EXECUTIVE SUMMARY

Diseases of the kidney, bladder, and prostate exact an enormous human and economic toll on the population of the United States. According to the 1993 Annual Data Report from the U.S. Renal Data System, in the United States, some 165,000 people with irreversible renal failure received renal-replacement therapy for end-stage renal disease (ESRD) in 1990 with the aid of chronic dialysis therapy, and 9,800 renal-transplant procedures were performed in the same year. The federal government spent $5.22 billion in 1990 to provide maintenance dialysis, kidney transplantation, and all other health services to ESRD patients. With regard to cancer, the figures are equally striking. In 1989, 47,000 new bladder-cancer cases and 10,000 bladder-cancer deaths were reported. About 18,000-20,000 new cases of cancer of the kidney are diagnosed each year in the United States, and they result in 8,000 fatalities a year. Prostatic cancer, the most frequent cancer in men in the United States, resulted in about 36,000 deaths in 1992 and carries with it an annual cost for diagnosis and care of more than $1 billion.

With the sponsorship of the Agency for Toxic Substances and Disease Registry (ATSDR) and the National Institute of Environmental Health Sciences (NIEHS), the National Research Council formed the Subcommittee on Biologic Markers in Urinary Toxicology of the Committee on Biological Markers to undertake a study of biologic markers in the urinary tract. Previous subcommittees of the Committee on Biological Markers have published separate volumes on reproductive and developmental toxicology, pulmonary toxicology, and immunotoxicology. The Subcommittee on Biologic Markers in Urinary Toxicology, which prepared this report, comprised scientists with diverse backgrounds in and knowledge of nephrology, urology, pathology, renal toxicology and metabolism, pharmacokinetics, immunology, risk assessment, pharmacology, renal physiology, and other disciplines.

In response to the charge to the subcommittee, this report discusses current



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Biologic Markers in Urinary Toxicology EXECUTIVE SUMMARY Diseases of the kidney, bladder, and prostate exact an enormous human and economic toll on the population of the United States. According to the 1993 Annual Data Report from the U.S. Renal Data System, in the United States, some 165,000 people with irreversible renal failure received renal-replacement therapy for end-stage renal disease (ESRD) in 1990 with the aid of chronic dialysis therapy, and 9,800 renal-transplant procedures were performed in the same year. The federal government spent $5.22 billion in 1990 to provide maintenance dialysis, kidney transplantation, and all other health services to ESRD patients. With regard to cancer, the figures are equally striking. In 1989, 47,000 new bladder-cancer cases and 10,000 bladder-cancer deaths were reported. About 18,000-20,000 new cases of cancer of the kidney are diagnosed each year in the United States, and they result in 8,000 fatalities a year. Prostatic cancer, the most frequent cancer in men in the United States, resulted in about 36,000 deaths in 1992 and carries with it an annual cost for diagnosis and care of more than $1 billion. With the sponsorship of the Agency for Toxic Substances and Disease Registry (ATSDR) and the National Institute of Environmental Health Sciences (NIEHS), the National Research Council formed the Subcommittee on Biologic Markers in Urinary Toxicology of the Committee on Biological Markers to undertake a study of biologic markers in the urinary tract. Previous subcommittees of the Committee on Biological Markers have published separate volumes on reproductive and developmental toxicology, pulmonary toxicology, and immunotoxicology. The Subcommittee on Biologic Markers in Urinary Toxicology, which prepared this report, comprised scientists with diverse backgrounds in and knowledge of nephrology, urology, pathology, renal toxicology and metabolism, pharmacokinetics, immunology, risk assessment, pharmacology, renal physiology, and other disciplines. In response to the charge to the subcommittee, this report discusses current

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Biologic Markers in Urinary Toxicology ly known genitourinary tract biologic markers, emphasizes the need to identify and evaluate promising technologies to find new markers, and identifies important research opportunities. The report discusses the structure and function of the urinary tract, toxic effects associated with the urinary tract, and their risk factors. Relationships between exposure, susceptibility, and the associated markers are described, and the usefulness of markers in monitoring urinary diseases is discussed. The report presents a rationale, based on epidemiologic studies, for the use of biologic markers in the protection of human health and the extrapolation of data from animals to humans. Currently available biologic markers in the genitourinary tract are discussed throughout the report and summarized in Chapter 4, although exhaustive descriptions of these are readily available elsewhere. Several characteristics of the normal genitourinary tract increase the risk of damage by toxic chemicals. For example, the total amount of noxious substances delivered to the kidneys can be high, owing to the large amount of blood flowing to them. Furthermore, the capacity of the kidneys to concentrate substances by processes of filtration, reabsorption, and secretion can increase the toxicity of agents that would otherwise not lead to tissue damage. This is particularly important in the bladder, which is routinely exposed to concentrated toxicants. Also important are the mechanisms of biotransformation by which the kidney and bladder epithelium can metabolize xenobiotics and produce substances that might be more toxic than the parent substance. Biologic markers can be useful in confirming toxic exposures (i.e., biologic markers of exposure), estimating their results (i.e., biologic markers of effect), and identifying persons most likely to be adversely affected if exposures continue (i.e., biologic markers of susceptibility). Markers of exposure. A biologic marker of exposure is a xenobiotic chemical or its metabolite or a product of interaction between the chemical and some target cell. Markers of exposure most commonly used are the concentrations of such materials in urine, blood, or other body tissue, including hair and nails. Markers of exposure alone give no indication whether an exposure has produced a biologically significant result. The same dose in persons who are susceptible and resistant to a given xenobiotic can have different results. Urine is one source of markers of exposure. High exposures to a toxic substance can result in increased concentrations of the substance or its metabolites in urine. When sufficient pharmacokinetic information is available, urinary markers of exposure can be used to estimate the total exposure of a person to a substance. Markers of effect. A marker of effect is a measurable cellular, physiologic, or biochemical alteration within an organism caused by interaction with a toxicant. Markers of adverse effect can be biochemical or cellular signals of tissue

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Biologic Markers in Urinary Toxicology dysfunction, increased enzyme activity, the appearance of excessive waste products in the urine or other sampling media, and physiologic signs of abnormal function, such as increased blood pressure or blood in the urine. The effects themselves might not be directly adverse, but rather might indicate a potential for health impairment (e.g., DNA adducts). Biologic markers of effect include changes in the components of urine itself (such as an increase in urinary protein excretion or cellularity) and changes in the volume or composition of other body fluids caused by kidney dysfunction. With impaired renal function, excretion products such as creatinine and urea can accumulate in the blood. Increased blood concentrations of these products can be markers of renal damage, although they are not particularly useful as markers except in cases of severe damage. Other markers of renal toxicity can be present in urine because of altered renal function or damage to the kidney. Many of these can be detected in examination of the urine, including color, volume, pH, specific gravity, albumin, electrolytes, enzymes, and elements in the urinary sediment. Markers that could show up there include white and red blood cells, kidney epithelial cells, casts, and crystals. Markers of susceptibility. A marker of susceptibility is an indicator of an inherited or acquired limitation of an organism's ability to resist the adverse effects of exposure to a xenobiotic substance. A biologic marker of susceptibility can be a genetic characteristic or a pre-existing disease that results in an increase in the amount of a toxicant absorbed, an alteration in its metabolism, or an increase in the target-tissue response. It can be difficult to distinguish between susceptible and nonsusceptible persons, either because of multiple interactive influences and genetic polymorphisms or because of difficulties in measuring markers of susceptibility. Potential sources of normal variability in markers of susceptibility can be the result of concurrent disease or genetic, environmental, or bio-rhythmic influences other than the specified toxicologic events that are the object of study. Such influences can cause differences between populations, differences between individuals, and differences within individuals over time. Decreased detoxification and excretory function are often important factors in susceptibility. Thus, elderly persons with declining organ function and young persons with immature and developing organs are likely to be more vulnerable to toxic substances than healthy adults. EFFECTS OF TOXIC EXPOSURE OF THE URINARY TRACT Advances in understanding and using biologic markers should assist in identifying xenobiotics that are toxic to the urinary tract. The functional role of the urinary tract, including clearance of toxic substances from the blood, predisposes it to xenobiotic exposure and toxicity. Historically, identification of the type and amount of xenobiotic exposure

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Biologic Markers in Urinary Toxicology has been difficult, frequently because of the interval between exposure and the onset of disease. Blacks and other minority groups, for reasons that are not entirely apparent, are at higher risk of disease. In diseases such as bladder cancer, xenobiotics associated with particular occupations are strongly implicated, and their mutagenic effects may be important. However, in kidney cancer and other renal diseases, a number of host factors, as well as the typically low levels of exposure to multiple xenobiotics and such confounding variables as smoking and genetic susceptibility, often mask the epidemiologic importance of individual xenobiotics. A powerful approach toward unraveling the complexities of xenobiotic exposure is to integrate biologic markers of susceptibility with biologic markers of effect. Some xenobiotics are known to cause acute renal failure. Heavy metals and organic solvents stand out in this regard. There are several well-established associations between xenobiotic exposure and the development of chronic renal failure, as exemplified by exposures to lead and cadmium. The association of bladder cancer and occupational exposure to aniline dyes serves as a paradigm for the potential adverse health effects of xenobiotics. Environmental agents have also been implicated in the development of neoplasms in the kidney. Some of these can be facilitated by acquired or inherited genetic defects. The association of xenobiotic exposure and cancer of the prostate and interstitial cystitis is less certain but merits attention. BIOLOGIC MARKERS OF SUSCEPTIBILITY AND EXPOSURE For diseases of the urinary tract, the 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 for understanding risk, but much more information needs to be collected than is currently available. Targeting populations at risk for future evaluation and follow-up is the most efficient strategy for the identification of patients early in the

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Biologic Markers in Urinary Toxicology 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 genetic conditions that predispose people to develop disease, such as the absence of a tumor-suppressor gene, have been identified. People who inherit one defective copy of a tumor-suppressor gene are at much greater risk for cancer than those 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. The susceptible individual 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 the linkages between cell growth, differentiation, proliferation, and malignant transformation. Consequently, these issues are addressed in detail in this report. The goal of identifying these markers is not to separate one population from another, but rather to identify exposures that can be tolerated by all. BIOLOGIC MARKERS OF EFFECT The ideal cytologic marker of nephrotoxicity would represent a nonspecific, if not universal, cellular response to injury. Such a marker should be produced in the kidney and secreted into urine in a readily detectable form. Substantial changes in urinary concentration of the marker should correlate well with pathophysiologic or histopathologic manifestations of kidney injury. The marker should be expressed soon after injury is sustained. Persistence of marker expression would increase its clinical value. The marker should be relatively easy to measure. It should be stable in storage, resistant to degradation, and unambiguously identifiable. In the search for suitable markers, more emphasis should be placed on the response to injury of tubules and interstitium, because these compartments appear to be the major sites of susceptibility to toxic injury. Finally, extensive use must be made of appropriate animal models to evaluate potential markers, because complex responses of intact organisms (vis-a-vis isolated systems) can influence response to injury, inflammation, and repair in vivo. Several markers that fulfill many of the above criteria have already been identified. Urinalysis and clearance measurements will continue to provide important functional markers of renal injury. Of particular use in that regard would be a nonisotopic technique for analyzing iodothalamate or chromium ethylenediaminetetraacetic acid (Cr-EDTA), both markers of glomerular filtration rate.

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Biologic Markers in Urinary Toxicology There is no ''ideal'' marker, i.e., a single marker able to provide all the information necessary to identify people at risk. The main priority for research should be the identification of strong markers that define preclinical, potentially dangerous disease. Addressing disease at this point minimizes costs, morbidity, and mortality and is now possible because of the availability of biologic markers. BIOLOGIC MARKERS IN EXTRAPOLATION Extrapolation from animal models is a common and necessary component of risk assessment for humans. To improve the validity of such extrapolations, a better understanding of the relationship between these markers and disease is needed. In most cases, the scientific basis for assuming that animals are good surrogates for humans, and therefore a suitable basis for extrapolation to humans, is overwhelming. It is reasonable to use animal models for extrapolation to humans unless specific information on specific chemicals indicates otherwise. Identification of chemical hazards should include assimilation and evaluation of all relevant information, including appraisal of physical and chemical properties and structure-activity relationships, which often can provide important indications of potential toxicity. Difficulties in diagnosing renal injury and predicting its health consequences are considerable, primarily because the kidneys can undergo substantial chemically induced injury without any clinical manifestation, and subtle injury can be negligible because of the considerable functional reserve of the kidneys. Standard diagnostic criteria are needed that are sensitive enough to serve as markers of renal damage in the presence of renal functional reserve. Only whole-animal studies or observations in humans can provide information on the operation of multiple cells, tissues, and organs under the influence of complicated feedback mechanisms. Animals are necessary in the study of chemically induced toxicity, because studies that involve modulation of cellular responses and tissue-sampling cannot be appropriately performed in humans. The first stage of any investigation of nephrotoxicity of a xenobiotic should be in vivo studies. In the absence of any knowledge about potential toxicity and target-organ specificity, the first step should be to determine whether toxicity occurs and the tissue distribution of the toxic response. More detailed studies, both in vivo and in a variety of in vitro models, can then be pursued to elucidate modes of chemical action, specific mechanisms of toxicity, and potential protective or preventive strategies. A variety of experimental model systems are available for study of renal metabolism, function, and nephrotoxicity. Such systems range from whole-animal studies to those in the isolated perfused kidney, kidney slices, isolated nephron segments, isolated tubule fragments, and isolated renal cells. Each model has advantages and limitations that must be taken into account when developing conclusions and extrapolating animal data to human risk assessment. In vitro

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Biologic Markers in Urinary Toxicology models of nonrenal urinary tract epithelia have also been developed and applied primarily to examination of carcinogenesis. Development of markers of exposure and susceptibility has not been addressed directly with such nonrenal models and should be pursued for better extrapolation of data for risk assessment. 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. Consequently, patterns observed and conclusions reached in one species might not apply to another species. The sub-committee recommends that species and strain differences in disposition and metabolism be evaluated for each chemical or class of chemicals. For assessing risk, any experimental model should account for individual variability in response and in health and environmental status. Differences in those factors will alter susceptibility to potentially toxic chemicals. 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 importance of urinary excretion of alpha2u-globulin. Cell repair can occur in response to cell injury. Thus, markers of cell growth, regeneration, and proliferation can indicate injury and can be particularly useful when an injury is difficult to detect. In this circumstance, markers of repair might 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. Changes in metabolic pathways can 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. Improved understanding of the mechanisms of cell growth and metabolism will enable 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. 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. Compre-

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Biologic Markers in Urinary Toxicology hending 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 improving risk assessment and should be a long-term objective. In an increasingly complex technical and industrial society, exposure to xenobiotics is unavoidable. Health hazards are undeniably associated with such exposure, and they should be monitored to prevent or modify disease. Some forms of parenchymal renal disease and cancer of the kidney and bladder are among the conditions associated with xenobiotic exposure. The development of reliable markers of susceptibility, exposure, and effect is among the first steps to be taken toward prevention of diseases of the kidney, bladder, and prostate. Indeed, the advent of new technologies in molecular biology and sophisticated understanding of metabolic pathways holds promise that markers can be developed and prevention of the diseases achieved. Classical approaches to the study of nephrotoxicants and carcinogens should not be disregarded, however; for example, the utility of animal studies in the study of xenobiotics has been emphasized in this report. THE SUBCOMMITTEE'S RECOMMENDATIONS The subcommittee's recommendations follow the contents of this report: General (toxic exposure to the urinary tract overall—kidney, bladder, and prostate); Biologic Markers of Exposure and Susceptibility; Biologic Markers of Effect; Biologic Markers in Extrapolation; and New Technologies. General The Kidney For patients entering programs for treatment of end-stage renal disease (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. Studies should be performed to determine whether an association between anatomic or physiologic differences of the kidney at birth and a 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

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Biologic Markers in Urinary Toxicology of progression of renal disease due to other causes. Basic studies are needed to determine 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 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. 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 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. Biologic Markers of Exposure and Susceptibility Populations at risk of identifiable 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. 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. Markers of exposure and susceptibility should be identified to determine the relationship between coincident exposure to nephrotoxicants and development or progression of chronic renal disease. Particular attention should be paid to the role of widespread and sometimes excessive use of analgesics, including nonsteroidal anti-inflammatory drugs, in diseases of the urinary tract. Clinicians should be aware of the danger associated with abuse of such 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.

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Biologic Markers in Urinary Toxicology Biologic Markers of Effect 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, adequate initial 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 in urinary 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. 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 (IAP); both reflect some specificity of localization along the nephron and of cellular origin. 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. 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. 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 specific markers of effect will be identified and allow early intervention. Markers that define preclinical disease should be identified. In addition, markers that detect xenobiotic-induced mutational events should be identified. Use of Biologic Markers in Extrapolation Models for the identification and validation of markers should continue to be developed. The models must 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 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

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Biologic Markers in Urinary Toxicology 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 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. Research should continue toward better understanding of the metabolic pathways of the kidney in relation to the effects of xenobiotics and susceptibility to them. 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. 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. The general relationship between nephrotoxicity and renal carcinogenesis should be explored. 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.

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