the urinary tract. Clinicians should be aware of the danger associated with abuse of these agents and should query renal-disease patients about their use. In particular, patients with established renal disease should be wary of exposure to these agents and other potential nephrotoxicants. BIOLOGIC MARKERS OF EFFECT Biologic markers of effect are pivotal in defining preclinical genitourinary and premalignant disease and are key to the prevention of nephrotoxicity and cancer. Biologic markers of effect are key to relating biologic markers of exposure and susceptibility to disease. Conclusion The "ideal" biologic marker of effect has been described in this report. No such ideal marker has been developed for the kidney, but a variety of markers have found wide acceptance. Because they might reflect different aspects of renal function, become detectable at different stages of exposure, or have different sensitivities and analytic reliability, no single test should be relied on for the demonstration of renal effects. Understanding the functional role of markers of effect is important in defining pathogenesis. Recommendation A battery of relatively simple and noninvasive tests should be used as a first step in screening populations at risk. On the basis of available information and technology, adequateinitial screening results should be obtained by testing for proteinuria with dipsticks and then measuring urinary concentrating ability and serum creatinine and, for more sensitive measurements of tubular integrity, monitoring for an increase inurinary enzyme or low-molecular-weight protein excretion. Application of those tests to a population exposed, for instance, to diagnostic procedures or treatment with nephrotoxicants might identify early renal damage with adequate sensitivity.

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Biologic Markers in Urinary Toxicology Conclusion Among established procedures for screening populations at risk, urinalysis and clearance measurements will continue to yield important functional markers of renal injury. The usefulness of clearances for evaluation of glomerular filtration would be much increased by the development of nonisotopic techniques for measuring, e.g., iodothalamate or chromium ethylenediaminetet-raacetic acid in plasma or urine. A number of testing procedures in addition to the well-established ones have been cited. Recommendation Several of the newer testing procedures hold promise of future usefulness and should be further investigated. Among them are tests of urinary excretion of various growth factors, such as epidermal growth factor (EGF), and other tubular enzymes, such as intestinal alkaline phosphatase (LAP); both reflect some specificity of localization along the nephron and of cellular origin. Conclusion Molecular techniques have identified a variety of potentially useful markers of renal-cell injury. These include the products of expression of some early genes and changes in the expression of renal cytokines, growth factors, and growth factor receptors. Recommendation It is highly likely that studies of these and similar molecular events will yield better markers of effect, and continued research in this area should be encouraged. Conclusion Fundamental advances have been made in the last decade in understanding the genetic basis of cancer and how it results from the subversion of normal growth controls by genetic and epigenetic mechanisms. Important species differences have been identified, and itis important to study cancer in humans, in whom stromal-epithelial interactions and the specific genetics of growth control are manifested. Recommendation Understanding fundamental cellular and molecular mechanisms of growth control in human tissues undergoing carcinogenesis (e.g., high-risk occupationally exposed populations or patients with premalignant processes) should be emphasized, because it is highly likely that more

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Biologic Markers in Urinary Toxicology specific markers of effect will beidentified and allow early intervention. Conclusion Cancer and many other diseases can have an important preclinical phase. Markers that define progress along the course of disease would be of value. Recommendation Markers that define preclinical disease should be identified. Conclusion Carcinogenesis involves mutational events that are primary and events that occur as a result of genetic instability. Recommendation Markers that detect xenobiotic-induced mutational events should be identified. USE OF BIOLOGIC MARKERS IN EXTRAPOLATION Conclusion The human being is the best systemto study for the identification of biologic markers. However, practical concerns and the expanding number of potential biologic markers mandate selected studies of nonhuman systems to develop an understanding of the biology underlying marker expression. Suchstudies have proved to be of considerable value and are necessary for a full appreciation of the effects of xeno-biotics. Information gained from the study of environmental and occupational nephrotoxicants has been of fundamental value in identifying susceptible populations, reducing exposure, and modifying effects. Animal models and in vitro systems have utility for studying basic mechanisms and for identifying potential biologic markers and the effects of xenobiotics on whole organisms. The importance of living organisms for studies of xenobiotic tissuesis recognized. Despite the advent of alternative research methods, animal studies continue to be necessary to prevent or minimize the impact on human populations. Recommendation Models for the identification and validation of markers should continue to be developed. The modelsmust have sufficient sensitivity to distinguish between normal and abnormal function and must correlate well with known human toxicities. The models also must distinguish between functional alterations and pathologic changes. To obtain those

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Biologic Markers in Urinary Toxicology characteristics, it will be necessary to develop and apply new technologies. Issues related to cost effectiveness should be considered. Whole-animal studies should be used to establish target-organ specificity and to assess renal function in relation to survival. Species, sex, and strain differences must be taken into account in selecting animal models for particular uses. In vitro methods should be used for mechanistic studies; the choice of models should depend on compatibility and validation with whole-animal studies. Metabolic studies should be conducted to ascertain whether xenobiotics (or other agents) are biotransformed to reactive and toxic species and to identify sites of transformation, including renal tissue and other tissue in the urinary tract. NEW TECHNOLOGIES Two branches of study are central to the development of new markers: research into the mechanisms of cell growth, regeneration, and proliferation; and further study of the metabolic capacities of the kidney. Two categories of dispute are acknowledged: the problems that can emerge from the too rapid and widespread use of a single marker for a specific disease, as typified by the introduction of the test for prostate-specific antigen (PSA) for the detection of prostatic cancer; and the problems associated with extrapolation from animal studies to human conditions, as illustrated by the interpretation of the importance of renal accumulation of alpha2u-globulin. Conclusion Cell repair can occur in response to cell injury. Thus, markers of cell growth, regeneration, and proliferation can indicate injury and be particularly useful when an injury is difficult to detect. In this circumstance, markers of repair may be the only indication that injury has occurred. This class of markers is not fully developed and holds promise as a new generation of markers. Recommendation Research should continue toward better understanding of the mechanisms of cell injury, because they can underlie the development of new markers. Emphasis should also be placed on understanding the mechanisms of cell growth, regeneration, and proliferation. Insight into the factors that control the cell cycle, regulate various growth factors, influence gene expression, and modulate nucleic acid synthesis might be critical in the development of new classes of markers. Conclusion Changes in metabolic pathways can

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Biologic Markers in Urinary Toxicology also occur in response to cell injury. Thus, biochemical markers associated with these pathways can be of value in detecting nephrotoxicity and carcinogenesis. Like markers of cell growth, regeneration, and proliferation, this class of markers is not fully developed and holds substantial promise. Recommendation Research should continue toward better understanding of the metabolic pathways of the kidney in relation to the effects of xenobiotics and susceptibility to them. Conclusion Understanding of the mechanisms of both cell growth and metabolism will allow further definition of the steps in the initiation and progression of various urinary tract cancers. It is anticipated that parallels will emerge that will yield insight into the progression of parenchymal renal disease. Recommendation Attention should be directed toward a deeper understanding of the mechanisms by which proto-oncogenes, tumor-suppressor genes, and epigenetic factors regulate the cell cycle and how damage to these mechanisms is related to disease. Attention should also be directed toward the elucidation of metabolic pathways, particularly as they are related to the production of toxic metabolites. Additional markers should be identified that help to identify populations at risk and to study the mechanisms by which environmental and occupational toxicants promote cancer. Conclusion Observations of the effects of growth factors on the prostate are conflicting. There are several reasons for the differences. First, assay methods are not uniform. Second, cells under study might have both low and high-affinity receptors for a given peptide; cell response could depend on the strength of the signal and the concentrations of peptide. Third, both normal and neoplastic tissues are heterogeneous, and the expression of a given protein can vary widely among cells in different regions. Fourth, tumors might be hormonally sensitive or insensitive. Recommendation Research on the relation of growth factors to the prostate requires rigorous experimental approaches and designs and must consider multiple variables. Studies of biochemical changes in the areas next to a prostatic tumor might be more informative than analysis of the cancer itself.

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Biologic Markers in Urinary Toxicology Conclusion Several agents share a curious relationship between nephrotoxicity and renal carcinogenesis. One example involves the response to lead exposure, which can lead to either acute or chronic lead nephropathy and under some circumstances can be associated with renal tumors. Recommendation The general relationship between nephrotoxicity and renal carcinogenesis should be explored. Conclusion The technology that is likely to yield new markers is complex. Equally complex is the identification of susceptible populations with the appropriate clinical assessment of exposure and effect. The use of biologic markers is essential in the examination of xenobiotic-induced diseases and other diseases of the human kidney, bladder, and prostate. Comprehending the sequences of events is an iterative process that involves a complex data set derived from scientific advances in molecular biology, epidemiology, pathology, biochemistry, and clinical medicine. Assembly of those data into an organized framework will be a major step toward individual risk assessment and should be a long-term objective. Recommendation To achieve the desired goal of identifying more-useful markers, cooperation between laboratory scientists, epidemiologists, and clinical researchers should be encouraged. Assays, particularly those involving enzymes or molecular probes, must be replicable in different laboratories.